UEG Week 2017 Oral Presentations

MONDAY, OCTOBER 30, 201708:00-10:00

OPENING SESSION: PART I - HALL 6____________________

OP001 DIAGNOSTIC YIELD OF “ARTIFICIAL INTELLIGENCE”-ASSISTED ENDOCYTOSCOPY FOR COLORECTAL POLYPS: A PROSPECTIVE STUDY

Y. Mori 1 , S. Kudo 1 , M. Misawa 1 , K. Takeda 1 , K. Ichimasa 1 , Y. Ogawa 1 , Y. Maeda 1 , T. Kudo 1 , K. Wakamura 1 , T. Hayashi 1 , T. Baba 1 , F. Ishida 1 , H. Inoue 2 , M. Oda 3 , K. Mori 3

1 Digestive Disease Center, Showa University Northern Yokohama Hospital, Yokohama/Japan

2 Digestive Disease Center, Showa University Koto-Toyosu Hospital, Tokyo/Japan

3 Graduate School Of Informatics, Nagoya University, Nagoya/Japan

Contact E-mail Address: ibusiginjp@gmail.com

Introduction: Computer-aided diagnosis (CAD) powered by artificial intelligence is attracting increased attention as an option to improve the performance of optical biopsy for evaluating colorectal polyps [1]. Although positive preliminary data have been shown for applying CAD to endocytoscopy (EC) (500-fold ultra-magnifying endoscopy; Olympus Corp., Tokyo, Japan) [2, 3], no prospective studies have been reported.

Aims & Methods: The present study is an initial prospective trial to validate the feasibility of applying CAD to endocytoscopy in a routine colonoscopy practice. A total of 88 patients (38 women, 50 men; mean age 64 years) in whom colorectal polyps had been detected using EC for colonoscopy were prospectively enrolled in the study between January and March 2017. When a polyp was detected, an on-site endoscopist predicted the polyp pathology using the CAD system [2], which was designed to output the predicted pathology of the target lesion—whether neoplastic or non-neoplastic—together with the probability of the diagnosis (0–100%) immediately after obtaining a methylene blue-stained EC image. The endoscopists obtained as many images as they thought were needed, each of which was evaluated using image-based analysis. The diagnostic ability of the CAD for each image was assessed with reference to the final pathology of the resected specimen. The main outcome measures were diagnostic sensitivity specificity, accuracy, positive predictive value, and negative predictive value of the CAD system for identifying neoplastic change with high confidence (probability ≥90%). Prior to initiating the trial, 13,861 EC images were used for machine-learning the CAD model.

Results: Overall, 126 lesions (62 neoplastic lesions, 64 non-neoplastic lesions; mean size 6 mm) were detected, all of which were successfully analyzed using the CAD system. A total of 1014 EC images of neoplastic lesions and 1480 EC images of non-neoplastic lesions were obtained during the colonoscopies of these patients. Among them, 55% (1378/2494) were diagnosed with high confidence (CAD probability was ≥90%). The sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of the CAD system in identifying neoplastic change with high confidence were 97%, 67%, 83%, 78%, and 95%, respectively (Table). No complications occurred during the study.

Conclusion: This prospective trial revealed that applying CAD to EC was feasible, with a negative predictive value of >90%, which is likely to meet the threshold required for optical biopsy of colorectal polyps. Our next goal is to increase the proportion of high confidence diagnoses, which is currently limited to 55%. (This study is registered as UMIN Clinical Trial Registry No. 000013917 and supported by Grants-in-Aid for Scientific Research No. 15K19351 from the Japan Society for the Promotion of Science.)

Disclosure of Interest: All authors have declared no conflicts of interest.

References

1. Mori Y, Kudo SE, Berzin TM, et al. Computer-aided diagnosis for colonoscopy. Endoscopy , in press

2. Mori Y, Kudo SE, Chiu PW, et al. Impact of an automated system for endocytoscopic diagnosis of small colorectal lesions: an international web-based study. Endoscopy 2016 48: 1110–1118

3. Misawa M, Kudo SE, Mori Y, et al. Characterization of colorectal lesions using a computer-aided diagnostic system for narrow-band imaging endocytoscopy. Gastroenterology 2016 150: 1531–1532

OP002 GENOME-WIDE ASSOCIATION STUDY IDENTIFIES INVERSION IN THE CTRB1-CTRB2 LOCUS TO MODIFY RISK FOR ALCOHOLIC AND NON-ALCOHOLIC CHRONIC PANCREATITIS

J. Rosendahl 1 , H. Kirsten 2 , E. Hegyi 3 , P. Kovacs 4 , F.U. Weiss 5 , H. Laumen 6 , P. Lichtner 7 , C. Ruffert 8 , J. Chen 9 , E. Masson 9 , S. Beer 10 , C. Zimmer 10 , K. Seltsam 10 , A Pan-European Working Group On Alcoholic Chronic Pancreatitis (All Names Will Be Displayed At The Conference) 11 , J. Mössner 10 , C. Férec 9 , P. Michl 1 , J.P. h. Drenth 12 , H. Witt 13 , M. Scholz 2 , M. Sahin-Tóth 14

1 Clinic For Internal Medicine I, University Clinic Halle (Saale), Halle (Saale)/Germany

2 Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany, Leipzig/Germany

3 Center for Exocrine Disorders, Department of Molecular and Cell Biology, Boston University Henry M. Goldman School of Dental Medicine, Boston, MA 02118, USA, Boston/United States of America

4 Leipzig University Medical Center, IFB Adiposity Diseases, University of Leipzig, Leipzig, Germany, Leipzig/Germany

5 Department of Internal Medicine A, Ernst-Moritz-Arndt University, Greifswald, Germany, Greifswald/Germany

6 Else Kröner-Fresenius-Zentrum für Ernährungsmedizin (EKFZ), Paediatric Nutritional Medicine, Technische Universität München (TUM), Freising, Germany, München/Germany

7 Institute of Human Genetics, Helmholtz Centre Munich, German Research Centre for Environmental Health, Neuherberg, Germany, München/Germany

8 Department of Internal Medicine I, Martin Luther University, Halle, Germany, Halle (Saale)/Germany

9 Institut National de la Santé et de la Recherche Médicale (INSERM), U1078; Etablissement Français du Sang (EFS) – Bretagne; Faculté de Médecine et des Sciences de la Santé, Université de Bretagne Occidentale; Laboratoire de Génétique Moléculaire et d'Hist, Brest/France

10 Department of Internal Medicine, Neurology and Dermatology, Division of Gastroenterology, University of Leipzig, Leipzig, Germany, Leipzig/Germany

11 Universities in Europe, Europe/Germany

12 Gastroenterology And Hepatology, Radboud University Nijmegen Medical Centre - Gastroenterology and Hepatology, Radboud University Nij, Nijmegen/Netherlands

13 Department Of Pediatrics, Technical University Munich, Munich/Germany

14 Boston University, Boston/United States of America

Contact E-mail Address: jonas.rosendahl@uk-halle.de

Introduction: Alcohol-related pancreatitis is associated with a disproportionately large number of hospitalizations among gastrointestinal disorders. Despite its clinical importance, genetic susceptibility to alcoholic pancreatitis is poorly characterized. Our aim was to identify risk genes for alcoholic chronic pancreatitis (CP) and to evaluate their relevance in non-alcoholic CP. Therefore, we performed a genome-wide association study and functional characterization of a new pancreatitis locus.

Aims & Methods: Patients with CP were collected according to a standardized protocol throughout Europe. DNA extracted from peripheral blood samples was used for genetic investigations with Illumina technology, PCR, and melting curve assays. In total, 1959 European alcoholic CP patients and population-based controls from the KORA, LIFE and INCIPE study (n = 4708) as well as chronic alcoholics from the GESGA consortium (n = 1332) were investigated. Replication was performed in three European cohorts comprising 1650 patients with non-alcoholic CP and 6695 controls originating from the same countries.

Results: We replicated previously reported risk loci PRSS1-PRSS2, CLDN2-MORC4, SPINK1 and CTRC in alcoholic CP patients. We identified CTRB1-CTRB2 (chymotrypsin B1 and B2) as a new risk locus with lead SNP rs8055167 (odds ratio, 1.35 [95% CI 1.23 to 1.6]; P = 4.2 × 10 −9 ). We found that a 16.6 kb inversion in the CTRB1-CTRB2 locus was in linkage disequilibrium with the CP-associated SNPs and best tagged by rs8048956. The association was also successfully replicated in three independent European non-alcoholic CP cohorts of 1, 650 patients and 6695 controls (odds ratio, 1.62 [95% CI 1.42 to 1.86]; P = 1.64 × 10 −12 ). The inversion changes the expression ratio of CTRB1 and CTRB2 isoforms and thereby affects protective trypsinogen degradation and ultimately pancreatitis risk.

Conclusion: Our GWAS identified CTRB1-CTRB2 as a new risk locus for ACP and NACP. The association within the CTRB1-CTRB2 locus was linked to a 16.6 kb inversion that altered CTRB1/CTRB2 expression thereby affecting protective trypsinogen degradation. Furthermore, we confirmed association of ACP with the PRSS1-PRSS2 , CLDN2-MORC4, CTRC and SPINK1 loci. Taken together, the identified risk variants explained about 18% of the variance in ACP. Our discovery provides strong evidence for common pathogenic mechanisms underlying the complex etiology of ACP and NACP.

Disclosure of Interest: All authors have declared no conflicts of interest.

MONDAY, OCTOBER 30, 201710:30-12:00

OPENING SESSION: PART II - HALL 6____________________

OP003 DIFFERENTIALLY O-GLYCOSYLATED CARBOXYL ESTER LIPASE CAUSES A MODY8-LIKE PHENOTYPE IN MICE

B. Mercanoglu , G. Wolters-Eisfeld, C. Güngör, J.R. Izbicki, M. Bockhorn

Department Of General, Visceral And Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg/Germany

Contact E-mail Address: b.mercanoglu@uke.de

Introduction: Maturity-onset diabetes of the young type 8 (MODY8) is a monogenic syndrome of diabetes and a pancreatic exocrine dysfunction caused by mutations in exon 11 of the Carboxyl Ester Lipase ( CEL ) gene where clustered O-GalNAc glycosylation sites are encoded. 1 C-terminal truncated CEL reduces the viability of pancreatic acinar and beta cell models, indicating the induction of apoptosis in pancreatic cells. 2

Aims & Methods: The aim of the present study was to establish a mouse model that might allow for the investigation of the pathophysiological mechanisms in MODY8. Therefore, we hypothesized that truncated O-glycosylation of Cel (Cel-Tn) is responsible for the MODY8 phenotype and investigated the pathogenicity of differentially glycosylated Cel. For this purpose, we generated a transgenic mouse model with a conditional Cosmc knockout mediated by the pancreas specific transcription factor 1a ( Ptf1a )-cre mouse strain to induce Tn antigen expression in pancreatic acinar cells and thereby truncated O-glycan formation.

Results: In accordance with the reported cluster of symptoms in MODY8 patients, characterization of Cosmc -deficient mice revealed symptoms of exocrine pancreatic insufficiency with maldigestion, altered stool formation, impaired zymogen granule release and decreased enzymatic elastase and lipase activity. Moreover, examination of fasting serum glucose and HbA1c displayed elevated levels and reduced amount of fasting serum C-peptide conformable with diabetes based on beta-cell failure. Furthermore, we observed reduced numbers of pancreatic islets in Cosmc knockout mice indicating cytotoxicity of Cel-Tn. Our results indicate that the impairment of O-glycosylation on Cel was responsible for the observed MODY8-related phenotype, similar to mutation induced C-terminal truncation.

Conclusion: In summary, this study demonstrates that deletion of Cosmc in pancreatic acinar cells leads to the loss of O-glycosylation, with consecutive expression of Tn-modified Cel, thus resulting in a MODY8 phenotype. These findings demonstrate the first generation of a MODY8-like phenotype in a mouse model and implicate the relevance of O-glycan formation.

Disclosure of Interest: All authors have declared no conflicts of interest.

References

1. Raeder, H., Johansson, S., Holm, P.I., Haldorsen, I.S., Mas, E., Sbarra, V., Nermoen, I., Eide, S.A., Grevle, L., Bjorkhaug, L., et al. (2006). Mutations in the CEL VNTR cause a syndrome of diabetes and pancreatic exocrine dysfunction. Nat Genet 38, 54–62.

2. Torsvik, J., Johansson, B.B., Dalva, M., Marie, M., Fjeld, K., Johansson, S., Bjorkoy, G., Saraste, J., Njolstad, P.R., and Molven, A. (2014). Endocytosis of secreted carboxyl ester lipase in a syndrome of diabetes and pancreatic exocrine dysfunction. J Biol Chem 289, 29097–29111.

OP004 BENEFITS OF H. PYLORI ERADICATION IN PREVENTING GASTRIC CANCER IN THE OLDER POPULATION: RESULTS FROM A POPULATION-BASED STUDY

W.K. Leung 1 , I. O. Wong 2 , E.W. Chan 3 , A.Y. Wong 3 , K.F. Yeung 2 , L. Chen 4 , I.C. Wong 5 , K.S. Cheung 1

1 Department Of Medicine, University of Hong Kong, Hong Kong/Hong Kong PRC

2 School Of Public Health, University of Hong Kong, Hong Kong/Hong Kong PRC

3 Department Of Pharmacology And Pharmacy, The University of Hong Kong, Queen Mary Hospital, Hong Kong, Hong Kong/Hong Kong PRC

4 Department Of Medicine, The University of Hong Kong, Hong Kong/Hong Kong PRC

5 UCL School Of Pharmacy, University College London, London/United Kingdom

Contact E-mail Address: waikleung@hku.hk

Introduction: Although H. pylori (HP) eradication has been shown to reduce the risk of gastric cancer development, it remains elusive whether there is a point of no return on the HP-associated gastric carcinogenesis cascade. In particular, there are limited data on the benefits of HP eradication on gastric cancer prevention in the older population (≥60 years).

Aims & Methods: We aimed to compare the age-specific risk of gastric cancer development in a large cohort of HP infected subjects who had received HP eradication therapy with the local general population.

Methods: The results were based on a retrospective cohort study that included all HP-infected subjects who had received a ≥7-day course of clarithromycin-based triple therapy between 2003 and 2012 in Hong Kong. These subjects were identified from a territory-wide health database, which captured all patients’ clinical information in the local public health care system. We excluded subjects with history of gastrectomy, were diagnosed to have gastric cancer prior to or within 12-month of HP therapy, and those who failed clarithromycin-based triple therapy. Person-years at risk were derived for each patient from the first date of HP therapy until the date of gastric cancer diagnosis, death or the date of censoring. Expected number of gastric cancer cases in the general population were estimated on data from the population-based Hong Kong Cancer Registry. We determined the standardized incidence ratio (SIR) of the HP eradicated cohort and the general population of the same age group which included both HP-infected and non-infected subjects. All analyses were conducted by a priori age groups of <40, 40–59.9 and ≥60 years.

Results: Among the 63,397 eligible HP-infected subjects (median age 54.0 years, 46.5% male) who had received clarithromycin-based triple therapy, 153 (0.2%) developed gastric cancer with a median follow-up of 7.4 years (overall incidence: 3.2 per 10,000 person-years). The cumulative gastric cancer incidence rates in the HP-eradicated cohort at 12 years were 0.1%, 0.3% and 0.8% for the <40, 40–59.9 and ≥60 years groups, as compared to 0.1%, 0.3% and 1.1% for the estimated cumulative incidence rates in the matched age groups of the general population. Among the ≥60 years group, the risk of gastric cancer was significantly lower in the HP eradicated group as compared to the general population (SIR = 0.75; 95% CI, 0.61 to 0.92), corresponding to a 25% reduction in gastric cancer incidence. In contrast, the corresponding SIR was 1.37 (95% CI, 0.43 – 3.30) in the <40 years and 1.07 (95% CI, 0.82 – 1.38) in the 40–59.9 years groups.

Conclusion: In this large population-based study of HP-eradicated subjects, we found that the risk of gastric cancer was significantly lower among those who received HP eradication at ≥60 years than the age-matched general population. Our results suggest benefits of HP eradication on gastric cancer prevention even in the aged population.

Disclosure of Interest: All authors have declared no conflicts of interest.

MONDAY, OCTOBER 30, 201710:30-12:00

CLINICAL TRIALS IN CROHN'S DISEASE - ROOM F3____________________

OP005 EFFECT OF DISEASE DURATION AND LOCATION ON CLINICAL REMISSION IN CROHN’S DISEASE PATIENTS TREATED WITH FILGOTINIB, A SELECTIVE JAK1 INHIBITOR: POST-HOC ANALYSIS FROM THE PHASE 2 FITZROY STUDY

S. Vermeire 1 , A. Van Der Aa 2 , C. Jamoul 2 , C. Tasset 2 , P. Harrison 2 , G. R. D'Haens 3

1 Department of Gastroenterology, University Hospitals Leuven, Leuven/Belgium

2 Galapagos NV, Mechelen/Belgium

3 Gastroenterology, Academic Medical Centre, Amsterdam/Netherlands

Contact E-mail Address: Severine.Vermeire@uzleuven.be

Introduction: Filgotinib is an oral, selective Janus kinase 1 (JAK1) inhibitor, with demonstrated efficacy in rheumatoid arthritis. This 20-week Phase 2 study evaluated the efficacy and safety of filgotinib in patients with active Crohn’s disease (CD). The primary endpoint (CDAI remission at Week 10) was met with an acceptable safety profile 1 .

Aims & Methods: The effect of disease duration and location has been assessed post-hoc on the primary endpoint. 174 patients with moderate-to-severely active CD (CDAI: 220 to 450) and ulcerations confirmed by centrally read endoscopy were randomized 3:1 to receive 200 mg filgotinib (FIL) or placebo (PBO) QD for 10 weeks. Immunosuppressants were discontinued prior to treatment initiation but corticosteroid-treated patients remained stable until Week 10 (W10). Patients naïve to anti-TNF therapy as well as patients previously exposed to anti-TNF with no response or loss-of-response were included. Clinical remission at W10 was analysed by disease duration (<5 years (yrs), 5–10 yrs and >10 yrs) and historical location (ileal, ileo-colonic, colonic).

Results: Baseline disease characteristics were similar in both initial treatment groups, showing a population of active Crohn’s patients (mean CDAI 293, mean SES-CD 14.6, mean CRP 15.6 mg/L, 41% >10 mg/L, oral corticosteroids use 51%, mean daily dose 21.6 mg). Forty-two percent of patients were anti-TNF naïve, 58% were anti-TNF non-responder. Forty-three percent were diagnosed for less than 5 yrs, 30% between 5 and 10 yrs and 27% for >10 yrs. Most anti-TNF naïve patients (63%) had <5 yrs CD, whereas 71% of anti-TNF non-responders were diagnosed >5 yrs. A total of 62% of patients had ileo-colonic disease, whereas 18% had ileal involvement only and 20% had only colonic involvement. The percentage of FIL-treated patients in clinical remission at W10 is not impacted by longer disease duration while for PBO-treated patients the percentage of remitters was lower with disease duration of >10 yrs. In FIL-treated patients, consistently high remission rates in both anti-TNF naïve and (to a lesser extent) anti-TNF non-responders were seen, independently of disease duration (anti-TNF naïve: 59%, 60%, 62%; anti-TNF non-responders: 42%, 37%, 32%, for respectively <5 yrs, 5–10 yrs and >10 yrs). FIL treatment effect was also shown independent of disease location, although a higher percentage of remitters was observed in the subgroup with colonic disease only (Table 1).

Conclusion: This post-hoc analysis of the Phase 2 FITZROY study indicates that inhibition of JAK1 with filgotinib in Crohn’s patients is consistently associated with clinical remission, independently of disease duration and location.

Disclosure of Interest: S. Vermeire: • Grant support: AbbVie, MSD, Takeda • Lectures: AbbVie, Falk Pharma, Ferring, Hospira, MSD, Takeda, Tillotts • Consultancy: AbbVie, Celgene, Ferring, Galapagos, Genentech/Roche, Hospira, J&J, MSD, Mundipharma, Pfizer, Second Genome, Shire, Takeda

A. Van der Aa: employee of Galapagos NV

C. Jamoul: consultant for Galapagos NV

C. Tasset: employee of Galapagos NV

P. Harrison: employee of Galapagos NV

G.R. D'Haens: Abbvie, Ablynx, Biogen, BMS, BoehringerIng., Celgene, Celltrion, Ferring, Galapagos, Gilead, GSK, Hospira, Immunic, J&J, Lycera, Millen./Takeda, MitsubishiPh., MSD, Mundiph., NovoNordisk, Pfizer, Protagonist, Robarts, Salix, Sandoz, Shire, Teva, Tigenix, Tillotts, a.o.

Reference

1. Vermeire S., et al. Lancet . 2016; 389(10066):266–275

OP006 EXPOSURE-RESPONSE TO SC USTEKINUMAB IN MODERATE – SEVERE CROHN’S DISEASE: RESULTS FROM THE IM-UNITI MAINTENANCE STUDY

O. J. Adedokun 1 , Z. Xu 1 , C. Gasink 1 , D. Jacobstein 1 , P. Szapary 1 , J. Johanns 1 , L. Gao 1 , H. M. Davis 1 , S. Hanauer 2 , B.G. Feagan 3 , S. Ghosh 4 , W. Sandborn 5

1 Janssen Research & Development, LLC, Spring House/United States of America/PA

2 Northwestern University Feinberg School of Medicine, Chicago/United States of America/IL

3 Robarts Clinical Trials Inc., Robarts Research Institute, Western University, London/Canada

4 Institute of Translational Medicine, Birmingham/United Kingdom

5 University of California San Diego, La Jolla/United States of America/CA

Contact E-mail Address: OAdedoku@its.jnj.com

Introduction: Subcutaneous (SC) Ustekinumab (UST) maintenance was previously shown to maintain clinical response and remission in mod-severe Crohn’s disease (CD) in the Phase 3 IM-UNITI maintenance trial, but detailed exposure-response analyses using clinical efficacy, biomarkers of inflammation, and endoscopic substudy data have not yet been presented.

Aims & Methods: Patients achieving clinical response after a single IV dose of UST in the UNITI-1&2 induction studies were randomized 1:1:1 in IM-UNITI to SC placebo (PBO), UST 90 mg q12w, or q8w. Ustekinumab concentration data were categorized into quartiles (Q) and ER relationships were assessed based on wk24 steady-state (ss) trough or average ss trough values vs clinical remission, CRP, and endoscopic remission and response (SES-CD < 2 or 50% decrease, respectively) in endoscopic substudy patients. The association between ss trough and efficacy outcomes was assessed using a one-sided Cochrane Armitage trend test. Optimal concentration cut-offs for remission were evaluated using ROC analysis.

Results: Median ss troughs were approximately 3x greater with q8w SC UST (2.11 µg/mL and 0.62 µg/mL for the q8w and q12w regimen respectively). UST levels were lower in patients with higher baseline CRP (likely reflecting greater inflammatory burden), while oral AZA, 6-MP, or MTX use and weight did not have any notable effect. Both q8w and q12w were associated with higher proportions achieving clinical remission (eg > 0.92 µg/ml in q8w Qs), lower CRP concentrations (in Qs > 1.05 µg/ml), and endoscopic response and remission (in Qs > 0.5 µg/ml) compared to PBO (Table). By ROC analyses, trough concentrations between 0.8 and 1.4 µg/mL or greater were associated with greater maintenance of clinical remission.

Conclusion: In Crohn’s disease patients in the IM-UNITI maintenance study, ustekinumab concentrations were positively associated with clinical efficacy outcomes and inversely related to CRP concentrations.

Disclosure of Interest: O.J. Adedokun: Janssen Scientific Affairs, LLC employee

Z. Xu: Janssen Scientific Affairs, LLC employee

C. Gasink: Janssen Scientific Affairs, LLC employee

D. Jacobstein: Janssen Scientific Affairs, LLC employee

P. Szapary: Janssen Scientific Affairs, LLC employee

J. Johanns: Janssen Scientific Affairs, LLC employee

L. Gao: Janssen Scientific Affairs, LLC employee

H.M. Davis: Janssen Scientific Affairs, LLC employee

S. Hanauer: Investigator for Janssen Research & Development, LLC

B.G. Feagan: Janssen Scientific Affairs, LLC investigator

S. Ghosh: Investigator for Janssen Research & Development, LLC

W. Sandborn: Investigator for Janssen Research & Development, LLC

OP007 SAFETY AND EFFICACY OF UPADACITINIB (ABT-494), AN ORAL JAK1 INHIBITOR, AS INDUCTION THERAPY IN PATIENTS WITH CROHN’S DISEASE: RESULTS FROM CELEST

W. J. Sanborn 1 , B. Feagan 2 , J. Panes 3 , G. D’Haens 4 , J. Colombel 5 , Q. Zhou 6 , B. Huang 6 , J.V. Enejosa 6 , A. L. Pangan 6 , A. P. Lacerda 6

1 University of California San Diego, La Jolla/United States of America/CA

2 Robarts Clinical Trials, Western University, London/Canada/ON

3 Hospital Clínic Barcelona, Department of Gastroenterology, Baecelona/Spain

4 Academic Medical Centre, Amsterdam/Netherlands

5 Icahn School of Medicine at Mount Sinai, New York/United States of America

6 AbbVie Inc., North Chicago/United States of America

Contact E-mail Address: wsandborn@ucsd.edu

Introduction: The efficacy and safety of upadacitinib (UPA), an oral JAK1 inhibitor, were assessed in patients with moderate-to-severe Crohn’s disease (CD) who had inadequate response/intolerance to an immunomodulator or tumor necrosis factor (TNF) antagonist.

Aims & Methods: Adult patients with active CD, with a CDAI 220–450, an average daily liquid/soft stool frequency (SF) ≥2.5 or daily abdominal pain (AP) score ≥2.0, and Simplified Endoscopic Score for CD (SES-CD) ≥6 (or ≥4 for those with isolated ileal disease), were randomized 1:1:1:1:1:1 to double-blind induction therapy with placebo (PBO) or UPA at 3, 6, 12, 24 mg twice daily (BID) or 24 mg once daily (QD) for 16 weeks, followed by blinded extension therapy for 36 weeks. Patients were also randomized 1:1 at baseline for follow-up ileocolonoscopy at either Week 12/16. From Week 2, steroid doses were to be tapered in patients on corticosteroids at baseline. Co-primary endpoints were clinical remission (SF ≤ 1.5 and AP ≤ 1, and both not worse than baseline) at Week 16, and endoscopic remission (SES-CD ≤4 and ≥2 point reduction from baseline, no subscore >1) at Week 12/16. Secondary endpoints included clinical response (≥30% reduction from baseline in AP or SF with neither worse than baseline), and endoscopic response (≥25% decrease in SES-CD). The overall dose-response relationship between multiple UPA doses and PBO was tested by Multiple Comparison Procedures Modeling (MCP-Mod); pairwise comparison between each UPA dose with PBO was tested by Cochran-Mantel-Haenszel test stratified by baseline SES-CD.

Results: Of the 220 enrolled patients, 180 (82%) completed 16 weeks of induction. Mean age was 40.7 ± 12.9 yrs, CDAI 302.7 ± 63.4 and disease duration 13.2 ± 10.0 yrs. Ninety six percent had failed, or were intolerant to TNF antagonists. Significantly more patients on 6 mg BID achieved clinical remission. A significant dose-response relationship was observed with UPA vs PBO for endoscopic remission ( Table 1) . Compared with PBO, more patients achieved clinical response with 6 and 24 mg BID, and endoscopic response with UPA doses ≥6 mg BID at Week 16 (Table 1) . Adverse events (AEs) and infections were numerically higher with UPA. Serious AEs and discontinuations were similar in all groups, except for 12 mg BID. One case each of non-melanoma skin cancer and herpes zoster were reported in the 24 mg BID group, two gastrointestinal perforations were reported, one each in the 24 mg BID and 24 mg QD groups). Two adjudicated cardiovascular events (myocardial infarction) were reported in the 12 mg BID group. One death was reported during screening; the patient did not receive study drug. Laboratory abnormalities were mostly ≤Grade 2, with 3 events of Grade 3 hemoglobin decrease (0 on PBO) and 5 Grade 3 CPK elevations (1 on PBO/ 4 on UPA).

Conclusion: This dose-ranging study demonstrated endoscopic improvement and clinical benefit of upadacitinib at doses of 6 mg BID and higher as induction therapy in patients with moderate-to-severe refractory CD, and a safety profile as expected with a JAK inhibitor in this population.

Disclosure of Interest: W.J. Sanborn: Consultant for AbbVie, ActoGeniX NV, AGI Therapeutics, Inc., Alba Therapeutics Corporation, and others. Received speakers fees from AbbVie, Bristol-Myers Squibb, and Janssen; financial support for research from AbbVie, Bristol-Myers Squibb and others.

B. Feagan: Consultant/advisory board member for AbbVie, Allergan, ActoGeniX, Albireo, Amgen, and others; received speaker’s fees from AbbVie, JnJ/Janssen; and financial support for research from AbbVie Inc., Amgen Inc., AstraZeneca/MedImmune Ltd., and others.

J. Panes: Consultant or advisory member for AbbVie, Arena Pharmaceuticals, Boehringer Ingelheim, BMS, and others; speaker for AbbVie, Ferring, Janssen, MSD, Shire Pharmaceuticals and Tillots; received research funding from AbbVie and MSD;

G. D’Haens: Consulting/lecture fees from AbbVie, ActoGeniX, AIM, Boehringer Ingelheim GmbH, Centocor, Chemo Centryx, and others; research grants from AbbVie, Janssen, Given Imaging, and others; speaking honoraria from AbbVie, Tillotts, and others.

J. Colombel: Consultant or advisory board: AbbVie, Amgen, Boehringer-Ingelheim, and others. Speaker: AbbVie, Ferring. Speaker’s bureau: Amgen. Stock options: Intestinal Biotech Development, Genefit. Research Grants: AbbVie, Takeda, Janssen and Janssen.

Q. Zhou: Employee of AbbVie Inc. and may own stock and/or options.

B. Huang: Employee of AbbVie Inc. and may own stock and/or options.

J.V. Enejosa: Employee of AbbVie Inc. and may own stock and/or options.

A.L. Pangan: Employee of AbbVie Inc. and may own stock and/or options.

A.P. Lacerda: Employee of AbbVie Inc. and may own stock and/or options.

OP008 EFFICACY AND SAFETY OF OPEN-LABEL MAINTENANCE THERAPY WITH SUBCUTANEOUS RISANKIZUMAB IN PATIENTS WITH MODERATE-TO-SEVERE CROHN’S DISEASE

B. G. Feagan 1 , J. Panés 2 , M. Ferrante 3 , A. Kaser 4 , G. R. D'Haens 5 , W.J. Sandborn 6 , E. Louis 7 , M.F. Neurath 8 , D. Franchimont 9 , O. Dewit 10 , U. Seidler 11 , K. Kim 12 , C. Selinger 13 , S. J. Padula 14 , I. Herichova 15 , A. M. Robinson 16 , K. Wallace 16 , J. Zhao 16 , A. Soaita 17 , S. Visvanathan 17 , D. Hall 17 , W. O. Böcher 14

1 Robarts Clinical Trials, London/Canada

2 Hospital Clinic Barcelona, Barcelona/Spain

3 University Hospitals Leuven, Leuven/Belgium

4 University of Cambridge, Addenbrooke's Hospital, Cambridge/United Kingdom

5 Academic Medical Center, University of Amsterdam, Amsterdam/Netherlands

6 IBD Center University of California San Diego and UC San Diego Health System, San Diego/United States of America/CA

7 University Hospital CHU Liège, Liège/Belgium

8 University of Erlangen, Erlangen/Germany

9 Erasme University Hospital, Brussels/Belgium

10 Cliniques Universitaires Saint-Luc, Brussels/Belgium

11 Hannover Medical School, Hannover/Germany

12 Asan Medical Center, Seoul/Korea, Republic of

13 St James University Hospital, Leeds/United Kingdom

14 Boehringer Ingelheim Pharma Gmbh & Co. KG, Ingelheim/Germany

15 Boehringer Ingelheim RCV GmbH & Co KG, Vienna/Austria

16 AbbVie Inc., North Chicago/United States of America

17 Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield/United States of America/CT

Contact E-mail Address: brian.feagan@robartsinc.com

Introduction: The IL-23 pathway is implicated in the pathogenesis of Crohn’s disease (CD) both genetically and biologically.

Aims & Methods: The efficacy and safety of risankizumab (RZB), a humanised monoclonal antibody that inhibits IL-23 through specific targeting of the IL-23 p19 subunit, was assessed in a randomised Phase II study in patients with moderate-to-severe active CD ( NCT02031276 ). The study included a 12-week (wk) double-blind intravenous (iv) induction period (P1), a 14-wk open-label (OL) iv re-induction (600 mg RZB)/wash out period (P2) and a 26-wk OL subcutaneous (sc) 180 mg RZB maintenance period (P3). RZB was more effective than placebo for inducing clinical and endoscopic remission at 12 wks. Re-induction therapy with 600 mg RZB increased clinical remission rates further at Wk 26, and was well tolerated over 26 wks. Here, the efficacy and safety of OL sc maintenance therapy with RZB is reported. Non-responder imputation was used for missing data.

Results: At Wk 26, 62/121 patients were in clinical remission and entered RZB maintenance treatment, with 54 patients completing treatment to Wk 52. At Wk 52, 71.0% of patients (44/62) had clinical remission (Table) and 80.6% (50/62) had clinical response. Of those patients who entered P3 and had clinical remission at Wk 12, 87.5% (21/24) were still in clinical remission at Wk 52. The rate of endoscopic response and remission at Wk 52 was 54.8% (34/62) and 35.5% (22/62), respectively. Of those patients who entered P3 and had endoscopic remission at Wk 12, 69.2% (9/13) were still in endoscopic remission at Wk 52. Overall, 29.0% of patients (18/62) were in deep remission at Wk 52. During P3, two patients discontinued due to an AE (worsening and exacerbation of CD).

Conclusion: In patients in clinical remission at Wk 26, OL sc RZB was effective in maintaining clinical and endoscopic remission and response up to Wk 52. Early achievement of clinical or endoscopic remission at Wk 12 was associated with better outcome at Wk 52. Overall, RZB was well tolerated with no new safety signals detected during sc maintenance treatment.

Disclosure of Interest: B.G. Feagan: AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Janssen Biotech/Centocor, Johnson & Johnson/Janssen, Pfizer, Receptos, Takeda, ActoGeniX, Akros, Albireo Pharma, Allergan, Avaxia Biologics Inc., Avir Pharma, Axcan Pharma, Baxter Healthcare Corporation

J. Panés: AbbVie, Arena, Boehringer Ingelheim, Galapagos, Genentech/Roche, Janssen, MSD, Pfizer, Takeda, TiGenix and TopiVert.

M. Ferrante: Boehringer Ingelheim, Takeda, AbbVie, Falk, Ferring, Janssen, MSD, Tillotts, Chiesi, Mitsubishi Tanabe and Zeria Pharmaceutical Co.

A. Kaser: Boehringer Ingelheim, Ferring, Genentech, GlaxoSmithKline, Hospira, Janssen, Kymab, Second Genome and VHsquared Ltd.

G.R. D'Haens: AbbVie, Ablynx, Amakem, AM Pharma, Avaxia, Biogen, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Celltrion, Cosmo, Covidien, enGene, Ferring, Dr FALK Pharma, Galapagos, Gilead, GlaxoSmithKline

W.J. Sandborn: Boehringer Ingelheim, AbbVie, Amgen, Janssen, Lilly and AstraZeneca/MedImmune.

E. Louis: AbbVie, MSD, Ferring, Takeda, Celltrion, Mundipharma, Hospira and Janssen.

M.F. Neurath: AbbVie Deutschland GmbH & Co. KG, Bionorica SE, Boehringer Ingelheim GmbH & Co. KG, e.Bavarian Health GmbH, Falk Foundation, F. Hoffmann La Roche GmbH, Genentech Inc., Hexal AG, Index Pharmaceuticals AB, Janssen-Cilag GmbH, MSD Sharp and Dohme GmbH,

D. Franchimont: AbbVie, MSD, Amgen, Ferring, Takeda, Mundipharma, Hospira and Pfizer.

O. Dewit: AbbVie, MSD, Ferring, Takeda, Mundipharma and Hospira.

U. Seidler: Boehringer Ingelheim, Pfizer, Janssen, Roche, Gilead, Salix, Mitsubishi, MSD and Takeda.

C. Selinger: Warner Chilcott, AbbVie, Dr Falk, Takeda, Janssen and MSD

S.J. Padula: Employee of Boehringer Ingelheim.

I. Herichova: Employee of Boehringer Ingelheim.

A.M. Robinson: Employee of AbbVie.

K. Wallace: Employee of AbbVie.

J. Zhao: Employee of AbbVie.

A. Soaita: Employee of Boehringer Ingelheim.

S. Visvanathan: Employee of Boehringer Ingelheim.

D. Hall: Employee of Boehringer Ingelheim.

W.O. Böcher: Employee of Boehringer Ingelheim.

All other authors have declared no conflicts of interest.

OP009 ENDOSCOPIC AND CLINICAL EFFICACY DEMONSTRATED WITH ORAL OZANIMOD IN MODERATELY TO SEVERELY ACTIVE CROHN’S DISEASE

B. G. Feagan 1 , W. J. Sandborn 2 , G. D'Haens 3 , B. G. Levesque 1 , B. E. Skolnick 4 , C. Li 4 , D. Penenberg 4 , R. Aranda 4 , A. Olson 4

1 Robarts Research Institute, London/Canada/ON

2 Division Of Gastroenterology, University of California, La Jolla, San Diego/United States of America/CA

3 Academic Medical Center, Amsterdam/Netherlands

4 Receptos, a wholly owned subsidiary of Celgene, San Diego/United States of America/CA

Contact E-mail Address: brian.feagan@robartsinc.com

Introduction: Ozanimod, an oral, once-daily immunomodulator designed to selectively target S1P 1R and S1P 5R , has demonstrated clinical efficacy in ulcerative colitis (UC) ( Sandborn NEJM 2016 ) and is being evaluated in active Crohn’s Disease (CD). This Phase 2 open-label study in CD examined endoscopic and clinical outcomes following treatment with ozanimod 1 mg daily for 12 weeks.

Aims & Methods: Patients with active CD (Crohn’s Disease Activity Index [CDAI] score 220–450, total simple endoscopic score for CD [SES-CD] ≥6 (or in isolated ileum disease SES-CD ≥4) were dosed with ozanimod 1 mg daily. All endoscopic assessments were read in a blinded manner by an imaging core lab. Daily electronic diary records were used to collect CD symptoms (including abdominal pain and soft/loose stool frequency). SES-CD was evaluated at baseline and Week 12, and CDAI was assessed at baseline and Weeks 4, 8, and 12.

Results: Sixty-nine patients were enrolled. At baseline, mean age was 37.7 years, mean SES-CD was 13.3, and mean CDAI was 320. Mean CD duration was 10.0 years, with 54% of patients having had prior exposure to biologic therapy (i.e., TNF-α, vedolizumab). Patients with available data at baseline and Week 12 were included in the analyses, including SES-CD matched endoscopic segments (n = 60) and CDAI (n = 59). SES-CD score reductions of ≥25% and ≥50% from baseline was seen in 43.3% and 26.7% of patients respectively. Patients with less endoscopic disease activity (baseline SES-CD ≤12) had a greater endoscopic response with 50.0% of patients and 35.7% having a reduction of ≥25% and ≥50% respectively. In line with the improvements in SES-CD, reductions in mean CDAI scores from baseline were seen as early as Week 4 (first post-baseline assessment) with further reductions through Week 12. CDAI response (CDAI decrease ≥100) was demonstrated in 66% of patients and CDAI remission (CDAI < 150) was demonstrated in 46% of patients with a mean reduction at Week 12 of 130 points. Adverse event and serious adverse event rates appeared to be related to underlying moderate to severe Crohn’s disease. The overall safety profile in CD was similar to that observed in UC.

Conclusion: Oral ozanimod demonstrated meaningful clinical improvements as early as Week 4 and endoscopic improvements at Week 12 in patients with moderate to severe CD. No new safety signals were identified.

Disclosure of Interest: B.G. Feagan: Consultancy: Celgene, Directorship(s): Robarts Clinical Trials.

W.J. Sandborn: Financial support for research: Celgene, Janssen, AbbVie, Prometheus Laboratories, Pfizer, Amgen, Genentech, Takeda/Consultancy: Celgene, Jansen, AbbVie, UCB Pharma, Shire, Salix, Actavis, Prometheus Laboratories, Pfizer, Amgen, Genentech, Takeda

G. D'Haens: Consultancy: Celgene. Directorship(s): Robarts Clinical Trials. Shareholder: Engene.

B.G. Levesque: Directorship(s): Robarts Clinical Trials. Consultancy: Tillotts Pharma, Gilead, Roche, Prometheus.

B.E. Skolnick: Shareholder: Celgene/other: Celgene.

C. Li: Shareholder: Celgene/other: Celgene.

D. Penenberg: Shareholder: Celgene/other: Celgene.

R. Aranda: Shareholder: Celgene/other: Celgene.

A. Olson: Shareholder: Celgene/other: Celgene.

Reference

Sandborn WJ, Feagan BG, Wolf DC, D'Haens G, et al. Ozanimod Induction and Maintenance Treatment for Ulcerative Colitis. N Engl J Med . 2016 May 5;374(18):1754–62.

OP010 EXPOSURE-RESPONSE RELATIONSHIPS FOR THE EFFECT OF UPADACITINIB ON CLINICAL AND ENDOSCOPIC EFFICACY ENDPOINTS IN SUBJECTS WITH MODERATELY TO SEVERELY ACTIVE CROHN’S DISEASE – ANALYSIS OF CELEST STUDY

M. F. Mohamed 1 , B. Klünder 2 , A. P. Lacerda 3 , A. A. Othman 1

1 Clinical Pharmacology And Pharmacometrics, AbbVie, North Chicago/United States of America

2 Clinical Pharmacology And Pharmacometrics, AbbVie Deutschland GmbH & Co. KG, Ludwigshafen am Rhein/Germany

3 Immunology Development, AbbVie Inc., North Chicago/United States of America

Contact E-mail Address: mohamed-eslam.mohamed@abbvie.com

Introduction: Upadacitinib (ABT-494) is an oral selective JAK1 inhibitor currently in development for the treatment of several inflammatory diseases including Crohn’s disease (CD). Upadacitinib demonstrated clinical and endoscopic efficacy with an acceptable safety profile in subjects with moderately to severely active CD during the induction period of the Phase 2 dose-ranging CELEST study ( NCT02365649 ). 1

Aims & Methods: The objective of these analyses was to characterize the relationships between upadacitinib plasma exposures and the clinical and endoscopic efficacy endpoints in the CELEST study. The analyses datasets included data from 220 subjects with moderately to severely active CD who had inadequate response or were intolerant to immunomodulators or anti-tumor necrosis factor therapy. Subjects were randomized in a 1:1:1:1:1:1 ratio to receive 3 mg twice daily (BID), 6 mg BID, 12 mg BID, 24 mg BID, or 24 mg once daily doses of upadacitinib immediate-release formulation, or matching placebo. Clinical efficacy assessments and sparse blood samples for pharmacokinetics were collected from each subject over a 16-week induction period. Endoscopic evaluation was conducted at Baseline and at Weeks 12 or 16. Clinical response and modified clinical remission were assessed based on the average daily very soft or liquid stool frequency and average daily abdominal pain score; and the Clinical Disease Activity Index (CDAI). Endoscopic response, improvement, and remission were assessed based on Simplified Endoscopic Score for CD (SES-CD). The relationships between model-predicted upadacitinib plasma exposures and the different clinical and endoscopic endpoints were evaluated using quartile plots, continuous-time Markov chain models for the clinical endpoints, and regression analyses for the endoscopic endpoints. The final exposure-response models were used to predict the efficacy of selected ABT-494 regimens of interest.

Results: The percentage of subjects achieving clinical response, modified clinical remission, CDAI remission, endoscopic response, endoscopic improvement, and endoscopic remission were correlated with upadacitinib plasma exposures. Upadacitinib plasma exposures associated with 12 mg BID dose achieved the majority of therapeutic benefit for clinical endpoints. The highest efficacy for endoscopic endpoints was achieved in subjects within upadacitinib plasma exposure quartile corresponding to 24 mg BID dose. The predicted percentage of subjects achieving the aforementioned endpoints based on the exposure-response analyses is presented in Table 1 for a range of upadacitinib doses. Clinical efficacy was comparable between Weeks 12 and 16.

Conclusion: Upadacitinib exposures associated with 18 mg BID to 24 mg BID are predicted to maximize the response for clinical and endoscopic endpoints.

Disclosure of Interest: M.F. Mohamed: employee and shareholder of AbbVie

B. Klünder: employee and shareholder of AbbVie

A.P. Lacerda: employee and shareholder of AbbVie

A.A. Othman: employee and shareholder of AbbVie

Reference

1. Safety and Efficacy of ABT-494 (upadacitinib), an oral JAK1 inhibitor, as induction therapy in patients with Crohn’s disease: results from Celest. Sandborn WJ et al. DDW 2017 Abstract 874 h

MONDAY, OCTOBER 30, 201710:30-12:00

FATTY LIVER DISEASE: UPDATE 2017 - ROOM A2____________________

OP011 AN ESCHERICHIA COLI PATHOGEN ISOLATED FROM A NON-ALCOHOLIC STEATOHEPATITIS PATIENT PROMOTES THE DEVELOPMENT OF NON-ALCOHOLIC FATTY LIVER DISEASE IN HIGH FAT DIET MICE

Z. Wu 1 , N. Wu 2 , J. Tan 1 , J. Xu 1 , Y. Song 1 , F. Zhang 1 , Y. L. Liu 1

1 Department Of Gastroenterology, Peking University People's Hospital, Beijing/China

2 Institute Of Clinical Molecular Biology & Central Laboratory, Peking University People’s Hospital, Beijing/China

Contact E-mail Address: wuna1030@163.com

Introduction: The role of the gut microbiota in the pathogenesis of non-alcoholic fatty liver disease (NAFLD) has emerged into an important research area. We found that the relative abundance of Escherichia both in fecal and mucosa-associated microbiota was significantly increased in NASH patients in our former study. To explore the causative role it may have in NAFLD development, we isolated one clinical Escherichia coli stain from a NASH patient’s gut mucosa sample, and then evaluate the metabolic function, liver steatosis pathology and gut barrier function of NAFLD C57BL/6 mice inoculated by this clinical Escherichia coli strain.

Aims & Methods: We obtained one clinical isolate (NP1) enriched in relative abundance 81% of the NASH patient’s gut mucosa bacteria, and identified it as Escherichia coli through biochemical tests and 16S ribosomal RNA gene sequencing. To test whether NP1 can overcome this resistance to NASH by colonizing the gut of mice, we infused 10 8 cells of NP1 or Lactobacillus (Lac) , or Luria-Bertani (LB) culture medium as control every day for two weeks into C57BL/6 J mice by gastric gavage, which have been fed under either normal chow diet or high fat diet (HFD) for 12 weeks, and mice were sacrificed by 20 th week. Body weight, blood glucose, systemic lipid metabolism, intestinal barrier function, and hepatic inflammation and fibrosis were assessed to explore the causative role of NP1 in the development of NASH.

Results: We compared three groups of HFD mice, including HFD + NP1, HFD + Lac and HFD + LB groups. The body weight, oral glucose tolerance test and serum lipid profiles exhibited no significant difference among three groups. However, HFD + NP1 group showed the worst liver pathology and the highest NAFLD activity score (P < 0.01), compared with the HFD + Lac and HFD + LB groups. What’s more, liver fibrosis was the most serious in the HFD + NP1 group, which was confirmed by Masson staining and Sirius-Red staining. Consistent with this, the mRNA expression of MCP-1 (P < 0.05), IL-6 (P < 0.05) and TNF-α (P < 0.01) in liver of HFD + NP1 group were significantly higher than the other two groups, and the mRNA expression of IL-10 (P < 0.01) were the lowest in HFD + NP1 group. Besides, the gut mucosa of HFD + NP1 mice developed inflammation phenotype with the highest level of IL-6 (P < 0.01) and the lowest level of IL-10 (P < 0.01) by the RT-PCR results. The mRNA expression of ZO-1 (P < 0.05) and Occludin (P < 0.01) in gut mucosa of HFD + NP1 group were reduced, indicating the dysfunction of gut barrier. The three groups fed with normal chow diet did not show hepatic inflammation and fibrosis.

Conclusion: The HFD mice with the strain of Escherichia coli NP1 isolated from the NASH patient shows aggravated intestinal inflammatory conditions. What’s more, strain of Escherichia coli NP1 promotes hepatic inflammation and fibrosis, without affecting the systemic lipid or glucose metabolism, whereas the control mice on normal chow diet don’t exhibit the same disease phenotypes. This work suggests that the overgrowth of Escherichia coli gut bacterium isolated from NASH patient may be a contributing factor to NAFLD via injuring the intestinal barrier, rather than a bystander.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP012 DIET-DEPENDENT ACID LOAD IS ASSOCIATED WITH NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD) IN THE GENERAL POPULATION: THE ROTTERDAM STUDY

L. J.M. Alferink 1 , J. C. Kiefte- De Jong 2 , N. S. Erler 3 , J. D. Schoufour 4 , E. J. Hoorn 5 , M. a. Ikram 4 , H. L. a. Janssen 6 , H. J. Metselaar 1 , O. H. Franco 4 , S. Darwish Murad 1

1 Gastroenterology And Hepatology, Erasmus Medical Center, Rotterdam/Netherlands

2 Global Public Health, Leiden University College, Leiden/Netherlands

3 Biostatistics, Erasmus Medical Center, Rotterdam/Netherlands

4 Epidemiology, Erasmus Medical Center, Rotterdam/Netherlands

5 Internal Medicine, Division Of Nephrology And Transplantation, Erasmus Medical Center, Rotterdam/Netherlands

6 Hepatology, Toronto Centre for Liver Disease, Toronto/Canada/ON

Contact E-mail Address: l.alferink@erasmusmc.nl

Introduction: A healthy lifestyle is the cornerstone of treatment in patients with NAFLD and likewise, an unhealthy diet is implicated in the etiology of this disease. We recently found high animal protein intake to be associated with NAFLD and we hypothesize that this may be explained by increased diet-dependent acid load.

Aims & Methods: The aim of this study is to examine if dietary acid load is associated with NAFLD. The Rotterdam Study is an ongoing prospective population-based cohort study in a suburb of Rotterdam, The Netherlands. Based on a validated 389-item food frequency questionnaire, the dietary acid load was estimated by calculating the net endogenous acid production (NEAP, using protein intake and potassium), potential renal acid load (PRAL, using protein, phosphorus, potassium, calcium and magnesium), and animal-to-potassium ratio (A:P). Subsequently, these determinants were analysed in quartiles (Q4 vs. Q1). NAFLD was defined as presence of steatosis on ultrasound in absence of steatogenic drugs, viral hepatitis and alcohol abuse. Logistic regression was performed and all analyses were adjusted for total energy intake as well as for environmental and metabolic traits.

Results: A total of 3440 participants were included. The mean age was 70.7 ± 8.7 years old, 1999 were female (58%) and mean BMI was 27.4 ± 4.3 kg/m 2 . NAFLD was present in 1191 participants (34.6%). Dietary NEAP, PRAL and A:P were all higher in the NAFLD group (37.1 vs. 35.0 mEq/d, −2.8 vs. −5.7mEq/d and 13.3 vs. 12.4mEq/d respectively, all P < 0.001) and all were also associated with higher odds for NAFLD in the social-demographic and lifestyle confounding models ( Table ). Although the association attenuated after adjustment for metabolic covariates, NEAP and PRAL remained associated with NAFLD.

Conclusion: This is the first large-scale Western study suggesting that high diet-dependent acid load is associated with NAFLD in adults. This finding may potentially provide the mechanistic explanation, i.e. low-grade metabolic acidosis, as to why increased animal protein intake is associated with NAFLD. Future studies are needed to confirm our results and to study this association also in relation to acid-base balance biomarkers.

Disclosure of Interest: All authors have declared no conflicts of interest.

MONDAY, OCTOBER 30, 201710:30-12:00

HOT TOPICS FROM LATIN AMERICA - ROOM A3____________________

OP013 IN VIVO DETECTION OF COLONIC MUCOSA MICRO-INFLAMMATION BY CONFOCAL LASER ENDOMICROSCOPY PROBE (P-CLE) IN PATIENTS WITH IRRITABLE BOWEL SYNDROME

C. Robles-Medranda , M. Valero, J. Ospina, M. Puga-Tejada, G. Muñoz-Jurado, M. Soria, H. Alvarado-Escobar, R. Oleas-Narea, H. Pitanga-Lukashok

Gastroenterology, Instituto Ecuatoriano de Enfermedades Digestivas, Guayaquil/Ecuador

Contact E-mail Address: carlosoakm@yahoo.es

Introduction: Irritable bowel syndrome (IBS) is one of the most common gastrointestinal disorders (prevalence of 5–20%), however many patients are undiagnosed. Diagnosis is based on the Rome III criteria. However, combination of the Rome III criteria have a sensitivity, specificity, PPV and NPV of 65%, 100%, 100% and 76%. Current tests commonly fail to obtain an objective diagnosis. Most colonoscopies are performed to rule out other etiologies, and >50% are normal, being considered as a “ functional disease” . Impaired intestinal barrier function with mucosal inflammation in the small and large intestine of these patients has previously been described, and recent reports evidence a possible organic disease involving IBS. However, this fact has not been completely evaluated.

Aims & Methods: We aim to determine the utility of Confocal Laser Endomicroscopy ( p-CLE) in identifying colorectal mucosa micro-inflammation in patients with IBS. We undertook a prospective, controlled, non-randomized and simple blind study, performed from Jan-2016 to Mar-2017, including patients with IBS according to Roma III criteria (IBS group), and healthy patients (control group). The exclusion criteria were patients receiving nonsteroidal anti-inflammatory drugs, corticosteroids or antibiotics in the last 4 weeks, heart, kidney, liver or severe metabolic disease, inflammatory bowel disease, bacterial overgrowth, gastrointestinal bleeding, history of any king of colitis (actinic, infectious, ischemic, microscopic colitis), suspected colonic obstruction or history of previous obstruction, history of colectomy, allergy to fluorescein, pregnancy, poor bowel preparation (Boston Bowel Preparation Scale <6). Both groups underwent colonoscopy using p-CLE with target-biopsy of each colorectal section. Altered crypt architecture, epithelial gaps with fluorescein leaks and dilated and prominent branching vessels were the considered p-CLE criterion for inflammation. Following Geboes Scale, biopsies were evaluated by one pathologist blinded to endoscopic findings. Overall diagnostic accuracy was determined by sensitivity, specificity, PPV, NPV, observed and inter-rater agreement (Cohen kappa).

Results: 37 patients and 222 biopsies were included in each group (total: 444 biopsies and 74 patients). Mean age was 53.1 (25–90) years old and 64.9% were women. There was not significant statistical difference in demographic data between groups. Normal colonoscopy was observed in all cases. There was a significant increased number of inflammatory lesions at p-CLE in the IBS group (65.8%) compared with control group (23.4%) (OR 6.28 (4.14 – 9.52; p < 0.001). (Table 1) Geboes grade >0 was more frequently in IBS group (60.8% vs. 27.5%; p < 0.001). p-CLE for inflammatory findings in IBS, considering target biopsy as gold standard, reached a sensitivity, specificity, PPV, NPV, observed and inter-rater agreement of 86.7%, 88.7%, 85.9%, 89.4%, 87.8% and 75.4%.

Conclusion: p-CLE proved to be a reliable method for detecting colorectal mucosa micro-inflammation in patients with IBS, showing that patients with IBS have 6 times more prevalence of mucosal colorectal microinflammatory than healthy patients.

Disclosure of Interest: C. Robles-Medranda: KOL for Pentax Medical, Boston Scientific Consulting, US Endoscopy consulting.

All other authors have declared no conflicts of interest.

Reference

1. Fritscher-Ravens A, Schuppan D, Ellrichmann M, et al. Confocal endomicroscopy shows food-associated changes in the intestinal mucosa of patients with irritable bowel syndrome. Gastroenterology . 2014 Nov;147:1012–20

OP014 STRUCTURAL ANALYSIS OF VARIABILITY AND INTERACTION OF HELICOBACTER PYLORI ONCOGENIC EFFECTOR CAGA N-TERMINAL WITH PHOSPHATIDYLSERINE

C. P. Ulloa , M. D.P. Delgado, C. A. Jaramillo

Biological Sciences, Universidad de los Andes, Bogota/Colombia

Contact E-mail Address: cp.ulloa530@uniandes.edu.co

Introduction: Human Helicobacter pylori cytotoxin-associated gene A protein (CagA) has been correlated with the increase in virulence and risk of developing gastric cancer [1]. In several studies, the number and type of EPIYA has been associated with the presented pathology, nevertheless, in Colombia, a direct association has not been observed [2]. Generally, the interactions with motifs that are localized in the C-terminal have been studied [2]. Nonetheless, little attention has been given to the possible role that the N-terminal may play in the observed pathophysiology. However, studies have demonstrated that CagA's translocation is dependent on its N-terminal interaction with phosphatidylserine (PS) [3].

Aims & Methods: In this study we evaluated the variability of the N-terminal CagA from 127 sequences. The major sites of conservation of the residues involved in the PS interaction were 617, 621 and 626, which had no amino acid variation. Position 636 had the lowest conservation score, so mutations in this position were evaluated in order to observe the differences in intermolecular forces of the CagA-PS complex. We evaluated the docking of 3 mutations: K636A, K636R and K636N.

Results: The models of the crystal and mutations K636A, K636R and K636N presented a ΔG of −8.919907, −8.665261, −8.701923, −8.515097 Kcal/mol, respectively. While, mutations K636A, K636R, K636N presented 0, 3, and 4 H-bonds, respectively; and the crystal structure had 1 H-bond. Likewise, the bulk effect of the ΔG and amount of H-bonds was estimated on the entire docking models. The type of mutation affected both, the ΔG (χ 2 (1) = 93.82, p-value <2.2 × 10 −16 ) and the H-bonds (χ 2 (1) = 91.93, p-value <2.2 × 10 −16 ). Of all the data, 76.9% of the strains that exhibit the K636N mutation produced a severe pathology. The average of the H-bond count diminished when comparing the mutations with the crystal structure of all the docking models. This means that other molecular forces are involved in the CagA-PS complex interaction.

Conclusion: The study of molecular forces involved in the interaction of CagA binding with proteins in host cells helps to have a better understanding on how it could cause different degrees of pathology. The interaction of CagA with PS requires a set of positively charged residues that is highly conserved among the sequences analyzed. The most variable position naturally found was the K636N mutation, which generated a higher free energy change and a lower hydrogen count with respect to the crystal structure 4DVY when evaluating the entire docking models. Nevertheless, the amount of hydrogen bonds increased when comparing the best model of all the mutations; specifically, when there was lysine to asparagine change it generated two additional hydrogen bonds. This mutation was also associated with a severe pathology, which means that there could be other molecular forces involved in the CagA-PS complex interaction that were not taken into account.

Disclosure of Interest: All authors have declared no conflicts of interest.

References

1. Pelz C, Steininger S, Weiss C, et al. (2011) A novel inhibitory domain of Helicobacter pylori protein CagA reduces CagA effects on host cell biology. J Biol Chem 286:8999–9008. doi: 10.1074/jbc.M110.166504

2. Acosta N, Quiroga AA, Delgado P, et al. (2010) Helicobacter pylori CagA protein polymorphisms and their lack of association with pathogenesis. World J Gastroenterol 16:3936–3943. doi: 10.3748/wjg.v16.i31.3936

3. Murata-Kamiya N, Kikuchi K, Hayashi T, et al. (2010) Helicobacter pylori Exploits Host Membrane Phosphatidylserine for Delivery, Localization, and Pathophysiological Action of the CagA Oncoprotein. Cell Host Microbe 7:399–411. doi: 10.1016/j.chom.2010.04.005

MONDAY, OCTOBER 30, 201710:30-12:00

DISEASE BURDEN IN IBD - ROOM B2____________________

OP015 IMPACT OF INTERVENTIONS FOR MODERATE TO SEVERE ULCERATIVE COLITIS ON HEALTH-RELATED QUALITY OF LIFE: SYSTEMATIC REVIEW AND NETWORK META-ANALYSIS

P. Paschos 1 , A. Katsoula 1 , O. Giouleme 2 , M. Sarigianni 1 , E. Athanasiadou 1 , A. Tsapas 1

1 Clinical Research And Evidence-based Medicine Unit, Second Medical Department, aristotele university of thessaloniki, Thessaloniki/Greece

2 Second Propedeutic Medical Department, Aristotle University, Thessaloniki, Greece, Thessaloniki/Greece

Contact E-mail Address: pashospas@hotmail.com

Introduction: We performed a systematic review and network meta-analysis to assess the impact of pharmacological therapies on health-related quality of life (HRQL) of patients with moderate to severe ulcerative colitis (UC).

Aims & Methods: Medline, Embase, CENTRAL, and grey literature sources were systematically searched up to February 2017. We included randomized controlled trials in adults with moderate to severe UC that compared infliximab, adalimumab, golimumab, vedolizumab and tofacitinib to each other or placebo. Outcomes were change in mean difference in Inflammatory Bowel Disease Questionnaire (IBDQ) score, in Short Form-36 (SF-36) physical and mental component summary scores (PCS and MCS respectively), IBDQ response (a ≥ 16-point increase from baseline) and IBDQ remission (total IBDQ score of ≥170 points). We combined direct and indirect evidence through multivariate random-effects network meta-analyses and relative ranking of treatments was assessed using surface under the cumulative ranking (SUCRA) probabilities. We also estimated Predictive intervals (PrI), which indicate the interval within which the relative effect of a future study is expected to be, in order to facilitate interpretation of the results in the light of the magnitude of heterogeneity.

Results: We included 12 randomized, double-blind, placebo-controlled trials (3 with infliximab, 3 with adalimumab, 1 with golimumab, 1 with vedolizumab and 4 with tofacitinib). All interventions as induction therapy resulted in significantly improved mean IBDQ score compared to placebo (table). They also had significantly higher mean SF-36 scores and higher rates of IBDQ remission and response than placebo. However, only infliximab (MD18.58; 95%CI 13.19 to 23.97) and vedolizumab (MD 18.00; 95%CI 11.08 to 24.92) achieved a clinically meaningful improvement in HRQL, with an increase in IBDQ score of more than 16 points. Compared to each other, differences among agents did not remain significant when Predictive Intervals were included, since respective Predictive Intervals crossed the line of no effect. In terms of relative ranking, infliximab, vedolizumab and tofacitinib had comparable high probability of being the best treatment across all outcomes. Due to limited data on impact of maintenance therapy on quality of life a network meta-analysis for maintenace therapy could not be conducted. Maintenance with vedolizumab (MD 21.10; 95%CI 11.93 to 30.27) and tofacitinib (MD 20.80; 95%CI 13.55 to 28.05) resulted in clinically significant improvement in IBDQ score compared to placebo.

Network meta-analysis results of mean difference in IBDQ score. Data indicate column-to-row mean difference (MD), 95% CI and 95%PrI for change in IBDQ score (i.e. a MD higher than 0.00 favours the column-defining treatment).

Conclusion: Short-term treatment with all pharmacological therapies improved quality of life. Evidence suggests that no single agent is superior to other although infliximab and vedolizumab seems to have greater impact on HRQL. More research is needed to assess the long-term effect of therapies on HRQL.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP016 THE INCIDENCE OF MILD OPPORTUNISTIC SELF-REPORTED INFECTIONS IN PATIENTS WITH IMMUNE-MEDIATED INFLAMMATORY DISEASES

L. E. Van Wijnen 1 , A. Wolters 1 , M.J. Pierik 2 , D.M. Jonkers 1 , M. De Jong 1 , A. Peters 1 , A. A. m. Masclee 3 , P. Steijlen 4 , A. Tubergen 5

1 Department Of Internal Medicine, Division Of Gastroenterology, Maastricht University Medical Centre, Maastricht/Netherlands

2 Dept Of Gastroenterology And Hepatology, Maastrich University Medical Center Dept. of Gastroenterology, Maastricht/Netherlands

3 Gastroenterology Hepatology, UMC Maastricht, Maastricht/Netherlands

4 Department Of Dermatology, Maastricht University Medical Centre, Maastricht, Maastricht/Netherlands

5 Department Of Internal Medicine, Division Of Rheumatology, Maastricht University Medical Centre, Maastricht/Netherlands

Contact E-mail Address: l.vanwijnen@student.maastrichtuniversity.nl

Introduction: Thiopurines and biologicals are important for maintenance of remission in immune-mediated inflammatory diseases (IMID). Since they modulate the immune system, the risk for (opportunistic) infections is theoretically increased. Several studies report an increased risk for severe infections associated with these drugs. However, few data are available on mild opportunistic infections in these patients. Since 2012, we use the telemedicine systems “myIBDcoach” (MIBDC) for inflammatory bowel disease (IBD) patients and “myBiologicalcoach” (MBC) for all other IMID patients in our centre for monitoring and registration of medication (side-) effects and self-reported infections. We aimed to 1) validate the questionnaire on self-reported infections used in these systems and 2) describe the incidence of self-reported mild opportunistic infections in IMID patients.

Aims & Methods: Patients using MIBDC or MBC were asked to fill out the questionnaire on self-reported infections every three months. For validation of the questionnaire, data on infectious events and their according therapy was collected from patients using MIBDC from September 2014 through May 2016 and compared to pharmacy records and general practitioners’ and hospitals’ electronic patient records. Subsequently, data on infections reported by all patients using MIBDC and MBC were included to calculate the incidence, nature, and severity of the infections. An infection was defined as mild if no antibiotic (AB) or antiviral medication (AV) was prescribed, as moderate if AB or AV was required and as severe in case of a hospitalisation.

Results: During the validation phase, 631 questionnaires were filled out by 86 patients. We found a 97% agreement between pharmacy data and questionnaires regarding infections and AB or AV use and a sensitivity and specificity of 58.3% (95% CI: 40.9–74.0) and 99.3% (95% CI: 98.1–99.8) respectively. In total, 425 IBD patients using MIBDC and 197 IMID patients using MBC were included for evaluation of the incidence of self-reported infections. During a mean follow-up of 11 ± 4 months, 949 infections were reported, of which 75.8% were mild infections, 23.0% were moderate and 1.2% was severe (table 1).

Conclusion: The patient-reported infectious diseases questionnaire used in the telemedicine tools MIBDC and MBC is a valid method to monitor infections in IMID patients. The overall incidence of self-reported infections in IMID patients was 1.7 infections per patient-year. The mild and moderate infections are underreported in previously published post-marketing surveillance studies. Systematic registration of all infections in relation with therapy is important to optimise country specific screening and vaccination protocols.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP017 TREAT TO TARGET FOR CROHN’S DISEASE WITH ADALIMUMAB TREATMENT IS COST EFFECTIVE OVER 48 WEEKS: AN ECONOMIC ASSESSMENT OF THE CALM TRIAL

R. Panaccione 1 , J. Colombel 2 , P. Bossuyt 3 , M. Lukas 4 , F. Baert 5 , T. Vanásek 6 , A. Danalıoğlu 7 , G. Novacek 8 , A. Armuzzi 9 , W. Reinisch 8 , S. Johnson 10 , M. Davis 10 , E. Neimark 11 , J. Petersson 11 , A.M. Robinson 11 , R. Thakkar 11 , W. Lee 11 , M. Skup 11

1 University of Calgary, Calgary/Canada

2 Icahn School of Medicine at Mount Sinai, New York/United States of America/NY

3 Imelda General Hospital, Bonheiden/Belgium

4 Charles University, Prague/Czech Republic

5 AZ Delta Roeselare-Menen, Menen/Belgium

6 Hepato-Gastroenterologie HK, s.r.o., Hradec Králové/Czech Republic

7 Bezmialem Vakif University, İstanbul/Turkey

8 Medical University of Vienna, Vienna/Austria

9 Presidio Columbus, Fondazione Policlinico Gemelli Università Cattolica, Rome/Italy

10 Medicus Economics, LLC, Boston/United States of America/MA

11 AbbVie Inc., North Chicago/United States of America/IL

Contact E-mail Address: rpanacci@ucalgary.ca

Introduction: In an open-label, multicenter, 48-week randomized controlled trial of patients with moderate to severe Crohn’s disease (CALM), treat to target (T2T) approach, using biomarkers (C-reactive protein and fecal calprotectin) in addition to Crohn's disease Activity Index (CDAI) and corticosteroid use, was shown to improve the rate of mucosal healing compared to conventional clinical management (CM). 1 As to whether favorable the health economic effects associated with the clinical benefits have not been evaluated.

Aims & Methods: A model was developed to evaluate the cost-effectiveness of T2T versus CM from the CALM trial using costs reflecting a United Kingdom (UK) setting. CDAI was used to map patients into four health states (remission: CDAI < 150, moderate: CDAI ≥ 150 to <300, severe: CDAI ≥300 to <450, very severe: CDAI ≥450) weekly over the 48-week trial. Each health state was associated with corresponding health utility from a UK analysis. 2 Average number of CD-related hospitalization was obtained from CALM. Hospital and health state cost data were derived from published UK-based research from the perspective of the National Health Service. Number of adalimumab (ADA) injections was estimated from CALM and current UK list prices were used for ADA costs. Proportion of patients in remission, CD-related hospitalizations, ADA injections, direct medical costs (including outpatient visits, lab tests, endoscopic procedures), quality-adjusted life years (QALYs), incremental cost-effectiveness ratio (ICER) and net monetary benefit (NMB) were calculated over 48 weeks. Deterministic and probabilistic sensitivity analyses (PSA) were conducted to assess uncertainty. Work productivity and activity impairment (WPAI) data from the CALM trial were also used in sensitivity analysis.

Results: At week 0, in the T2T cohort (n = 122), 73.0% were in moderate and 27.0% were in severe state; for the MC cohort (n = 122), 75.4%, 23.8%, and 0.8% were in moderate, severe, and very severe states, respectively. Over the 48 weeks, T2T was associated with higher remission rate (62.1% vs 47.3%), fewer CD-related hospitalizations (mean 0.13 vs 0.28), and more ADA injections (mean 30.87 vs 24.72) than CM. Total medical costs were £13, 296 in the T2T and £12, 627 in the CM treatment algorithms; 0.684 QALYs were observed for T2T and 0.652 for CM (table) . T2T had 0.032 higher QALYs (95% confidence interval [CI]: 0.042 to 0.021) and £669 higher total medical costs (95% CI: £2, 529 to -£1, 994). The ICER was £20, 913 per QALY (95% CI: £94, 116 to -£61, 457 [TC dominant]), which was below the National Institute for Health and Care Excellence (NICE) threshold of £30,000. 3 Analyses that included WPAI data from the trial also favored the T2T treatment algorithm. Results were robust in the sensitivity analyses.

Table. Economic outcomes and cost-effectiveness of treat to target versus clinical management using the CALM trial

Conclusion: In an economic model using clinical data from the CALM trial, T2T appears cost-effective compared to CM even after considering higher drug costs, by providing increases in remission, decreases in CD-related hospitalization and improvements in quality of life for patients with CD.

Funding Statement: Financial support for the study was provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the abstract. All authors contributed to the development of the publication and maintained control over the final content.

Acknowledgement: Medical writing support was provided by Suchin Virabhak, Medicus Economics LLC, Boston, MA, United States; this support was funded by AbbVie.

Disclosure of Interest: R. Panaccione: Consultant/lecturer: AbbVie, Amgen, AstraZeneca, Axcan, Biogen Idec, BMS, Centocor, ChemoCentryx, Eisai, Elan, Ferring, Genentech, GSK, Janssen, MSD, Millennium, Ocera, Otsuka, Pfizer, Shire, Prometheus, Schering-Plough, Synta, Teva, UCB, Warner Chilcott

J. Colombel: Consultant/ad board: AbbVie, Amgen, Boehringer-Ing, Celgene, Celltrion, Enterome, Ferring, Genentech, Janssen, Medimmune, Merck, Pfizer, Protagonist, Second Genome, Seres, Shire, Takeda, Theradiag; Speaker: AbbVie, Ferring; Speaker: Amgen …

P. Bossuyt: Educational grants: AbbVie; Speaker fees: AbbVie, Takeda, and Vifor Pharma; Advisory board fees: Hospira, Janssen, MSD, Mundipharma, Roche, Pfizer, and Dr Falk Benelux.

M. Lukas: Consultant or speaker or advisory member: Abbvie, MSD, Takeda, Egis, Hospira, Celltrion, Janssen and Vifor

F. Baert: Research grants: Abbvie, Chiesi, Ipsen, MSD, Roche; Speakers and consultancy fees: Abbvie, Falk, Ferring, Janssen, Mundipharma, MSD, Pfizer, Takeda, Vifor

T. Vanásek: Advisory member: Hospira, Pfizer and Takeda; Lecture fees: Takeda

G. Novacek: Consultant/advisory board member/speaker: AbbVie, MSD, Takeda, Ferring, Vifor, Merck

A. Armuzzi: Consultant/ad: AbbVie, Biogen, Celltrion, Ferring, Hospira, Janssen, Lilly, MSD, Mundipharma, Pfizer, Samsung, Sofar and Takeda; Lecture fees: AbbVie, AstraZeneca, Chiesi, Ferring, Hospira, MSD, Mundipharma, Otsuka, Pfizer, Takeda and Zambon …

W. Reinisch: Speaker: AbbVie, Aesca, Aptalis, Astellas, Centocor, Celltrion, Danone Austria, Elan, Falk, Ferring, Immundiagnostik, Mitsubishi, MSD, Otsuka, PDL, Pharmacosmos, PLS Education, Schering-Plough, Shire, Takeda, Therakos, Vifor, Yakult; Consultant: AbbVie …

S. Johnson: Employee: Medicus Economics, which received payment from AbbVie to assist with the model development

M. Davis: Employee: Medicus Economics, which received payment from AbbVie to assist with the model development

E. Neimark: Employee, stockholder: AbbVie

J. Petersson: Employee, stockholder: AbbVie

A.M. Robinson: Employee, stockholder: AbbVie

R. Thakkar: Employee, stockholder: AbbVie

W. Lee: Employee, stockholder: AbbVie

M. Skup: Employee, stockholder: AbbVie

All other authors have declared no conflicts of interest.

References

1. Colombel et al. Oral presentation (no. 718). Digestive Disease Week, Chicago, IL, USA, 2017.

2. Buxton et al. Value in Health. 2007;10(3):214–20.

3. NICE, Guide to the methods of technological appraisal. 2013.

OP018 HEALTHCARE RESOURCE UTILIZATION AND QUALITY OF LIFE IN PATIENTS WITH ULCERATIVE COLITIS BY DISEASE SEVERITY: BASELINE DATA FROM ICONIC

S. Ghosh 1 , L. Peyrin-Biroulet 2 , F. Casellas 3 , C. O'Shea 4 , W.J. Lee 5 , B. Pappalardo 5 , J. Petersson 5

1 University of Birmingham, Birmingham/United Kingdom

2 University of Lorraine, Nancy/France

3 Crohn-Colitis Care Unit, Hospital Universitari Vall d'Hebron, Barcelona/Spain

4 Abbvie Ltd., Dublin/Ireland

5 AbbVie Inc., North Chicago/United States of America

Contact E-mail Address: ghoshs@bham.ac.uk

Aims & Methods: Adult pts with early UC (diagnosed ≤ 36 months) were enrolled in ICONIC irrespective of disease severity or treatment. For this analysis, we evaluated pts stratified by physician assessment of disease severity into severe, moderate, mild and remission groups. The following BL characteristics were described for the four groups: Simple Clinical Colitis Activity Index (SCCAI), UC-related HCRU measured during the 6 months prior to study enrollment (i.e., visits to treating physicians or other IBD-associated healthcare professionals, emergency room (ER) visits, hospitalizations and hospital admissions for surgeries); Health Related Quality of Life (HRQoL) (i.e., Short Inflammatory Bowel Disease Questionnaire (SIBDQ), pt-reported employment/UC-related sick leave status and Work and Productivity Activity Index (WPAI:GH; including work time missed (absenteeism), impairment while working (presenteeism), overall work productivity impairment, and daily activity impairment domains). Data are presented as observed and summarized as means or proportions, as appropriate. Only available observed data are shown.

Results: A total of 1816 UC pts were enrolled in ICONIC; mean ± SD age was 38.5 ± 14.6 years and 833 (45.9%) were female. At BL, 230 pts (12.7%) were in remission, 672 pts (37.0%) had mild UC, 668 pts (36.8%) had moderate UC, and 234 (12.9%) had severe UC.* SCCAI, HCRU and HRQoL measures at BL by disease severity are summarized in Table. Compared to pts in remission, pts with moderate to severe UC had 1.8 to 2.6-fold higher rates of hospitalizations and 1.6 to 2.5-fold higher rates of ER visits over the past 6 months. The total number of visits to the treating physician did not appear to differ across the disease severity groups. Pt with moderate and severe disease were associated with lower SIBDQ scores and higher WPAI:GH domain scores (i.e., greater impairment on work productivity) than pts with mild disease or those in remission. Of 172 (9.5%) pts, who reported to be unemployed at BL, 24.4% (n = 42) considered their unemployment to be directly related to UC. Rates of unemployment due to UC were highest in severe UC (39.4%), followed by moderate (21.6%) and mild UC (18.4%) and lowest in pts in remission (16.7%). A total of 183 (10.1%) reported sick leave at BL. Sick leave time ranged from <2 months (59.6%), 2–4 months (12.6%), >4 months (22.4%). Among pts on sick leave, 81.4% (n = 149) indicated that it was UC-related, however for pts with severe UC in this group, 100% (n = 48) associated sick leave with UC. In pts with moderate UC, 43.6% (n = 65) reported UC-related sick leave. Table. Baseline SCCAI, HCRU, and HRQoL by UC severity.*

Introduction: ICONIC is the largest ongoing, prospective, multi-country (n = 33) observational study, assessing cumulative burden in adult ulcerative colitis (UC) patients (pts) under routine care. Assessments of healthcare resource utilization (HCRU), disease severity and impact on quality of life will be captured at 6 month intervals through 2 years. This analysis evaluated baseline (BL) HCRU, work productivity, and quality of life among UC pts with different level of disease severity.

Conclusion: The direct and indirect burden of UC is substantial, as measured by healthcare resource utilization and work-life impact in the ICONIC study. Pts with moderate and severe UC not only were associated with higher rates of urgent care in hospitalization and ER visits, but also with poorer quality of life, higher unemployment, sick leave and impaired work productivity than pts with mild UC or in remission. For pts with mild UC, despite comparable HCRU to pts in remission, increased impact on work productivity remains a concern.

Disclosure of Interest: S. Ghosh is a steering committee member for Pfizer, Janssen, AbbVie, BMS, Celgene and receives speaker honorarium from AbbVie, Janssen, Takeda, Shield, and Falk Pharma.

L. Peyrin-Biroulet receives consulting/lecture fees from Merck, Abbvie, Janssen, Genentech, Mitsubishi, Ferring, Norgine, Tillots, Vifor, Therakos, Pharmacosmos, Pilège, BMS, UCB-pharma, Hospira, etc

F. Casellas receives research finding from AbbVie, MSD, Shire, Ferring, and Zambon and speaker fees from AbbVie, MSD, Shire, Ferring, Zambon, and Gebro.

C. O'Shea Abbvie employee; may own AbbVie stock and/or options

W.J. Lee: Abbvie employee; may own AbbVie stock and/or options

B. Pappalardo: Abbvie employee; may own AbbVie stock and/or options

J. Petersson: Abbvie employee; may own AbbVie stock and/or options

OP019 RISK FACTORS FOR POSTOPERATIVE INFECTION AFTER LOWER GASTROINTESTINAL SURGERY IN PATIENTS WITH INFLAMMATORY BOWEL DISEASE: FINDINGS FROM A LARGE EPIDEMIOLOGICAL STUDY

H. Liang 1 , B. Jiang 2 , T. Lissoos 3 , S. Manne 2 , P. Dolin 4

1 Pharmacoepidemiology, Takeda Development Center Americas, Inc., Deerfield/United States of America/IL

2 Safety & Observational Research Analytics, Takeda Development Center Americas, Inc., Deerfield/United States of America/IL

3 Takeda Pharmaceuticals U.S.A., Inc., Deerfield/United States of America/IL

4 Pharmacoepidemiology, Takeda Development Centre Europe Ltd., London/United Kingdom

Contact E-mail Address: trevor.lissoos@takeda.com

Introduction: Lower gastrointestinal (GI) surgery continues to play an important role in the management of inflammatory bowel disease (IBD). Some patients develop postoperative infections which increase morbidity and prolong the length of hospitalization. Currently there is little data on the risk factors for developing a postoperative infection in the ulcerative colitis (UC) and Crohn’s disease (CD) patient population.

Aims & Methods: This study was conducted to identify risk factors for a postoperative infection after lower GI surgery in the UC and CD patient population. A retrospective cohort study was undertaken using the Optum Insurance Claims Databases through 30 September 2016. This database includes over 70 million people insured with UnitedHealthcare in the US. The study population was adult UC and CD patients who underwent lower GI surgery defined as surgeries of the small intestine, colon, rectum and anus and categorized as resection, repair, bypass or drainage surgeries as defined by ICD-10-PCS. Patients were coded by relevant ICD-9-CM procedure codes, ICD-10-PCS codes and Current Procedural Terminology (CPT) codes) after 1 September 2014 and had at least two diagnoses claims for UC or CD prior to surgery; were continuously enrolled for at least 6 months before and at least 30 days after the surgery. Cases of postoperative infection within the study population were defined as postoperative wound infection, peritonitis, retroperitoneal infection, or sepsis occurring 2–30 days after the lower GI surgery [1]. Patient demographics, IBD characteristics, surgery-related variables, medical histories and medications use before surgery were assessed. Multivariate logistic regression analyses were used to identify risk factors for a postoperative infection.

Results: A total of 3360 IBD patients (mean age 51.2 ± 17.9 years, women 52.5%, 1362 UC and 1998 CD, with mean age 55.1 and 48.6 years, respectively) had lower GI surgery during the study period and fulfilled the study criteria of being at risk of a postoperative infection. With some patients having 2 or more types of surgery, the index lower GI surgery performed was as follows: resection 60.8%, repair 17.5%, bypass 30.3%, and drainage 23.5%. The 30-day postoperative infection incidence after the surgery was 15.1% (95% confidence interval [CI]: 14.0%–16.4%) and was similar for UC (14.4%, 95% CI: 12.6%−16.4%) and CD (15.7%, 95% CI: 14.1%−17.3%) patients. Multivariate analysis in IBD patients identified the following as risk factors for a postoperative infection: prior history of postoperative infection (odds ratio[OR]=3.99, 95% CI: 3.11–5.12), open procedure (OR = 2.33, 95% CI: 1.88–2.89), preoperative hospital stay at least 4 days (OR = 1.90, 95% CI: 1.27–2.82), lower GI bypass surgery (OR = 1.72, 95% CI: 1.39–2.13), lower GI resection (OR = 1.61, 95% CI: 1.27–2.04), history of chronic obstructive pulmonary disease (OR = 1.59, 95% CI: 1.14–2.23), use of systemic corticosteroids within 14 days before surgery (OR = 1.53, 95% CI: 1.21–1.92), history of C. difficile infection (OR = 1.53, 95% CI: 1.03–2.25), and anemia (OR = 1.45, 95% CI: 1.17–1.80). The risk factor profile was similar for UC and for CD patients.

Conclusion: This study identified several risk factors for postoperative infection. Patients with these risk factors should be considered at an increased risk of postoperative infection.

Disclosure of Interest: H. Liang is an employee of Takeda Pharmaceuticals and receives stocks or stock options from Takeda at the time of the study.

B. Jiang is an employee of Takeda Pharmaceuticals and receives stocks or stock options from Takeda at the time of the study.

T. Lissoos is an employee of Takeda Pharmaceuticals and receives stocks or stock options from Takeda at the time of the study.

S. Manne is an employee of Takeda Pharmaceuticals and receives stocks or stock options from Takeda at the time of the study.

P. Dolin is an employee of Takeda Pharmaceuticals and receives stocks or stock options from Takeda at the time of the study.

Reference

1. Olsen MA, Nickel KB, Wallace AE, Mines D, Fraser VJ, Warren DK. Stratification of surgical site infection by operative factors and comparison of infection rates after hernia repair. Infection Control & Hospital Epidemiology 2015;36(3):329–35.

OP020 DISEASE BURDEN AND FACTORS ASSOCIATED WITH ULCERATIVE COLITIS PROGRESSION IN SWEDEN

J. Stålhammar 1 , P. Hällström 2 , L. Agréus 3 , H. Beydogan 4 , L. Arnheim Dahlström 4 , M. Skup 5 , W. Lee 5

1 Department Of Public Health And Caring Sciences, Family Medicine And Preventive Medicine, Uppsala University, Uppsala/Sweden

2 Department Of Medical Sciences, Uppsala University, Uppsala/Sweden

3 Department Of Neurobiology, Care Sciences And Society, Karolinska Institutet, Stockholm/Sweden

4 QuintilesIMS, Stockholdm/Sweden

5 AbbVie Inc., North Chicago/United States of America/IL

Contact E-mail Address: Per.Hellstrom@medsci.uu.se

Introduction: Ulcerative colitis (UC) is a systemic and debilitating disease 1 ; however, evidence regarding its progressive nature is limited. The objective of this study was to assess the disease burden associated with UC progression and to identify factors related to the progression in UC.

Aims & Methods: A retrospective cohort study was conducted using data obtained from electronic medical records in Uppsala County in Sweden and the Swedish longitudinal integration database for health insurance and labour market studies (LISA) between 2005 and 2014. Patients with UC aged ≥18 years with moderate disease activity (partial Mayo clinic score of 2–4 and treated with betamethasone or <40 mg of other steroids) were identified and followed to observe the progression to severe UC. Severe UC was defined as having partial Mayo score 5–9 and being treated with prednisone or ≥40 mg/day of other steroids. Risk of all-cause hospitalization, UC-related hospitalization and UC-related surgery within one year were estimated among patients with progression vs non-progression using odds ratio (OR) estimated by logistic regression. Annual indirect costs were calculated and compared between patients who progressed and those who did not (age 18–65) based on the average number of sick leave days and the average annual Swedish salary (in 2014 SEK and Euro). Logistic regression models were used to examine the demographic and clinical factors associated with UC progression.

Results: Among 1361 patients with moderate UC identified, 321 (23.6%) progressed to severe UC in a median follow-up of 6.26 (interquartile range: 4.8) years. Use of biologic therapy was low (8.6%) during the follow-up. Compared to patients who did not progress, those who progressed to severe UC had a 1.45 times higher risk of all-cause hospitalization (95%CI 1.12–1.87) and a 2.56 times higher risk of UC-related hospitalization (95%CI 1.86–3.52) within one year, adjusting for age and gender (table) . A high but not statistically significant risk of UC-related surgery was observed (OR 1.76, 95%CI 0.86–3.59) in patients who progressed. Average sick leave days were significantly higher in patients who progress than those who did not (64.4 vs 38.6 days, p < 0.001), which translated to higher indirect costs of 141,574 SEK (or 15558 Euro) for progressed patients compared to 86,585 SEK (or 9515 Euro) for non-progressed patients (p < 0.001). Patients who were younger (OR 0.99, 95%CI 0.98–1.00, p = 0.005), with a longer disease duration (OR 1.10, 95%CI 1.05–1.16, p < 0.001) and who used steroids (OR 11.84, 95%CI 4.74–29.59, p < 0.001) were more likely to progress from moderate to severe UC. Table. Comparison of health care utilization and costs associated with sick leave days between UC patients with and without progression.

Conclusion: The disease burden associated with hospitalizations and sick leave days was significantly higher in patients who progressed to severe UC compared to those who did not. Younger age, longer disease duration and steroid use were significant factors associated with disease progression. Use of biologics was low in UC patients. Early identification of disease progression and intervention with appropriate treatment should be implemented to prevent considerate disease burden associated with UC progression.

Funding Statement Financial support for the study was provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the abstract. All authors contributed to the development of the publication and maintained control over the final content.

Disclosure of Interest: J. Stålhammar: Consultant fees: AbbVie

P. Hällström: Consultant fees: AbbVie

L. Agréus: Consultant fees: AbbVie

H. Beydogan: Employee: Quintiles IMS Health, Stockholm, Sweden, and received payment from AbbVie to assist the analyses of this study

L. Arnheim Dahlström: Employee: Quintiles IMS Health, Stockholm, Sweden, and received payment from AbbVie to assist the analyses of this study

M. Skup: Employee, stockholder: AbbVie

W. Lee: Employee, stockholder: AbbVie

Reference

1. Farrell D, et al. J Crohns Colitis . 2016;10:315–22.

MONDAY, OCTOBER 30, 201710:30-12:00

IMAGING, SCREENING AND SURVEILLANCE OF COLORECTAL CANCER - ROOM 7.1____________________

OP021 DIFFERENCES IN ADENOMA AND PROXIMAL SERRATED POLYP DETECTION AND ITS EFFECT ON THE LONG-TERM IMPACT OF A BIENNIAL FIT-BASED COLORECTAL CANCER SCREENING PROGRAM – A MICROSIMULATION STUDY

M. Bronzwaer 1 , M. Greuter 2 , A. Bleijenberg 1 , J. Ijspeert 1 , E. Dekker 1 , V.M. h. Coupé 2

1 Gastroenterology And Hepatology, Academic Medical Center, Amsterdam/Netherlands

2 Epidemiology And Biostatistics, VU Medical Center Epidemiology and Biostatistics, Amsterdam/Netherlands

Contact E-mail Address: m.e.bronzwaer@amc.uva.nl

Introduction: Both adenoma detection rate (ADR) as well as the proximal serrated polyp detection rate (PSPDR) are known to vary widely among endoscopists. However, little is known about the consequences of variances in both detection rates on the effectiveness of a screening program using biennial fecal immunochemical testing (FIT) as a triage modality. Using a microsimulation model, we aimed to evaluate the long-term CRC incidence and mortality, as well as the total number of colonoscopies needed per year 30 years after the implementation of a FIT-based CRC screening program. Overall ADR and PSPDR levels of the participating endoscopists were varied in this model to evaluate its independent effect.

Aims & Methods: The Adenoma and Serrated pathway to Colorectal CAncer (ASCCA) model was set up to simulate the Dutch nationwide FIT-based screening program between 2014 and 2044. In this screening program, individuals aged 55–75 years are biennially invited, and FIT-positives referred for colonoscopy. We assumed a 73.0% participation rate for FIT testing and a 92.0% colonoscopy uptake. FIT test characteristics for adenomas were obtained by calibrating against the positivity rate, detection rates and positive predictive values of a Dutch screening pilot study. Whereas for serrated polyps the positivity rate was assumed to be equal to one minus the specificity. Besides a ‘no screening scenario’, we evaluated several screening scenarios with varying ADRs and PSPDRs. Based on recent literature, we assumed an ADR of 59.0% and PSPDR of 11.0% as the base-case scenario. Both base-case ADR and PSPDR were in- and decreased with intervals of 3.0% and 2.0%, respectively. We assumed a minimal ADR of 44% and a minimal PSPDR of 3%. The maximal ADR (61.5%) and PSPDR (14.5%) were reached under the assumption that all adenomas or serrated polyps were detected during FIT positive colonoscopies.

Results: The model predicted that the FIT-based screening program in the base-case scenario was associated with a long-term CRC incidence and mortality reduction 36.7% and 51.8% when compared to no screening. After 30 years of implementation of this screening program, an additional 102,862 colonoscopies per year are needed within the total Dutch population. At a fixed PSPDR of 11.0%, an increase in ADR from 44.0% to 61.5% would result in a decrease in CRC incidence of 24.9% when comparing both scenarios. Similarly, long-term CRC mortality would decrease with 22.7%. For this increase in ADR, an additional 21,726 colonoscopies per year would be needed 30 years after the implementation of the FIT-based screening program. Using a fixed ADR of 59.0% and variable PSPDR (from 3.0% to 14.5%) model outcomes did not substantially change; long-term CRC incidence reduction of 35.7% to 37.4%, mortality reduction of 51.0 to 52.3%, number of additional colonoscopies needed per year of 120,834 to 120,872.

Conclusion: Based on the ASCCA model, an increase in ADR gradually reduces CRC incidence and mortality in a biennial FIT-based screening program, whereas an increase of the PSPDR does not decrease long-term CRC incidence and mortality on a population-level. This limited effect of the increase in the PSPDR might be explained by the limited diagnostic accuracy of FIT for serrated polyps and the fact that serrated polyps, once detected, are most often co-occurring with adenomas. Other triage modalities, also aiming to detect advanced serrated polyps, should be further explored.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP022 HEAD-TO-HEAD COMPARISON OF DIAGNOSTIC PERFORMANCE OF NINE QUANTITATIVE FAECAL IMMUNOCHEMICAL TESTS FOR COLORECTAL CANCER SCREENING

A. Gies 1 , K. Cuk 2 , P. Schrotz-King 1 , H. Brenner 2

1 Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg/Germany

2 Clinical Epidemiology And Aging Research, German Cancer Research Center (DKFZ), Heidelberg/Germany

Contact E-mail Address: anton.gies@nct-heidelberg.de

Introduction: Faecal immunochemical tests (FITs) are increasingly used for colorectal cancer (CRC) screening. A variety of FIT brands are being used whose diagnostic performance has been evaluated in different study populations. It is therefore unclear to what extent differences in reported sensitivities and specificities reflect true differences in diagnostic performance or differences in study populations or study logistics. We therefore aimed to provide an evaluation and head-to-head comparison of the diagnostic performance of nine different quantitative FITs (qFITs) within a single screening study.

Aims & Methods: In the BLITZ study, conducted in Southern Germany, pre-colonoscopy native stool samples were obtained from participants of screening colonoscopy and stored frozen at −80°C. Stool samples were thawed, homogenized and for every qFIT, a defined amount of stool was extracted and stored using each brand’s specific buffer-filled faecal sampling device. On the next day, blinded analyses were conducted. Four point-of-care and five laboratory-based tests were investigated. Sensitivities and specificities for CRC, advanced adenoma (AA) and their combination, advanced neoplasm (AN) were calculated. Comparative evaluations were performed at pre-set manufacturers´ cut-offs, at adjusted cut-offs yielding defined levels of specificity (97% and 93%) and at one uniform cut-off (15 µg haemoglobin (Hb)/g stool).

Results: Out of 1667 participants, recruited between 2005 and 2010, who fulfilled predefined inclusion criteria, every AN-case (n = 216) and 300 randomly selected controls without AN at screening colonoscopy were included in the study. Mean age was 63 years and 56% were male. At pre-set cut-offs the sensitivities for AN of the various qFITs ranged from 22% (95% confidence interval (CI), 16–28) to 46% (95% CI, 40–53), with specificities between 86% (95% CI, 81–89) to 98% (95% CI, 95–99) (Table). Adjusting cut-offs to yield a specificity of 97% for each test, the sensitivities for AN ranged from 21% (95% CI, 16–27) to 24% (95% CI, 18–30); with cut-offs between 6.11 µg/g and 29.54 µg/g. Adjusting cut-offs to yield a specificity of 93%, the sensitivities for AN ranged from 30% (95% CI, 24–36) to 35% (95% CI, 29–42); with cut-offs between 1.70 µg/g and 12.27 µg/g. Setting all cut-offs to 15 µg/g, the sensitivities for AN ranged from 16% (95% CI, 12–22) to 34% (95% CI, 28–41), with specificities between 94% (95% CI, 91–96) and 98% (95% CI, 96–99).

Conclusion: Using cut-offs recommended by the manufacturers or a uniform cut-off, sensitivities and specificities strongly varied between the nine different qFITs. However, most of this apparent strong variation disappeared when cut-offs were adjusted to yield defined levels of specificity, suggesting that various qFITs may achieve almost equal diagnostic performance. However, rather than simply applying cut-offs recommended by the manufacturers or a uniform cut-off, cut-offs for each qFIT should be adapted in such a way that they ensure defined diagnostic performance criteria (such as a minimum level of specificity) or a defined maximum positivity proportion (which is close to 100-specificity and reflects the subsequent colonoscopy workload) in the screening setting in which the test is to be applied.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP023 ADENOMA DETECTION RATE ACCORDING TO AGE: COLONOSCOPY SCREENING SHOULD START AT 45 YEARS OLD

D. Karsenti , G. Tharsis, F. Venezia, P. Cattan, G. Tordjman, A. Gillet, K. Nahon-Uzan, J. Samama, M. Cavicchi

Pôle Digestif Paris Bercy, Clinique de Bercy, Charenton-le-Pont/France

Contact E-mail Address: karsenti@club-internet.fr

Introduction: Most scientific societies such as French Society of Digestive Endoscopy (SFED) or American College of Gastroenterology agree that colonoscopy screening programs for average risk patients should enroll patients from 50 to 75 years of age. Thus, little is known about adenoma detection rate (ADR) outside this range. However, we routinely detect polyps and cancer before 50. Thanks to the constitution of a prospective colonoscopy database, we evaluated polyp detection rate in a large population to determine the best age to start screening.

Aims & Methods: In this prospective monocentric study, we have recorded all colonoscopies performed in 2016, in the population referred to the 25 gastroenterologists of our endoscopy unit (Pôle Digestif Paris-Bercy). The following data have been prospectively collected: age, gender, indication for colonoscopy, preparation procedure and quality of the preparation (Boston scale), number and size of polyps and polyp histology (hyperplastic polyps of the rectum and sigmoid colon were not considered as lesions at risk and therefore have not been included in the study). We determined ADR, polyp detection rate (PDR), mean number of polyps (MNP), large polyp detection rate (polyps of 1 cm or more; LPDR) and neoplasia detection rate (NDR). Neoplasia was defined as grade 4 or 5 of the Vienna classification (4: non-invasive high grade neoplasia (high grade adenoma/dysplasia, non-invasive carcinoma and suspicion of invasive carcinoma) 5: invasive neoplasia (intramucosal carcinoma, submucosal carcinoma or beyond)). PDR, ADR and NDR were analysed in each age group in the whole population, and in the population with average risk of colorectal cancer (excluding patients with personal or familial history of adenoma or cancer).

Results: During the period study, 6027 colonoscopies were performed in 3308 women (55%) and 2719 men (45%) with a median age of 57 (range, 15–96). PDR, ADR and NDR in the whole population were 34.1%, 32.1% and 3.6%, respectively. Raw MNP, ADR, LPDR and NDR upon age are indicated in the following table showing a strong increase in all parameters from 45 years of age.

Conclusion: In this large monocentric cohort of consecutive colonoscopies, we found a two-fold increase in mean number of polyps and adenoma detection rate from 45 years of age, whether or not there was a personal or familial history of polyp or cancer. In addition, we demonstrate a marked increase (x3) in neoplasia detection rate. We then suggest that colonoscopy screening programs should include these patients in order to improve prevention of colo-rectal cancer.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP024 TAILORING COLONOSCOPY COLORECTAL CANCER SCREENING IN CHILDHOOD CANCER SURVIVORS: A MODELING STUDY

A. Gini 1 , D. C. Hodgson 2 , R. G. S. Meester 1 , H. Keshavarz 2 , S. Ahmed 2 , I. Lansdorp-Vogelaar 1

1 Department Of Public Health, Erasmus Medical Center, Rotterdam/Netherlands

2 Department Of Radiation Oncology, Princess Margaret Cancer Centre, University of Toronto, Toronto/Canada

Contact E-mail Address: a.gini@erasmusmc.nl

Introduction: Childhood Cancer Survivors (CCS) develop colorectal cancer (CRC) more frequently than the general population. This increased risk varies according to the age of diagnosis of primary cancer and its treatment. The US Children’s Oncology Group has suggested tailoring CRC screening recommendations for those patients at highest risk of CRC (treated with abdominal, pelvic, and/or spinal radiation ≥30 Gray). In this study, we used a modeling-based method to evaluate cost-effectiveness of CRC screening in CSS.

Aims & Methods: We adjusted the existing Microsimulation Screening Analysis-Colon (MISCAN-Colon) model for the US general population to reflect CRC and other-cause mortality risk in CCS. CRC risks were based on epidemiologic studies investigating risk of secondary gastrointestinal cancer in CCS. 1, 2 Other-cause mortality assumptions were informed by data from Surveillance, Epidemiology, and End Results (SEER, 1973–2013). Costs and benefits of 75 colonoscopy screening strategies varying in screening intervals (3, 5, and 10 years), age to start (30, 35, 40, 45, 50), and age to stop screening (55, 60, 65, 70, 75) were separately evaluated for CCS with primary cancer diagnosis at age 5, 15, and 20 years. A willingness-to-pay threshold of $100,000 per life-year gained (LYG) was assumed to assess cost-effectiveness of CRC screening. Separate analyses were carried out to investigate optimal colonoscopy screening strategies in CCS at highest risk of CRC (Hodgkin Lymphoma, HL, or Wilms tumor, WT, survivors treated with abdominal and/or chest radiation). 1, 3

Results: Without screening, the number deaths due to CRC in CCS not at higher CRC risk varied according to age of primary cancer diagnosis: from 23 to 46 per 1000 CCS for primary cancers diagnosed at age 5 to 20 years. Screening with colonoscopy every 10 years at age 50 could prevent more than 68% of all CRC deaths. Screening was most effective when started at age 40, preventing 74–80% of CRC deaths in CCS at acceptable costs (incremental cost-effectiveness ratios varied $67,000–99,000 per LYG according to age at primary cancer diagnosis). Further analyses suggested that a more intensive screening may be considered in CCS at higher risk of CRC: 3-yearly colonoscopy starting at age 35 years was optimal in WT survivors, reducing 86% of CRC deaths; and, among HL survivors, 10-yearly colonoscopy screening starting at age 35 was optimal, averting 78% of CRC mortality.

Conclusion: In CCS, colonoscopy screening may be considered from earlier starting ages and with shorter screening intervals compared to the general population, due to their higher risk of CRC.

Disclosure of Interest: All authors have declared no conflicts of interest.

References

1. Henderson TO, Oeffinger KC, Whitton J, et al. Secondary gastrointestinal cancer in childhood cancer survivors: a cohort study. Ann Intern Med 2012;156:757–66, W-260.

2. Nottage K, McFarlane J, Krasin MJ, et al. Secondary colorectal carcinoma after childhood cancer. J Clin Oncol 2012;30:2552–8.

3. Armstrong GT, Chen Y, Yasui Y, et al. Reduction in Late Mortality among 5-Year Survivors of Childhood Cancer. N Engl J Med 2016;374:833–42.

OP025 FOLLOW-UP OF COLORECTAL CANCER (CRC) PATIENTS INCLUDING 18FDGPET-CT (PET-CT): AN OPEN-LABEL MULTICENTER RANDOMIZED TRIAL (CLINICAL TRIAL: NCT 00624260 )

I. Sobhani 1 , I. Baumgaertner 2 , C. Tounigand 3 , E. Ette 4 , F. Brunetti 5 , C. Gagniere 1 , A. Luciani 6 , I. Durand-Zaleski 7 , S. Bastuji-Garin 8 , G. Itep Study 9

1 Dept. De Hepato-gastroenterologie, Universite Paris 12 Hopital H. Mondor Dept. of Hepato-Gastroenterology, Créteil/France

2 Hopital Henri Mondor, Cretail/France

3 Oncology, Hopital Henri Mondor, Cretail/France

4 Nuclear Medicine, Hopital Henri Mondor, Cretail/France

5 Surgery, Hopital Henri Mondor, Creteil/France

6 Radiology, Hopital Henri Mondor, Creteil/France

7 Medico-economics, Hopital Henri Mondor, Creteil/France

8 Public Health And Statistics, Hopital Henri Mondor, Creteil/France

9 Gi Oncology, APHP, Paris/France

Contact E-mail Address: iradj.sobhani@aphp.fr

Introduction: Curative surgery is the best therapy of CRC and related recurrences if detected early and of small numbers. We have previously shown that 18FDG PET-Scan is a valuable tool in this field (1). Here, we assess whether adding semi-annual PET-CT to the usual surveillance would be cost-effective in high-risk recurrent CRC patients.

Aims & Methods: CRC patients (stage II tumor perforated, stages III and IV) in remission after curative surgery were randomly assigned (1:1) to trimester usual surveillance (control) or usual surveillance + semi-annual course PET-CT (intervention) for a 3-yr follow up period. At each visit (every 3 months), multidisciplinary committee decided about recurrence by yes/no/doubtful. If yes, curative surgery alone (when relevant), or chemotherapy alone (unresecable recurrence) were conducted. Additional exams could be performed if doubtful. Primary composite endpoint (failure) as defined in the current study comprised unresectable recurrence and death. The economic assessments according to standards (CHEERS) were performed and costs were compared between groups. The relative risk (RR) were estimated and survival was analyzed using Kaplan-Meier method, Log-Rang test and Cox models.

Results: Among 239 patients (120/119) enrolled in 12 centers, baseline characteristics were balanced. The failure rates for interventional and control group were 29.2% (31 unresectable recurrences & 4 deaths) and 23.5% (27 & 1), respectively with no significant difference (RR = 1.24, 95% CI: 0.81–1.90; P = .32). Similar results were observed in multivariate analysis (Cox models) adjusted for stage and tumor differentiation (HR = 1.33, 95% CI: 0.8–2.19, P = .27). Period until the unresectable recurrence was significantly shorter in the interventional (median = 7; IQR: 3–20 months) than in the control group (14.3; 7.3–27; P = 0.016). This was consistent with lower elevation (median; IQR) of tumour marker in interventional (3.8; 2.8–19) than in control group (10; 5.2–28.6) at the first recurrence time as compared to the baseline (p = 0.007). Overall (mean; SD) cost (euros)/patient was higher in the PET-Scan (9385; 11658) than in the control group (7027; 7656).

Conclusion: Although recurrences were detected earlier in PET-CT group, the strategy was dominated (more expensive, not effective). This exam should not be advised routinely.

Disclosure of Interest: All authors have declared no conflicts of interest.

Reference

Sobhani et al, Early detection of recurrence by 18FDG-PET in the follow-up of patients with colorectal cancer. Br J Cancer . 2008 Mar 11;98(5):875–80.

OP026 MRI TO PREDICT SUCCESSFUL SPHINCTER PRESERVATION AFTER PREOPERATIVE CHEMORADIOTHERAPY FOR DISTAL RECTAL TUMOURS

D.M. Lambregts 1 , J. Krdzalic 2 , M. Maas 1 , S. M. Engelen 3 , J. J. Van Griethuysen 1 , G.L. Beets 4 , R. G. h. Beets-Tan 1

1 Department Of Radiology, The Netherlands Cancer Institute, Amsterdam/Netherlands

2 Radiology, Zuyderland Medical Centre, Heerlen/Netherlands

3 Surgery, Maastricht University Medical Centre, Maastricht/Netherlands

4 Department Of Surgery, The Netherlands Cancer Institute, Amsterdam/Netherlands

Contact E-mail Address: doenja.lambregts@gmail.com

Introduction: The main aim of chemoradiotherapy (CRT) in rectal cancer is to obtain tumour downsizing and downstaging in order to increase the chance of achieving a curative (complete) resection. In distal rectal tumours (<5 cm from the anorectal junction) CRT is also believed to increase the chance of sphincter preserving surgery.

Aims & Methods: The aim of this study was [1] to quantify the effect of CRT on the chance of sphincter preversation in distal rectal cancer using MRI by comparing the height of tumours measured from the anorectal junction (ARJ) on pre- and post-CRT MRI and [2] to assess whether MRI can accurately predict successful sphincter preservation after CRT.

Methods: The primary staging and post-CRT MRIs of n = 88 patients with distal rectal tumours (<5 cm from the anorectal junction) were retrospectively assessed by a dedicated radiologist. The reader measured the distance from the lower tumour pole to the ARJ pre- and post-CRT. Additionally he scored the likelihood of achieving successful sphincter preservation using a 5-point confidence score (CL = 0 definitely no sphincter preservation possible, CL1 = probably no sphincter preservation possible, CL2 = uncertain, CL3 = sphincter preservation probably possible, CL4 = sphincter preservation definitely possible). Diagnostic performance to predict successful sphincter preservation was assessed using Receiver Operator Characteristics (ROC)-curves with the final surgical outcome as the standard of reference. Successfull sphincter preservation was defined as a complete (R0) surgical resection of the rectum with preservation of the anal sphincter complex, without evidence of anastomotic tumour recurrence for a follow-up period of >2 years.

Results: Successful sphincter preservation was achieved in 57 out of 88 patients (65%). Mean distance from the ARJ on MRI increased significantly during CRT from 20.6 mm pre-CRT to 29.4 mm post-CRT (P < 0.001). In 48% of patients sphincter preservation was deemed not feasible by the expert radiologist on pre-CRT MRI, which decreased to 27% after CRT. Area under the ROC-curve (AUC) to predict successful sphincter preservation based on the confidence level score on post-CRT MRI was 0.81, sensitivity 91%, and specificity 61%. When using the post-CRT height measurements instead of the confidence level score, AUC was 0.86, sensitivity 70%, and specificity 90% (using a cut off of 28 mm).

Conclusion: The distance from the anorectal junction in distal rectal tumours increases as a result of CRT, thereby increasing the chance for successful sphincter preservation. Successful sphincter preservation can accurately be predicted on MRI. The best predictive criterion is the height (distance from the anorectal junction) of the tumour on post-CRT MRI.

Disclosure of Interest: All authors have declared no conflicts of interest.

MONDAY, OCTOBER 30, 201710:30-12:00

ADVANCED ENDOSCOPIC TREATMENT OF UPPER GI NEOPLASIA - ROOM E2____________________

OP027 LONG-TERM OUTCOMES OF ENDOSCOPIC SUBMUCOSAL DISSECTION FOR EARLY GASTRIC CANCER IN ELDERLY PATIENTS

Y. Sato 1 , T. Michida 2 , M. Kato 1 , H. Saiki 3 , Y. Tokuda 3 , K. Yamamoto 3 , N. Tatsumi 3 , T. Ito 3

1 Gastroenterology And Hepatology, Osaka University Hospital, Suita, Osaka/Japan

2 Internal Medicine, Teikyo University Chiba Medical Center, Ichihara/Japan

3 Department Of Gastroenterology, Japan Community Healthcare Organization Osaka Hospital, Osaka/Japan

Contact E-mail Address: tottotto269@gmail.com

Introduction: As endoscopic submucosal dissection (ESD) has been widely used as a minimally invasive treatment for early gastric cancers (EGC), opportunity to perform it for elderly patients is increasing. The benefit of ESD for them should be evaluated including their physical decline, and our previous reports showed its short-term outcomes (Kato et al. Endosc Int Open 2016; 04: E521-E526). However, the long-term outcomes are not yet elucidated.

Aims & Methods: The purpose of this study is to evaluate the efficacy of ESD for elderly patients who are 75 years over recruited in a prospective study regarding the expanded indication of ESD for early gastric cancer (Soetikno et al. J Clin Oncol 2005; 23: 4490–4498). Totally 847 cases of EGCs were treated with ESD at Japan Community Healthcare Organization Osaka Hospital from May 2006 to March 2013. The resected lesions were classified into curative resection, curative resection for tumor of expanded indication, and non curative resection according to Japanese Gastric Cancer Association (JGCA) guideline ( Gastric Cancer (2011) 14; 113). The 847 cases were divided into elderly group (75 y/o over; 288 cases) and non-elderly group (the rest; 556 cases). We compared the two groups about median observation period and 5-year overall survival rate. We separated the elderly group into curative resection group; 273 cases, according to JGCA Guideline, and non curative resection group; 16 cases. We compared the median observation period and 5-year overall survival rate, too. The survival rates were analyzed by Kaplan-Meier curves. Cox hazard model was used to analyze their background.

Results: The median observation period and 5-year overall survival rate of elderly group were 52.2 ± 1.8 months and 90.0%, which is higher than the 75-year-old Japanese people’s general 5-year survival rate calculated by the national life tables, 88.5%; non elderly group were 69.6 ± 1.3 months and 96.0%. Among elderly group, curative resection cases showed 52.8 ± 1.7 months median observation period and 90.7% overall survival rate; though there was no significant difference, non curative group showed 41.9 ± 7.1 months median observation period and 77.9% overall survival rate. 11 of 14 non curative resection cases turned down additional surgical treatment. None of them was dead of recurrence.

Conclusion: The present study demonstrates that the ESD provides acceptable long term outcomes for elderly patients of EGCs. More discussion might be needed about additional treatment in non curative resection cases among elderly patients.

Disclosure of Interest: All authors have declared no conflicts of interest.

References

1. Kato M. Michida T. Kusakabe A. et al. Safety and short-term outcomes of endoscopic submucosal dissection for early gastric cancer in elderly patients. Endosc Int Open 2016; 4: E521-E526

2. Soetikno R. Kaltenbach T. Yeh R. et al. Endoscopic mucosal resection for early cancers of the upper gastrointestinal tract. J Clin Oncol 2005; 23: 4490–4498

OP028 INCIDENCE OF SUBSEQUENT PRIMARY CANCERS AFTER ENDOSCOPIC RESECTION OF OESOPHAGEAL SQUAMOUS CELL CARCINOMAS

M. Nikaido 1 , S. Miyamoto 1 , M. Muto 2 , T. Setoyama 1 , T. Horimatsu 2 , H. Seno 1

1 Gastroenterology And Hepatology, Kyoto University, Kyoto/Japan

2 Therapeutic Oncology, Kyoto University, Kyoto/Japan

Contact E-mail Address: sunkaido@kuhp.kyoto-u.ac.jp

Introduction: The incidence rate of a subsequent primary cancer (SPC) has been reported to be high in patients with oesophageal squamous cell carcinoma (ESCC) from postoperative patients’ data and population-based registry data. Among patients after endoscopic resection (ER) for ESCCs, few studies have been reported the incidence rates of SPCs.

Aims & Methods: This study was conducted to investigate the incidence rate of a SPC and long-term prognosis after ER of patients with ESCC and to clarify the recommended surveillance for early detection of SPC. We retrospectively reviewed the electronic medical records of patients who underwent ER for an ESCC in Kyoto University Hospital from December 2001 to March 2016. SPC was defined as the primary cancer occurring at a site other than the oesophagus, diagnosed more than 180 days after the ER. Incidence rates of SPCs were measured per 1000 person-years. The expected incidence rates in the general population calculated by the data reported from the Monitoring of Cancer Incidence in Japan Project 2012 were used as standards for comparison. The standardized incidence ratio (SIR) was obtained by dividing the observed incidence rate by the expected one.

Results: A total of 245 patients with an ESCC were analysed. The median age was 67 years (range 45–90). The median follow-up period was 4.0 years (0.5–14.8). Subsequently, 57 primary cancers were found in 50 patients (SIR, 2.70; 95% confidence interval (CI), 2.03–3.51). The risk of head and neck cancers was markedly elevated (15 patients; SIR, 28.33; 95% CI, 16.87–43.07), followed by liver cancer (seven patients; SIR, 6.39; 95% CI, 2.85–13.23), lung cancer (nine patients; SIR, 3.13; 95% CI, 1.56–5.99), and gastric cancer (nine patients; SIR, 3.12; 95% CI, 1.59–5.65). Five of seven liver cancers were hepatocellular carcinomas. All patients with liver cancer were negative for hepatitis B and C. The histopathology types of nine lung cancers consisted of three adenocarcinomas, two squamous cell carcinomas, two small cell carcinomas, and two with no diagnosis. The 5- and 10-year overall survival rates after ER were 88% and 78%, respectively. Five patients died of metastatic ESCCs. SPCs led to death in nine patients: four with lung cancers, two with liver cancers, one with head and neck cancer, one with pancreatic cancer and one with myelodysplastic syndrome.

Conclusion: Because patients have extremely high risks of head and neck cancers after ER for ESCCs, these regions should be carefully surveyed by oesophagogastroduodenoscopy. The liver, lungs, and stomach also have higher risks of SPCs. In addition to oesophagogastroduodenoscopy, regular screening of the lungs and liver is recommended for such patients.

Disclosure of Interest: All authors have declared no conflicts of interest.

References

1. Matsubara T, Yamada K, Nakagawa A. Risk of second primary malignancy after esophagectomy for squamous-cell carcinoma of the thoracic esophagus. J Clin Oncol 2003; 21: 4336–4341.

2. Tabuchi T, Ito Y, Ioka A, et al. Incidence of metachronous second primary cancers in Osaka, Japan: update of analyses using population-based cancer registry data. Cancer Sci 2012; 103: 1111–1120.

3. Cancer Information Service, National Cancer Center, Japan. National estimates of cancer incidence based on cancer registries in Japan (1975–2012). http://ganjoho.jp/en/professional/statistics/table_download.html

OP029 SHOULD TAKING BIOPSY SAMPLES FROM APPARENTLY NON-CANCEROUS TISSUES AROUND THE LESION BE PERFORMED TO DETERMINE RESECTION MARGINS BEFORE GASTRIC ENDOSCOPIC SUBMUCOSAL DISSECTION?

M. Shibata 1 , N. Kawata 1 , K. Takizawa 1 , N. Kakushima 1 , M. Tanaka 1 , M. Yoshida 1 , S. Ito 1 , K. Imai 1 , H. Ishiwatari 1 , K. Hotta 1 , H. Matsubayashi 1 , H. Ono 1

1 Divison Of Endoscopy, Shizuoka Cancer Center, Nagaizumi/Japan

Contact E-mail Address: m.shibata@scchr.jp

Introduction: Endoscopic submucosal dissection (ESD) is widely performed for treating early gastric cancer (EGC) with little risk of lymph node metastasis. The preoperative identification of horizontal margin of EGC is important before ESD. There are some EGCs the margins of which cannot be determined by chromoendoscopy and magnifying endoscopy with narrow-band imaging (ME-NBI). Therefore, we generally take biopsy samples from apparently non-cancerous tissues around the lesion (surrounding biopsy) to determine resection margins before ESD.

Aims & Methods: The aim of this study was to assess the predictors of cancer-positive results in surrounding biopsy before gastric ESD. From January 2015 through December 2016, EGCs which we performed more than two surrounding biopsies after the identification of the horizontal margin of EGC using by conventional endoscopy, chromoendoscopy and ME-NBI, were enrolled in this study. To assess the predictors of cancer-positive results in surrounding biopsy, we performed univariate and multivariate analysis on the following factors; age (<75 vs. ≥75), sex (Male vs. Female), Helicobacter pylori (HP) infection (positive vs. negative vs. unknown), atrophy gastritis (positive vs. negative), macroscopic type (elevated type vs. depressed type vs. mixed type), location (Upper vs. Middle vs. Lower), color (reddish vs. discolored), lesion border by chromoendoscopy (clear vs. unclear), lesion size (<30 mm vs. ≥30 mm), ulcerration (UL) (positive vs. negative), corkscrew vascular pattern (CVP) by ME-NBI (positive vs. negative), endoscopic diagnosis of invasion depth (cT1a vs. cT1b).

Results: A total of 811 EGCs in 768 patients (499 males, median age 72 years old, range 32–96 years old) were analyzed. Of these 60 lesions (7%) in 60 patients were cancer-positive results in the surrounding biopsies. Univariate analysis revealed that location, HP infection, macroscopic type, UL, lesion size and CVP were significant associated with cancer-positive results in the surrounding biopsy. Multivariate logistic regression analysis revealed that HP infection negative (OR 3.0 [95% CI 1.5–6.0], P = 0.001), lesion size ≥ 30 mm (OR 3.1 [95% CI 1.3–6.8], P = 0.01), UL positive (OR 2.7 [95% CI 1.2–5.7], P = 0.01) and CVP positive (OR 4.0 [95% CI 1.4–10.4], P = 0.007) were independent predictors for cancer-positive results in the surrounding biopsies. Four of 60 cases (7%) underwent surgery due to be out of ESD indications because of surrounding biopsies being cancer-positive. Among the 807 lesions in 764 patients who underwent ESD, only three (0.7%) were cancer-positive horizontal margin in ESD specimen.

Conclusion: This study successfully identified predictors of positive results in the surrounding biopsy. It can be difficult to identify the horizontal marign of EGCs when lesions are ≥30 mm in size, negative for HP infection, UL positive and CVP by ME-NBI. When EGC have these findings, the evaluation of resection margins by surrounding biopsy would be necessary.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP030 ARGON PLASMA COAGULATION FOR THE TREATMENT OF EARLY ESOPHAGEAL AND GASTRIC TUMORS IN HIGH-RISK PATIENTS: A RETROSPECTIVE, MULTICENTER, COLLABORATIVE STUDY

S. Tanabe 1 , H. Nagase 2 , Y. Sato 3 , T. Sagawa 4 , M. Murakami 5 , K. Niimi 6 , M. Fujishiro 7 , J. Fujisaki 8 , H. Doyama 9 , N. Muguruma 3 , Y. Takeda 10 , K. Ishido 11 , C. Katada 11

1 Therapeutic Endoscopy, Kitasato University, Sagamihara/Japan

2 Gastroenterology, Yokohama Rosai Hospital, Yokohama/Japan

3 Gastroenterology And Oncology, Tokushima University, Tokushima/Japan

4 Gastroenterology, Hokkaido Cancer Center, Sapporo/Japan

5 Gastroenterology, Murakami Memorial Hospital, Saijo/Japan

6 Endoscopy And Endoscopic Surgery, the University of Tokyo Hospital, Tokyo/Japan

7 Endoscopy & Endoscopic Surgery, University of Tokyo Endoscopy &Endoscopic; Surgery, Tokyo/Japan

8 Gastroenterology, Cancer Institute Hospital JFCR, Tokyo Koto/Japan

9 Ishikawa prefectural central hospital, Kanazawa/Japan

10 Endoscopy, Showa General Hospital, Kodaira/Japan

11 Gastroenterology, Kitasato University School of Medicine, Kanagawa/Japan

Contact E-mail Address: s-tanabe@kitasato-u.ac.jp

Introduction: Endoscopic resection, including endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD), is widely used to treat early esophageal and gastric tumors in Japan, but is sometimes difficult to perform in high-risk patients who are elderly or who have difficult serious underlying diseases.

Aims & Methods: We aimed to clarify the local effectiveness and safety of endoscopic argon plasma coagulation (APC) for the curative treatment of early esophageal and gastric tumors in high-risk patients.

Subjects and Methods: We retrospectively studied high-risk patients with early esophageal and gastric tumors who met the inclusion criteria and underwent APC by May 2013 in several hospitals. The inclusion criteria defining high-risk patients in whom endoscopic resection was difficult to perform were as follows: a) patients undergoing maintenance hemodialysis because of renal failure, b) patients in whom it was difficult to discontinue long-term anticoagulant or antiplatelet therapy, c) patients with a bleeding tendency due to factors such as liver cirrhosis and hematologic disease, d) patients in whom prolonged sedation was difficult, and e) patients in whom endoscopic resection was judged by their attending physicians to be difficult.

Results: APC therapy was performed in 208 patients with early esophageal or gastric tumors (esophageal tumors, 74 patients; gastric tumors, 134 patients). The median follow-up period was 33 months (range, 1 to 137) in patients with esophageal tumors and 31 months (range, 1 to 131) in patients with gastric tumors. The median age was 70 years (range, 47 to 92) in patients with esophageal tumors and 78 years (range, 52 to 95) in patients with gastric tumors. The male:female ratio was 66:8 for esophageal tumors, and 103:31 for gastric tumors. The esophageal tumor diameter was 10 mm or less in 24 patients, 11 to 20 mm in 19 patients, and 21 mm or greater in 31 patients. The gastric tumor diameter was 10 mm or less in 63 patients, 11 to 20 mm in 51 patients, and 21 mm or greater in 20 patients. The histopathological diagnosis of the esophageal tumors was high-grade intraepithelial neoplasia in 23 patients, squamous-cell carcinoma in 44 patients, differentiated adenocarcinoma in 1 patient, and unclear in 6 patients. The histopathological diagnosis of the gastric tumors was adenoma in 27 patients, differentiated adenocarcinoma in 96 patients, poorly differentiated carcinoma in 10 patients, and unknown in 1 patient. The preoperative depth of invasion of the esophageal tumors was the epithelium or lamina propria mucosae in 67 patients, the muscularis mucosae or first layer of the submucosa in 6 patients, and the second layer of the submucosa in 1 patient. The preoperative depth of invasion of the gastric tumors was the mucosa in 116 patients, the superficial layer of the submucosa in 11 patients, and the middle layer of the submucosa or deeper in 7 patients. The macroscopic appearance of the esophageal tumors was protruding type in 12 patients, flat depressed type in 60 patients, and mixed type in 2 patients. The macroscopic appearance of the gastric tumors was protruding type in 70 patients, flat depressed type in 60 patients, and mixed type in 4 patients. The median treatment time was 21 minutes (range, 3 to 67) for esophageal tumors and 11 minutes (range, 1 to 60) for gastric tumors. APC was performed for the following reasons: the physician in charge considered endoscopic resection difficult in 130 patients (62.5%), difficulty in maintaining prolonged anesthesia in 36 patients (17.3%), a bleeding tendency due to conditions such as liver cirrhosis in 23 patients (11.1%), inability to discontinue anticoagulant therapy in 11 patients (5.3%), and hemodialysis in 8 patients (3.8%). Adverse events in patients with esophageal tumors were 1 case of hypoxemia and 1 case of grade 3 or higher events. Adverse events in patients with gastric tumors were 5 cases of postoperative bleeding, 2 cases of hypotension, 1 case of perforation, and 1 case of gastrointestinal injury. Local recurrence occurred in 10 patients (13.5%) with esophageal tumors and 22 patients (16.4%) with gastric tumors. APC was repeated in 5 patients with recurrent esophageal tumors and 14 patients with recurrent gastric tumors, and local control was achieved. There were no deaths from esophageal tumors. Five patients (3.7%) died of their gastric tumors.

Conclusion: APC can be a safe and straightforward treatment option for high-risk early esophageal and gastric tumors that are difficult to resect endoscopically.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP031 PHASE II STUDY OF COLD SNARE POLYPECTOMY FOR SUPERFICIAL NON-AMPULLARY DUODENAL EPITHELIAL TUMOR (D-CSP TRIAL)

K. Takizawa 1 , N. Kakushima 1 , M. Tanaka 1 , N. Kawata 1 , M. Yoshida 1 , K. Imai 1 , S. Ito 1 , H. Ishiwatari 1 , K. Hotta 1 , H. Matsubayashi 1 , K. Mori 2 , H. Ono 1

1 Division Of Endoscopy, Shizuoka Cancer Center, Shizuoka/Japan

2 Clinical Trial Coordination Office, Shizuoka Cancer Center, Nagaizumi/Japan

Contact E-mail Address: k.takizawa@scchr.jp

Introduction: Small superficial non-ampullary duodenal epithelial tumor (SNADET) is often observed without any treatment in consideration of high complication rates in endoscopic treatment such as endoscopic submucosal dissection (ESD) and endoscopic mucosal resection (EMR). However, it becomes more difficult to resect after tumor growth or many biopsies. Cold snare polypectomy (CSP) has been reported to minimize the risk of complications, and it has become a standard treatment for small colorectal polyps. We considered that CSP might also be suitable for small duodenal polyps.

Aims & Methods: The aim of this study was to evaluate the safety of CSP for SNADET. The major indication criteria were as follows: 1) endoscopically diagnosed SNADET (biopsy before treatment was not necessary, but definitive cancer was excluded), 2) ≤10 mm in size, 3) a single primary lesion. After registration, CSP was performed using an electrosurgical snare without electrocautery. Follow-up endoscopy and biopsy from scar was performed at 3 months after CSP. The primary endpoint was the rate of delayed complications (perforation and bleeding), secondary endpoints were the rate of spurting bleeding just after CSP, en block resection, residual tumor 3 months after CSP, adverse events. All patients provided written informed consent. This study was approved by the ethical committee of Shizuoka Cancer Center (no. 27-20-27-3-3) and registered with University Hospital Medical Information Network Clinical Trials Registry(UMIN000019157).

Results: A total of 21 patients (pts) (male/female: 16/5, median age 71 years (range 49–80)) were enrolled from October 2015 to February 2017. Lesion location was bulbs 2/2nd portion 19, and median lesion size was 8 mm (range 3–10), and macroscopic type was 0-I 2/0-IIa 16/0-IIa+IIc 1/0-IIc 1, respectively. Biopsy before CSP was performed in 16 pts (76%). CSP was attempted for all lesions, and 3 lesions could not be resected without electrocautery and were thus removed by conventional EMR with electrocautery (CSP was completed in 89%). The rate of spurting bleeding just after CSP was 0%. After CSP, ulcer was closed using endoclips in 15 pts (71%). Median procedure time (from scope insertion to scope removal) was 12 minutes (range 3–29), and median resected specimen size was 12 mm (range 8–20), the rate of en bloc resection was 95% (21/20). No adverse events were observed during procedure, and no delayed complications (bleeding and perforation) were also observed after CSP. Histopathological assessments revealed 15 adenomas, 4 cancers (intramucosal), 2 non-neoplastic lesions. The horizontal margins were negative 9/positive 1/undetermined 11. The vertical margins were negative in all cases. In follow-up endoscopy at 3 months after CSP, all ulcers became scar and no recurrence was detected endoscopically. All biopsies from scar revealed non-neoplastic.

Conclusion: CSP could be performed safely for small SNADET. Efficacy of CSP should be evaluated at next phase III study.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP032 ENDOSCOPIC AMPULLECTOMY FOR NON-INVASIVE AMPULLARY LESIONS: A SINGLE-CENTRE 10 YEAR RETROSPECTIVE COHORT STUDY

R. Lee , A. Huelsen, L. Hourigan

Gastroenterology And Hepatology, Princess Alexandra Hospital, Brisbane/Australia

Contact E-mail Address: avantgarde84@gmail.com

Introduction: Benign tumours of the ampulla of Vater are rare, but the majority have malignant potential. Surgical resection was traditionally considered the standard of care; however, endoscopic ampullectomy is a minimally invasive alternative. Only a few case series have been published with relatively small sample sizes and short follow-up.

Aims & Methods: This study aims to retrospectively evaluate the safety and efficacy of endoscopic ampullectomy in a single tertiary referral centre over a 10-year period. All patients who underwent endoscopic ampullectomy were identified through the hospital endoscopy and pathology databases, and included in this study. The medical records were retrieved and reviewed with an extensive questionnaire. The data points analysed included patient details, lesion characteristics, efficacy, adverse outcomes and recurrence rates.

Results: Fifty-three ampullectomies were performed on 26 female and 27 male patients with a mean age of 64 years (range 35–88 years). Patients with familial adenomatous polyposis (FAP) (n = 14) were significantly younger than those with sporadic lesions (n = 39) (51 vs. 69 years; P < 0.001). Ampullary tumours were most commonly detected during surveillance endoscopy in FAP patients ( P < 0.001), followed by incidental discovery in patients without FAP who were investigated for abdominal pain ( P = 0.01). Pre-ampullectomy assessments included side-viewing endoscopy and biopsies in all patients, endoscopic ultrasound (EUS) in 36% and magnetic resonance cholangiopancreatography (MRCP) in 19% of patients. The mean ampullary lesion size was 20 mm (range 6–50 mm) and in 37 patients confined to the ampulla. A lateral spreading tumour of the papilla (LST-P) was present in 16 patients. Lesions were resected en bloc when possible (57%), and the pancreatic duct was stented if feasible as prophylaxis against pancreatitis (83%). In addition, biliary sphincterotomy was performed in 28% of patients to mitigate the risk of cholangitis. Endoscopic resection was performed successfully in all patients. Histological review of the resected specimens revealed low grade dysplasia (40.4%), high grade dysplasia (44.2%), intramucosal carcinoma (3.8%) and gangliocytic paraganglioma (1.9%). Invasive adenocarcinoma was identified in five patients (9.6%) and were referred for surgery. Histological concordance with initial biopsy was 58.5% while upstaging occurred in 37.7%. Mean length of hospital stay was 5.5 days. Complications were observed in 10 patients (18.9%) consisting of early haemorrhage (<48 hours) (11.3%), moderate pancreatitis (1.9%), retroperitoneal perforation (1.9%) and delayed papillary stenosis (3.8%). Female gender ( P < 0.01) and advanced age ( P < 0.05) were associated with development of complications. Follow-up was managed in 85% of patients over a mean of 31 months. Persistent residual adenoma was present in three patients and recurrence occurred in four patients (8.9%) at an average of 16.3 months. LST-P lesions were found to have a greater risk of recurrence ( P < 0.05) compared to lesions confined to the ampulla. Four patients required surgery for endoscopically unmanageable persistence/recurrence. Overall curative resection rate was 90.2%, achieved at an average of 1.3 procedures.

Conclusion: This study substantiates that endoscopic ampullectomy is a safe and highly efficacious procedure for managing non-invasive ampullary tumours. Aside from its therapeutic utility, endoscopic resection also confers the additional benefit of assessing the true histological diagnosis of the tumour which has implications in regard to prognosis and further management. A structured approach to initial lesion assessment, endoscopic treatment and surveillance is required to ensure the best outcomes in patient safety and lesion clearance.

Disclosure of Interest: All authors have declared no conflicts of interest.

MONDAY, OCTOBER 30, 201710:30-12:00

DIAGNOSIS AND MANAGEMENT OF CIRRHOSIS: UNMET NEEDS - ROOM E3____________________

OP033 VON WILLEBRAND FACTOR ANTIGEN IS LINKED TO BACTERIAL TRANSLOCATION, INFLAMMATION, AS WELL AS PROCOAGULANT IMBALANCE AND PREDICTS COMPLICATIONS OF CIRRHOSIS INDEPENDENTLY OF PORTAL HYPERTENSION SEVERITY

M. Mandorfer 1 , P. Schwabl 1 , R. Paternostro 1 , K. Pomej 1 , J. Thaler 2 , C. Ay 2 , M. Fritzer-Szekeres 3 , P. Quehenberger 3 , M. Trauner 1 , M. Peck-Radosavljevic 1 , T. Reiberger 1 , A. Ferlitsch 1

1 Department Of Gastroenterology And Hepatology, Department Of Internal Medicine III, Medical University of Vienna, Vienna/Austria

2 Division Of Hematology And Hemostaseology, Department Of Internal Medicine I, Medical University of Vienna, Vienna/Austria

3 Department Of Laboratory Medicine, Medical University of Vienna, Vienna/Austria

Contact E-mail Address: mattias.mandorfer@meduniwien.ac.at

Introduction: Von Willebrand factor (vWF) antigen has been shown to indicate the presence of clinically significant portal hypertension (CSPH), and thus predict the development of clinical events in patients with cirrhosis.

Aims & Methods: We aimed to investigate the impact of bacterial translocation and inflammation on vWF, as well as the association between vWF and procoagulant imbalance. Moreover, we assessed whether vWF predicts complications of cirrhosis, independently of the severity of portal hypertension. Our study population comprised 225 patients with CSPH (hepatic venous pressure gradient [HVPG] ≥ 10 mmHg) without active bacterial infections or a history of hepatocellular carcinoma.

Results: Patient characteristics: Child-Turcotte-Pugh class [CTP]:A:32%/B:42%/C:26%; median HVPG:19 (interquartile range [IQR]:7) mmHg; median vWF antigen levels: 337(IQR:137)%. In addition to indicators of liver function and HVPG (Spearman’s ρ = 0.333; P < 0.001), we observed statistically significant correlations between vWF and markers of bacterial translocation (interleukin 6 [IL-6] [ρ = 0.426; P < 0.001]) and lipopolysaccharide binding protein [LBP] [ρ = 0.201; P = 0.021]), inflammation (C-reactive protein [CRP]; ρ = 0.249; P < 0.001), and procoagulant imbalance (factor VIII/protein C ratio; ρ = 0.507; P < 0.001). The associations between vWF and IL6/LBP, CRP, as well as factor VIII/protein C ratio, were independent of HVPG. The median follow-up was 2 years. vWF (per 10%-increase) was an independent predictor of portal hypertensive bleeding (OR:1.07[95%CI:1–1.14]; P = 0.049; adjusted for prior portal hypertensive bleeding/HVPG) and bacterial infections (OR:1.04 [95%CI:1–1.08]; P = 0.045; adjusted for age/CTP/CRP) including spontaneous bacterial peritonitis (OR:1.09[95%CI:1–1.18]; P = 0.045; adjusted for HVPG/CTP/CRP). Furthermore, vWF levels predicted transplant-free survival in a model including age/HVPG/CTP/CRP. After backward elimination, only age (per year; OR:1.05[95%CI:1.03–1.07]; P < 0.001), vWF (per 10%; OR:1.04[95%CI:1.01–1.08]; P = 0.01), and CRP (per mg/dL;OR:1.51[95%CI:1.13–2.02]; P = 0.007) remained in the final model.

Conclusion: Our results demonstrate that vWF is not only a marker of portal hypertension but also independently linked to bacterial translocation, inflammation, and procoagulant imbalance. This might explain why vWF predicts the development of clinical events independently of the severity of portal hypertension. Interestingly, its prognostic value was further improved by adding CRP.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP034 CLASS 1 OBESITY IS ASSOCIATED WITH INCREASED RISK FOR PORTAL VEIN THROMBOSIS IN HOSPITALIZED PATIENTS WITH CIRRHOSIS: A NATIONWIDE ANALYSIS

P.T. Kroener 1 , J. E. Corral 2 , J. P. Gutierrez 3 , M. A. D'Assunção 4 , I. Jovanovic 5 , G. Schwingel 6 , K. Mönkemüller 7

1 Mt. Sinai St. Luke's/West, New York/United States of America

2 Mayo Clinic Florida, Jacksonville/United States of America

3 Hospital Italiano, Montevideo/Uruguay

4 Endoscopy, Hospital Sírio-Libanês, Sao Paulo/Brazil

5 Clinic of Gastroenterology and Hepatology, Belgrade/Serbia

6 CEMOX, Heliopolis/Brazil

7 Gastroenterology, Frankenwald Klinikum, Kronach/Germany

Contact E-mail Address: jpgutierrezaguiar@hotmail.com

Introduction: Cirrhosis is a well-recognized risk factor for portal vein thrombosis (PVT). Obesity has been described to be a risk factor for thrombosis. However, limited information is available on how obesity impacts the development of PVT in cirrhotic patients. As no large study has examined this relationship, the aim of this study is to determine the impact of obesity on PVT development in cirrhotic patients.

Aims & Methods: This was a retrospective cohort study using the 2013 National Inpatient Sample, the largest publically available inpatient database in the US. Patients older than 18 years with an ICD-9 CM code for any diagnosis of liver cirrhosis (ICD 9-CM 571.2, 571.5, 571.6) were included. There were no exclusion criteria. The primary outcome was the impact of obesity on development of PVT (ICD 9-CM 452). Obesity was further sub-classified according to body-mass index (BMI) using ICD 9-CM codes. Secondary outcomes were in-hospital mortality, resource utilization measured by length of hospital stay (LOS) and total hospitalization charges. Odds ratios and means were adjusted for age, gender, ethnicity, median income in the patient’s zip code, Charlson Comorbidity Index, hospital region, rural location, size and hospital teaching status on multivariate regression.

Results: 589,420 patients with liver cirrhosis were included. 69,934 (12%) were obese, of which 1125 patients had PVT (mean age 59 years, 35% female). Overall in-hospital mortality rates were 9% (11% with PVT vs. 5% without PVT). On multivariate analysis for the primary outcome, cirrhotic obese patients did not have a significantly different adjusted OR of PVT when compared to the non-obese. However, when stratifying by obesity subtype, obesity class 1 was associated with increased odds of PVT (OR:1.45, 95%CI 1.06–1.96, p = 0.02), while obesity class 3 was associated with a decreased odds of PVT (OR:0.72, 95%CI:0.58–0.88, p < 0.01) compared to the non-obese. For secondary outcomes, only increased odds of abdominal CT scan were evident (OR:3.75, 95%CI:1.18–11.02, p = 0.02). Patients with PVT had longer lengths of stay and hospitalization charges compared to patients without PVT, though these were not significant on multivariate analysis. There were no statistically significant differences in morbidity or in-hospital mortality when compared with patients without PVT.

Conclusion: Class 1 obesity is associated with increased odds of PVT, while class 3 obesity is associated with decreased odds of PVT in patients with cirrhosis. PVT is not associated with increased morbidity, mortality or resource utilization. A diagnosis of PVT in this population leads to an approximate four-fold increase in utilization of CT scan.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP035 EVALUATION OF CONTROLLED ATTENUATED PARAMETER (CAP) FOR ASSESSMENT OF LIVER STEATOSIS IN AN UNSELECTED POPULATION: A SINGLE CENTER REAL-LIFE EXPERIENCE

S. Baumeler 1 , I. Bergamin 1 , B. Becker 1 , W. Jochum 2 , J. Neuweiler 1 , D. Semela 1

1 Gastroenerologie, KSSG, St. Gallen/Switzerland

2 KSSG, St. Gallen/Switzerland

Contact E-mail Address: stephan.baumeler@kssg.ch

Introduction: Non-alcoholic steatosis of the liver (NAFLD) has become the most common liver disease in industrialized western countries (1, 2). Patients with NAFLD are at increased risk for chronic liver disease (CLD), liver-related morbidity and mortality caused by complications of cirrhosis and hepatocellular carcinoma (HCC). The gold standard in evaluation of liver steatosis and inflammation to differentiate non-alcoholic fatty liver (NAFL) from non-alcoholic steatohepatitis (NASH) is the liver biopsy. Unfortunately liver biopsy is invasive with some risk of complications, it’s costly and contains risk of sampling error. Therefore non-invasive steatosis measurement is preferred whenever biopsy is not mandatory. With Controlled Attenuation Parameter (CAP) integrated in the widely used Elastography tool Fibroscan a new tool was introduced for non-invasive quantitative and qualitative steatosis measurement recently. To date CAP was evaluated in several selected collectives mostly in Europe and Asia. These collectives largely included patients with metabolic syndrome and hepatitis B (3, 4). Data for an unselected population in the sense of a real-life scenario is still missing.

Aims & Methods: The aim of this study was to analyse the accuracy of CAP values compared to the histologically quantified steatosis and to define cut-off values in an unselected collective undergoing liver biopsy for any reason in a tertiary liver centre in Switzerland. Method: Between March 2015 and August 2016, all patients who underwent liver biopsy for any reason were screened to meet the inclusion criteria. The CAP measurement had to be done within the same week as the biopsy and quality standards for CAP measurement were defined. Liver biopsies were classified according NAS Score: S0 <5%; S1 5–33%; S2 34–66%; S3 > 66%. In addition data about fibrosis, inflammatory activity, body mass index (BMI) and liver disease were recorded. For diagnosis NAFLD/NASH SAF Score was used.

Results: From 3/2015 to 8/2016 290 subjects were screened and 224 were included. 146 (65%) were male. Steatosis grades were S0 (0–5%) n = 85 (38%), S1 (6–33%) n = 82 (37%), S2 (34–66%) n = 33 (15%) and S3 (>66%) n = 24 (11%). Mean BMI was 26.8 kg/m 2 (SD 5.0). Mean BMI for the S0: 24.9 kg/m 2 (SD 3.3), for S1: 26.5 kg/m 2 (SD 4.2), for S2: 27.3 kg/m 2 (SD 4.9) and for S3: 32.5 kg/m 2 (SD 7.1). 114 patients had BMI ≥ 25 kg/m 2 . Median CAP values for S0: 227 dB/m (IQR 199–249), S1: 265 dB/m (IQR 228–295), S2: 307 dB/m (IQR 283–338), S3: 335 dB/m (IQR 319–358), p < 0.0001. Steatosis groups compared separately to the next high or lower group showed the following p values: S0 vs S1: p < 0.0001, S1 vs S2: p = 0.00012 and S2 vs S3: p = 0.03. The group BMI < 25 kg/m 2 had median CAP: 229 dB/m (IQR 206–267) and for BMI ≥ 25 kg/m 2 : 280 dB/m (IQR 232–321), p < 0.0001. In the subgroup NAFLD and NASH (n = 52) median CAP was 324.5 dB/m (IQR 297–352.25), the group including all the other diagnoses (n = 172) median CAP was 239.5 dB/m (IQR 214.75–280), p < 0.0001. Median CAP of the NASH group (n = 38) vs NAFLD group (n = 14) were not significantly different, 330 dB/m (IQR 305–358) vs CAP 310 dB/m (IQR 276–324), p = 0.506. Optimal cut-off values using the maximum Youden index were: 258 dB/m for S0 vs S1, 2, 3; 282.5 dB/m for S0, 1 vs S2, 3: and 307.5 dB/m for S0, 1, 2 vs S3. AUROC see table.

Conclusion: CAP shows strong association to steatosis grading also in an unselected population. Especially the groups NAFLD/NASH vs other liver diseases and the groups BMI < vs. >25 kg/m2 showed highly significant different CAP values. Comparing CAP for NAFLD vs NASH showed no significant difference.

Disclosure of Interest: All authors have declared no conflicts of interest.

References

1. Angulo P. Nonalcoholic fatty liver disease. N Engl J Med 2002; 346: 1221–1231

2. Bellentani S. The epidemiology of non-alcoholic fatty liver disease. Liver Int 2017; 37 Suppl 1: 81–84.

3. Cardoso AC, et al. Diagnostic performance of controlled attenuation parameter for predicting steatosis grade in chronic hepatitis B. Ann Hepatol 2015; 826–836

4. de Ledinghen V, et al. Controlled attenuation parameter for the diagnosis of steatosis in non-alcoholic fatty liver disease. J Gastroenterol Hepatol 2016; 848–855.

OP036 A RANDOMIZED CONTROLLED TRIAL COMPARING NITAZOXANIDE PLUS LACTULOSE VERSUS LACTULOSE ALONE IN TREATMENT OF OVERT HEPATIC ENCEPHALOPATHY

S. Abd-Elsalam , R. Badawi, N. Elwan, A. Elfert

Tropical Medicine Department, Tanta university, Tanta/Egypt

Contact E-mail Address: sherif_tropical@yahoo.com

Introduction: Hepatic encephalopathy (HE) is a reversible neuropsychiatric syndrome associated with acute and chronic liver dysfunction. Lactulose is a non-absorbable disaccharide currently used as a first-line agent for treatment of HE. Nitazoxanide has a broad-spectrum activity against urease-producing bacteria, so it decreases ammonia production and is therefore expected to reverse the symptoms of hepatic encephalopathy.

Aims & Methods: The aim of this study was to compare the safety and efficacy of nitazoxanide plus lactulose versus lactulose alone in treatment of overt hepatic encephalopathy.

Methods: 120 patients with liver cirrhosis suffering from overt hepatic encephalopathy were randomly assigned to receive either nitazoxanide plus lactulose (n = 60) or lactulose and placebo (n = 60). The Clinical Hepatic Encephalopathy Staging Scale (CHESS score) was assessed for all patients on inclusion to the study and one week from the start of treatment.

Results: Both groups evinced an improvement in CHESS score at one week, yet the improvement was significantly better in the nitazoxanide group as the score decreased from 4.15 ± 2.09 to 0.00 ± 0.00 compared with 4.96 ± 2.29 to 1.28 ± 0.91 in patients receiving lactulose and placebo (P value = 0.000).

Conclusion: Nitazoxanide significantly decreases the CHESS score and improves mental status in the form of patient alertness, orientation and ability to respond and talk. Nitazoxanide is safe and well tolerated with primarily mild gastrointestinal side effects.

(ClinicalTrials.gov Identifier: NCT02464124 )

Disclosure of Interest: All authors have declared no conflicts of interest.

OP038 FFECT OF GRANULOCYTE COLONY-STIMULATING FACTOR (G-CSF) ON MORTALITY AND COMPLICATIONS VIZ. SEPSIS, ENCEPHALOPATHY, HEPATORENAL SYNDROME, AND GASTROINTESTINAL BLEED IN SEVERE ALCOHOLIC HEPATITIS- A RANDOMIZED CONTROLLED STUDY

A. Sharma , A. Setia, R. R. Rai

Gastroenterology And Hepatology, Fortis Escorts Hospital Jaipur, Jaipur/India

Contact E-mail Address: abhinav_11005@yahoo.com

Introduction: Severe alcoholic hepatitis has very high short-term mortality. Compared to standard medical therapy (SMT), GCSF improves clinical and biochemical profiles, morbidity and mortality in these patients. We evaluated efficacy of GCSF in modulating the disease course of severe alcoholic hepatitis over a period of 3 months in terms of mortality, morbidity by Discriminant function (mDF), Child–Turcotte–Pugh (CTP) and Model for End-Stage Liver Disease (MELD) scores and various complications viz. sepsis, GI bleed, encephalopathy, hepatorenal syndrome (HRS) in comparison to SMT. We also studied the mobilising effect of GCSF on bone marrow stem cells measured by counting CD34+ cells from peripheral blood.

Aims & Methods: The present study was performed to evaluate the safety and efficacy of GCSF on mortality and complications viz. sepsis, encephalopathy, hepatorenal syndrome (HRS) and gastrointestinal bleed (GI Bleed) and also to investigate whether G-CSF therapy could improve the indices of severity of liver disease, such as Discriminant function (mDF), Child–Turcotte–Pugh (CTP), Model for End-Stage Liver Disease (MELD) score in patients with severe alcoholic hepatitis. 50 patients with severe alcoholic hepatitis were randomly assigned to groups A and B (25 in each). Both groups were given SMT, while in addition, patients in group A were given 5μ/kg GCSF subcutaneous (10 doses for 5 days). We assessed survival, changes in CTP, MELD and mDF scores and the development of complications till 90 days.

Results: The baseline parameters in both groups were comparable. On day 6 group A had higher mean leukocyte and CD34 counts than group B (P < .001). On 90 days follow up 17 patients in group A (68%) and 9 in group B (36%) survived (p = .04). Mean changes for different scores were greater in group A then group B i.e. CTP (−41.97% vs −8.84%), MELD (−50.89% vs 10.09%) and mDF (−74% vs 18%) (p < .001). The percentages of patients who developed HRS, HE, or sepsis were lower in group A than in group B (28% vs 64%, 32% vs 64%, and 28% vs 68%, respectively) (p < .001). There was no significant difference in GI bleed in both groups.

Conclusion: In severe alcoholic hepatitis, GCSF therapy significantly improves the survival. It also significantly reduces CTP, MELD, and mDF scores and prevents the development of complications.

Disclosure of Interest: All authors have declared no conflicts of interest.

References

1. Terai S, Ishikawa T, Omori K, Aoyama K, Marumoto Y, Urata Y, Yokoyama Y, Uchida K, Yamasaki T, Fujii Y, OkitaK, Sakaida I. Improved liver function in patients with liver cirrhosis after autologous bone marrow cell infusion therapy. Stem Cells 2006; 24: 2292–2298

2. Tseleva T, Brenner DA. The phenotypic fate and functional role for bone marrow-derived stem cells in liver fibrosis. J Hepatol 2012; 56: 965–972

3. Spahr L, Lambert JF, Brandt LR et al. Granulocyte-colony stimulating factor induces proliferation of hepatic progenitors in alcoholic steatohepatitis: a randomized trial. Hepatology 2008; 48: 221–9.

4. Virendra Singh et al Granulocyte Colony-Stimulating Factor in Severe Alcoholic Hepatitis: A Randomized Pilot Study. Am J Gastroenterol 2014; 109: 1417– 1423.

5. Theocharis SE, Papadimitriou LJ, Retsou ZP, et al. Granulocytecolony stimulating factor administration ameliorates liver regeneration in animal model of fulminant hepatic failure and encephalopathy. Dig Dis Sci 2003; 48: 1797–1803.

6. Gaia S, Smedile A, Omede P, et al. Feasibility and safety of G-CSF administration to induce bone marrow derived cells mobilization in patients with end stage liver disease. J Hepatol 2006; 45: 13–19.

7. Garg V, Garg H, Khan A et al. Granulocyte-colony stimulating factor mobilizes CD34+ cells and improves survival of patients with acute on chronic liver failure. Gastroenterology 2012; 142: 505–12.

MONDAY, OCTOBER 30, 201710:30-12:00

BARIATRIC SURGERY, OBESITY AND WEIGHT LOSS - ROOM B5____________________

OP039 INTRAGASTRIC BALLOON-INDUCED WEIGHT LOSS PRIOR TO SURGERY IN SUPER-OBESE PATIENTS – A SINGLE CENTER EXPERIENCE

I. Mocanu 1 , A. Laranjo 1 , S. Pires 1 , N. Veloso 1 , I. Medeiros 1 , M. Rocha 2 , S. Silva 2 , M. Amaro 2 , M. Carvalho 2

1 Gastroenterology, Hospital Espirito Santo de Évora, Évora/Portugal

2 Surgery, Hospital Espirito Santo de Évora, Évora/Portugal

Contact E-mail Address: irina.mocanu.24@gmail.com

Introduction: Bariatric surgery remains the most effective treatment for morbid obesity, and laparoscopic Roux-en-Y gastric bypass (LRYGB) continues to be the preferred operation. However, extreme obesity increases morbi-mortality in bariatric surgery. In super-obese patients (BMI > 50Kg/m 2 ), pre-operative weight loss can be achieved with minimally invasive endoscopic intragastric balloon (IGB) placement.

Aims & Methods: We aimed to explore the potential benefits of preoperative IGB on the outcomes of LRYGB in super-obesity. Methods: We performed a retrospective analysis of the patients with a BMI > 50Kg/m 2 treated at our obesity center between 2008 and 2016 with LRYGB alone (controls) or with prior placement of an IGB (cases). Clinical success of IGB was considered a body weight loss (BWL) of ≥10% and surgical success – an excess body weight loss (EBWL) ≥50% by the second year of post-operative follow-up (FU).

Results: 133 patients were included (82% females, mean age 45.8years, 85% with comorbidities): 46 cases Vs. 87 controls. Cases were significantly more overweight than controls (BMI 57.5 vs. 53Kg/m 2 ; p < 0.05, excess body weight 83.7 vs. 70.2 Kg; p < 0.01). The median time of IGB therapy was 196.8 days with 100% technical success rate in placement and removal of the device. 16 patients (34, 8%) had any complaint during IGB treatment (nausea, vomiting, epigastric pain) and in two (4%) of these, the IGB was removed before the scheduled date. Average weight effects of IGB were: weight loss: 27kg, BWL: 18.1%, BMI loss 10.7kg/m 2 and EBWL of 32.6%, with a clinical success rate for IGB of 87%. 71, 7% of cases had more than 25% EBWL at time of removal. 26.1% improved fitness for surgery as assessed by ASA score (drop from III to II) and 6.5% reported improvement in comorbidities during IGB treatment. The average delay from removal of IGB to surgery was 139 days, with a mean weight increase of 4.9kg. At time of surgery, average BMI was lower in cases than controls (48.6 vs. 53kg/m 2 , p < 0.01). There were no records of major surgical complications. Average EBWL effect of LRYGB in cases vs. controls was: 46.6 vs. 53% (p < 0.05) at 6 months, 56.9 vs. 70% (p < 0.05) at 12 months and 51.2 vs 73.8% (p < 0.05) at 2 years after surgery. When initial excess body weight was compared, EBWL in controls maintained superiority over the cases (73.8% vs. 64%, p < 0.05) at 24 months. 74.4% (n = 99) had a post-surgical FU of more than 2 years and of these, 81% had reached a clinical success (EBWL ≥ 50%). At most recent post-surgical FU (average 42.8 months), there was no difference between the two groups in total EBWL (63.7 vs. 66.5, p > 0.05). 57.8% (n = 77) reported improvement in comorbidities after surgery. Dyslipidemia, type II diabetes and joint pain were the comorbidities that most frequently improved.

Conclusion: IGB is a safe and effective method to promote weight loss in super-obese patients awaiting bariatric surgery, with subsequent improvement in anesthetic risk in a quarter of patients. Prior to surgery, patients submitted to IGB had lower BMI, despite initially being more overweight and at last post-surgical follow-up, there was no statistical difference in EBWL between the two groups. Another variable that has been previously demonstrated to improve with IGB was surgery time. We decided not to analyze this due to the long timespan of the study and the inherent improvement of the technical skills during these nine years, which could deliver biased results.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP040 EROSIVE ESOPHAGITIS IS PREVALENT AND PREDICTABLE BY PRE-OPERATIVE GERDQ QUESTIONNAIRE IN OBESE INDIVIDUALS AND IS ASSOCIATED WITH THE NEED FOR CONTINUED PPI USE AFTER LAPAROSCOPIC SLEEVE GASTRECTOMY

A.I. Sharara , H. H. Rimmani, A.I. Al Abbas, B. Safadi, R. H. Shayto, H. Aridi, Y. Shaib, R. Alami

Internal Medicine, American University of Beirut Medical Center, Beirut/Lebanon

Contact E-mail Address: husseinrimmani@gmail.com

Introduction: Gastroesophageal reflux disease (GERD) is common in obese individuals and following laparoscopic sleeve gastrectomy (LSG). There is limited information on the true prevalence, risk factors, and outcome of GERD before and after LSG.

Aims & Methods: We aimed to prospectively evaluate the prevalence of gastroesophageal reflux disease in obese patients considered for bariatric surgery and to identify risk and predictive factors for erosive esophagitis (EE) and continued PPI therapy post-LSG.

Methods: Consecutive patients undergoing routine esophagogastroduodenoscopy (EGD) prior to bariatric surgery were enrolled after informed consent. Patients completed the GERDQ and Nocturnal GERD Symptom Severity and Impact Questionnaires (N-GSSIQ). Demographic data included gender, age, BMI, waist circumference, and use of PPI or H 2 -antagonists. Endoscopic data included presence of erosive esophagitis (EE), hiatal hernia (HH), and gastroesophageal flap valve endoscopic grading (Hill grade). Patients were assessed 6 months post-LSG for BMI, GERDQ, and need for PPI.

Results: 175 consecutive patients have been recruited to date (76 males and 99 females). The mean age was 38.4 ± 11.7 and mean BMI was 40.0 ± 6.1, nearly equally divided between BMI ≤ or >40. Forty four patients (25.1%) were on PPIs at baseline. EE was documented in 48 of 131 patients on no PPI (36.6%). The total prevalence of gastroesophageal reflux (EE + PPI users) was 52.6%. On multivariate analysis, presence of HH and a high GERDQ score ( 3 8) were significantly associated with EE (p = 0.025 and <0.001 respectively). Patients with high probability GERDQ scores had a significantly higher prevalence of EE compared to low scorers (45.8% vs. 21.6%, p = 0.001). EE was more common in males vs. females (40.8% vs. 24.2%, p = 0.019) and in patients with HH vs. those without (48.4% vs. 27.8%, p = 0.025). BMI (≤40 vs. >40) and WC were not associated with the presence of EE. Logistic regression analysis showed that GERDQ scores of ≥8 was the only independent risk factor for EE (OR 3.077, 95% CI 1.58–5.96). Forty-seven patients had LSG and completed the follow-up assessment. At 6 months post-LSG, mean BMI declined to 29.8 ± 4.3 (D = -11.05) and 15 of 47 patients (31.9%) required continued PPI therapy to control their symptoms. EE on baseline EGD was the only factor associated with need for continued PPI use (58.8% in EE patients vs. 16.7% without EE; p = 0.003). BMI, HH repair, baseline PPI use were not predictive of continued post-operative PPI use.

Conclusion: Gastroesophageal reflux disease is very prevalent in obese patients considered for bariatric surgery. A high GERDQ score correlates with the presence of erosive disease in this population. The presence of erosive esophagitis, but not PPI use pre-operatively is highly predictive of the need for continued PPI requirement post-laparoscopic sleeve gastrectomy.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP041 DEFECTS IN ENTEROENDOCRINE CELL DEVELOPMENT IN MORBIDLY OBESE HUMANS ARE NORMALIZED AFTER SLEEVE GASTRECTOMY

A.C. Meyer-Gerspach 1 , A. W. Moran 2 , B. K. Wölnerhanssen 1 , G. Burdyga 2 , R. Peterli 3 , M. Manz 4 , M. Thumshirn 4 , K. Daly 2 , C. Beglinger 1 , S. P. Shirazi-Beechey 2

1 Department Of Research, Clara Hospital Basel, Basel/Switzerland

2 Institute Of Integrative Biology, University of Liverpool, Liverpool/United Kingdom

3 Department Of Surgery, Clara Hospital Basel, Basel/Switzerland

4 Department Of Gastroenterology, Clara Hospital Basel, Basel/Switzerland

Contact E-mail Address: ac.meyergerspach@gmail.com

Introduction: Morbidly obese patients exhibit impaired secretion of gastrointestinal peptides that may contribute to the development of obesity and its associated conditions. Bariatric surgery induces an increase in gastrointestinal peptide release. The mechanisms associated with these changes are unclear. A better understanding of the underlying mechanisms may contribute to the development of non-invasive therapeutic strategies.

Aims & Methods: Gastric and duodenal tissues were endoscopically collected from lean controls and morbidly obese subjects before and 3 months after laparoscopic sleeve gastrectomy (LSG). Gastrointestinal peptides were measured after a standardized nutrient drink pre- and post- LSG. Tissue morphology was determined by morphometric analysis. Tissue expression levels of chromogranin A, gut hormones, α-defensin, mucin 2 and Na+/glucose co-transporter 1 (SGLT1) were assessed by combination of immunohistochemistry, western blotting and quantitative PCR. Protein abundance of transcription factors (Hes1, HATH1, NeuroD1, and Ngn3) were determined by western blotting.

Results: In the obese, the total number of enteroendocrine cells (EEC) containing gastrointestinal peptides was significantly reduced (p < 0.001); they were restored post-LSG (p < 0.001). This profile matched the levels of circulating gastrointestinal peptides (p < 0.001, respectively). A significant increase in SGLT1 (p < 0.05) expression was detected in the obese duodenum. Expression levels of transcription factors required for differentiation of absorptive and secretory cell lineages were reduced (p < 0.05, respectively).

Conclusion: In conclusion, in obesity, there is a deregulation of developmental programming of intestinal epithelial cell lineages. The programing is restored post-surgery leading to an increase in secretion of gut hormones and reduced blood glucose levels.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP042 A WEIGHT LOSS INTERVENTION REDUCES BOWEL SYMPTOMS: A PROSPECTIVE STUDY IN SUBJECTS WITH MORBID OBESITY

M. Aasbrenn 1 , S. Lydersen 2 , P. Gronaas Farup 1

1 Department Of Cancer Research And Molecular Medicine, Norwegian University of Science and Technology, Trondheim/Norway

2 Regional Centre For Child And Youth Mental Health And Child Welfare, Norwegian University of Science and Technology, Trondheim/Norway

Contact E-mail Address: Martin.Aasbrenn@gmail.com

Introduction: Low-grade inflammation and dietary habits are possible explanations for the high prevalence of irritable bowel syndrome (IBS) in subjects with morbid obesity.

Aims & Methods: We aimed to study changes in bowel symptoms, BMI, physical and mental health and a selection of blood tests during a weight loss intervention, and to study the associations between the changes in bowel symptoms and the other variables. Subjects referred to a hospital for treatment of morbid obesity were included. The intervention included personalized advice on lifestyle (regular, healthy meals and physical activity) and frequent group-based follow-up for six months. IBS was diagnosed with the Rome III criteria. Bowel symptoms were assessed with the irritable bowel syndrome symptom severity scale (IBS-SSS) and gastrointestinal symptom rating scale for IBS (GSRS-IBS). Health was assessed with eight questionnaires including WHO-5 Well-Being Index for emotional well-being and the Sense of Humor Questionnaire. CRP, lactoferrin, neopterin, low-density lipoprotein, high-density lipoprotein, cholesterol, HbA1c, thyroid stimulating hormone, T4 and vitamins B 1 , B 6 , B 12 and D were measured in the blood.

Results: Eighty-eight subjects (71(81%) females) with mean age 44 years (SD 8) were included. BMI was reduced from 42 (SD 4) to 39 (SD 4) kg/m 2 (p < 0.001). The prevalence of IBS was 24/88 (27%) before and 17/88 (19%) after the intervention (p = 0.19). The IBS-SSS was reduced from 116 (SD 104) to 81 (SD 84) (p = 0.001). The GSRS-IBS was reduced from 1.8 (SD 0.8) to 1.6 (SD 0.6) (p = 0.006). Scores on GSRS-IBS subscales changed significantly: Bloating, diarrhoea and satiety decreased while constipation increased. The markers of low-grade inflammation and most of the other health scores and blood tests improved significantly. The reduction in IBS-SSS was negatively associated with reduction in BMI (partial correlation (pc) = −0.29, p = 0.012) and associated with improved sense of humor (pc = −0.30, p = 0.012). The reduction in GSRS-IBS was associated with improvement in emotional well-being (pc = −0.23, p = 0.038) and increased vitamin D (pc = −0.29, p = 0.010). Neither the changes in IBS-SSS nor GSRS-IBS were significantly associated with changes in the inflammatory markers, the other health scores or blood tests.

Conclusion: The bowel symptoms were markedly reduced during the weight loss intervention, but the reduction was not associated with the changes in low-grade inflammation. These results weaken the hypothesis that low-grade inflammation from adipose tissue is the cause of the high prevalence of IBS in subjects with obesity. Dietary habits (size of meals, fat intake) or psychosocial factors are alternative explanations.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP043 DYNAMICS OF DECREASE OF ABDOMINAL FAT AFTER BARIATRIC SURGERY: A NONINVASIVE ASSESSMENT OVER 24 MONTHS BY MRI

A.C. Meyer-Gerspach 1 , B. K. Wölnerhanssen 1 , D. Nabers 2 , M. Moor 3 , S. Borgwardt 4 , R. Peterli 5 , C. Beglinger 1 , O. Bieri 3

1 Department Of Research, Clara Hospital Basel, Basel/Switzerland

2 Division Of Medical And Biological Informatics, German Cancer Research Center, Heidelberg/Germany

3 Department Of Radiology, University Hospital Basel, Basel/Switzerland

4 Department Of Psychiatry, University Hospital Basel, Basel/Switzerland

5 Department Of Surgery, Clara Hospital Basel, Basel/Switzerland

Contact E-mail Address: ac.meyergerspach@gmail.com

Introduction: Non-alcoholic fatty liver disease (NAFLD) is characterized by atherogenic dyslipidemia. NAFLD patients are at an increased risk for both cardiac and non-cardiac vascular diseases. The effect of bariatric surgery on fat distribution in the liver has so far been studied with liver biopsies and single voxel MR techniques. The objective of this study was to assess liver fat fraction (LFF), subcutaneous (SAT) and visceral adipose tissue (VAT) using MRI in combination with blood lipids to monitor the efficiency of bariatric surgery.

Aims & Methods: In 15 morbidly obese patients an iterative decomposition of water and fat with echo asymmetry and least-squares estimation (IDEAL) approach was used for whole liver fat quantification in combination with a 2-point Dixon technique for volumetric fat imaging of adipose tissue pre- and 3, 6, 12, and 24 months after surgery. SAT and VAT adipose tissue volumes were assessed from fat images and separated by statistical shape models. Serum: total cholesterol, HDL, LDL and TG were measured.

Results: LFF, SAT and VAT volumes decreased postoperatively with a good phenomenological description using an exponential model of form. t is the time (in days) after intervention, A = [ A 1 , A 2 , …, A 11 ] refers to the individual patient specific LFF, SAT or VAT volumes, in combination with a global time constant T LFF , VAT , SAT for each measure. The LFF reduced the fastest, (time constant: T LFF = 96 ± 28 d), followed by SAT ( T SAT = 140 ± 18 d), and VAT ( T VAT = 170 ± 21 d). LFF measures showed a clear correlation with total cholesterol, cholesterol/HDL ratio and LDL (each: p < 0.001) and a trend for HDL (p = 0.006). Decrease in VAT and SAT did not correlate with blood lipids.

Conclusion: In conclusion, the decrease of body fat after bariatric surgery follows a distinct time pattern: liver fat decreases fastest followed by subcutaneous and last visceral fat, and decrease in liver fat correlates with changes in blood lipids.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP044 FINAL RESULTS OF MULTI-CENTER, PROSPECTIVE, CONTROLLED TRIAL OF THE DUODENO-JEJUNAL BYPASS LINER FOR THE TREATMENT OF TYPE 2 DIABETES MELLITUS IN OBESE PATIENTS: EFFICACY AND FACTORS PREDICTING A SUBOPTIMAL EFFECT

M. Benes , P. Drastich, T. Hucl, J. Spicak

Department Of Hepatogastroenterology, Institute for Clinical and Experimental Medicine, Prague/Czech Republic

Contact E-mail Address: marek.benes@ikem.cz

Introduction: The global increase in obesity incidence results in an increase of type 2 diabetes mellitus (T2DM). Surgical treatment has proven to be effective; however, it carries a high risk of complications. The duodenal-jejunal bypass liner (EndoBarrier®, GI Dynamics, EB) is an endoscopic implant that mimics the intestinal bypass portion of the Roux-en-Y Gastric Bypass. It results in weight loss and improvements in glucose control in obese patients with T2 diabetes mellitus (T2DM).

Aims & Methods: This is a final report of a prospective, controlled, multicentre study aimed to determine the effectiveness of EB and to identify factors associated with a sub-optimal outcome of EB.

Results: Seventy subjects (45 with an implant, 25 controls) were included in the study. The groups were comparable with respect to age, gender, BMI (mean 41.7 vs. 39.5 kg/m 2 ), T2DM duration (7.8 vs. 8.3 years), HbA1c level (88 vs 86 mmol/mol) and T2DM treatment. In the EB group, all devices were successfully implanted. Only 6 devices had to be explanted prior to the end of the 10 months study period (bleeding, dislocation and need for ERCP because of choledocholithiasis). The mean procedure time was 17 minutes for an implantation and 16 minutes for an explantation. At 10 months there was significantly greater weight loss and %EWL (19% vs. 7% and 43 vs. 12) and significantly improved long-term compensation of T2DM marker HbA1c (decreased by 25 vs. 10 mmol/mol) in the EB group. T2DM medicinal treatment could be reduced in more device subjects than controls. There was no serious adverse event. Mild abdominal pain and nausea after implantation were experienced by 60% of patients during first 14 days after implantation, 30% of patients during the first month and 10% of patiens after one month. Lower initial BMI and lower body height were identified as negative prognostic factors for pain, but positive for efficacy of EB.

Conclusion: The EB is safe when implanted for 10 months, and results in significant weight loss and HbA1c reduction. This suggests that this novel device is a candidate for the primary therapy of morbid obesity and T2DM. Lower initial BMI and lower body height could be negative prognostic factor for pain, but positive for efficacy.

Disclosure of Interest: All authors have declared no conflicts of interest.

MONDAY, OCTOBER 30, 201710:30-12:00

ABSTRACTS ON FIRE: ADVANCES IN ENDOSCOPIC RESECTION OF EARLY COLORECTAL NEOPLASIA - HOTSPOT____________________

OP045 UNDERWATER ENDOSCOPIC COLORECTAL POLYP RESECTION IS A SAFER AND MORE EFFECTIVE TECHNIQUE THAN GAS INSUFFLATION POLYPECTOMY FOR EVERYDAY CLINICAL PRACTICE

M. Liggi 1 , S. Cadoni 2 , P. Gallittu 2 , D. Mura 1 , M. Koo 3

1 Digestive Endoscopy Unit, Sirai Hospital, Carbonia/Italy

2 Digestive Endoscopy Unit, CTO Hospital, Iglesias/Italy

3 Dalla Lana School Of Public Health, University Of Toronto, Department of Medical Research, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chiayi, Taiwan, Toronto/Canada/ON

Contact E-mail Address: liggim@gmail.com

Introduction: Endoscopic mucosal resection (EMR) is a well-established technique for resecting flat or sessile benign colon polyps. Underwater endoscopic mucosal resection (UEMR) is a novel technique that eschews submucosal injection. Reports about the feasibility, efficacy and safety of the technique were limited to small series of single and/or tertiary-care referral centers.

Aims & Methods: To demonstrate that underwater polypectomy (UWP, here includes UEMR) can be efficaciously and safely used in routine clinical practice also by endoscopists with various levels of expertise (2 experts; 2 fellows). Main outcomes: en bloc resection rate, R0 resection rate, residual or recurrent adenoma (RRA) at follow-up (median 14 months) of piecemeal resections of flat and sessile lesions ≥10 mm, and adverse events. Analyses were also conducted with stratification by the colonoscopists’ expertise. Colonoscopy records maintained at our two community hospitals in Italy about UWP, traditional EMR for flat and sessile lesions ≥6 mm and for resections of pedunculated polyps ≥6 mm performed from 01/2015 to 12/2016 were included in the current retrospective analysis. Data on UWP and gas insufflation polypectomy (GIP) were compared.

Results: Table 1 shows that a total of 318 polypectomies (195 UWP and 186 GIP) were performed. Demographic and procedural data were comparable, as well as the distribution, morphology and histology of resected lesions. Pathology record median size (interquartile range, IQR) in the UWP group (10 mm; 7–15) vs. the GIP group (10 mm; 17–12.5) was comparable. Median (IQR) resection time was significantly shorter in the UWP group (1.5 minutes; 0.8–3.8) than in the GIP group (3.4 minutes; 2.5–5.4) (p < 0.001), respectively. En bloc and R0 resections, as well as RRA proportions, irrespective of polyp morphology and size, were comparable. Immediate bleeding for pedunculated lesions was significantly lower in the UWP than in the GIP group: 3.4% vs. 13.5%, p = 0.031. No post-polypectomy syndrome or perforation cases occurred. Analyses according to colonoscopist expertise showed that fellows performed 41% of UWP and 61.8% of GIP. Polyp morphology, size, en bloc and R0 resections were comparable between study groups and with those of experts. Fellows’ UWP resection times for flat and sessile lesions (1.1 minutes; IQR 0.7–3.3) and for pedunculated lesions (0.8 minutes; IQR 0.6–1.1) were significantly shorter than experts’ [3.3 minutes; IQR 2.0–6.0 (p = 0.006) and 3.3 minutes; IQR 2.0–8.0 (p < 0.001), respectively] and than GIP resection times (3.5 minutes; IQR 2.8–6.7 and 3.5 minutes; IQR 2.6–5.0, respectively; both p < 0.001). UWP of pedunculated lesions performed by fellows showed significantly less immediate bleeding that GIP (0% vs 17.8%; p = 0.006).

Conclusion: Compared with GIP, UWP (including UEMR) achieved comparable proportions of en bloc and R0 resections, and RRA; with a significantly shorter resection time (all polyps) and lower bleeding episodes (pedunculated polyps) despite different colonoscopists’ expertise. This evidence suggests that UWP can be easily and safely used in routine clinical practice, also by not very expert colonoscopists. Its use should be encouraged.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP046 HAS THE SAFETY OF COLORECTAL ENDOSCOPIC SUBMUCOSAL DISSECTION BEEN MAINTAINED EVEN IN THE REGIONAL GENERAL HOSPITAL IN JAPAN?: A MULTICENTER PROSPECTIVE COHORT STUDY

Y. Hiraga , S. Tanaka, S. Oka, K. Boda, S. Nagata, M. Kunihiro, R. Higashi, T. Kuwai, A. Furudoi, K. Nakadoi, H. Kanao, M. Terasaki, H. Okanobu, M. Higashiyama, K. Chayama

Hiroshima Endoscopy Research Group, Hiroshima/Japan

Contact E-mail Address: penguist@ktb.biglobe.ne.jp

Introduction: In Japan since April 2012, colorectal endoscopic submucosal dissection (ESD) has been covered under health insurance, and now it has certainly become one of the treatment options of early colorectal neoplasms. There are a lot of reports of good outcomes of colorectal ESD, but that were performed by very skillful experts at advanced high-volume centers.

Aims & Methods: The aim of this study was to investigate the clinical outcomes of colorectal ESD performed in our region, Hiroshima prefecture in Japan, included many non-specialized general hospitals. We recruited prospectively 1126 consecutive patients (681 male, mean age 69 years) with 1118 colorectal tumors resected by ESD at 26 hospitals (1 academic center and 25 community hospitals) in Hiroshima prefecture between August 2013 and June 2016. We categorized the 26 hospitals into high- (Group H) or low-volume centers (Group L), based on the median number (80 lesions) of ESD performed during the study period. We compared the groups with respect to the clinicopathological characteristics of the lesions and the clinical outcomes of ESD.

Results: Regarding the clinicopathological characteristics of 1118 tumors, 594 (50%) were located in the right colon, 253 (21%) in the left colon, and 341 (29%) in the rectum. The average tumor size was 30 mm (range 5–120 mm). Laterally spreading tumors of the granular type (LST-G), LST of the non-granular type (-NG) and polypoid type were 500 lesions (42%), 433 (36%) and 255 (22%), respectively. Histologically, there were 531 (45%) intramucosal carcinomas (Tis), 81 (7%) shallow submucosal invasive cancers (<1000 µm; T1a), 144 (12%) deep submucosal invasive cancers (>1000 µm; T1b) and 432 (36%) dysplasias. 198 (17%) tumors had severe submucosal fibrosis and 484 tumors (41%) had the poor scope operability. As for the procedural outcomes of ESD, the mean procedure time was 90 minutes (range 5–660 minutes), and the ratios of the en bloc resection, histological complete resection and R0 resection were 95% (1133/1188), 93% (1101/1188) and 83% (986/1188), respectively. The delayed bleeding and perforation during procedure occurred in each 2% (24/1188), 4% (42/1188, included 3 patients shifted to surgery). There were no significant differences between the groups in relation to the sex ratio, the patients’ average age, the ratio of taking antithrombotic drugs, the mean tumor size, the tumors’ locations and the mean procedure times. The ratios of additional ESD after endoscopic resection, of polypoid lesions, of severe submucosal fibrosis and of poor scope operability were significantly higher in Group H compared with that in Group L. The histological complete resection rates were significantly higher in Group H than in Group L, but the en bloc resection rate and the adverse events rates were not.

Conclusion: In our region, the safety of colorectal ESD has been maintained, because we appropriately choose the lesions which ourselves should do according to the skill level of each institutions after having judged the degree of procedure difficulty of them.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP047 WHAT ARE THE RESULTS OF RECTAL ESD IN FRANCE: A LARGE RETROSPECTIVE MULTICENTRE STUDY IN EXPERTS CENTERS

J. Albouys 1 , M. Guillaumot 2 , V. Lepilliez 3 , S. Chaussade 4 , M. Pioche 5 , S. Leblanc 6 , M. Barret 2 , R. Legros 1 , F. Prat 7 , J. Rivory 5 , D. Sautereau 8 , T. Ponchon 9 , J. Jacques 8

1 CHU Limoges, Limoges/France

2 Gastroenterology, Cochin Hospital, Paris/France

3 Hopital prive Jean Mermoz, Lyon/France

4 Service De Gastro-entérologie, CHU Cochin Dept. de Gastroenterologie, Paris/France

5 Hepatogastreoenterology, Hopital Edouard Herriot, Lyon/France

6 CHU Cochin Dept. of Gastroenterology, Paris/France

7 Department of Gastroenterology, Cochin Hospital, Assistance Publique-Hôpitaux de Paris, Paris/France

8 Hepato-gastro-enterology, CHU Limoges - Hepato-Gastro-Enterology, CHU Limoges; Limoges/FR, Limoges/France

9 Dept. of Digestive Diseases, Edouard Herriot University Hospital, Lyon/France

Contact E-mail Address: jeremie.albouys@gmail.com

Introduction: Endoscopic Submucosal Dissection has become the standard of care for large superficial rectal precancerous and cancerous lesions. Despite increasing practice in the western world, few European studies have been reported. First French results were far from those reported by Japanese teams: En bloc resection: 64%; R0 resection: 53%. Since these first results, experts teams have trained with animal models and in Japanese centers. We report here the largest European retrospective multicenter study of four French leading teams in rectal ESD.

Aims & Methods: We performed a retrospective multicenter study of all cases of rectal ESD performed for precancerous or superficial cancerous lesions in four French teams that performed more than 150 ESDs in the last 5 years. All these teams had individual databases of their cases of rectal ESDs that were merged. Primary Endpoint was to evaluate the En bloc, R0 and curative resection rate. Secondary endpoints were: -evaluation of risk factors for non R0 resection -evaluation of risk factors for non en bloc resection -evaluation of the effect of learning curve (before and after 40 ESDs) on the results

Results: 349 rectal ESDs were performed between 01/06/2010 and 31/12/2016. Descriptive results: male 49%, mean size of the specimen: 56.4 mm, mean duration of procedure 118.9 min, mean speed of ESD: 23.9 mm 2 /min, perforation rate: 6%, post procedural bleeding rate: 6.3%, secondary surgery 6.6% (0% for a complication; 95% for a failure or pathological risk factor or lymph node metastasis; 5% for ulcerative colitis). Pathological analysis: low grade dysplasia in 22%, high grade dysplasia in 32, 4%, intra-mucosal carcinoma in 29%, superficial submucosal carcinoma in 6, 3%, deep submucosal carcinoma in 4.6% and T2 adenocarcinoma in 2.3%. Only 5 patients (1.5%) had a recurrent disease during endoscopic follow up: 2 that had an ESD failure and a piece-meal resection, 2 that had low-grade dysplasia in lateral margin and one high-grade dysplasia lesion R0 resected. Primary Endpoint: En bloc resection rate: 95.3%, R0 resection rate: 73%, curative resection rate: 68.5% Secondary endpoints: - non en bloc resection was associated with a longer procedure duration (221 vs 113 min, p = 0.002); a lower speed (12.9 vs 24.2 mm 2 /min, p = 0.0005); a higher perforation rate (21.05% vs 5.2%, p = 0.005); a higher rate of secondary surgery (21% vs 5.2% p = 0.02) and a higher rate of recurrent disease (10.5% vs 0.9%, p = 0.02) -non R0 resection was associated with a longer procedure duration (165.2 vs 105 min, p = 0.002)); a lower speed (17.4 vs 25.9 mm 2 /min, p = 0.0005); a higher rate of non exclusive ESD (17.2% vs 1.7%, p = ….) and and a higher rate of recurrent disease (4.3% vs 0.4%, p = 0.02) -the beginning of the learning curve (<40 ESDs whatever the location) was associated with a longer procedure duration (167 vs 107 min, p = 1.2 × 10 −6 ); a lower speed (15.49 vs 25.83 mm 2 /min, p = 1.6 × 10 −6 ), a higher rate of post procedural bleeding (13.3% vs 4.4%, p = 0.004) a lower rate of deep sm or T2 adenocarcinoma (0% vs 5% and 0% vs 2.%, p = 0.05), a lower rate of secondary surgery (0% vs 8.4%, p = 0.009) and longer hospital stay (3.76 vs 2.82 days, p = 0.0001)

Conclusion: ESD allows a high en bloc and R0 resection in rectal lesions with a low recurrence rate in French expert teams. French experts centres are able to report results close to those of Japanese experts when an adequate training has been performed. This retrospective study represent the largest study of rectal ESD in the western world.

Disclosure of Interest: All authors have declared no conflicts of interest.

References

Farhat S, Chaussade S, Ponchon T, Coumaros D, Charachon A, Barrioz T, et al. Endoscopic submucosal dissection in a European setting. A multi-institutional report of a technique in development. Endoscopy . 2011 May 27;43(08):664–70.

Rahmi G, Hotayt B, Chaussade S, Lepilliez V, Giovannini M, Coumaros D, et al. Endoscopic submucosal dissection for superficial rectal tumors: prospective evaluation in France. Endoscopy . 2014 Aug; 46(8): 670–6.

OP048 EFFICACY OF TRACTION-ASSISTED COLORECTAL ENDOSCOPIC SUBMUCOSAL DISSECTION USING CLIP AND THREAD: A PROSPECTIVE RANDOMIZED STUDY

Y. Yamasaki 1 , Y. Takeuchi 2 , N. Uedo 2 , T. Kanesaka 2 , R. Ishihara 2 , H. Okada 1 , H. Iishi 2

1 Department Of Gastroenterology And Hepatology, Okayama University Graduate School of Medicine, Okayama/Japan

2 Department Of Gastrointestinal Oncology, Osaka International Cancer Institute, Osaka/Japan

Contact E-mail Address: yasshifive@yahoo.co.jp

Introduction: Colorectal endoscopic submucosal dissection (ESD) is still challenging because of its technical difficulties, long procedure time, and high risk of adverse events. To facilitate colorectal ESD, we developed a novel simplified traction method “traction assisted colorectal ESD using clip and thread (TAC-ESD)” [1, 2]. Here, we conducted a prospective randomized controlled trial to fully evaluate the efficacy of TAC-ESD.

Aims & Methods: Patients with superficial colorectal neoplasms (SCNs) >20 mm were enrolled and randomly assigned to conventional-ESD group or TAC-ESD group. SCNs < 50 mm were treated by 2 intermediates, and SCNs > 50 mm were treated by 2 experts. Primary endpoint was the procedure time. Secondary endpoints were successful rate of TAC-ESD, self-completion rate by the intermediates, and adverse events. Procedural success of TAC-ESD was defined as successful sustained application of clip and thread until the end of procedure. In the colon, TAC-ESD was performed as follows. Before the endoscope was inserted, a 3–0 polyester surgical thread 0.25 mm in diameter (Natsume Seisakusho Co., Ltd, Tokyo, Japan) was inserted into its accessory channel by grasping the thread with hemostatic forceps, and pulling it up through the working channel. Then the ends of the thread were tied together outside the endoscope. After that, the endoscope was inserted as usual and the actual ESD procedure started. After submucosal injection, the mucosa was incised on the anal side of the lesion. Next, the thread was cut externally at the hand control end of the endoscope and the accessory channel end of the thread tied to the teeth of the clip (HX-610-090; Olympus, Tokyo) attached to an applicator. At this stage, it was important not to fully open the clip. The clip and thread were then retracted into the applicator and the applicator inserted into the accessory channel. The clip was fully opened in the colon and used to grasp the anal side of the specimen, after which the thread was pulled gently by hand to provide good visibility of the submucosal layer. Finally, the submucosal layer was dissected easily under direct visualization [1]. In the rectum, TAC-ESD was performed as follows. First, a polyester thread was tied to the teeth of a clip, which was attached to an applicator. The clip and thread was then retracted into the applicator as in preparation. Next, the endoscope was inserted into the rectum. After a mucosal incision on the anal side of the lesion was performed, the endoscope was withdrawn outside of the rectum. The applicator was inserted into the accessory channel of the endoscope, and the thread was pulled back up through the working channel. Then, the endoscope was reinserted into the rectum. The clip was fully opened within the rectum and used to grasp the anal side of the lesion. Since then, the procedure was same as above [2].

Results: In total, 42 SCNs in conventional-ESD group and 42 SCNs in TAC-ESD group were analyzed between August 2015 and October 2016. The procedure time (median [range]) in TAC-ESD group was significantly shorter than in conventional-ESD group (40 [11–86] min vs. 70 [30–180] min, respectively; P < 0.0001). In subgroup analyses, the procedure time was significantly shorter in TAC-ESD group than in conventional-ESD group for both colonic (37 [21–86] min vs. 68 [30–180] min, respectively; P < 0.0001) and rectal (44 [11–84] min vs. 73 [32–120] min, respectively; P = 0.02) lesions. Successful rate of TAC-ESD was 95% (40/42). The self-completion rate by the intermediates was significantly higher in TAC-ESD group than in conventional-ESD group (100% [39/39] vs. 90% [36/40], respectively; P = 0.04). There were 1 intra-operative perforation in conventional-ESD group, and 1 delayed perforation in TAC-ESD group.

Conclusion: TAC-ESD reduced the procedure time and raised the self-completion rate without increasing adverse events.

Disclosure of Interest: All authors have declared no conflicts of interest.

References

1. Yamasaki Y, Takeuchi Y, Uedo N et al. Traction-assisted colonic endoscopic submucosal dissection using clip and line: a feasibility study. Endosc Int Open . 2016; 4: E51-5.

2. Yamasaki Y, Takeuchi Y, Uedo N et al. Feasibility of Simple Traction Technique for Rectal Endoscopic Submucosal Dissection. Dig Dis Sci . 2016; 61:2127–31.

OP049 EFFICACY OF ENDOSCOPIC SUBMUCOSAL DISSECTION USING THE “CLIP-FLAP METHOD” FOR COLORECTAL TUMORS

K. Yamamoto 1 , S. Hayashi 2 , H. Saiki 1 , T. Nishida 2 , N. Tatsumi 1 , T. Michida 3 , T. Ito 1

1 Department Of Gastroenterology, Japan Community Healthcare Organization Osaka Hospital, Osaka/Japan

2 Department Of Gastroenterology, Toyonaka Municipal Hospital, Osaka/Japan

3 Teikyo University Medical Center, Chiba/Japan

Contact E-mail Address: yamamoto-kts@umin.ac.jp

Introduction: Endoscopic submucosal dissection (ESD) is technically challenging because of poor visualization and instability in the operative field. Although mucosal flap formation improves visualization of the cutting area, it is difficult to achieve, especially in colorectal ESD. To facilitate mucosal flap creation, we developed the “clip-flap method” using the endoclip as a substitute for the mucosal flap until the flap is completed (K. Yamamoto, et al. Endoscopy 2012·2015).

Aims & Methods: We retrospectively studied 497 cases in which ESD for superficial colorectal tumors was performed between August 2008 and April 2017. The primary object lesions were large laterally spreading tumor. We compared the treatment outcomes after the adoption of the clip-flap method (Clipflap-ESD: 377 cases) with those before the adoption of the clip-flap method (Conventional-ESD: 120 cases) to evaluate the efficacy and safety of the clip-flap method. Furthermore, we investigated the cases for which clip-flap method was especially effective in difficult lesions. The procedure of the clip-flap method is as follows. The lesions were moved upward as far as possible against gravity following a postural change to take advantage of the counter-traction of gravity. After submucosal injection, the mucosa around the lesion on the anal side was incised with an adequate margin, and the submucosal layer was cut deeply. The edge of the exfoliated mucosa was clipped with an endoclip (EZ CLIP, HX-610-135; Olympus). The distal attachment was inserted under the endoclip, and then the submucosal layer was dissected with the endoknife. A single endoclip was generally used, and the cross pattern of endoclips, created by attaching one endoclip to another endoclip, was also used according to the situations. We mainly used a short-needle electrosurgical endoknife with a water-jet function (FlushKnifeBT; Fujifilm).

Results: Median tumor diameter, resected specimen diameter, procedure time, en bloc resection rate, and perforation rate of Conventional-ESD and Clipflap-ESD were 26 mm vs 27 mm, 32.5 mm vs 36 mm, 88.5 minutes vs 47 minutes, 90 % vs 97.1 %, and 4.2 % vs 1.6 %, respectively. The procedure time of Clipflap-ESD was statistically significantly shorter than that of Conventional-ESD (P < 0.01), and en bloc resection rate of Clipflap-ESD was significantly higher than that of Conventional-ESD (P < 0.01). Application rate of the clip-flap method in Clip-flap-ESD was 61.8 %. In all the cases which the clip-flap method was applied, the exfoliated mucosa was lifted by the endoclip attached to the exfoliated mucosa after the distal attachment was inserted under the endoclip, allowing for clear visualization and efficient dissection of the submucosal layer, and effective creation of the mucosal flap. In technically difficult lesions for ESD, the difficulties in the cases for which clip-flap method was especially effective caused poor elevation of submucosal layer despite after submucosal injection due to the presence of submucosal fibrosis or vessels (68.2%), and poor visualization of submucosal layer due to vertical approach (31.8%). Clip-flap method greatly improved the visualization of the cutting area even those challenging situations.

Conclusion: The clip-flap method facilitated the mucosal flap creation and its adoption allowed our treatment outcomes to be greatly improved. This study demonstrates that the clip-flap method is a simple, safe, and effective option for colorectal ESD. In technically difficult cases, the clip-flap method seems to be especially effective for poor elevation of submucosal layer due to the presence of submucosal fibrosis or vessels, and vertical approach for the lesions.

Disclosure of Interest: All authors have declared no conflicts of interest.

References

1. Yamamoto K, Hayashi S, Nakabori T, et al. Endoscopic submucosal dissection using endoclips to assist in mucosal flap formation (novel technique: “clip flap method”). Endoscopy 2012, 44 Suppl 2 UCTN: E334-5.

2. Yamamoto K, Hayashi S, Saiki H, et al. Endoscopic submucosal dissection for large superficial colorectal tumors using the “clip-flap method.” Endoscopy 2015; 47:262–265.

3. Yamamoto K, Michida T, Nishida T, et al. Colorectal endoscopic submucosal dissection: Recent technical advances for safe and successful procedures. 2015; 7:1114–28.

OP050 EFFICACY AND SAFETY OF ENDOSCOPIC FULL-THICKNESS RESECTION IN THE COLORECTUM WITH THE FTRD SYSTEM – INTERIM RESULTS OF A GERMAN REGISTRY

A. Schmidt 1 , B. Meier 2 , A. Fischer 1 , M. Wegener 3 , T. Wiedbrauck 3 , M. Repp 4 , G. Fitzel 4 , G. Hübner 5 , D. Albers 6 , B. Schumacher 6 , A. Erhardt 7 , K. Gutberlet 8 , A. Bielich 9 , D. Scholz 9 , M. Caselitz 10 , T. Frieling 11 , M. Breidert 12 , C. Rasch 13 , K. Fellermann 14 , K. Caca 2

1 Gastroenterology, Interdisciplinary Endoscopy, University of Freiburg, Freiburg/Germany

2 Klinikum Ludwigsburg, Ludwigsburg/Germany

3 Malteser Krankenhaus St. Anna, Duisburg/Germany

4 Klinikum Altenburgerland GmbH, Altenburg/Germany

5 Diankonie Krankenhaus Halle a.d. Saale, Halle/Germany

6 Elisabethkrankenhaus Essen, Essen/Germany

7 Petrus Krankenhaus Wuppertal, Wuppertal/Germany

8 St. Josef Stift Delmenhorst, Delmenhorst/Germany

9 Mathilden Hospital Herford, Herford/Germany

10 Donau-Isar Klinikum Deggendorf, Deggendorf/Germany

11 Internal Medicine, Krankenhaus Krefeld, Krefeld, Germany, Krefeld/Germany

12 Klinik Köchin, Kösching/Germany

13 Marienhospital Düsseldorf, Düsseldorf/Germany

14 UKSH Campus Lübeck, Lübeck/Germany

Contact E-mail Address: arthur.schmidt@gmx.de

Introduction: The Full-Thickness Resection Device (FTRD) is an over-the-scope system approved for endoscopic full-thickness resection (EFTR) in the lower GI tract. Small retrospective studies and a recent prospective study have shown good efficacy and acceptable safety of the device. We present the interim analysis of the German multicenter registry.

Aims & Methods: The prospective multicenter German online registry was designed to generate “real-life” data on efficacy and safety of the device. Data of patients (n = 250) which was entered by 31 German centers between 09/2015 and 10/2016 was analysed.

Results: 250 FTRD procedures were registered. Major indications for EFTR were non-lifting adenomas (49%), early carcinomas (23%), adenomas at the appencical orifice (7%) and subepithelial tumors (6%). 173/250 lesions (69%) were located in the colon and 77/250 (31%) were located in the rectum. Median lesion size was 20 × 15 mm. Median procedure time was 45 min (5−150 min). R0 resection rate was 79%. Adverse events were recorded in 20/250 (8%) of cases including 8 perforations (3.2%; 5/8 were due to wrong sequence of procedural steps) and 7 minor bleedings (2.8%). Follow-up was available from 200 cases, median follow up time was 10 weeks (0.5−77). Residual or recurrent lesions were observed in 12% of cases.

Conclusion: The preliminary results of this registry show good efficacy and safety of EFTR with the FTRD System. These “real-life” results are consistent with previous studies.

Disclosure of Interest: A. Schmidt received lecture fees and a study grant from ovesco endoscopy

K. Caca has recieved lecture fees and a study grant from ovesco endoscopy

All other authors have declared no conflicts of interest.

References

Schurr MO, Baur F, Ho C-N, et al. Endoluminal full-thickness resection of GI lesions: a new device and technique. Minim Invasive Ther Allied Technol . 2011; 20:189–92.

Schurr MO, Baur FE, Krautwald M, et al. Endoscopic full-thickness resection and clip defect closure in the colon with the new FTRD system: experimental study. Surg Endosc . 2015; 29:2434–41.

Schmidt A, Damm M, Caca K. Endoscopic full-thickness resection using a novel over-the-scope device. Gastroenterology . 2014; 147:740–2.e2.

Schmidt A, Bauerfeind P, Gubler C, et al. Endoscopic full-thickness resection in the colorectum with a novel over-the-scope device: first experience. Endoscopy 2015; 8:719–25.

OP051 MINIMISING THE RISK OF DELAYED BLEEDING IN COLONIC ENDOSCOPIC SUBMUCOSAL DISSECTION: IS THERE A ROLE FOR A NOVEL HAEMOSTATIC PEPTIDE?

S. Subramaniam 1 , K. Kandiah 1 , A. Fujimoto 2 , N. Yahagi 3 , T. Uraoka 4 , P. Bhandari 2

1 Gastroenterology, Queen Alexandra Hospital, Portsmouth/United Kingdom

2 Division Of Research And Development For Minimally Invasive Treatment, Cancer Center, Keio University, School of Medicine, Tokyo/Japan

3 Cancer Center, Keio University, School Of Medicine, Tokyo/Japan

4 Gastroenterology, National Hospital Organization Tokyo Medical Center, Tokyo/Japan

Contact E-mail Address: shar811@googlemail.com

Introduction: Endoscopic submucosal dissection (ESD) is now an established technique to treat precancerous and early cancerous lesions in the colon. Delayed bleeding is a well-recognised complication following colonic ESD that can occur in up to 5% of patients. The risk of bleeding may be increased depending on the lesion size, location, anticoagulant use, age and co-morbidities. The endoscopic management of delayed bleeding conventionally includes electrocautery of visible vessels although there has been growing interest in topical haemostatic products that can be applied over the ESD resection site. Purastat® is a novel extracellular scaffold matrix that gels upon blood contact for haemostasis. It is hypothesised that it can reduce the risk of delayed bleeding when applied prophylactically over the ESD resection base.

Aims & Methods: We aimed to compare the rate of delayed bleeding in a cohort of patients who had received prophylactic application of Purastat® following colonic ESD with a control group where no bleeding prophylaxis was used. Methods: Data on the lesion size, location, age, gender and delayed bleed rate was collected from a cohort of patients who had received Purastat® prophylactically and compared to a recent historic control group. A delayed bleed was defined as a significant bleed occurring after the completion of ESD necessitating further intervention, hospital readmission or blood transfusion.

Results: There were 76 patients in the Purastat® group compared to 202 in the control cohort. The table below shows the patient demographics, location and size of lesions as well as delayed bleeding rates in both groups.

Conclusion: This study has demonstrated that the rate of bleeding in colonic ESD was reduced by just over 50% in the group of patients receiving Purastat® prophylaxis. The risk of bleeding may be higher in large rectal lesions (>50 mm). The device was easy to use with complete coverage of the resection base achieved. Despite the limitation of this study with unmatched controls, the results do support its potential in reducing the risk of bleeding following colonic ESD. A prospective randomised controlled trial is required to evaluate its haemostatic efficacy in greater detail.

Disclosure of Interest: P. Bhandari: Receives research grant from 3D-Matrix

All other authors have declared no conflicts of interest.

OP052 ENEMA OF MESENCHYMAL STEM CELL CULTURE SUPERNATANT PREVENTS RECTAL STRICTURE FORMATION AFTER CIRCUMFERENTIAL ENDOSCOPIC SUBMUCOSAL DISSECTION IN PIGS

M. Tsuda 1 , S. Ohnishi 1 , T. Mizushima 1 , S. Abiko 1 , Y. Shimizu 2 , N. Sakamoto 1

1 Department Of Gastroenterology And Hepatology, Hokkaido University Graduate School of Medicine, Sapporo/Japan

2 Division Of Endoscopy, Hokkaido University Hospital, Sapporo/Japan

Contact E-mail Address: momoko0221tsuda@gmail.com

Introduction: Endoscopic submucosal dissection (ESD) for colorectal tumors has been widely accepted in the last decades as a minimally invasive treatment option with higher en bloc resections and a lower recurrence rate. Although stricture formation after ESD of large colorectal tumors has been reported, underlying mechanisms in developing stricture is not fully understood. Mesenchymal stem cells (MSCs) are a valuable cell source in regenerative medicine, and MSC culture supernatant (MSC-CS) has reportedly inhibited inflammation and fibrosis.

Aims & Methods: The aims of this study were to investigate whether circumferential ESD in the colorectum causes stricture formation, and to examine the effect of MSC-CS enema on post-ESD stricture. We performed circumferential ESD with 5 cm long axis in the rectum or distal colon in 20 kg pigs. We prepared MSC-CS gel by mixing MSC-CS with 5% carboxymethyl cellulose and administered into the rectum immediately after ESD from day 1 through day 4. We applied standard medium gel as a control group. We euthanized the pigs on day 22, measured the stricture rate, and performed histological analysis. The experimental protocol was approved by the Animal Care and Use Committee of Hokkaido University.

Results: Severe stricture was observed in the rectum but not distal colon (Stricture rate: 60.7 ± 16.8% versus 16.1 ± 12.6%, P < 0.01, n = 4 in each group). Moreover, extensive fibrosis and hypertrophy of the muscularis propria were observed in the rectum, but not distal colon. In addition, the numbers of infiltrated neutrophils and activated myofibroblasts were significantly higher in the rectum than in the distal colon. Rectal stricture rate was significantly lower in the MSC-CS group compared with control group on day 22 (14.7 ± 0.6% versus 63.9 ± 27.4%, P < 0.05, n = 3 in each group). Furthermore, MSC-CS significantly attenuated the numbers of infiltrated neutrophils and activated myofibroblasts as well as fiber accumulation on day 22.

Conclusion: Stricture after circumferential ESD was developed only in the rectum, and associated with the activation of myofibroblasts and fiber accumulation. In addition, MSC-CS enema prevented the stricture formation after circumferential ESD in the rectum by suppressing the infiltration of neutrophils and following myofibroblast activation and fibrosis. MSC-CS enema would be a promising treatment to prevent post-ESD stricture.

Disclosure of Interest: All authors have declared no conflicts of interest.

References

1. Ohara Y, Toyonaga T, Tanaka S, et al. Risk of stricture after endoscopic submucosal dissection for large rectal neoplasms. Endoscopy 2016;48:62–70.

2. Abe S, Sakamoto T, Takamaru H, et al. Stenosis rates after endoscopic submucosal dissection of large rectal tumors involving greater than three quarters of the luminal circumference. Surg Endosc 2016;30:5459–5464.

3. Mizushima T, Ohnishi S, Hosono H, et al. Oral administration of conditioned medium obtained from mesenchymal stem cell culture prevents subsequent stricture formation after esophageal submucosal dissection in pigs. Gastrointest Endosc 2017 (in press)

OP053 A NOVEL TEMPERATURE-RESPONSIVE, BIODEGRADABLE AND INJECTABLE COLLAGEN SOL FOR ENDOSCOPIC CLOSURE OF COLONIC PERFORATION HOLE: AN ANIMAL STUDY

T. Uraoka 1 , S. Kinoshita 2 , S. Yunoki 3 , T. Narita 3 , Y. Takatori 2 , H. Mori 2 , Y. Hirai 2 , S. Banno 2 , Y. Kubosawa 2 , Y. Sunata 2 , M. Shimoda 4 , N. Yahagi 1

1 Division Of Research And Development For Minimally Invasive Treatment, Cancer Center, Keio University, Tokyo/Japan

2 Gastroenterology, National Hospital Organization Tokyo Medical Center, Tokyo/Japan

3 Biotechnology Group, Tokyo Metropolitan Industrial Technology Research Institute, Tokyo/Japan

4 Department Of Pathology, Keio University, Tokyo/Japan

Contact E-mail Address: turaoka@a3.keio.jp

Introduction: Endoscopic submucosal dissection (ESD) can remove large size of early stage colorectal cancer en bloc; however, this procedure has a risk of intraprocedure perforation. Although an appropriate endoscopic closure using endoclipping is required, this technique is sometimes technically difficult. Recently, we have developed a biodegradable injectable collagen sol that forms liquid to gel formation in response to body temperature 1 .

Aims & Methods: The aim of this study was to determine the feasibility of this novel injectable collagen sol for endoscopic closure of iatrogenic perforation hole. The ethics committee of our institution approved the use of four living 25–30 kg female pigs under the general anesthesia in this experiment. An ESD knife with an electric current made a 3–5 mm perforation hole in the colon at 30 to 40 cm from the anal verge resulting in the collapse of the colonic lumen. We performed two studies using 12 and 5 perforation holes on 4 and 3 pigs, respectively. Study 1: At the beginning of the collapse of the colon due to perforation, the 1.4–1.6% neutral collagen sol containing 4 mM of genipin was delivered to the perforation hole using an endoscopic catheter. When the colon was expanded by CO 2 insufflation after one-minute pass, three endoclips were applied to the perforation area. Study 2: We only included the use of the collagen sol for endoscopic closure. Collagen sol which was adjusted based on the result of Study 1 was delivered to perforation holes in the same manner to Study 1. After confirming an expanded colon by CO 2 insufflation after one-minute pass, an endoscope was withdrawn. All pigs were euthanized immediately after clipping and an hour after endoscopic evaluation in Study 1 and 2, respectively. A leak test was performed for every colon and we also evaluated histology of all perforation sites.

Results: In both studies, collagen sol was smoothly delivered to the target area and fixed as a gel on perforation hole in response to body temperature. Study 1: Although collagen gel was not fixed on two perforation holes, ten of 12 perforation holes were completely closed and then all endoclips were placed with composure. There was no leak from the perforation hole. Study 2: An endoscope confirmed complete closure of the perforation holes with collagen gel in the all pigs. There was also no leak from the perforation hole. Histology revealed a fixation of collagen gel as a thrombus agent in the perforation hole.

Conclusion: A novel temperature-responsive, biodegradable and injectable collagen sol may be used for endoscopic closure of intraprocedure perforation. Further studies are necessary to determine the clinical feasibility and safety of this collagen sol.

Disclosure of Interest: All authors have declared no conflicts of interest.

Reference

1. Narita T, Yunoki S, Ohyabu Y, Yahagi N, Uraoka T. In situ gelation properties of a collagen-genipin sol with a potential for the treatment of gastrointestinal ulcers. Med Devices (Auckl) . 2016:15;9:429–39

MONDAY, OCTOBER 30, 201714:00-15:30

IMAGING AND ENDOSCOPY IN IBD - ROOM A1____________________

OP054 EARLY MUCOSAL HEALING IN PATIENTS WITH MODERATE TO SEVERE ULCERATIVE COLITIS TREATED WITH GOLIMUMAB PREDICTS FAVORABLE OUTCOMES: DATA FROM THE REAL-LIFE BE-SMART COHORT

P. Bossuyt 1 , F. Baert 2 , F. D’Heygere 3 , A. Nakad 4 , E. Louis 5 , F. Fontaine 6 , D. Franchimont 7 , O. Dewit 8 , P. Van Hootegem 9 , S. Vanden Branden 10 , G. Lambrecht 11 , M. Ferrante 12

1 Imelda General Hospital, Bonheiden/Belgium

2 AZ Delta, Roeselare/Belgium

3 Department Of Gastroenterology, AZ Groeninge, kortrijk/Belgium

4 Depatment Of Gastroenterology, CHWAPI, Tournai/Belgium

5 University Hospital CHU of Liège, Liège/Belgium

6 Department Of Gastroenterology, CHC Liege, Liege/Belgium

7 Free University of Brussels Erasme Hospital Dept. of Gastroenterology, Bruxelles/Belgium

8 UCL Saint Luc, Brussels/Belgium

9 Gastro-entero-hepatology, AZ Sint-Lucas Brugge, Brugge/Belgium

10 Department Of Gastroenterology, OLV Ziekenhuis Aalst, Aalst/Belgium

11 Department Of Gastroenterology, AZ Damiaan, Oostende/Belgium

12 Department Of Gastroenterology And Hepatology, University Hospitals Leuven, Leuven/Belgium

Contact E-mail Address: peter.bossuyt@imelda.be

Introduction: Golimumab (GOL) is registered for moderate to severe ulcerative colitis (UC). Data on the use of GOL in daily clinical practice are limited. Currently, it is unclear which factors are predictive for a favorable outcome.

Aims & Methods: The aim of the study is to evaluate the mid-term outcome of GOL in patients with moderate-to-severe UC and to determine predictors of favourable outcome. Patients included in the SMART study ( NCT02155335 ) were evaluated for their mid-term outcome. Demographic data, disease characteristics and medical history were recorded retrospectively. Data on disease activity based on total MAYO score, previous and concomitant medication, GOL dosing, mucosal healing (Mayo 0 or 1), adverse events (colectomy, hospitalization) and biomarkers (C-reactive protein, fecal calprotectin, hemoglobin and albumin) were collected at baseline, week 2, 6, 14, 26 and 52. The primary endpoint was steroid-free GOL continuation at week 26.

Results: Eight out of 100 patients from the SMART study had to be excluded (low baseline disease activity, misdiagnosis, loss of follow-up). From the 92 patients (42% female, median age 41 years, median disease duration 5 years) 4% were active smokers, 25% had extensive colitis, and 38% had an endoscopic Mayo score of 3 at baseline. The median (IQR) baseline Mayo score was 9 (8–10). While 76% of patients had previously failed immunomodulators (IMM), the majority (87%) were anti-tumor necrosis factor (TNF) naive. GOL was started in combination with IMM and steroids in 38% and 64%, respectively. The median (IQR) follow-up on GOL therapy was 36 (12–106) weeks. Twenty six weeks after GOL induction, 38 patients (41%) were steroid-free and still on GOL, of whom 6 required GOL dose optimization. Short-term mucosal healing (STMH) at week 14 could be evaluated in 52% of the patients and was achieved in half of them. In multivariate analysis, only concomitant systemic steroids (p = 0.044) were predictive of STMH. Patients with STMH more frequently achieved the primary endpoint [67% vs. 29%, OR 4.86 (95%CI 1.43–16.50), p = 0.011]. During a median (IQR) follow-up of 26 (23–30) months, 78% needed a therapeutic intervention and 63% discontinued GOL. STMH was significantly associated with intervention free survival (p = 0.030) and prolonged treatment of GOL (p = 0.002).

Conclusion: Real-life data confirm the effectiveness of GOL on the mid-term in moderate to severe UC, although therapeutic interventions are needed frequently. Short-term mucosal healing predicts a favorable outcome.

Disclosure of Interest: P. Bossuyt: has received educational grants from AbbVie; speaker fees from AbbVie, Takeda, and Vifor Pharma; and advisory board fees from Hospira, Janssen, MSD, Mundipharma, Roche, Pfizer, and Dr Falk Benelux

F. Baert: has received research grants from Abbvie, Chiesi, Ipsen, MSD, Roche, speakers and consultancy fees from Abbvie, Falk, Ferring, Janssen, Mundipharma, MSD, Pfizer, Takeda, Vifor

All other authors have declared no conflicts of interest.

OP055 PREDICTION OF CLINICAL OUTCOMES IN CROHN’S DISEASE BY USING CONFOCAL LASER ENDOMICROSCOPY: A PROSPECTIVE MULTICENTER STUDY

G.E. Tontini 1 , J. Mudter 2 , M. Vieth 3 , C. Günther 2 , V. Milani 4 , R. Atreya 5 , T. Rath 5 , A. Nägel 2 , G. Hatem 6 , G.C. Sturniolo 6 , M. Vecchi 1 , M.F. Neurath 2 , P. R. Galle 7 , A. Buda 8 , H. Neumann 9

1 Gastroenterology And Digestive Endoscopy Unit, IRCCS Policlinico San Donato, San Donato Milanese/Italy

2 Department Of Medicine I, University of Erlangen-Nürnberg, Erlangen/Germany

3 Abt. Pathologie, Klinikum Bayreuth Abt. Pathology, Bayreuth/Germany

4 IRCCS Policlinico San Donato, San Donato Milanese/Italy

5 Medical Department I, University Erlangen-Nuremberg, Erlangen/Germany

6 Department Of Surgical, Oncological, And Gastroenterological Sciences, University of Padua, Padua/Italy

7 First Medical Department, University Medical Center Mainz, Mainz/Germany

8 Gastroenterology And Digestive Endoscopy Unit, Ospedale di Feltre, Feltre/Italy

9 Universitätsmedizin Johannes Gutenberg University Mainz, Mainz/Germany

Contact E-mail Address: gianeugeniotontini@libero.it

Introduction: Emerging evidence clearly shows that the precise assessment of prognostic factors is of pivotal importance for early intervention and treat-to-target strategies in Crohn’s disease (CD) patients. Confocal Laser Endomicroscopy (CLE) is an advance endoscopic imaging technique that enables on demand in vivo characterization of mucosal architectural changes during ongoing endoscopy.

Aims & Methods: We prospectively assessed the value of CLE for the prediction of relevant clinical outcome parameters in CD. Patients undergoing colonoscopy for disease assessment were consecutively included in this multicentre study at two referral IBD units (Erlangen, Germany and Padua, Italy). CLE imaging focused on two highly reproducible histological hallmarks of colonic inflammation: focal cryptitis and crypt architectural abnormality [1]. We have evaluated whether CLE, CD endoscopic index of severity (CDEIS), serum C-reactive protein (CRP) and CD activity index (CDAI) were associated with the risk of medical treatment escalation, transmural complications, and CD-related hospitalisation or surgery during a four-year follow-up.

Results: Forty-nine patients (53% men, 39 years [IQR = 30–47years]) met the inclusion and exclusion criteria. Among them, the baseline (CRP) was ≥5 mg/L in 47%, CDEIS was ≥3 in 75%, and CDAI was >150 in 51%. Focal cryptitis and crypt architectural abnormality were observed in 63% of them (i.e., positive CLE group). Patients with positive CLE at baseline showed an increased incidence of medical treatment escalation ( P < 0.001, RR = 3.27) and transmural lesions ( P = 0.025, RR = 1.70), while patients with high level of CRP with CD-related hospitalisation and surgery ( P = 0.020, RR = 2.71) at one-year follow-up. No association was found over the one-year follow-up, and for CDEIS as well as CDAI at any time.

Conclusion: This prospective multicenter study confirms that CLE can reveal CD-related features of mucosal inflammation during ongoing endoscopy, threby predicting two higly reproducible histopathological hallmarks of active large-bowel mucosal inflammation. In addition, the CLE assessment allows for early prediction of relevant clinical outcomes related to CD such as the need for treatment escalation and the risk of transmural complications at one-year follow-up. Further studies should now address whether this promising prognostic tool could refine the timing of treatment strategies in patients suffering from CD.

Disclosure of Interest: All authors have declared no conflicts of interest.

Reference

1. Tontini GE, Mudter J, Vieth M, et al. Confocal laser endomicroscopy for the differential diagnosis of ulcerative colitis and Crohn's disease: a pilot study. Endoscopy 2015;47(5):437–43.

OP056 HISTOLOGICAL PREDICTORS OF RELAPSE IN ULCERATIVE COLITIS: WHICH FEATURES MATTER MOST?

B. Gonzalez Suarez 1 , E. U. Yee 2 , T. Zenlea 1 , L. Rosenberg 1 , K.S. Nande 1 , J. D. Goldsmith 2 , A. C. Moss 1

1 Gastroenterology Department, Center for Inflammatory Bowel Disease, Beth Israel Deaconess Medical Center, Boston/United States of America/MA

2 Department Of Pathology, Beth Israel Deaconess Medical Center, Boston/United States of America/MA

Contact E-mail Address: bgonzals@clinic.ub.es

Introduction: Histological scores used in Ulcerative Colitis (UC) contain many morphological features. The comparative association of the individual score components with clinical relapse has not been validated to date. Our goal was to compare components of the Geboes Scale and their association with clinical relapse over 12 months.

Aims & Methods: Patients with UC in clinical and endoscopic remission (Mayo score < 1) had their Geboes Scale determined at baseline by an experienced GI pathologist. They were then prospectively followed after colonoscopy and relapse was evaluated 12 months later. We categorized Geboes Scale as a continuous variable to generate a ROC Curve and establish a cut-off point predictive for relapse.

Results: We included 89 patients in clinical and endoscopic remission. Biopsies on the Geboes Scale were scored >3.1 in 29% of subjects at enrollment. Fourteen patients (16%) developed relapse after 12 months of follow-up. All individual components of the Geboes Scale were significantly associated with relapse, except the presence of eosinophils, in univariate analysis. However, in a multivariate analysis, only the presence of crypt destruction was an independent predictive factor for relapse (p < 0.00001). Using the Geboes Scale to generate an ROC curve, the AUC was 0.73, and the optimal sensitivity and specificity (71% and 68%) for clinical relapse over 12 months was at a cutoff of 1.2 (5.5 when converted to a continuous scale).

Conclusion: Most components of the Geboes Scale associate with risk of clinical relapse, but only crypt destruction is independently associated with this outcome. This may allow development of more simple histological scores of prognostic importance.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP057 DEVELOPMENT AND VALIDATION OF THE “MINI INDEX” (MUCOSAL INFLAMMATION -NON INVASIVE INDEX) FOR CROHN’S DISEASE ON A LARGE PROSPECTIVE PEDIATRIC COHORT

A. Ben Shoham 1 , M. A. Cozijnsen 2 , B. Kang 3 , B. Choe 3 , Y.H. Choe 4 , R. K. Russell 5 , F. M. Ruemmele 6 , J. C. Escher 2 , L. De Ridder 2 , S. Koletzko 7 , J. Martin De Carpi 8 , J. S. Hyams 9 , T. D. Walters 10 , A. M. Griffiths 10 , D. Turner 1

1 Shaare Zedek Medical Center, Jerusalem/Israel

2 Erasmus, Rotterdam/Netherlands

3 Kyungpook, Seoul/Korea, Democratic People's Republic of

4 Samsung, Seoul/Korea, Democratic People's Republic of

5 Royal Hospital, Glasgow/United Kingdom

6 Hôpital Necker, Paris/France

7 Dr. von Hauner Children’s Hospital, München/Germany

8 Hospital Sant Joan de Déu, Barcelona/Spain

9 Connecticut Children’s Medical Center, Hartford, United States of America/CT

10 SickKids, Toronto/Canada/ON

Contact E-mail Address: turnerd@szmc.org.il

Introduction: Mucosal healing (MH) has become an important therapeutic goal in Crohn’s disease (CD). Repeated assessments by ileocolonoscopy are less feasible, especially in children. The Pediatric Crohn’s Disease Activity Index (PCDAI) does not correlate well with mucosal inflammation. We aimed to develop and validate a multi-item index, based on clinical and laboratory parameters, which could reflect MH in clinical trials as well as for clinical practice.

Aims & Methods: This study utilized data from the prospective ImageKids study where children with CD underwent ileocolonoscopy concurrent with recording of explicit clinical and laboratory data, including fecal calprotectin (FC), at disease onset or thereafter. PCDAI items, laboratory tests and FC, were associated with the Simple Endoscopic Score for CD (SESCD) in a multivariate analysis and validated on an independent prospective cohort from Korea of children whose workup included ileocolonoscopy, clinical and lab assessment and FC. We employed a blended clinimetric judgmental and psychometric mathematical approach.

Results: The derivation and validation cohorts included 154 and 86 children, respectively (n = 240; age 14.6 ± 2.6 years; SES-CD 7.8 ± 8.2), of whom 24 (16%) and 56 (65%) had MH (i.e. SESCD < 3), respectively. In a multivariate regression analysis, the stool and weight items of the PCDAI, ESR and FC were associated with SESCD (all p < 0.05). Judgmentally, we removed the weight item and included CRP, to form a weighted categorized MINI index (Table). In the validation cohort the sensitivity, specificity, PPV and NPV of the MINI to reflect MH using a cutoff of <8 was 91%, 67%, 84% and 80% (AUROC curve 0.90 (95%CI 0.84–0.96)). In the entire cohort (n = 216) the correlation between MINI and SESCD was r = 0.783 (p < 0.001).

Conclusion: In children with ileocolonic CD, the MINI-index can reflect MH with a good accuracy. The likelihood of MH with a MINI<8 points is 84%.

Disclosure of Interest: B. Kang: received speaker’s fees, travel support and participated in medical board meetings with Celltrion, Eisai, Janssen, and Antrogen

B. Choe: received speaker’s fees, travel support and participated in medical board meetings with Celltrion, Eisai, Janssen, and Antrogen

Y.H. Choe: received speaker’s fees, travel support and participated in medical board meetings with Celltrion, Eisai, Janssen, and Antrogen

R.K. Russell: speaker’s fees, travel support, and participated in medical board meetings with Abbvie, Janssen, Shire, Celltrion, NAPP and, Nestle

F.M. Ruemmele: speaker’s fees, travel support, honorarium for scientific advisory board or research support from Shire, Jannssen Biologics, AbbVie, MSD, Celgene, TAKEDA, Nestlé Nutrition, Danone

L. de Ridder: speaker’s fees and participated in medical board meetings with Shire, Merck, Janssen biologics, Abbvie and Pfizer (former Hospira)

S. Koletzko: received speaker’s fees and honorarium for scientific advisory board from h Shire, Merck, Janssen biologics, Abbvie, Nestle Nutrition, Danone and R-Biopharm

J. Martin de Carpi: received speaker’s fees, travel support, and participated in medical board meetings with Abbvie, MSD, Celltrion, Otsuka, and, Nestle

D. Turner: Last 3 years DT received consultation fee, research grant, royalties, or honorarium from Janssen, Pfizer, Hospital for Sick Children, Ferring, MegaPharm, AstraZeneca, Abbvie, Takeda, Rafa, Boehringer Ingelheim, Biogen, Atlantic Health, Shire

All other authors have declared no conflicts of interest.

OP058 LITTLE BENEFIT OF ENDOSCOPIC-BASED THERAPEUTIC MANAGEMENT IN POSTOPERATIVE RECURRENT CROHN'S DISEASE: RESULTS OF A RETROSPECTIVE STUDY

P. Rivière 1 , S. Vermeire 2 , G. Van Assche 2 , P. Rutgeerts 2 , A. De Buck Van Overstraeten 3 , A. Wolthuis 3 , A. D'Hoore 3 , M. Ferrante 2

1 Gastroenterology, Bordeaux University Hospital, Bordeaux/France

2 Department of Gastroenterology, University Hospitals Leuven, Leuven/Belgium

3 Abdominal Surgery, University Hospitals Leuven, Leuven/Belgium

Contact E-mail Address: riviere.paulin@gmail.com

Introduction: The Rutgeerts’ score (RS) is widely used to guide post-operative management of patients with Crohn’s disease (CD) undergoing a resection with ileo-colonic anastomosis. The modified RS differentiates lesions at the anastomosis with or without <5 isolated neo-terminal ileal erosions (i2a) from presence of ≥5 isolated neo-terminal ileal erosions with or without anastomotic lesions (i2b), but its clinical relevance has not been validated.

Aims & Methods: We investigated if clinical relapse (CR) and need for endoscopic dilatation (ED) or new surgical intervention (NSI) differ between i2a and i2b endoscopic recurrence (ER). Our secondary objective was to evaluate the effect of therapy modification based on endoscopic findings in patients with an i2a or i2b RS, or a RS > = i3. This was a single-center retrospective study, including all patients operated between 2000 and 2013 with a colonoscopy <12 months after ileo-colonic anastomosis and >3 years of follow-up after endoscopy. The modified RS was attributed based on the available endoscopic report and images. CR was defined as the occurrence of CD related symptoms along with objective signs of disease activity. Kaplan-Meier curves were plotted for time from index endoscopy to CR, ED and NSI and compared through Log rank tests.

Results: The study population consisted of 296 patients [123 males, median age 40 years]. At index endoscopy, 61 patients (20.6%) had a RS i0, 24 (8.1%) i1, 81 (27.4%) i2a, 69 (23.3%) i2b, 35 (11.8%) i3 and 26 (8.8%) i4. Medical treatment was optimized according to index colonoscopy in 4 (4.7%) patients with i0/i1 and 88 (41.7%) with > = i2a [Odds ratio 11.0 (95%CI 5.6–24.4), p < 0.001]. During a median (IQR) follow-up of 76 (48–113) months, CR, ED and NSI were observed in 150 (50.7%), 51 (17.2%) and 36 (12.2%) patients, respectively. Patients with i2a and i2b had a similar risk for CR, ED or NSI (Log Rank p = 0.19, p = 0.10 and p = 0.30, respectively). Also after exclusion of patients with immediate post-endoscopy treatment optimization, i2a and i2b scores were not predictive (Log Rank p = 0.22, p = 0.21 and p = 0.41, respectively). Probability of CR was higher in patients with an i3 or i4 compared to the others (Log Rank p < 0.001). A RS > = i2a [1.62 (1.06–2.50), p = 0.03], active smoking at endoscopy [1.61 (1.08–2.39), p = 0.02] and CRP >5 mg/l at endoscopy [1.76 (1.17–2.65), p = 0.01] were associated with CR during the follow-up in patients without clinical relapse at endoscopy. In patients with a RS = i2, initiation of an immunosuppressant or biological therapy after endoscopy was not associated with a different outcome in terms of CR or NSI (p = 0.59 and p = 0.66, respectively). Only a modest benefit in terms of CR was observed for patients with a RS = i3 or i4 when an immunosuppressant or biological therapy was introduced after endoscopy (p = 0.03), but the risk of NSI was not influenced (p = 0.14).

Conclusion: No difference was observed in terms of clinical relapse and need for endoscopic/surgical intervention between patients with i2a or i2b endoscopic recurrence after ileo-colonic resection with ileo-colonic anastomosis. In patients with a RS = i2, no effect on probability of clinical relapse or need for a new surgery was observed when an immunosuppressant or a biological treatment were initiated after the index endoscopy. Despite intensification of therapy based on endoscopic findings, outcomes of i3 and i4 patients remain poor in our cohort.

Disclosure of Interest: S. Vermeire: AbbVie, MSD, Takeda, Ferring, Dr. Falk Pharma, Hospira, Pfizer Inc, Tillots, Genentech/Roche, Shire, Galapagos, Mundipharma, Hospira, Celgene, Second Genome and Janssen

G. Van Assche: Abbvie, MSD, Ferring, Janssen, Takeda

P. Rutgeerts: Centocor, Merck, UCB, Abbvie, Millenium/Takeda, Genentech/Hoffman LaRoche, Merck/Serono, Bristol Myers Squibb, Robarts, Tillotts, Pfizer, Falk Pharma

M. Ferrante: Takeda, Abbvie, Boehringer-Ingelheim, Chiesi, Falk, Ferring, Janssen, Mitsubishi Tanabe, MSD, Tillotts, Zeria

All other authors have declared no conflicts of interest.

OP059 TOFACITINIB FOR MAINTENANCE THERAPY IN PATIENTS WITH ACTIVE ULCERATIVE COLITIS IN THE PHASE 3 OCTAVE SUSTAIN TRIAL: RESULTS BY LOCAL AND CENTRAL ENDOSCOPIC ASSESSMENTS

B. G. Feagan 1 , S. Vermeire 2 , W. J. Sandborn 3 , W. Reinisch 4 , J. Panés 5 , D. Tarabar 6 , C. Su 7 , W. Niezychowski 7 , H. Zhang 7 , G. Friedman 7 , D. Woodworth 7 , B.E. Sands 8

1 Robarts Research Institute, Western University, London/Canada/ON

2 Department Of Gastroenterology, University Hospitals Leuven, Leuven/Belgium

3 Division Of Gastroenterology, University of California, La Jolla, San Diego/United States of America/CA

4 Division Of Gastroenterology, McMaster University, Hamilton/Canada/ON

5 Hospital Clinic de Barcelona, IDIBAPS, CIBERehd, Barcelona/Spain

6 Clinic For Gastroenterology And Hepatology, Military Medical Academy, Belgrade/Serbia

7 Pfizer Inc, Collegeville/United States of America/PA

8 Dr. Henry D. Janowitz Division Of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York/United States of America/NY

Contact E-mail Address: brian.feagan@robartsinc.com

Introduction: Tofacitinib is an oral, small molecule Janus kinase inhibitor that is being investigated for ulcerative colitis (UC). A Phase 3, randomised, double-blind, placebo-controlled maintenance study (OCTAVE Sustain, NCT01458574 ) demonstrated the efficacy of tofacitinib 5 and 10 mg twice daily (BID) vs placebo in patients (pts) with moderate to severe UC.

Aims & Methods: We describe the clinical efficacy endpoints assessed by local endoscopy readings and previously reported results assessed by central readings. Pts who completed one of two studies (OCTAVE Induction 1, NCT01465763 ; OCTAVE Induction 2, NCT01458951 ) and achieved clinical response were eligible to participate in OCTAVE Sustain. Clinical response was defined by a decrease from induction study baseline in Mayo score of ≥3 points and ≥30%, with an accompanying decrease in rectal bleeding subscore ≥1 or an absolute rectal bleeding subscore ≤1. 593 pts were randomised (1:1:1) to receive placebo, tofacitinib 5 or 10 mg BID for 53 weeks (wks) in OCTAVE Sustain. Pts’ eligibility was assessed based on central endoscopic reading. Pts entering OCTAVE Sustain were permitted concomitant treatment with oral corticosteroids, although tapering was mandatory from study baseline. Concomitant treatment with immunosuppressants and biologics was prohibited. Efficacy endpoints assessed at Wk 52 included remission (primary endpoint: Mayo score ≤2, no individual subscore >1 and rectal bleeding subscore of 0), mucosal healing (Mayo endoscopic subscore ≤1) and clinical response.

Results: At Wk 52, remission was achieved by significantly more pts treated with tofacitinib 5 or 10 mg BID compared with placebo, as demonstrated by both central and local endoscopic readings (Table). Similar results were observed at Wk 52 with mucosal healing, clinical response and sustained, steroid-free remission among pts in remission at baseline. Efficacy assessed by local endoscopic readings was numerically greater than central readings, except for clinical response. There was good agreement between locally and centrally read endoscopic subscores (kappa = 0.6 [95% CI 0.5, 0.6]).

Conclusion: Efficacy assessed by local endoscopic readings was numerically greater than efficacy assessed by central readings for tofacitinib 5 and 10 mg BID compared to placebo. Overall, local endoscopic readings were consistent with central readings. Both methods demonstrated that tofacitinib 5 and 10 mg BID were both more effective than placebo for maintenance therapy in pts with moderately to severely active UC.

Disclosure of Interest: B.G. Feagan: Grant support/ Consultancy/ Advisory/member boards: Pfizer Inc.

S. Vermeire: Grant support/Speaker Fees/Consultancy: AbbVie, MSD, Takeda. Speaker fees: Ferring, Dr Falk Pharma, Hospira, Tillots. Consultancy: Ferring, Genentech/Roche, Shire, Pfizer Inc, Galapagos, Mundipharma, Hospira, Celgene, Second Genome, Janssen.

W.J. Sandborn: Grant support, personal fees and non-financial support: Pfizer Inc

W. Reinisch: Consultancy and Advisory board member: Pfizer Inc

J. Panés: Consulting fees from Pfizer Inc

C. Su: Personal fees: Boehringer Ingelheim, Salix, Luitpold, Shire, Lilly, TiGenix, Immune, Arena, Akros Pharma, Forward, Theravance, Receptos, Vedanta Biosciences, Synergy, Topivert.

W. Niezychowski: Employee and shareholder of Pfizer Inc

H. Zhang: Employee and shareholder of Pfizer Inc

G. Friedman: Employee and shareholder of Pfizer Inc

D. Woodworth: Employee and shareholder of Pfizer Inc

B.E. Sands: Grant support/personal fees: Amgen, AZ, Celgene, Millennium, Pfizer Prometheus, AbbVie, Takeda, Janssen, BMS, Boehringer, Salix, Luitpold, Shire, Lilly, TiGenix, Immune, Arena, Akros, Forward, Theravance, Receptos, Vedanta, Synergy, Topivert

All other authors have declared no conflicts of interest.

MONDAY, OCTOBER 30, 201714:00-15:30

CELIAC DISEASE AND WHEAT-RELATED DISORDER - ROOM B2____________________

OP060 GLUTEN INGESTION AND INTRADERMAL INJECTION OF PEPTIDES THAT ACTIVATE GLUTEN-SPECIFIC CD4+ T CELLS ELICIT A CYTOKINE SIGNATURE DOMINATED BY INTERLEUKIN-2 IN CELIAC DISEASE

J. A. Tye-Din 1 , J. J. Dzuris 2 , A. K. Russell 1 , S. Wang 2 , K. E. Goldstein 2 , L. J. Williams 2 , R. P. Anderson 2

1 Walter and Eliza Hall Institute, Parkville/Australia

2 ImmusanT, Cambridge/United States of America

Contact E-mail Address: bob@immusant.com

Introduction: The explanation for symptoms experienced by celiac disease (CeD) patients within hours of gluten ingestion has puzzled researchers because the early onset seems incompatible with a T-cell mediated (delayed hypersensitivity) effect. We hypothesized the role for gluten-specific CD4+ T cells in gluten-responsive symptoms could be tested by comparing acute immune effects of ingesting gluten with intradermal injection of Nexvax2®, an experimental adjuvant-free therapeutic vaccine that is a mixture of three short peptides including immunodominant epitopes for gluten-specific CD4+ T cells.

Aims & Methods: To assess changes in circulating cytokines in CeD volunteers on GFD after eating gluten or after intradermal administration of Nexvax2. Methods: A time course assessment of 19 cytokines and chemokines in plasma and sera from adult HLA-DQ2.5+ CeD volunteers on a GFD were compared from two separate studies. The first was a double-blind, placebo-controlled food challenge (DBPCFC) with ∼3 g wheat gluten flour compared to a matched gluten-free drink over 10 min. The second study was a double-blind, placebo-controlled phase 1 clinical trial of Nexvax2 (Goel et al. Lancet Gastro Hepatol 2017) with plasma assessed after the first dose of Nexvax2 150 mg or normal saline i.d. in 0.1 mL. Chemokines (eotaxin, MIP-1β, eotaxin-3, TARC, IP-10, MIP-1α, MCP-1, MDC, MCP-4) and cytokines (IFN-γ, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, TNF-α) were measured by the Meso Scale Discovery multiplex ELISA platform.

Results: Cytokine and chemokine assessments were performed in 19 subjects after DBPCFC (11 administered gluten, & 8 non-gluten), and in 14 subjects in the final “biopsy” cohort of the phase 1 study of Nexvax2 (7 administered Nexvax2, & 7 placebo). In the first 5 subjects after gluten ingestion, hourly profiling indicated IL-2 elevation from 2 h (median 5-fold rise compared to predose, range 1.1–117) and plateauing between 3 to 5 h (median maximal fold-change 21, range 2.6–94). Median fold increase in IL-8 was between 1.8 and 2.4 from 3 to 6 h (median maximal fold-change 2.5, range 1.3–28). Median fold increases were less than 2 for other cytokines and chemokines for all time points. Overall, serum assessed from before, and at 4 and 6 h showed median IL-2 fold change of 15 at 4 h after gluten (range: 1.9–39, n = 11) compared to 1.0 for non-gluten (0.5–1.6, n = 8; p < 0.0001 Mann Whitney). For IL-8, median fold change at 4 h after gluten was 2.4 (range: 1.0–8.4, n = 11) compared to 1.1 for placebo (0.7–1.3, n = 8; p = 0.012 Mann Whitney). Apart from IL-2 at 6 h, no other cytokines or chemokines showed median elevation above 2-fold at any time points after gluten ingestion. After Nexvax2, median fold changes at 2, 4 and 6 h post-dose in IL-2 were 14 (range: 1.3–68), 127 (range: 2.1–915), and 70 (range: 1.6–396), and in IL-8 were 1.6 (range: 0.9–2.8), 11 (range: 2.1–28), and 5.3 (range: 2.0–12). Weaker median fold rises of at least 2 were observed after Nexvax2 but not placebo in MCP-1, IL-1β, IL-10, IFN-γ, MIP-1β, IP-10, IL-4, eotaxin, and TNFα.

Conclusion: Il-2, a T-cell specific cytokine, dominates the cytokine signature present between 2–6 h after gluten ingestion or intradermal administration of Nexvax2. These findings suggest ingestion of gluten or injection of peptides activate T cells rapidly, and could account for symptoms triggered by gluten.

Disclosure of Interest: J.A. Tye-Din: JAT-D is coinventor of patents relating to treatment and diagnosis of coeliac disease, and shareholder in Nexpep Pty Ltd.

J.J. Dzuris: JJD is an employee of ImmusanT, Inc

S. Wang: SW is an employee of ImmusanT, Inc.

K.E. Goldstein: KEA is an imployee of ImmusanT, Inc

L.J. Williams: LJW is an employee and shareholder in ImusanT, Inc.

R.P. Anderson: RPA is employed by and sharholder of ImmusanT, a shareholder in Nexpep Pty Ltd, and is coinventor of patents relating to treatment and diagnosis of celiac disease

All other authors have declared no conflicts of interest.

Reference

1. Goel G., King T., Daveson A.J., Andrews J.M., Krishnarajah J., et al., Epitope-specific immunotherapy targeting CD4-positive T cells in coeliac disease: two randomised, double-blind, placebo-controlled phase 1 studies. Lancet Gastro Hepatol 2017 in press

OP061 BACTERIAL MODULATION OF INTESTINAL INNATE ACTIVATION INDUCED BY WHEAT AMYLASE TRYPSIN INHIBITORS (ATIS) IN NOD-DQ8 MICE

V.F. Zevallos 1 , J. McCarville 2 , A. Caminero 2 , E. Verdu 2 , D. Schuppan 1

1 Institute Of Translational Immunology, University of Mainz, Mainz/Germany

2 Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton/Canada/ON

Contact E-mail Address: zevallos@uni-mainz.de

Introduction: Wheat alpha-amylase/trypsin inhibitors (ATIs) are nutritional activators of intestinal innate immunity via the toll like receptor 4 (TLR4)-MD2-CD14 complex in myeloid cells. We have observed that wheat ATIs enhance innate immune responses towards gluten in a host at risk, such as SPF NOD-DQ8 mice.

Aims & Methods: The aim of the study was to screen, identify and test bacterial strains with a capacity to degrade ATIs and therefore reduce their immune stimulatory activity in-vitro and in-vivo. Supernatants of a large group of intestinal bacterial species were incubated with ATI and degradation was monitored using Western blotting with polyclonal antibodies against the most prevalent ATI subtypes (CM3 and 0.19). The in vivo effects of two groups of bacteria with low and high ATI degrading capacities were assessed in by concomitant gavage with a single dose of ATIs in NOD-DQ8 mice on a gluten-free diet after 6 h.

Results: We identified commensal bacteria in vitro that have the capacity to degrade the main ATI subtypes. When the ATI-degrading bioactivity of those bacterial strains was tested in mice gavaged with ATIs, the bacteria combined or individually significantly reduced intestinal expression of TLR4-dependent proinflammatory cytokines and chemokines, and serum levels of IL-6 when compared to mice that received the ATIs without the bacteria. Data were confirmed in myeloid cell cultures in vivo that were exposed to bacterial or control supernatants of ATIs with and without prior depletion of potential traits of LPS.

Conclusion: Some Lactobacillus strains have the capacity to modulate the innate inflammatory effects of ATIs in vitro and in vivo. Since wheat-ATIs are implicated in the pathogenesis of celiac disease as well as non-celiac wheat sensitivity (NCWS), including the modulation of autoimmunity, therapeutic intestinal colonization with ATI degrading bacteria may be an attractive therapeutic target.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP062 HLA-DQ:GLUTEN TETRAMER TEST IN BLOOD GIVES BETTER DETECTION OF CELIAC PATIENTS THAN BIOPSY AFTER 14-DAY GLUTEN CHALLENGE

V.K. Sarna 1 , G.I. Skodje 2 , H. M. Reims 3 , L. F. Risnes 4 , S. Dahal-Koirala 4 , L. Sollid 4 , K.E. A. Lundin 5

1 Immunology And Transfusion Medicine, Oslo University Hospital, Oslo/Norway

2 Nutrition, Oslo University Hospital, Oslo/Norway

3 Pathology, Oslo University Hospital, Oslo/Norway

4 Centre For Immune Regulation, Oslo University Hospital and University of Oslo, Oslo/Norway

5 Gastroenterology, Oslo University Hospital, Oslo/Norway

Contact E-mail Address: v.sarna@hotmail.com

Introduction: Initiation of a gluten-free diet without proper diagnostic work-up of coeliac disease is a frequent and demanding problem. Recent guidelines suggest a gluten challenge of at least 14 days followed by duodenal biopsy to establish a diagnosis in such patients. The rate of false negative outcome of this approach remains unclear. We aimed to study responses to 14-day gluten challenge in subjects with treated coeliac disease.

Aims & Methods: We challenged 20 subjects with biopsy-verified coeliac disease, all in confirmed mucosal remission, for 14 days with 5.7 g per oral gluten daily. Duodenal biopsies were collected. Blood was analyzed by flow cytometry using HLA-DQ:gluten tetramers, and by multiplex assay for cytokine detection.

Results: Nineteen participants completed the challenge. Villous blunting appeared at end of challenge in five of 19 subjects. Villous height to crypt depth ratio reduced with at least 0.4 concomitantly with an increase in intraepithelial lymphocyte count of at least 50% in nine of 19 subjects. IL-8 concentration increased by more than 100% after four hours in seven of 19 subjects. Number of blood CD4 + effector-memory gut-homing HLA-DQ:gluten tetramer-binding T cells increased by more than 100% on day 6 in 12 of 15 evaluated participants.

Conclusion: A 14-day gluten challenge is not enough to trigger significant mucosal architectural changes in majority of coeliac disease patients (sensitivity ≈ 25 – 50%). Increase in CD4 + effector-memory gut-homing HLA-DQ:gluten tetramer-binding T cells in blood six days after gluten challenge is a more sensitive and less invasive biomarker that should be validated in a larger study. Registered at www.clinicaltrials.gov ( NCT02464150 ).

Disclosure of Interest: All authors have declared no conflicts of interest.

OP063 RAPID HOME TESTS THAT REVEAL GLUTEN-FREE DIET TRANSGRESSIONS

A. Rodriguez-Herrera 1 , R. Domínguez-Flores 2 , C. Sousa 3 , A. Muñoz-Suano 4 , M. Arévalo-Rodríguez 2 , F. León 5 , A. Cebolla 4

1 Gastroenterology And Nutrition, Instituto Hispalense Pediatria, Sevilla/Spain

2 Biomedal S.L., Sevilla/Spain

3 Departamento de Microbiología y Parasitología, Facultad de Farmacia, Universidad de Sevilla, Sevilla/Spain

4 Biomedal, Sevilla/Spain

5 Celimmune LLC, Bethesda/United States of America

Contact E-mail Address: alfonsorodriguez@ihppediatria.com

Introduction: To date, the only effective management of celiac disease is the adherence to a strict, lifelong gluten-free diet (GFD). However, there has been no reliable method to confirm adherence to a GFD or to ascertain whether the origin of acute symptoms in a celiac or gluten-sensitive patient may be related to gluten exposure. There is poor or no correlation of celiac serology and dietary questionnaires with gut mucosa recovery. To address this need, we recently developed laboratory tests to detect gluten immunogenic peptides (GIP) in faeces and urine, excreted after gluten consumption. Our studies demonstrated that 31–60% of adult celiac patients following a GFD have GIP in either faecal or urine samples. Additionally, there was a high correlation between GIP detection and gut mucosal damage [references 1 and 2]. To facilitate the self-monitoring of the GFD by consumers, we have adapted the method to be directly used at home.

Aims & Methods: Our goal was to develop and validate a novel, rapid, domestic test for the monitoring of GFD adherence, which will enable celiac patients and other subjects avoiding gluten to detect GIP in faecal and urine samples by means of a lateral flow immunoassay (LFIA). A total of 233 faecal samples (75 GIP positive (+) and 158 GIP negative (-) according to the reference ELISA method), were analyzed by the LFIA method. In addition, 290 urine samples from volunteers under different gluten exposure conditions were analyzed with the LFIA. The urine samples included positive samples from healthy volunteers who had ingested gluten 16 hours before urine collection (n = 110), and negative samples from celiac patients on a reportedly strict gluten-free diet (n = 180).

Results: For the faecal home test, 74 out of 75 GIP(+) samples were correctly detected as positives with the LFIA. Of the 158 GIP(-) samples, 151 were correctly classified as negative by the LFIA. These results thus indicated a diagnostic sensitivity of 99% and a diagnostic specificity of 96% for the home test versus the reference laboratory method. The positive predictive value of the home test method for faecal samples was of 91% and the negative predictive value was 99%. In urine, GIP were detected by the LFIA in 100 out of 110 samples of volunteers on a gluten-containing diet. No GIP were detected in 179 out of 180 samples from celiac patients on a GFD. The diagnostic sensitivity and specificity for the urine LFIA were thus 91% and 99% respectively. The positive predictive value for the urine home test was 99% and the negative predictive value was 95%.

Conclusion: The point-of-care/home tests for GIP detection in feces and urine are highly sensitive and specific to assess adherence to GFD and to detect dietary transgressions, with superior performance over other methods. These tests will enable monitoring of the GFD to subjects avoiding gluten, including celiac patients.

Disclosure of Interest: A. Rodriguez-Herrera: The urine method of this manuscript was included in a patent application and I am one of its inventors.

R. Domínguez-Flores: Employee of Biomedal S.L.

C. Sousa: The stool and urine methods of this manuscript have been included in patent applications and I am one of the inventors.

A. Muñoz-Suano: Employee of Biomedal S.L.

M. Arévalo-Rodríguez: Employee at Biomedal S.L.

F. León: I am a Biomdal's shareholder.

A. Cebolla: I am a employee at Biomedal S.L. and a company's shareholder. The stool and urine methods of this manuscript have been included in patent applications and I am one of the inventors.

References

1. Comino I, et al. Fecal Gluten Peptides Reveal Limitations of Serological Tests and Food Questionnaires for Monitoring Gluten-Free Diet in Celiac Disease Patients. Am J. Gastroenterol . 2016;111:1456–1465.

2. Moreno MDL, Cebolla Á, Muñoz-Suano A, et al. Detection of gluten immunogenic peptides in the urine of patients with coeliac disease reveals transgressions in the gluten-free diet and incomplete mucosal healing Gut 2017;66:250–257.

OP064 ‘CELIAC-LITE SCORE’: A PREDICTIVE SCORE OF RESPONSE TO A GLUTEN-FREE DIET IN PATIENTS WITH LYMPHOCYTIC ENTERITIS AND SUSPICION OF COELIAC DISEASE

F. Fernández-Bañares 1 , A. Carrasco 1 , M. Rosinach 1 , B. Arau 1 , R. García-Puig 2 , C. González 3 , Y. Zabana 1 , M. Esteve 1

1 Gastroenterology, Hospital Universitari Mutua de Tarrassa, Terrassa/Spain

2 Pediatrics, Hospital Universitari Mutua de Tarrassa, Terrassa/Spain

3 Pathology, Hospital Universitari Mutua de Tarrassa, Terrassa/Spain

Contact E-mail Address: ffbanares@mutuaterrassa.es

Introduction: The criteria to diagnose patients with lymphocytic enteritis as coeliac disease (CD) are not well established. Increase in gammadelta+ intraepithelial lymphocytes (IEL) has been suggested as a permanent marker of CD (1, 2). The IEL normal cut-off level is not well known, and we have observed that 30% of patients evaluated for suspected CD, irrespective of the number of IEL, had increased gammadelta+ IEL.

Aims & Methods: Aim: 1) To assess predictive variables of response to a GFD in patients with lymphocytic enteritis and suspicion of CD; 2) To develop a score for diagnosing CD with low-grade enteropathy (coeliac-lite). Methods: From 2010 to 2016 all patients in whom duodenal biopsies were taken to rule out CD were prospectively registered. The inclusion criteria for the present study were: 1) Duodenal biopsies performed on a normal diet; 2) Absence of villous atrophy; 3) Starting with a GFD; 4) Having a follow-up biopsy. Patients were excluded if they were taking NSAID or ARA2 drugs, if they had H. pylori or parasitic infection or in case of clinical but not histological response to GFD (since these patients could not be correctly classified). All included patients had clinical symptoms in the spectrum of CD and HLA-2.5/8+ or at least one allele of the DQ2.5 haplotype. Standard histological studies and IEL flow cytometry (gamma delta+ and CD3- IEL) on duodenal samples were routinely performed. In patients with sustained clinical response to a GFD, a follow-up biopsy was performed at 12 months. Response to a GFD was considered if there was a clinical and histological (or serological) response. The ‘gold standard’ in diagnosing a patient with CD was applied using the Catassi’s rule of ‘4 of 5’. A logistic regression analysis was performed to assess predictors of GFD response. The ORs were used to derive a new scoring system. ROC was used to define the better cut-off point.

Results: 135 patients fulfilled the inclusion criteria, 42 had normal histology and 93 lymphocytic enteritis (IEL ≥ 25%) (72% women; age, 39 ± 1.6 years). Seventy patients (52%) had response to GFD (IEL < 19% 4, IEL 19–24% 12, and IEL ≥ 25% 54). Multivariate analysis showed that presence of lymphocytic enteritis (IEL ≥ 25%), positive celiac serology, positive HLA-DQ2.5/8, and increase in gammadelta+ cells were independently associated with GFD response. A scoring system was derived which yielded an AUC of 0.83 (95% CI, 0.76–0.90), and an OR of 13 (95% CI, 5.5–30) to predict GFD response. A score ≥ 10 was associated with 70% sensitivity and 85% specificity, while a score ≥ 17 was associated with 100% specificity (25% sensitivity).

Conclusion: The ‘coeliac-lite score’ allowed to predict response to GFD and thus, to diagnose ‘coeliac-lite’ disease with an acceptable accuracy. In a quarter of patients this score provided a definitive diagnosis of CD at baseline.

Disclosure of Interest: All authors have declared no conflicts of interest.

References

1. Fernández-Bañares et al. Intestinal intraepithelial lymphocyte cytometric pattern is more accurate than subepithelial deposits of anti-tissue transglutaminase IgA for the diagnosis of celiac disease in lymphocytic enteritis. PlosOne 2014; 9:e101249.

2. Rosinach M, Fernández-Bañares F, Carrasco A, Ibarra M, Temiño R, Salas A, Esteve M. Double-Blind Randomized Clinical Trial: Gluten versus Placebo Rechallenge in Patients with Lymphocytic Enteritis and Suspected Celiac Disease. PLoS One . 2016 Jul 8;11(7):e0157879.

OP065 EFFECTIVE GLUTEN DEGRADATION IN NON-COELIAC GLUTEN-SENSITIVE SUBJECTS BY ASPERGILLUS NIGER DERIVED ENZYME: A PLACEBO-CONTROLLED RANDOMIZED CLINICAL TRIAL

J. König 1 , S. Holster 1 , M. J. Bruins 2 , R. J. Brummer 1

1 Nutrition-gut-brain Interactions Research Centre, School Of Medical Sciences, Örebro University, Örebro/Sweden

2 DSM Biotechnology Centre, Delft/Netherlands

Contact E-mail Address: julia.konig@oru.se

Introduction: Gluten may cause gastrointestinal complaints in individuals sensitive to gluten. Aspergillus niger derived prolyl endoprotease (AN-PEP) has previously been shown to degrade gluten into non-immunogenic compounds in an in vivo setting in healthy subjects in which AN-PEP was added to a liquid, intragastrically infused meal 1 .

Aims & Methods: The aim of the current study was to investigate the efficacy of AN-PEP to degrade gluten in a physiological meal setting in gluten-sensitive subjects. In this randomised placebo-controlled cross-over study, 18 self-reported gluten-sensitive subjects attended three test days. A multilumen nasoduodenal feeding catheter was placed to collect gastric and duodenal aspirates. Subjects consumed a porridge containing approximately 0.5 g gluten in the form of two crumbled wheat cookies as well as two tablets either containing 160 000 PPI of AN-PEP (high dose), or 80 000 PPI (low dose), or placebo in a double-blinded, randomised manner. Gastric and duodenal content was sampled at several time points over 180 minutes and analysed for gluten epitopes using the Gluten-Tec ELISA. The 180-min areas under the curve (AUC) of epitope concentration were calculated using curve fitting. Additionally, participants were asked to fill in questionnaires (GSRS) after each test day. The non-parametric Wilcoxon signed-ranked paired test at α = 0.05 with a Bonferroni correction was used to detect significant differences.

Results: AN-PEP significantly lowered the gluten concentrations in the stomach and in the duodenum compared to the placebo in both the high dose and the low dose. In the stomach, gluten levels were reduced from 218 ± 155 μg/ml (mean ± STD) in the placebo to 31 ± 24 μg/ml in the high dose ( p = 0.001) and to 31 ± 22 μg/ml in the low dose ( p = 0.001). In the duodenum, gluten levels were reduced from 65 ± 88 μg/ml in the placebo to 12 ± 13 μg/ml in the high dose ( p = 0.019) and to 8 ± 5 μg/ml in the low dose ( p = 0.015).

Conclusion: Even in a physiological meal setting, AN-PEP significantly degraded most gluten before it entered the duodenum in self-reported gluten-sensitive subjects. In those subjects, the consumption of AN-PEP was well tolerated.

Disclosure of Interest: M.J. Bruins: MJB is employed by DSM, the company that provided the enzymes.

All other authors have declared no conflicts of interest.

Reference

1. Salden et al. Aliment Pharmacol Ther 2015; 42:273–285.

MONDAY, OCTOBER 30, 201714:00-15:30

TSTM FREE PAPER: NEW CONCEPTS IN HOST-MICROBIOTA CROSSTALKS - ROOM E4____________________

OP066 EXOSOMES RELEASED FROM INTESTINAL EPITHELIAL CELLS INFECTED WITH CROHN’S DISEASE-ASSOCIATED ADHERENT-INVASIVE E. COLI TRANSFER MIRNAS INTO RECIPIENT CELLS TO INHIBIT AUTOPHAGY

A. Larabi 1 , J. Carriere 1 , G. Dalmasso 1 , J. Delmas 2 , N. Barnich 1 , H. T.T. Nguyen 1

1 M2ish, Inserm U1071Inra Usc2018, Université Clermont Auvergne, Clermont-Ferrand/France

2 Department Of Bacteriology, CHU Clermont-Ferrand, Clermont-Ferrand/France

Contact E-mail Address: anais.larabi@uca.fr

Introduction: Crohn’s disease (CD) is a chronic inflammatory disorder of the gastrointestinal tract characterized by an abnormal immune response against the intestinal microbiota in a genetically predisposed host. The intestinal mucosa of CD patients is abnormally colonized by the adherent-invasive E. coli (AIEC) strains, which are able to adhere to and to invade intestinal epithelial cells (IECs), to survive and replicate within macrophages and induce a strong pro-inflammatory response (1). We recently reported that AIEC infection of IECs induces secretion of exosomes, which are extracellular vesicles of 30–100 nm having a role in cell-to-cell communication (2). Exosomes secreted by AIEC-infected IECs can activate innate immune response and increase AIEC replication in exosomes-receiving IECs and macrophages (2).

Aims & Methods: This study aimed at investigating the mechanism underlying the exosomes-mediated increased AIEC replication in recipient cells. Exosomes released by uninfected human intestinal epithelial T84 cells (Exo-uninfected) or by T84 cells infected with the AIEC LF82 reference strain (Exo-AIEC), the non-pathogenic E. coli K12 MG1655 strain (Exo-K12) or the commensal E. coli HS strain (Exo-HS) were purified using the ExoQuick reagent and used to stimulate T84 cells or human THP-1 macrophages.

Results: We found that stimulation of T84 and THP-1 cells with Exo-AIEC inhibited autophagy activation in response to AIEC infection compared to Exo-uninfected, Exo-K12 or Exo-HS. This was due to decreased expression of several autophagy genes. In silico analysis revealed a subset of miRNAs potentially targeting these autophagy genes. Several autophagy gene-targeting miRNAs were found in exosomes with increased levels in Exo-AIEC compared to Exo-uninfected, Exo-K12 or Exo-HS. These exosomal miRNAs were then transferred from exosomes to recipient cells, inhibiting autophagy genes and therefore autophagy response to AIEC infection. This consequently led to increased AIEC replication in cells stimulated with Exo-AIEC compared to that in cells stimulated with Exo-uninfected, Exo-K12 or Exo-HS. Exo-AIEC derived from T84 cells transfected with antisenses of the autophagy gene-targeting miRNAs did not carry the corresponding miRNAs and failed to inhibit autophagy activation and to increase bacterial replication in recipient cells.

Conclusion: Our study shows that upon AIEC infection, IECs secrete exosomes that can transfer specific miRNAs to recipient IECs or macrophages, inhibiting autophagy gene expression and thus autophagy-mediated control of AIEC replication.

Disclosure of Interest: All authors have declared no conflicts of interest.

References

1. Carrière J, Darfeuille-Michaud A, Nguyen HT. Infectious etiopathogenesis of Crohn's disease. World Journal of Gastroenterology . 2014, 20(34):12102–12117.

2. Carrière J, Bretin A, Darfeuille-Michaud A, Barnich N, Nguyen HT. Exosomes released from cells infected with Crohn's disease-associated adherent-invasive Escherichia coli activate host innate immune responses and enhance bacterial intracellular replication. Inflammatory Bowel Disease . 2016, 22(3):516–28.

OP067 DIETARY EMULSIFIERS DIRECTLY IMPACT THE TRANSCRIPTOME OF A CROHN’S DISEASE-ASSOCIATED ESCHERICHIA COLI, INCREASING ITS ABILITY TO INDUCE INTESTINAL INFLAMMATION

B. Chassaing 1 , A. T. Gewirtz 1

1 Institute For Biomedical Sciences, Georgia State University, Atlanta/United States of America

Contact E-mail Address: bchassaing@gsu.edu

Introduction: In mice, consumption of dietary emulsifiers, which are detergent-like components of many processed foods, disturbs the intestinal microbiota in a manner that enhances its pro-inflammatory potential and promotes its encroachment into the mucosa [1]. Such disturbance of the microbiota promotes a range of chronic inflammatory diseases, including colitis. We recently demonstrated that such disturbance of the microbiota can be recapitulated, in part, in an in vitro microbiota model, arguing that at least a portion of the effects of emulsifiers in vivo result from direct action of these compounds on the microbiota [2]. Notably, carboxymethylcellulose (CMC), a commonly used synthetic emulsifier, was found to increase the pro-inflammatory potential of the microbiota by inducing expression of flagellar-related genes, without altering species composition.

Aims & Methods: We hypothesize that dietary emulsifier may directly impact the pathogenicity of adherent and invasive Escherichia coli (AIEC), which are associated with Crohn’s disease [], promoting their ability to induce intestinal inflammation. AIEC reference strain LF82 was treated with emulsifiers (Carboxymethylcellulose (CMC) or Polysorbate-80 (P80)) in vitro, and the impact on virulence genes expression, whole transcriptome, and adhesion/invasion properties were investigated. Germfree mice were mono-associated with LF82 strain, and the impact of dietary emulsifier consumption on LF82 virulence and intestinal inflammation was investigated.

Results: Transcriptomic analysis revealed that, in vitro, CMC altered gene expression of AIEC bacteria by favoring expression of genes related to virulence and induction of intestinal inflammation. Moreover, CMC dramatically increased the adhesion ability of AIEC LF82 bacteria to intestinal epithelial cells, while P80 only slightly impacted this process. Moreover, pre-treatment of AIEC LF82 bacteria with CMC significantly increased bacterial motility while use of an isogenic aflagellate LF82 strain demonstrated that flagella is playing a central role in AIEC penetration of mucus layer in vivo. AIEC LF82 mono-associated mice are currently being treated with dietary emulsifier in order to investigate if emulsifiers + AIEC combination is sufficient to induce intestinal inflammation.

Conclusion: Some dietary emulsifiers have the ability to directly impact microbiota members including AIEC in a manner that potentiates their ability to promote intestinal inflammation. Our demonstration that some dietary component may directly impact the virulence of Crohn’s disease associated bacteria may explain why only a subset of AIEC positive individual develop Crohn’s disease. Hence, this research may ultimately influence dietary recommendation for AIEC carriers at risk for IBD flares or disease development.

Disclosure of Interest: All authors have declared no conflicts of interest.

References

1. Chassaing B, Koren O, Goodrich JK, Poole AC, Srinivasan S, Ley RE, et al. Dietary emulsifiers impact the mouse gut microbiota promoting colitis and metabolic syndrome. Nature 2015;519:92–6.

2. Chassaing B, Van de Wiele T, De Bodt J, Marzorati M, Gewirtz AT. Dietary emulsifiers directly alter human microbiota composition and gene expression ex vivo potentiating intestinal inflammation. Gut 2017.

3. Darfeuille-Michaud A, Boudeau J, Bulois P, Neut C, Glasser AL, Barnich N, et al. High prevalence of adherent-invasive Escherichia coli associated with ileal mucosa in Crohn's disease. Gastroenterology 2004;127:412–21.

OP068 GUT DYSBIOSIS CAN LEAD TO VISCERAL HYPERSENSITIVITY AND DEPRESSION IN GERM-FREE RATS

L. Zhang , J. Zhang, S. Zhu, W. Zhang, L. Duan

Gastroenterology, Peking University Third Hospital, Beijing/China

Contact E-mail Address: zhanglu@bjmu.edu.cn

Introduction: Gut dysbiosis is implicated in both irritable bowel syndrome (IBS) and depression, which are often comorbid with each other, but the causal relationship is not verified. Our previous study found similar structure but different function of gut microbiota between IBS-D and depression patients.

Aims & Methods: Aim: To verify whether shift of gut microbiota function can disturb brain-gut axis function by transplanting fecal microbiota obtained from IBS-D patients and depression patients to germ-free (GF) rats respectively. Methods: Fecal samples from a health control, an IBS-D patient and a depression patient recruited in our previous study were transplanted to 7 weeks old GF rats by gavage (once/rat, n = 5–6/group). Fourteen days after transplantation, fecal samples of rats were collected for 16S rRNA gene sequencing on Illumina Miseq and short-chain fatty acids (SCFAs) measurement on UPLC-MS/MS; open field test, sucrose preference test, forced swimming test (FST) and colorectal barostat were performed for anxiety, depression behavior and visceral sensitivity, respectively.

Table. Visceral sensitivity, anxiety, depression behavior and fecal SCFAs levels of recipient rats (Mean ± SE)

Results: The abdominal withdrawal reflex (AWR) is higher in IBS-D recipient (GI) rats than in health control (GH) and depression (GD) recipient rats at colorectal distension of 20 mmHg, 40 mmHg and 60 mmHg, and higher in GI and GD rats than in GH rats at 80 mmHg. The percentage of time in open field center area of GD rats was lower than that of GH and GI rats; the sucrose preference rate is lower in GD rats than in GH and GI rats; the immobile time of GD and GI rats in the FST was longer than that of GH rats. Principle component analysis revealed that the fecal microbiota structure of the three groups of rats was significantly different. Fecal formate level was higher in GI rats than in GH and GD rats; fecal acetate and propionate levels were higher in GH rats than in GI and GD rats; fecal valerate level was lower in GD rats than in GH and GI rats (see Table).

Conclusion: Gut microbiota from IBS-D patients can lead to visceral hypersensitivity, from depression patients can lead to depression behavior in GF rats. Those suggest an important role of gut microbiota in the pathogenesis of IBS-D and depression; and provide clues for the influence of gut microbiota on brain-gut axis.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP069 INFLAMMATION MODULATION BY STOMACH MICROBIOTA VIA TLR2/NF-ΚB SIGNALING PATHWAY IN HP-INDUCED GASTRIC CANCER

Y. Dang , G. Zhang

Department Of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Najing/China

Contact E-mail Address: yeani_hi@126.com

Introduction: The mechanisms of Helicobacter pylori (Hp) initiated cancer have not been well studied. Our previous studies demonstrated that 1) stomach microbiota interacted dynamically within the development from gastritis to gastric cancer; 2) TLR2/NF-KB signaling pathway can be activated by Hp infection, the overexpression of TLR2 played an important role in the interaction between Hp and non-Hp bacteria; 3) significantly more butyrate was observed after Hp infection, it promoted the proliferation and migration of AGS cell, and up-regulated the expression of TLR2 and NF-KB.

Aims & Methods: This study investigated 1) how the stomach microbiota transforms within the development from gastritis to gastric cancer; 2) how the TLR2/NF-KB signaling pathway is activated via the interaction between Hp and non-Hp bacteria. Tissue samples of chronic gastritis, atrophic and IM gastritis, and early gastric cancer were collected through endoscopy. WT and TLR/KO mice were used to build Hp infection animal models. Comprehensive Illumina Mise microarray was used to analyze microbiota constructions in clinical samples and animal models. HPLC was used to detect short chain fatty acid (SCFA) in gastric tissue. IHC, Western blot were used to observe TLR2 and NF- KB expression. Inflammatory cytokines such as IL-1,IL-6,IL-8,TNF-α were tested by real-time PCR. Cell function tests including CCK8 and Transwell were performed in AGS and SGC7901 cells.

Results: Bacterial composition analysis in chronic gastritis, atrophic and IM gastritis, and early gastric cancer tissue by Illumina Mise microarray demonstrated that 1) Hp was detected in five samples, 2) the total amount of Neisseria in the atrophic and IM gastritis sample was nine times more than that in the chronic gastritis, 3) the total amount of Haemophilus parainfluenzae in the atrophic and IM gastritis sample was four times more than that in the chronic gastritis, 4) the worse the condition, the more the Pseudomonas, Sphingomonas, Chryseobacterium, Ruminococcus . In addition, it was also found that Hp infection can upregulate TLR2 expression, in turn TLR2-activated Rel/p65 can increase the levels of IL-1,IL-6,IL-8,TNF-α. The total amount of Hp , Clostridium, Clostridium leptum, Clostridium quasiball were increased and Lactobacillus, Enterobacteria, non-Helicobactea were decreased after Hp infection in WT mice. The amount of class Clostridia and class Bacilli showed no significant change after Hp infection in TLR2/KO mice. It was also observed that increased butyrate model can promote proliferation and migration of AGS cells after Hp infection.

Conclusion: Hp infection can induce the alteration of stomach microbiota via the up-regulation of TLR2, in turn leads to the imbalance of stomach microbiota characterized by the increase of butyrate-producing bacteria. Thereafter, TLR2/NF-KB signaling pathway can be activated by the overexpressed butyrate and the level of inflammatory cytokines at the downstream can also be up-regulated by RelA/p65. All the newly found interactions between bacteria and signaling pathway may finally contribute to the epithelial transformation.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP070 CARD9 MEDIATES SUSCEPTIBILITY TO INTESTINAL PATHOGENS THROUGH MICROBIOTA MODULATION AND CONTROL OF BACTERIAL VIRULENCE

B. Lamas 1 , M. L. Richard 1 , M. Michel 1 , N. Waldschmitt 2 , V. Zacharioudaki 2 , M. Delacre 2 , J. M. Natividad 1 , G. Da Costa 1 , J. Planchais 1 , C. Bridonneau 1 , P. Langella 1 , M. Chamaillard 2 , H. Sokol 1

1 Avenir Team Gut Microbiota and Immunity, INSERM U1157/UMR CNRS 7203, UPMC; UMR 1319 Micalis, Paris/France

2 Institut Pasteur de Lille, Center for infection and immunity of Lille; INSERM U1019, Team 7, Equipe FRM, Lille/France

Contact E-mail Address: lamasbruno@hotmail.fr

Introduction: In association with innate and adaptive immunity, the microbiota controls the colonization resistance against intestinal pathogens. Caspase recruitment domain 9 ( CARD9 ), an inflammatory bowel disease susceptibility gene, is required to shape a normal gut microbiota. Card9 –/– mice are more susceptible to the enteric mouse pathogen Citrobacter rodentium that mimics human infections with enteropathogenic and enterohemorrhagic Escherichia coli . Here, we examined how CARD9 controls C. rodentium infection susceptibility through microbiota-dependent and -independent mechanisms.

Aims & Methods: C. rodentium infection was assessed in conventional and germ-free (GF) wild-type (WT) and Card9 –/– mice. To explore the impact of Card9 –/– microbiota in infection susceptibility, GF WT mice were colonized with WT (WT→GF) or Card9 –/– ( Card9 –/– → GF) microbiota before C. rodentium infection. Mice were fed a standard diet or a customized version of standard diet in which polysaccharides (PS) or monosaccharides (MS) were used as hydrocarbon source. Microbiota composition was determined by 16S rDNA gene sequencing. Inflammation severity was determined by histology score and lipocalin level. Microbiota – host immune system interactions were assessed by qPCR analysis.

Results: The specific intestinal immunoglobulin (Ig) G response against C. rodentium was impaired in GF Card9 –/– mice compared to GF WT mice. Moreover, higher susceptibility to C. rodentium -induced colitis was observed in Card9 –/– → GF mice. Gut microbiota composition of Card9 –/– → GF mice was altered and inferred metagenomics revealed that Card9 –/– → GF gut bacteria used polysaccharides while WT→GF gut bacteria used monosaccharides. MS diet increased C. rodentium susceptibility in Card9 –/– → GF mice whereas PS diet rescued the phenotype. The specific intestinal IgG response against C. rodentium was increased in Card9 –/– mice fed the PS diet compared to Card9 –/– mice fed the MS diet. Interestingly, the specific intestinal humoral response was also defective in WT mice fed the MS diet compared to WT mice fed the PS diet.

Conclusion: CARD9 controls pathogen virulence in a microbiota-independent manner by supporting a specific humoral response. The microbiota of Card9 –/– mice failed to outcompete the monosaccharide-consuming C. rodentium, worsening the infection severity. A polysaccharide-enriched diet counteracted the ecological advantage of C. rodentium and the defective pathogen-specific antibody response in Card9 –/– mice. Thus, CARD9 modulates the susceptibility to intestinal infection by controlling pathogen virulence independently of the microbiota and by shaping a microbiota competing with pathogens. Genetic susceptibility to intestinal pathogens can be overridden by diet intervention that restores humoral immunity and a competing microbiota.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP071 A C-TYPE LECTIN TRIGGERS IMMUNE SURVEILLANCE BY INNATE LYMPHOID CELLS FOR ERADICATION OF ATTACHING-AND-EFFACING BACTERIA

N. Waldschmitt 1 , S. Kitamoto 2 , T. Secher 3 , V. Zacharioudaki 1 , E. Floquet 1 , M. Delacre 1 , B. Lamas 4 , P. Pham 5 , A. Six 6 , M.L. Richard 7 , J. Dagorn 8 , P. Langella 9 , G. Eberl 10 , B. Ryffel 11 , J.L. Iovanna 12 , L.F. Poulin 1 , H. Sokol 13 , N. Kamada 2 , M. Chamaillard 1

1 Institut Pasteur de Lille, Center for infection and immunity of Lille; INSERM U1019, Team 7, Equipe FRM, Lille/France

2 Division of Gastroenterology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan/United States of America/MI

3 CNRS, Orléans University, INEM, UMR 7355, Orléans/France

4 Sorbonne University - Université Pierre et Marie Curie, Paris, Inserm Equipe de Recherche Labélisée 1157, Avenir Team Gut Microbiota and Immunity, CNRS UMR 7203, Laboratoire de BioMolécules, CHU Saint-Antoine, Paris/France

5 ILTOO Pharma, iPEPS ICM, Hôpital Pitié Salpêtrière, Paris/France

6 Sorbonne Universités, UPMC Univ Paris 0 6 INSERM, UMRS959, Immunology-Immunopathology-Immunotherapy (I3), Paris/France

7 Commensals and Probiotics-Host Interactions Laboratory, Micalis Institute, INRA, AgroParisTech, Université Paris-Saclay, Jouy-en-Josas/France

8 Centre de Rechercheen Cancérologie de Marseille, Inserm U1068, CNRS UMR 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, Marseille/France

9 Commensals and Probiotics-Host Interactions Laboratory, Micalis Institute, INRA, AgroParisTech, Université Paris-Saclay, Jouy-en-Josas/France

10 Institut Pasteur, Microenvironment & Immunity Unit, INSERM U1224, Paris/France

11 DHU i2B, Paris/France

12 Centre de Recherche en Cancérologie de Marseille, Inserm U1068, CNRS UMR 7258, Marseille/France

13 Gastroenterology Department, Saint-Antoine Hospital, Paris/France

Contact E-mail Address: nadine.waldschmitt@tum.de

Introduction: Although gut protection to infection is ensured by innate lymphoid cells (ILCs), how ILCs are regulated remains poorly understood. Here, we show that secretion of the c-type lectin Reg3b downstream of Ripk2 signaling pathway was crucial for immune surveillance by ILCs against Citrobacter rodentium that mimics human infection with attaching-and-effacing bacteria.

Aims & Methods: In the present study, we aimed at identifying crucial factors that impact clearance of C. rodentium in mice. Ripk2 KO, Reg3b KO, and wild-type mice were orally inoculated with C. rodentium and infection course was monitored for three weeks. Samples were taken on days 0, 4, 12, and 20 of infection. Microarray analysis was performed on total tissue from caecum. Total tissue was further analyzed by histology, qPCR, Western blot, and flow cytometry. Lamina propria mononuclear cells (LPMCs) from C. rodentium -infected Ripk2 KO, Reg3b KO, and wild-type mice were isolated through cell sorting and co-culture experiments were performed with intestine-derived ILCs to assess cytokine secretion.

Results: We found that Ripk2 signaling significantly controls epithelial Reg3b expression, which is required for an efficient control of C. rodentium infection. Both, Ripk2 KO and Reg3b KO mice displayed an enhanced susceptibility to C. rodentium -induced colitis associated with an impaired clearance of the pathogen. Phosphorylation of signal transducer and activator of transcription 3 (STAT3) and secretion of both tumor necrosis factor alpha (Tnf-a) and interleukin-17A (IL-17A) were blunted in mutant mice contributing to their susceptibility to a primary infection. We further determined that Reg3b triggered influx of neutrophils through an intact IL-17A signaling. Loss of either Reg3b or Ripk2 weakened Tnf-a secretion by intestinal phagocytes lowering their propensity to promote IL17A secretion by ILCs early in infection.

Conclusion: These results provide a previously unrecognized mechanism by which intestinal epithelial cells reciprocally regulate production of IL-17A by ILCs preventing from overcolonization by opportunistic enteropathogenic bacterium.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP072 STUDY ON THE ANTI-INFLAMMATORY MECHANISMS OF ROSEBURIA INTESTINALIS MEDIATED BY INDUCING THE DIFFERENTIATION OF THE TREG CELLS VIA TLR5 OF THE INTESTINAL EPITHELIAL CELLS IN INFLAMMATORY BOWEL DISEASE

Z. Shen , C. Zhu, Y. Quan, W. Yuan, Z. Yang, S. Wu, X. Wang

Department Of Gastroenterology, Third Xiangya Hospital, Central South University, Changsha, Hunan, China, Changsha/China

Contact E-mail Address: szh0722@163.com

Introduction: IBD, a chronic recurrent autoimmune disease, is currently associated with poor prognosis. We need explore new therapeutic strategies for IBD. Intestinal flora is closely related to the pathogenesis of IBD. In order to clarify the characteristics of intestinal microflora in Crohn’s disease (CD) patients in our country, we analyzed the changes of intestinal flora in untreated patients with CD. The study provided the first evidence that Roseburia intestinalis ( R. intestinalis ) was significantly reduced in the intestinal tract of the patients with CD in China. R.intestinalis belongs to the family of Clostridium enteritidis XIVa, which has a strong regulatory effect on the development and differentiation of Treg cells, and its community stability in the intestine determines the homeostasis of intestinal mucosal tolerance [1]. Does R.intestinalis have an anti-inflammatory effect in IBD? Receptors which are associated with bacterial identification contain TLR2, TLR4 and TLR5 in the TLRs family [2]. Our early study has found that R. intestinalis was able to up-regulate expression of TLR5, whereas it had little effect on TLR2 and TLR4. Does the regulation of intestinal mucosal immunity by R.intestinalis achieve via TLR5 of the intestinal epithelial cells in IBD No reports have been reported at home and abroad.

Aims & Methods: To elucidate the anti-inflammatory effect and mechanism of R.intestinalis in IBD, we propose to investigate the effects of R.intestinalis on Disease Activity Index (DAI) score, intestinal pathology, the expressions of TLR5, TSLP, TGF-β, and the differentiation of Treg cells by using murine TNBS colitis models. At the cellular level, we use the human colon epithelial cell line Caco-2, overexpressing and silencing of TLR5 in HEK293 and Caco-2 cells respectively to conduct inflammatory cell model with LPS and then co-culture with different concentrations of R.intestinalis (Ratio of bacteria and cells were 10:1, 5:1 and 1:1, namely R.I1, R.I2 and R.I3) and detect changes of TSLP and TGF-β.

Results: R.intestinalis significantly decreased DAI scores (the day before mice were killed, the DAI score of the Control group, TNBS group and TNBS+ R.intestinalis were 0.4 ± 0.26, 2.33 ± 0.14 and 1.25 ± 0.3 respectively. Compared with the TNBS group, the DAI score of TNBS+ R.intestinalis group decreased, P < 0.05). R.intestinalis reduced the degree of shortening of the colon (P < 0.05), and played the anti-inflammatory role by up-regulating the levels of TLR5, TSLP and TGF-β and increasing the proportion of Treg cells (the proportion of the Control group, TNBS group and TNBS+ R.intestinalis were 6.42 ± 0.4, 1.25 ± 0.34 and 6.01 ± 0.3 respectively.P < 0.05 occurs between TNBS group and TNBS+ R.intestinalis group). In vitro, the co-culture of R.intestinalis and Caco-2 significantly increased secretion of TSLP and TGF-β levels of the cells (P < 0.05). The co-culture supernatant TSLP of the control group, LPS group, LPS + R.I1, LPS + R.I2 and LPS + R.I3 were (5.88 ± 0.45)pg/ml, (3.38 ± 0.19)pg/ml, (5.58 ± 0.85)pg/ml, (5.31 ± 0.12) pg/ml and (4.97 ± 0.62)pg/ml respectively. The co-culture supernatant TGF-β of the control group, LPS group, LPS + R.I1, LPS + R.I2 and LPS + R.I3 were (394.23 ± 79.55)pg/ml, (249.66 ± 18.50)pg/ml, (415.31 ± 123.58)pg/ml, (385.59 ± 31.78)pg/ml and (412.62 ± 30.94)pg/ml respectively. So it is with the results of Western blot and Realtime-PCR. While the silencing of TLR5 cells did not change theses cytokines.

Conclusion: R.intestinalis might promote the secretion of TSLP and TGF-β from intestinal epithelial cells via TLR5, thus inducing the differentiation of the Treg cells.

Disclosure of Interest: All authors have declared no conflicts of interest.

References

1. Koji Atarashi, Takeshi Tanoue, Kenshiro Oshima, et al. Treg induction by a rationally selected mixture of Clostridia strains from the human microbiota. Nature . 2013, 500(7461):232–236.

2. Elke Cario. Toll-like receptors in inflammatory bowel diseases: a decade later. Inflamm Bowel Dis . 2010, 16(9):1583–1597.

MONDAY, OCTOBER 30, 201714:00-15:30

IBS: SEARCHING FOR BIOMARKERS - ROOM 7.1____________________

OP073 IBS PATIENTS HAVE LOWER LEVELS OF COLONIC MUCOSAL PRO-INFLAMMATORY CYTOKINES WHICH REMAIN STABLE OVER TIME

B. Schmidt 1 , G. Saffouri 1 , J. Chen 2 , H. Lekatz 1 , M. Grover 1 , D. Knights 3 , G. Farrugia 1 , P. Kashyap 1

1 Gastroenterology And Hepatology, Mayo Clinic, Rochester/United States of America/MN

2 Genetics And Bioinformatics, Mayo Clinic, Rochester/United States of America/MN

3 Computer Science And Engineering, University of Minnesota, Minneapolis/United States of America/MN

Contact E-mail Address: schmidt.bradley1@mayo.edu

Introduction: Irritable bowel syndrome (IBS) is a chronic gastrointestinal (GI) disorder associated with abdominal pain and altered bowel pattern. The role of inflammatory mediators in the pathophysiology of symptoms in IBS has been widely studied but there is a lack of consistent findings across cohorts. The majority of studies rely on cross-sectional findings which fail to capture the variability of responses over time.

Aims & Methods: In this study we evaluated i) if cytokine changes are temporally stable and ii) differences in mucosal and serum cytokines in healthy individuals and IBS patients (constipation predominant; IBS-C and diarrhea predominant; IBS-D). Human sigmoid colon biopsies and serum from age matched healthy and IBS patients (mean age 38, range 20–59 years, n = 15 IBS-C; n = 14 IBS-D; n = 8 healthy) (IRB14-000365) were obtained. These measurements were repeated after 3–6 months in 8 IBS-C patients, 10 IBS-D patients, and 8 healthy controls. Biopsies were homogenized and the levels of 14 cytokines previously shown to be relevant in IBS (TGF β1, IL-17A, TNFα, IL-10, IL-6, IFNγ, IL-8, IL-1β, Leptin, IL-22, IL-18, VEGF, MIG, and IL-1RA) were measured in duplicate using ELISA. Data were analyzed using linear mixed effects model and Wald test, combining samples from two time points and p value adjusted (q value) to correct for multiple testing using 20% False Discovery Rate.

Results: There was no significant difference in the temporal variability of mucosal cytokine levels over the two time points when comparing patients with IBS and healthy controls. IFNγ was significantly decreased in patients with IBS-C compared to healthy controls (p = 0.0005; q = 0.007) and TNFα was significantly decreased in patients with IBS-D (p = 0.02; q = 0.16) and the same trend was seen at both time points. No other cytokines were found to be significantly different in mucosal biopsies. Additionally there were no significant differences in cytokine levels in the serum among patients with IBS and healthy controls.

Conclusion: Colonic cytokine levels did not vary over a period of 3–6 months in patients with IBS. The levels of pro-inflammatory cytokines were lower in patients with IBS with stable symptoms suggesting inflammation may not be the main cause of chronic symptoms in IBS.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP074 STRESS REGULATES SPECIFIC SEX-RELATED MOLECULAR ALTERATIONS IN EPITHELIAL BARRIER REGULATORY GENES IN THE JEJUNAL MUCOSA OF HEALTHY VOLUNTEERS

B.K. Rodiño Janeiro 1 , M. Pigrau 1 , A. Nieto 1 , T. Pribic 1 , L. Hernández 1 , E. Salvo-Romero 1 , B. Lobo Alvarez 1 , A.M. González-Castro 1 , M. Fortea 2 , M. Gallart 1 , C. Pardo-Camacho 2 , I. De Torres 3 , C. Martinez 1 , D. Guagnozzi 4 , T. Pérez-Berezo 1 , F. Azpiroz 5 , M. Vicario 2 , J. Santos 1 , C. Alonso Cotoner 1

1 Neuro-immuno-gastroenterology, Hospital General Vall d'Hebron, Vall d'Hebron Research Institute, CIBERehd, Barcelona/Spain

2 Translational Mucosal Immunology, Hospital General Universitari Vall d'Hebron. Vall d'Hebron Institut de Recerca. CIBERehd, Barcelona/Spain

3 Pathology Department, Hospital Vall d'Hebron, Barcelona/Spain

4 Translational Mucosal Immunology, Hospital General Universitari Vall d'Hebron. Vall d'Hebron Institut de Recerca, Barcelona/Spain

5 Gastroenterology Department, University Hospital General Vall d'Hebron - Gastroenterology Department, University Hospital General, Barcelona/Spain

Contact E-mail Address: bruno.rodino@vhir.org

Introduction: Irritable bowel syndrome (IBS) is a highly prevalent disorder that has been linked to intestinal epithelial dysfunction, mast cell activation and life stress. While female prevalence in IBS remains to be fully understood, we have previously shown that female gender per se determines increased susceptibility to intestinal barrier dysfunction in response to acute experimental stress. However, the underlying molecular mechanisms have not been elucidated.

Aims & Methods: We aim to identify sex-related molecular changes in the intestinal barrier in response to acute stress in healthy individuals as an initial step to understand the origin of gender bias in functional digestive diseases. Methods Twelve men (M) and 17 age-matched females (F) were recruited. In each participant, two consecutive jejunal biopsies were obtained by Watson’s capsule: the first at baseline and the second 90 min after 15 min of intermittent cold pain stress (CPS). Autonomic (blood pressure and heart rate), hormonal (plasma cortisol) and psychological responses (Subjective Stress Rating Scale) to CPS were monitored throughout the study. Total mucosal RNA was isolated and expression levels of epithelial barrier (CLDN2, SLC26A3, TJP1 and TJP3) and mast cell activation-related genes (tryptase: TPSAB1, SERPINA1) were analyzed by RT-qPCR.

Results: CPS induced a significant autonomic response characterized by increased heart rate, blood pressure, and plasma cortisol in association with enhanced stress perception in all participants. CPS increased CLDN2 and SERPINA1 expression (Fold vs. basal: 1.3, p = 0.002; 1.2, p = 0.027, respectively) and decreased SLC26A3 gene expression (Fold vs. basal: 0.7, p < 0.001). Interestingly, gene expression studies also uncovered differential responses to acute stress between M and F. Particularly, in the F group CPS induced an increase in TPSAB1 expression (Fold vs. basal: [F]: 1.1; [M]: 0.8, p = 0.042), along with a decrease in TJP1 (Fold vs. basal: [F]: 0.9; [M]: 1.1, p = 0.042) and a trend for TJP3 (Fold vs. basal: [F]: 1.0; [M]: 1.1; p = 0.08). Significant positive correlations between CPS-induced changes in TPSAB1 and CLDN2 (r = 0.706, p = 0.002), and between TJP1 and TJP3 (r = 0.838, p < 0.001) were found.

Conclusion: Specific and independent gender-related molecular responses in epithelial barrier regulation are unraveled by acute stress exposure in the jejunum of healthy subjects. These molecular differences may explain, in part, female predominance in IBS.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP075 ACUTE STRESS IMPACTS CLOCK GENES AND BARRIER INTEGRITY IN THE INTESTINAL MUCOSA IN HEALTH

M. Pigrau Pastor 1 , B.K. Rodiño Janeiro 1 , E. Salvo Romero 1 , A. Nieto 1 , L. Hernández 2 , T. Pribic 1 , B. Lobo Alvarez 1 , A.M. González-Castro 1 , M. Fortea 2 , C. Pardo-Camacho 2 , D. Guagnozzi 2 , C. Martinez 1 , T. Pérez-Berezo 1 , I. De Torres 3 , F. Azpiroz 4 , M. Vicario 3 , C. Alonso Cotoner 1 , J. Santos 1

1 Neuro-immuno-gastroenterology, Hospital General Vall d'Hebron, Vall d'Hebron Research Institute, CIBERehd, Barcelona/Spain

2 Translational Mucosal Immunology, Hospital General Universitari Vall d'Hebron. Vall d'Hebron Institut de Recerca, Barcelona/Spain

3 Pathology Department, Hospital Vall d'Hebron, Barcelona/Spain

4 Gastroenterology Department, University Hospital General Vall d'Hebron - Gastroenterology Department, University Hospital General, Barcelona/Spain

Contact E-mail Address: mpigrau@yahoo.com

Introduction: Stress has been related to development and perpetuation of functional gastrointestinal disorders (FGIDs) through intestinal barrier dysfunction. Recent studies have suggested that circadian rhythm disruption could increase epithelial permeability. However, whether acute stress impacts on circadian clocks in the human intestinal mucosa, and its relevance to FGIDs remains unknown

Aims & Methods: We aimed to identify stress-mediated circadian rhythm biomarkers of intestinal barrier dysfunction. Methods Thirty seven (17/20 M/F) healthy subjects were recruited. The Watson’s capsule was used to obtain two jejunal mucosal samples in each participant: one at baseline, and one 90 minutes after intermittent cold pain stress (CPS). Hand pain perception, autonomic (blood pressure and heart rate), hormonal (plasma cortisol) and psychological variables were recorded throughout the study. Mucosal RNA was isolated and analyzed by microarray analysis followed by differential gene expression and biological pathways identification and qPCR validation.

Results: CPS significantly increased heart rate, blood pressure and plasma cortisol, as well as stress perception in all participants. Stress significantly modified mucosal transcriptome, being circadian rhythm regulation the most relevant biological function (P < 0.00001), with a significant decrease in specific clock genes (NFE2L2, NFIL3, NR1D1, NR2D2, PER1, PER3; P < 0.05). Moreover, CPS altered epithelial barrier integrity gene expression (increasing CLDN2 and decreasing SLC26A3; P < 0.05), and inflammation-related genes (decreasing IL18, and increasing SOD1 and protease activity SERPINA1; P < 0.05). Notably, significant association was found between representative genes of the most significant biological functions altered by stress (table 1).

Conclusion: Clock gene expression in the intestinal mucosa is inhibited by acute stress (CPS) in association with molecular intestinal barrier alterations. These changes might help us to understand the mechanisms by which stress contributes to the development of FGIDs.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP076 DIFFERENT RELATIONSHIPS BETWEEN INTESTINAL PARASITES AND BACTERIAL RICHNESS AND DIVERSITY IN INDIVIDUALS WITH IRRITABLE BOWEL SYNDROME AND HEALTHY CONTROLS

L. Rindom Krogsgaard 1 , L. O ´brien Andersen 2 , T. Bech Johannesen 3 , A.L. Engsbro 4 , C. Rune Stensvold 2 , N. Larsen 5 , H. Vedel Nielsen 2 , P. Bytzer 1

1 Medicine, Zealand University Hospital, Køge/Denmark

2 Department Of Microbiology And Infection Control, Statens Serum Institut, Laboratory of Parasitology, Dept. of Microbiological Diagnostics, Copenhagen S/Denmark

3 Statens Serum Institut, Copenhagen/Denmark

4 Clinical Microbiology, Hvidovre hospital, Hvidovre/Denmark

5 Danish Genome Institute, Århus C/Denmark

Contact E-mail Address: lrk@dadlnet.dk

Introduction: Colonization with the parasites Dientamoba fragilis and Blastocystis is less common in individuals with IBS than in asymptomatic controls (1). Differences in gut microbiome structure in IBS patients compared with controls have been reported; however, studies of bacterial composition potentially linked to parasite colonization remain limited.

Aims & Methods: We aimed to reveal associations between parasites, including D. fragilis and Blastocystis , and microbiome diversity and richness in individuals with IBS, asymptomatic controls, and individuals with unspecific gastrointestinal (GI) symptoms. Fecal samples were collected by postal mail from the Danish background population classified into three groups: IBS, unspecific GI symptoms, and asymptomatic controls by a questionnaire based on the Rome III criteria for IBS (2). Samples were tested for parasites by microscopy, culture, and real-time PCR. Moreover, bacterial (16S) and eukaryotic (18S) ribosomal DNA was amplified and sequenced using next-generation sequencing for profiling of bacteria and parasites. Data were analyzed with BION software. The mean number of observed operational taxonomic units (OTUs) was reported as a measure of richness and Shannon’s Diversity Index as a measure of richness and diversity. Mean was compared between the IBS group and controls by a two-sided t-test and by one-way ANOVA for all three symptom groups. These were studied in relation to the three symptom groups and in relation to four defined categories of parasite colonization status: positive/negative for i) any parasite, ii) D. fragilis, iii) Blastocystis , and iv) multiple parasite species.

Results: We received samples from 119 individuals with IBS, 186 asymptomatic controls and 114 individuals with unspecific GI symptoms. There was no difference in richness between the IBS (117.6 (standard deviation (SD): 16.6)) and control group (115.8 (SD: 16.6), p = 0.36), but richness was higher in samples from individuals with unspecific GI symptoms (126.0, (SD: 21.0), p < 0.01). Diversity was also higher in the group with unspecific GI symptoms (3.07 (SD: 0.31), p = 0.06) and did not differ between the IBS (3.00 (SD: 0.29)) and the control group (2.98 (SD: 0.32), p = 0.59). Richness and diversity were significantly higher in parasite-positive samples across all four categories (Tables 1). For asymptomatic controls and those with unspecific GI symptoms, richness was higher for parasite-positive samples in all categories (Table 1). However, this did not apply to those with IBS symptoms. Diversity was higher for all categories of parasite-positive samples from individuals with unspecific GI symptoms and asymptomatic controls (with exception of multiple parasites) (Table 1). For those with IBS, diversity was only higher in relation to presence of Blastocystis or multiple parasites (Table 1). Number of observed operational taxonomic units and Shannons diversity index according to parasite colonization status, specified for symptom group. Difference in mean between positive and negative samples tested by two sided t-test.

Conclusion: Colonization with parasites, including D. fragilis and Blastocystis, was linked to increased microbiome diversity and richness. However, for individuals with IBS, the association to increased richness could not be confirmed and no association to increased diversity was observed for samples positive for any parasite or D. fragilis. This could reflect an altered relationship between bacteria and parasites in IBS. The clinical and public health significance of these findings should be explored in greater detail.

Disclosure of Interest: All authors have declared no conflicts of interest.

References

1. Krogsgaard et al. Clin Gastroenterol Hepatol , 2015; 13;507–13 2. Krogsgaard et al. Neurogastroenterol Motil , 2017; 29:e12986

MONDAY, OCTOBER 30, 201714:00-15:30

ADVANCES IN ENDOSCOPIC IMAGING: WHAT DOES THE FUTURE HOLD? - ROOM E2____________________

OP077 ENDOSCOPIC MACROSCOPIC TYPE IS A SIGNIFICANT PREDICTOR FOR HISTOLOGICAL TYPES OF EARLY GASTRIC CANCER

T. Kanesaka 1 , T. Nagahama 2 , N. Uedo 1 , H. Doyama 3 , T. Ueo 4 , K. Uchita 5 , H. Ishikawa 6 , K. Yao 7

1 Department Of Gastrointestinal Oncology, Osaka International Cancer Institute, Osaka/Japan

2 Endoscopy, Fukuoka University Chikushi Hospital, Chikusino/Japan

3 Dept. Of Gastroenterology, Ishikawa Prefectural Central Hosp., Kanazawa/Japan

4 Department Of Gastroenterology, Oita Red Cross Hospital, Oita/Japan

5 Dept. Of Gastroenterology, Kochi Red Cross Hospital, Kochi/Japan

6 Department Of Molecular-targeting Cancer Prevention, Kyoto Prefectural University of Medicine, Kyoto/Japan

7 Dept. Of Endoscopy, Fukuoka University Chikushi Hsopital, Chikushino/Japan

Contact E-mail Address: takashikanesaka@gmail.com

Introduction: Gastric cancer is classified into the differentiated and undifferentiated types according to the degree of histological differentiation. The risk of lymph node metastasis of undifferentiated-type early gastric cancer is higher than the differentiated type; 1, 2, 3 therefore these indication criteria for endoscopic resection are different. 4

Aims & Methods: This study aimed to clarify the diagnostic abilities of clinical predictors for distinguishing between differentiated-type early gastric cancer and undifferentiated-type early gastric cancer. This was a post hoc study of a multicenter prospective trial in five Japanese hospitals (clinical trial registration number: UMIN000014628). In the trial, 384 patients with cT1 gastric cancer were enrolled and 343 patients were analyzed. According to the protocol, age, gender, and the endoscopic findings of cancer (location, macroscopic type, diameter, and invasion depth) were evaluated and the final diagnosis using the resected specimen was confirmed. All data of the present study were evaluated before the final diagnosis using the resected specimens. In this study, associations between those clinical factors and histological types of cancer were evaluated. Then, those diagnostic abilities for differentiated-type early gastric cancer were calculated. Diagnostic abilities of forceps biopsy were also calculated as a reference.

Results: Multivariate analysis identified older age (≥72), male, elevated type, and shallower invasion depth (cT1a) as independent significant predictors for differentiated-type early gastric cancer. Elevated type showed the highest positive likelihood ratio among those factors. The sensitivity, specificity, accuracy, positive likelihood ratio, and negative likelihood ratio of it for differentiated-type early gastric cancer were 25%, 97%, 39%, 8.2, and 0.8. Those of the forceps biopsy were 96%, 86%, 95%, 7.0, and 0.04.

Conclusion: Endoscopic elevated type is a significant predictor for differentiated-type early gastric cancer and may exclude undifferentiated-type early gastric cancer without a forceps biopsy.

Disclosure of Interest: All authors have declared no conflicts of interest.

References

1. Gotoda T, Yanagisawa A, Sasako M, et al. Incidence of lymph node metastasis from early gastric cancer: estimation with a large number of cases at two large centers. Gastric Cancer 2000; 3:219–225.

2. Hirasawa T, Gotoda T, Miyama S, et al. Incidence of lymph node metastasis and the feasibility of endoscopic resection for undifferentiated-type early gastric cancer. Gastric Cancer 2009; 12:148–152.

3. Sekiguchi M, Oda I, Taniguchi H, et al. Risk stratification and predictive risk-scoring model for lymph node metastasis in early gastric cancer. J Gastroenterol . 2016; 51:961–970.

4. Japanese gastric cancer treatment guidelines 2014 (ver.4). Gastric Cancer 2017; 20:1–19.

OP078 IRREGULARLY BRANCHED MICROVESSELS ARE A RELIABLE MARKER FOR PREDICTING DEEP SUBMUCOSAL INVASION OF SUPERFICIAL ESOPHAGEAL CANCER WITH MAGNIFYING ENDOSCOPY

Y. Ono 1 , Y. Takaki 2 , K. Yao 3 , S. Ishikawa 1 , M. Miyaoka 4 , T. Nagahama 4 , H. Fumihito 1 , T. Ueki 1 , T. Matsui 1 , H. Tanabe 5 , A. Ohta 5 , S. Haraoka 5 , A. Iwashita 5 , K. Mikami 6 , T. Maekawa 6

1 Gastroenterology, Fukuoka University Chikushi Hospital, Chikushino/Japan

2 Gastroenterology, Ashiya Central Hospital, Onga-gun/Japan

3 Dept. Of Endoscopy, Fukuoka University Chikushi Hsopital - Dept. of Endoscopy, Fukuoka University Chikushi Hsopital; Chi, Chikushino/Japan

4 Endoscopy, Fukuoka University Chikushi Hospital, Chikusino/Japan

5 Pathology, Fukuoka University Chikushi Hospital, Chikushino/Japan

6 Surgery, Fukuoka University Chikushi Hospital, Chikushino/Japan

Contact E-mail Address: yono6110@gmail.com

Introduction: Histologic diagnosis of submucosal cancer invasion depth is divided into three equal parts and classified as SM 1, 2, and 3. It is important to differentiate between cancer that remains at a depth from the intramucosal to SM 1 (M/SM 1 cancers), for which a complete cure can be expected with endoscopic resection alone, and ≧SM 2 cancers, which require surgical resection with lymph node dissection or combined modality therapy such as chemoradiotherapy. However, esophagectomy is invasive, with high morbidity and mortality. Also, chemoradiotherapy is high toxicity. Magnifying endoscopy with narrow-band imaging (M-NBI) is reported to be useful in diagnosing invasion depth, but it is limited in terms of accurately diagnosing ≧SM 2 cancers [1]. However, we discovered that irregularly branched microvessels [2] observed with M-NBI are seen with a high frequency in deeply invasive cancer. We therefore planned this retrospective study to examine the diagnostic permormance of irregularly branched microvessels for deeply invasive ≧SM 2.

Aims & Methods: The subjects were 357 lesions (260 patients) with superficial esophageal squamous cell carcinoma that was endoscopically or surgically resected at the our hospital between September 2005 and December 2014; consecutive lesions for which preoperative M-NBI was performed were included in this study. Endoscopic findings by M-NBI of these subject lesions were presented to an experienced endoscopist unaware of the histopathological diagnosis, who then judged whether irregularly branched microvessels were present. Using the invasion depth from postoperative histopathological diagnosis as the gold standard, we examined the diagnostic performance of the presence of irregularly branched microvessels as an indicator for ≧SM 2 cancers. Irregularly branched microvessels was defined as abnormal microvessels without a loop-like formation that could not be traced to their starting and end points, and microvessels with an abundance of irregularly branches from the dilated abnormal vessels as a trunk.

Results: A total of 302 superficial esophageal cancer lesions were observed preoperatively by M-NBI and included in the analysis. Irregularly branched microvessels were seen with a frequency of 3.5% (11/268) in M/SM 1 cancers and 79.4% (27/34) in ≧SM 2 cancers. The frequency was thus significantly higher in ≧SM 2 cancers (p < 0.01). When irregularly branched microvessels were used as an indicator of ≧SM 2 cancers, the diagnostic accuracy was 94.0% (95% confidence interval [CI]: 91.4–96.7%), sensitivity was 79.4% (95%CI: 66.6–88.4%), specificity was 95.9% (95%CI: 94.3–97.0%), the positive predictive value was 71.1% (95%CI: 59.6–79.0%), and the negative predictive value was 97.3% (95%CI: 05.7–98.5%).

Conclusion: The present results suggest that irregularly branched microvessels may be a reliable M-NBI indicator for the diagnosis of cancers with deep submucosal invasion (≧SM 2).

Disclosure of Interest: All authors have declared no conflicts of interest.

References

1. Oyama T, et al. Prediction of the invasion depth of superficial squamous cell carcinoma based on microvessel morphology: magnifying endoscopic classification of the Japan Esophageal Society. Esophagus ;14;105–112, 2017

2. Arima M, et al. Evaluation of microvascular patterns of superficial esophageal cancers by magnifying endoscopy. Esophagus ;2;191–197, 2005

OP079 THE MOLECULAR BASIS OF 5-AMINOLEVULINIC ACID (ALA) MEDIATED LASER-BASED PHOTODYNAMIC ENDOSCOPIC DIAGNOSIS (LPDED) FOR DIVERSE EARLY GASTRIC CANCER

H. Kurumi 1 , K. Ogihara 2 , T. Kanda 1 , K. Yashima 1 , K. Kawaguchi 1 , K. Matsumoto 1 , Y. Takeda 1 , H. Isomoto 1

1 Division Of Medicine And Clinical Science, Tottori University Faculty of Medicine, Yonago/Japan

2 Department Of Gastroenterology And Hepatology, Nagasaki University Hospital, Nagasaki/Japan

Contact E-mail Address: kurumi_1022_1107@yahoo.co.jp

Introduction: Laser-based photodynamic endoscopic diagnosis (LPDED) is an optical imaging technology based on the fundamental biological features of porphyrin metabolism in cancer cells. We have found that 5-aminolevulinic acid (ALA) can provide a precise detection of early gastric cancer during LPDED ( Photodiagnosis Photodyn Ther 2015). However, there is an unresolved issue in the differences in fluorescence intensity among histopathological types. This study was conducted to compare clinicopathological features of the LPDED-positive group (with red fluorescence) and the LPDED-negative group (without the fluorescence), and to examine the expression of the proteins involved in porphyrin metabolism.

Aims & Methods: Study 1: Thirty-three gastric tumors in 30 patients were assessed by LPDED using a prototype endoscope equipped with a blue laser ray to cause excitation following oral ALA administration. Then, tumors were resected by endoscopic submucosal dissection or laparoscopic surgery. Oligopeptide-1 (PEPT-1), ATP-binding cassette transporter G2 (ABCG2), coproporphyrinogen oxidase (CPOX), and protoporphyrinogen oxidase (PPOX) expression was examined immunohistochemically in the excised specimens. The tumor immunoreactivity was scored either 0= negative; 1 = moderate, positive with minimal to moderate immunoreactivity; or 2 = strong, strongly positive with intense immunoreactivity after being compared with the corresponding surrounding non-tumor tissue. Study 2: To explore the mechanisms of histopathological diversity in CPOX and PPOX expression of early gastric cancer, we performed immunohistochemical analysis using 72 surgically resected specimens of diverse early gastric cancer.

Results: Study 1: Among 33 lesions, 26 tumors were detectable by LPDED, whereas 7 were undetectable. Between the LPDED-positive and negative groups, there was a significant difference in histopathology (positive: 23 tubular adenocarcinoma (tub), 0 signet-ring cell carcinoma (sig), and 3 adenoma; negative: 3 tub, 4 sig, and 0 adenoma) and in diameter (positive, 25 mm; negative, 7 mm). Expression of CPOX and PPOX was higher in tub than sig. Study 2: We confirmed that there were significant differences in CPOX and PPOX expression scores among tub, poorly differentiated adenocarcinoma, and sig in the surgically resected samples.

Conclusion: CPOX and PPOX protein expression could be involved in the fluorescence intensity of LPDED for early gastric cancer, possibly reflecting histopathologic features.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP080 VISUALIZATION OF ABSORBED LIPID IN NORMAL DUODENAL EPITHELIUM BY MAGNIFYING ENDOSCOPY WITH NARROW-BAND IMAGING: AN OPEN-LABEL, RANDOMIZED, CONTROLLED STUDY

H. Takahashi 1 , K. Yao 2 , T. Nagahama 2 , M. Miyaoka 2 , T. Ueki 1

1 Gastroenterology, Fukuoka University Chikushi Hospital, Chikushino/Japan

2 Endoscopy, Fukuoka University Chikushi Hospital, Chikushino/Japan

Contact E-mail Address: harutakahashi@fukuoka-u.ac.jp

Introduction: We previously reported on the epithelial presence of white opaque substance (WOS) in early gastric carcinomas, gastric adenomas, and intestinal metaplasia in the gastric mucosa, as visualized using magnifying endoscopy with narrow-band imaging (M-NBI) 1,2 . The nature of WOS was elucidated a phenomenon of lipid emulsion due to accumulation of minute lipid droplets (LDs) with intraepithelial and subepithelial distribution in neoplastic lesions 3 . However, to date, there have been no reports on whether LDs absorbed into the duodenal epithelium can be visualized as WOS after emulsified-fat loading of the duodenal mucosa. Accordingly, we aimed to establish whether WOS representing the presence of absorbed LDs in the duodenal epithelium is visualized after exogenous fat loading in an open-label, randomized, controlled study (UMIN000020107).

Aims & Methods: The patients consented to participate in the study. After enrollment in the study, the subjects were randomly assigned to a fat-loading (FL) group (to receive the enteral nutrition formulation containing emulsified fat (Ensure H®)) or a non-fat-loading (non-FL) group. The subjects underwent an initial endoscopic examination to image the duodenal mucosa before fat loading with M-NBI at the maximum magnification, and the images were stored in the image-recording system. The subjects underwent a second endoscopic examination two to three weeks later for observation of the duodenal mucosa using M-NBI. Each subject in the FL group consumed 250 ml of Ensure H® four hours before the second examination, and subjects in the non-FL group were asked not to consume anything before this examination. The endoscopists performing the examinations were not informed of subject group assignments. Assessable images from before and after the fat loading with the enteral nutrition formulation were retrieved from the image-recording system, and all clinical information was masked. Each image was submitted at random to two experienced endoscopists, who determined a WOS grade. The WOS grades were as follows: Grade 0 represented total absence of WOS from the image; Grade 1 represented a WOS area occupying up to one-third of the image; Grade 2 represented a WOS area occupying more than one-third but less than two-thirds of the image; and Grade 3 represented a WOS area occupying at least two-thirds of the image. Fat-loading test results were judged positive for subjects who showed a higher WOS grade at the second examination than the initial examination, and negative in other cases. The rate of positive test results was compared between the FL and non-FL groups.

Results: The study population included 20 subjects, 10 in the FL group and 10 in the non-FL group. No subject had clinically impaired lipid absorption. Fat-loading test results were positive for all 10 subjects in the FL group, yielding a positive test result rate of 100%. Conversely, fat-loading test results were negative for all 10 subjects in the non-FL group, yielding a positive test result rate of 0%. The FL group showed a markedly higher positive test result rate than the non-FL group (P < 0.001, Fisher’s exact test). No adverse events occurred during the course of this study.

Conclusion: Lipids loaded onto normal duodenal epithelium were absorbed, and the absorbed LDs was successfully visualized as WOS-positive findings with M-NBI. We suggest that M-NBI observation of duodenal mucosa has the potential to enable endoscopic visualization of duodenal malabsorption, with extension of the scope of future fat-formulation loading to subjects with impaired lipid absorption.

Disclosure of Interest: All authors have declared no conflicts of interest.

References

1. Kanemitsu T, Yao K, Nagahama T, et al. Extending magnifying NBI diagnosis ofintestinal metaplasia in the stomach: the white opaque substance marker. Endoscopy 2017 (in press).

2. Yao K, Iwashita A, Tanabe H et al. White opaque substance within superficial elevated gastric neoplasia as visualized by magnification endoscopy with narrow-band imaging: a new optical sign for differentiating between adenoma and carcinoma. Gastrointest Endosc 2008; 68: 574–580.

3. Yao K, Iwashita A, Nambu M et al. Nature of white opaque substance in gastric epithelial neoplasia as visualized by magnifying endoscopy with narrow-band imaging. Dig Endosc 2012; 24: 419–425

OP081 APPLICATION OF VIRTUAL REALITY IN ENDOSCOPY

A. Hann 1 , B. Walter 1 , S. Schmidt 2 , A. Meining 1

1 Department Of Internal Medicine I, Ulm University, Ulm/Germany

2 Department Of Diagnostic And Interventional Radiology, Ulm University, Ulm/Germany

Contact E-mail Address: Alexander.Hann@uniklinik-ulm.de

Introduction: The standard setting in endoscopy at present is manual manipulation of the endoscope guided by visual input of the screen mounted in front of the examiner. Virtual reality (VR) involving computer-generated replica of the environment or adding useful information to the perceived environment, has the potential of replacing the traditional interaction between examiner and the 2D flat screen.

Aims & Methods: In this work we explored different application scenarios of VR in endoscopy to overcome common problems in daily work and improve training experience. The head-mounted display (HMD) HTC VIVE was used to visualize the datasets generated during gastroenterological work-up. Training videos of different endoscopic procedures like advanced polypectomy, closure of a perforation and treatment of gastrointestinal bleeding were recorded in high-definition quality. Additionally a grab-and-pull navigation method through a CT colonography was designed and tested. Finally the real-time endoscopic image was projected into VR with the implementation of intuitive zoom due to the movement of the head forward during critical steps of the procedure. A survey of a hands-on training at a national endoscopy meeting involving 29 gastroenterologists with mostly over five years of experience in endoscopy was carried out. The survey measured physical and mental load, frustration and discomfort on a 10-point scale ranging from 1 (very low) to 10 (very high). Overall impression was measured also on a 10-point scale ranging from 1 (poor) to 10 (very good).

Results: Using the HMD we were able to generate a comfortable environment to watch training videos involving different endoscopic interventions. Due to the lack of common methods to acquire 3D content using a standard endoscope we used CT colonography datasets with different pathologies to demonstrate the method of the grab-and-pull navigation technique. All participants in the hands-on training completed these tasks and reported to have experienced a median 2 out of 10 for physical demand, 3 out of 10 for metal demand and 1 out of 10 for frustration. Discomfort involving nausea and vertigo was rated as median 1 out of 10. Overall impression was rated as 9 out of 10. Finally we were able to use the HMD during real-time endoscopy adding up the useful function of intuitive zoom to the area of interest during critical parts of an intervention like taking long-distance biopsies. Simultaneous tracking of the endoscope in VR with provision of the live image was able to help introduce different instruments in the working channel.

Conclusion: VR has a great potential for improving daily work in endoscopy and helping during training. The survey involving experienced physicians resulted in a very good rating of the overall impression. VR was successfully applied during real-time endoscopy and helped during interventions. Still interface problems like acquiring 3D images using standard endoscopes need to be investigated in future work. This work was supported by the German Science Foundation (DFG) under Grant FOR 1321.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP082 ARE WE MISSING OPPORTUNITIES TO DIAGNOSE UPPER GASTROINTESTINAL CANCER AT ENDOSCOPY?

S. Priestley , B. Ashall, V. Theis, A. Bassi

Gastroenterology, St Helens & Knowsley Teaching Hospitals NHS Trust, Prescot/United Kingdom

Contact E-mail Address: sue.priestley@sthk.nhs.uk

Introduction: Upper gastrointestinal (UGI) cancers (of the oesophagus and stomach) remain a common cause of cancer death in the UK 1 but early diagnosis can result in improved survival rates. In 2015, the National Institute of Clinical Excellence (NICE) published updated guidance on the indications for endoscopy in suspected UGI cancer 2 . However it is recognised that up to 11.3% of UGI cancers are missed at endoscopy up to 3 years before diagnosis 3 . As a result, as in colonoscopy, there is increasing awareness of the likelihood of missing early UGI cancers hence auditable endoscopy key performance indicators (KPIs) may need to be reviewed 4 .

Aims & Methods: The electronic patient records were studied of all patients diagnosed in 2016 with UGI cancer within our institution, with serves a population of 350, 000. For those patients who had undergone an UGI endoscopy, in the preceding 3 years, demographics, site and stage of lesion and outcomes were recorded. Endoscopy KPIs were reviewed for the prior examination.

Results: 9187 UGI endoscopies were performed in 2016. UGI cancer identified 95 patients of which 7 (7.38%) had an endoscopy in the preceding 3 years; however 1 within national guidance for gastric ulcer follow-up (initial histology negative for dysplasia). 85.7% were male. Mean age 68 years. All presented with UGI alarm symptoms: 4 oesophageal and 3 non-junctional gastric cancers. 42.3% have been offered treatment with curative intent, but unfortunately the remainder were offered palliation due to co-morbidity and/or advanced stage at diagnosis. The prior endoscopies were undertaken for investigation of persistent dyspepsia (4/7), anaemia (2/7) and variceal assessment. Mean interval between diagnostic and earlier endoscopy was 20 months (range 1–31 months). All past endoscopies were undertaken by different operators; 3 consultants, 3 nurse endoscopists and a speciality doctor. All but 1 endoscopist had an individual ‘miss’ rate of <1% of their mean annual UGI procedural numbers. 57.1% were done without sedation, all provided evidence of duodenal intubation but the ‘J’ manoeuvre was not recorded.

Conclusion: Our UGI cancer miss rates for individual endoscopists are low but could improve. The majority of patients were male and 28.6% had alarm symptoms at the time of their initial endoscopy, which are thought to be important factors when diagnosing UGI malignancy, and should maybe have been followed-up more closely. However NICE guidance on the management of dyspepsia 5 continues to state that patients with persistent symptoms, unless they develop alarm symptoms, should be treated as per their endoscopy findings. Therefore we have to continue to improve our endoscopy standards and as a unit we now undertake increased photographic documentation of completion of the procedure. This process of audit is likely to improve the quality of care and will continue.

Disclosure of Interest: All authors have declared no conflicts of interest.

References

1. Office for National Statistics, 2011

2. NICE Clinical Guideline NG12. Suspected cancer: recognition and referral, June 2015.

3. Menom S and Trudgill N. How commonly is upper gastrointestinal cancer missed at endoscopy? A meta-analysis. Endosc Int Open 2014 Jun, 2(2): E46-E50.

4. JAG Summary guide to quality and safety indicators, April 2016.

5. NICE Clinical Guideline CG184. Gastro-oesophageal reflux disease and dyspepsia in adults: investigation and management, updated November 2014.

MONDAY, OCTOBER 30, 201714:00-15:30

CHALLENGES IN PANCREATIC AND BILIARY SURGERY - ROOM E3____________________

OP083 INTERLEUKIN-13 RECEPTOR Α2 PREDICTS PROGNOSIS IN SURGICALLY RESECTED PANCREATIC CANCER PATIENTS

T. Fujisawa , H. Isayama

Department Of Gastroenterology, Juntendo University, Tokyo/Japan

Contact E-mail Address: tossshy@yahoo.co.jp

Introduction: Interleukin-13 Receptor α2 ( IL-13Rα2) is recognized as a tumor-associated antigen and overexpressed in about seventy percent of pancreatic cancer 1 . In the previous study, we revealed that IL-13Rα2 with its ligand promoted human pancreatic cancer cells invasion and metastasis in the immunodeficient mouse model 2 . Based on the results, the relationship between IL-13Rα2 expression in the pancreatic cancer and overall survival of the patient after surgical resection was examined.

Aims & Methods: Intensity (0 to 3+) of IL-13Rα2 expression was examined by immunohistochemistry in surgically resected pancreatic cancer specimens between in 1996 – 2012. Clinical samples were obtained from two independent hospitals in Japan, 107 samples in NTT Medical Center Tokyo and 129 samples in Yokohama City University Hospital, and independently analyzed of each hospital. The patients were divided into two groups because of IL-13Rα2 expression, weak expresser (0 and 1+) and strong expresser (2+ and 3+), and clinical data were compared between two groups.

Results: Firstly, overall survival was compared by Kaplan-Meier method. Median survival time of the strong expresser was significantly shorter than one of the weak expresser (18 months vs. 29 months, p = 0.024) in the samples of NTT Medical Center Tokyo. Clinico-pathological parameters were analyzed for relationship to patient survival using Cox’s proportional hazards model. Four parameters including IL-13Ra2 expression, tumor differentiation, invasion to lymph duct, and UICC-stage were found to be independent prognostic factors. Next, a correlation between variety of clinical factors and IL-13Rα2 expression level were examined using Spearman’s rank correlation test. Intensity of IL-13Rα2 expression was significantly correlated with only survival time and invasion into peripancreatic neuroplexus and nerve in the pancreas, but not correlated with tumor staging and histological differentiation. Same examination was repeated using another sample set from Yokohama City University Hospital as a validation of the results from NTT Medical Center Tokyo. Almost similar result was obtained in the overall survival and the correlation with clinical factors.

Conclusion: These results suggested that high level of IL-13Rα2 expression promoted perineural invasion of pancreatic cancer and shortened host survival time.

Disclosure of Interest: All authors have declared no conflicts of interest.

References

1. Shimamura T, Fujisawa T, Husain SR, Joshi B, Puri RK. Interleukin 13 mediates signal transduction through interleukin 13 receptor alpha2 in pancreatic ductal adenocarcinoma: role of IL-13 Pseudomonas exotoxin in pancreatic cancer therapy. Clin Cancer Res . 2010 Jan 15;16(2):577–86.

2. Fujisawa T, Joshi B, Nakajima A, Puri RK. A novel role of interleukin-13 receptor alpha2 in pancreatic cancer invasion and metastasis. Cancer Res . 2009 Nov 15;69(22):8678–85.

OP084 PERFORMANCE OF A MULTIDISCIPLINARY TEAM IN PREDICTING AND MANAGING RESECTABLE PANCREATIC CANCER

S. Singh , B. Rao, A. Gulati, M. Garg, A. Kulkarni, M. Mitre, K. Farah, S. Morrissey, M. Dhawan, S. Thakkar

Gastroenterology, Allegheny Health Network, Pittsburgh/United States of America/PA

Contact E-mail Address: shail121@gmail.com

Introduction: Surgery offers the only potential curative treatment for pancreatic ductal adenocarcinoma (PDA). Successful resection rates are highly heterogeneous, and rates of microscopic involvement (R1) vary markedly from 20% to over 75%. Furthermore, current guidelines recommend care of these patients to take place at large volume centers utilizing a multidisciplinary pancreatic cancer conference (MDPC) or clinic in order to appropriately manage patients. Initial studies have shown it is not uncommon for changes in staging and management plans after being referred to a MDPC at a large center. However, data is limited with respect to how accurate MDPC are in predicting resectable PDA.

Aims & Methods: The aims of this study are to report the performance of a MDPC in correctly predicting resectable PDA in addition to reporting the outcome of achieving negative surgical margins (R0). The records of consecutive patients presented at a tertiary center’s bi-monthly MDPC were prospectively collected from March 2013 to August 2016. A panel of gastroenterologists, medical, radiation and surgical oncologists, pathologists and body radiologists reviewed clinical history, endoscopic ultrasound results, cross-sectional imaging, and pathology to determine resectability. Patients were included if they were deemed to have resectable PDA by MDPC consensus and underwent upfront surgical exploration. Surgical outcomes were analyzed on an intention-to-treat basis as all patients underwent surgery with curative intent.

Results: A total of 278 patients with PDA were presented at the MDPC. Ninety-one (32.7 %) were determined as resectable by MDPC team members. Twenty-one patients were excluded (11 patients lost to follow or declined surgery, and 10 were medically unfit). Seventy patients underwent upfront surgical exploration with a curative intent and were included for final analysis. Patient demographics, tumor characteristics, surgical and pathological outcomes are summarized in Table 1. MDPC successfully predicted resection in 64 out of 70 patients (91.4%). Six patients were found to have metastatic disease on surgical exploration. 78.6% (55/70) patients had R0 resections and 12.8 % (9/70) patients had R1 margins. There were no grossly positive margins (R2 resection). Patients went to surgery at a median of 22 days from diagnosis and 15 days from the MDPC decision to resect. Table 1: The demographic, clinical characteristics, surgical and pathologic outcomes of 70 patients explored for ‘resectable’ pancreatic cancer. Outcomes were analyzed on an intention-to-treat basis as all patients underwent surgery with curative intent.

Conclusion: A MDPC demonstrated a high rate of predicting resectability along with achieving a high percentage of R0 resections at an experienced center. Data from other large centers may help validate the importance of utilizing a MDPC to predict resectability. Moreover, benchmark R0 resection rates are needed and can provide a quality metric for the treatment of resectable pancreatic cancer.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP085 DEFECTS IN PROTEIN PROCESSING MAY UNDERLIE THE DEVELOPMENT OF HEPATIC CYSTS IN PATIENTS WITH POLYCYSTIC LIVER DISEASE

L. F.m. Van De Laarschot 1 , S. A. B. Hermsen 1 , T. F. Wijnants 1 , E.S. Wills 1 , H. J. Wessels 2 , J.P. h. Drenth 1

1 Gastroenterology & Hepatology, Radboudumc, Nijmegen/Netherlands

2 Nijmegen Center For Mitochondrial Disorders, Radboud Proteomics Center, Translational Metabolic Laboratory, Department Of Laboratory Medicine, Radboudumc, Nijmegen/Netherlands

Contact E-mail Address: liyanne.vandelaarschot@radboudumc.nl

Introduction: Mutations in PRKCSH and SEC63 cause autosomal dominant polycystic liver disease. Both are involved in co-translational protein translocation and maturation of glycoproteins in the endoplasmic reticulum. Defects of either gene will have a significant impact on the biogenesis of polycystic liver disease (PLD)-associated proteins. We aimed to identify which proteins are affected in PLD.

Aims & Methods: Organoids cultured from PLD patients with and without known mutations were used for RNA sequencing. Heatmaps were generated with gene subsets created from the lists of significant genes. Functional analysis of identified genes was performed with Ingenuity Pathway Analysis. Hepatic cyst fluid from PLD patients who underwent aspiration-sclerotherapy or cyst fenestration was obtained for glycopeptides profiling using a mass-spectrometry based technique.

Results: We isolated RNA from organoids of 8 PLD patients (3 PRKCSH mutants) and 4 patients without known liver histopathology. Preliminary RNAseq data analysis revealed distinct gene expression profiles of organoids cultured from PLD patients with PRKCSH mutation, patients without mutations and normal patients. PLD organoids displayed a heterogeneous expression pattern within their group. PRKCSH mutants shared expression of a subset of genes. The changes indicate endoplasmic reticulum related processes, such as ‘protein folding in endoplasmic reticulum’ and ‘response to endoplasmic reticulum stress’. Mass-spectrometry analysis distinguishes glycopeptide profiles from cyst fluid of PLD patients with ( n = 4 ) and without ( n = 8 ) PRKCSH mutation.

Conclusion: These data strongly suggest a specific defect in protein maturation and localization in the endoplasmic reticulum, and protein glycosylation play a role in the development of hepatic cysts in PLD patients.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP086 A DEDICATED BILIARY THEATRE LIST IMPROVES EARLY DEFINITIVE MANAGEMENT AND REDUCES READMISSIONS IN ACUTE GALLSTONE PANCREATITIS

M. A. Goldsworthy 1 , P. J. Gardiner 1 , R. A. Adair 2 , A. M. Smith 2 , C. Macutkiewicz 2

1 University of Leeds, Leeds/United Kingdom

2 Leeds Teaching Hospitals NHS Trust, Leeds/United Kingdom

Contact E-mail Address: um12mg@leeds.ac.uk

Introduction: Patients with acute biliary pancreatitis require urgent management of gallstones to prevent recurrence of pancreatitis and other gallstone-related disorders. 1 This is achieved by laparoscopic cholecystectomy with on-table cholangiography or, in patients unfit for surgery, endoscopic sphincterotomy. Latest guidelines from the International Association of Pancreatology recommend that patients with mild biliary pancreatitis receive such procedures during their index hospital admission. 2 However, restricted access to acute theatre slots may limit compliance with this recommendation and place patients at risk of adverse outcomes due to delayed treatment.

Aims & Methods: This study aimed to evaluate the impact of a daily theatre list dedicated to acute biliary disease on the management and outcomes of mild biliary pancreatitis. Retrospective audits were conducted during two six-month periods, before and after the introduction of an acute biliary list at our UK centre. All patients admitted with acute pancreatitis were identified from coded diagnosis data. Those aged 18 years and older with a diagnosis of mild acute pancreatitis secondary to gallstones, as per the revised Atlanta classification 3 , were eligible for inclusion. The nature and timing of definitive gallstone management, perioperative complications, duration of hospital stay, and interval readmission details were recorded from electronic medical records. Patients were excluded if they were unsuitable for intervention due to significant co-morbidities or if they refused treatment. Changes between the audit periods were assessed using the Chi-squared test for categorical variables and the Mann-Whitney U test for continuous variables. p < 0.05 was considered statistically significant.

Results: In the first audit period (September 2013 – February 2014), 34 patients with mild biliary pancreatitis were included (median age 60 years; 79% female). Management of gallstones by laparoscopic cholecystectomy or endoscopic sphincterotomy was performed at the index admission in 14 cases (41.2%), while 17 (50.0%) had delayed treatment; 3 patients (8.8%) received no definitive management. In the second audit period (September 2015 – February 2016), 49 patients were included (median age 56 years; 55% female). Gallstone management was performed at the index admission in 42 cases (85.7%) and after a delay in 6 cases (12.2%); 1 patient (2.0%) received no definitive management. Between the first and second audit periods, the rate of definitive management of gallstones at the index admission increased by 44.5% (41.2% vs. 85.7%; p < 0.001). This was associated with an 18.6% reduction in the proportion of patients readmitted with gallstone-related disorders (20.6% vs 2.0%; p = 0.005). The median duration of total inpatient stay also decreased from 8 days to 6 days (p = 0.029), while there was no significant difference in the rate of perioperative complications (6.5% vs. 4.2%; p = 0.651).

Conclusion: The introduction of daily theatre slots dedicated to acute biliary disease led to a major improvement in the proportion of patients who received definitive management of acute gallstone pancreatitis at their index hospital admission. In turn, there was a significant reduction in readmissions and length of hospital stay. We therefore present a simple and effective intervention that could be rapidly adopted in other centres to improve the management of biliary pancreatitis, reduce the risk of recurrence, and achieve cost savings due to shorter hospital stays.

Disclosure of Interest: All authors have declared no conflicts of interest.

References

1. van Baal MC, Besselink MG, Bakker OJ, et al. Timing of cholecystectomy after mild biliary pancreatitis: a systematic review. Ann Surg . 2012; 255: 860–6.

2. IAP/APA evidence-based guidelines for the management of acute pancreatitis. Pancreatology . 2013; 13: e1–15.

3. Banks PA, Bollen TL, Dervenis C, et al. Classification of acute pancreatitis – 2012: revision of the Atlanta classification and definitions by international consensus. Gut . 2013; 62: 102–11.

OP087 GENERATION AND TRANSPLANTATION OF BIOENGINEERED BILE DUCTS FOR RECONSTRUCTION OF THE EXTRAHEPATIC BILIARY TREE

F. Sampaziotis 1 , A. Justin 2 , O. Tysoe 3 , S. Sawiak 4 , E. Godfrey 5 , S. Upponi 5 , N.L. Berntsen 6 , L. Valestrand 6 , T.H. Karlsen 7 , E. Melum 6 , A. Markaki 2 , K. Saeb-Parsy 3 , L. Vallier 8

1 Hepatology, Cambridge University Hospitals NHS Foundation Trust, Cambridge/United Kingdom

2 Engineering, University of Cambridge, Cambridge/United Kingdom

3 Surgery, University of Cambridge, Cambridge/United Kingdom

4 University of Cambridge, Cambridge/United Kingdom

5 Cambridge University Hospitals NHS Foundation Trust, Cambridge/United Kingdom

6 Department Of Transplantation Medicine, Division Of Cancer Medicine, Surgery And Transplantation, Oslo University Hospital Rikshospitalet, Oslo University Hospital Transplantation Center, Oslo/Norway

7 Norwegian Psc Researach Center, Oslo University Hospital Rikshospitalet - Norwegian PSC Researach Center, Oslo University Hospital R, Oslo/Norway

8 Cambridge Stem Cell Institute, University of Cambridge, Cambridge/United Kingdom

Contact E-mail Address: fotiss@yahoo.com

Introduction: The management of bile duct disorders such as biliary atresia, primary sclerosing cholangitis and biliary strictures is limited to liver transplantation and hepatojejunostomy due to the lack of bile duct tissue suitable for surgical replacement. We have recently developed a system for the generation of stem cell-derived cholangiocytes in organoid format 1, 2 . Here we apply this platform to propagate primary human extrahepatic biliary epithelium in the form of extrahepatic cholangiocyte organoids (ECOs), which are used in combination with biodegradable scaffolds for the generation of bioengineered biliary tissue. Subsequently, we explore the potential of this tissue to reconstruct the biliary tree of immune compromised mice following transplantation.

Aims & Methods: 1. Development of a method for the isolation and propagation of primary cholangiocytes in organoid format. 2. Characterization of the resulting ECOs. 3. Seeding of ECOs on biodegradable scaffolds for the generation of bioengineered tissue and characterization of this tissue in vitro. 4. Transplantation of this tissue in immune compormised mice and reconstruction of the extrahepatic biliary tree (bile duct and gallbladder). Primary human cholangiocytes were isolated by mechanical dissociation from deceased organ donors with ethical approval and informed consent (n = 8). Propagation of ECOs was achieved using our established protocol. The Illumina HumanHT-12v4 array was used for transcriptomic analysis. ECOs were seeded on Polyglycolic Acid (PGA) or densified collagen scaffolds. Biliary reconstruction was achieved in immunodeficient NSG mice by partially replacing the gallbladder wall with an ECO populated PGA-scaffold patch (ECO-patch; n = 8), or replacing a length of the native common bile duct with ECO populated collagen tubes (ECO-tubes) through end-to-end anastomosis (n = 4). Fibroblast-populated (n = 5, PGA; n = 4, collagen) or acellular scaffolds (n = 2, PGA) were used as negative controls. Biliary tree patency was confirmed using magnetic resonance cholangiopancreatography (MRCP) or cholangiography. Mouse serum samples were routinely processed for markers of cholestasis by the University of Cambridge Core biochemical assay laboratory (CBAL) using a Siemens Dimension EXL analyzer.

Results: ECOs closely correlate with primary cholangiocytes in terms of transcriptomic profile (r: 0.92) and functional properties (ALP, GGT, bile acid transfer). ECOs maintain their genetic stability and expand exponentially during long-term culture (20 passages). ECO-populated scaffolds form biliary tissue-resembling structures, maintain their functional properties (ALP, GGT) and marker expression (CK7, CK19, HNF1B). This bioengineered tissue can reconstruct the wall of the gallbladder and replace the native common bile duct, following transplantation in immunocompromised mice. All animals transplanted with ECO-populated scaffolds exhibited prolonged survival compared to controls (ECO-patch vs. acellular controls, P = 0.0027; ECO-tubes vs. fibroblasts, P = 0.0082; log-rank test). The transplanted cells integrated in the biliary epithelium, continued expressing biliary markers (CK7, CK19, HNF1B) and exhibited ALP activity. Lumen patency was confirmed on MRCP and cholangiogram. Animals with a neo-bile duct maintained normal levels of serum cholestasis markers up to one month post transplantation. All fibroblast reconstructions failed, the biliary epithelium was replaced by fibrotic tissue and the lumen of the gallbladder or neo-bile duct was occluded.

Conclusion: We demonstrate that ECO-populated biodegradable scaffolds maintain key biliary characteristics and can successfully reconstruct/replace parts of the biliary tree in vivo. To our knowledge, this is the first demonstration for the application of regenerative medicine in the management of cholangiopathies and first report of an organ reconstruction using human primary cells expanded in vitro.

Disclosure of Interest: L. Vallier: Ludovic Vallier is a founder and shareholder of Definigen

All other authors have declared no conflicts of interest.

References

1. Sampaziotis F. et al. Nat Biotechnol . 2015;33:845–52

2. Sampaziotis F. et al. Nat Protoc . 2017;12:814–827

OP088 A SYSTEMATIC REVIEW ON THE DEVELOPMENT OF MALIGNANCY IN 2904 PATIENTS WITH CONGENITAL CHOLEDOCHAL MALFORMATION

A. Ten Hove 1 , J. B. f. Hulscher 2 , V. E. De Meijer 1 , R. H. j. De Kleine 1

1 Department Of Hepato-pancreatico-biliary Surgery And Liver Transplantation, University of Groningen and University Medical Center Groningen, Groningen/Netherlands

2 Department Of Pediatric Surgery, University of Groningen and University Medical Center Groningen, Groningen/Netherlands

Contact E-mail Address: anneketenhove@me.com

Introduction: Choledochal malformation (CM) comprises a variety of rare congenital cystic dilatations of the extrahepatic and/or intrahepatic biliary tree, classified according to Todani. Its etiology remains unclear. Although CM is generally considered a premalignant condition, the literature with respect to the risk of malignancy and optimal surgical treatment has not been reviewed systematically. Partly due to its rarity, guidelines for treatment and follow-up are difficult to establish.

Aims & Methods: The aim of this systematic review was to assess the prevalence of malignancy in CM and the differences between its subtypes. Secondary goal was to investigate the risk of malignancy following a cystic drainage procedure versus complete cyst excision.

Methods: This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement and was registered in PROSPERO, the international prospective register of systematic reviews (CRD42016048392). A systematic search of PubMed and Embase was performed for articles published between January 1995 and June 2016 (cut-off date June 1st, 2016) relevant to malignant prevalence and/or malignant transformation in CM patients. A meta-analysis on the risk of malignancy following cystic drainage procedure versus complete cyst excision was carried out in accordance with the Meta-analysis Of Observational Studies in Epidemiology (MOOSE) guidelines.

Results: We included 18 observational studies with a total of 2904 patients, median age 36 years (range 0–87), 76% female. Overall, 312/2904 patients developed a malignancy (10.7%). In 212 patients (7.3%) tumors were present during initial surgery, in 100 patients (3.4%) tumors developed during follow-up. The median age at detection of malignancy was 49.5 years (range 12–82 years). Malignancy occurred mainly in CM type IV cysts (in 14%). In CM type I, II, III, and V the malignancy rate was 9%, 3%, 8%, and 6%, respectively (Pearson χ 2 , 17, 896, 4 df, P = 0.001). Of 18 observational studies identified, 9 studies including a total of 1270 patients were subjected to meta-analysis of the different surgical techniques. Compared with patients who underwent complete cyst excision followed by bilio-digestive reconstruction, those who underwent a cystic drainage procedure had a significantly increased risk to develop a biliary malignancy, with an odds ratio of 3.94 (95% confidence interval 2.39 to 6.51).

Conclusion: Overall, some 11% of patients with CM may develop a malignancy, especially those with type IV and type I cysts. Patients treated with a cystic drainage procedure had an up to fourfold increased risk to subsequently develop a malignancy following surgery, compared to those who underwent complete cyst excision. Reoperation with complete cyst excision in these patients should be considered. Malignant transformation may occur up to 30 years after initial surgery, therefore careful monitoring of these patients is mandatory, especially those patients who underwent cystic drainage procedures and those with CM types I and IV.

Disclosure of Interest: All authors have declared no conflicts of interest.

MONDAY, OCTOBER 30, 201714:00-15:30

DRUGS, LIVER AND PANCREAS - ROOM B5____________________

OP089 A NOVEL IN VITRO TEST FOR CAUSALITY ASSESSMENT IN POLYMEDICATED PATIENTS WITH DRUG-INDUCED LIVER INJURY: CASES WITH DRUG RECHALLENGE

A. Benesic 1 , D. Dragoi 1 , I. Rotter 2 , M. Buchholtz 3 , A. Leitl 2 , A. L. Gerbes 2

1 MetaHeps GmbH, Martinsried/Germany

2 Internal Medicine 2 Liver Centre Munich, University Hospital Munich (KUM), Munich/Germany

3 Laboratory Medicine, University Hospital Munich, Munich/Germany

Contact E-mail Address: abenesic@metaheps.com

Introduction: Idiosyncratic drug-induced liver injury (iDILI) is one of the most challenging diagnoses in hepatology [1]. Diagnosis is based on exclusion of other aetiologies of liver damage in combination with typical drug signatures. Correct causality assessment may be impossible in polymedicated patients. We have investigated a novel in vitro test employing monocyte-derived hepatocyte-like (MH) cells and its possible use to support causality assessment in polymedicated iDILI.

Aims & Methods: This study prospectively included patients with suspected iDILI referred to the University Hospital Munich. Patient data for causality assessment and blood samples for MH cell generation were collected. Diagnosis by expert review was used as reference standard. Additionally the RUCAM score was calculated. MH cells were generated by a proprietary protocol[2]. and were treated with the respective drugs and toxicity response was determined by release of lactate-dehydrogenase. Test analysis was performed as described in [3] Performance of MH testing in drug causality was analysed in a subset of patients with data on positive or negative drug rechallenge.

Results: A total of 146 patients were included, 93 adjudicated as iDILI and 53 patients with liver injury unrelated to medication. A majority of the iDILI patients was exposed to at least two drugs (n = 79; 85%). In the subset of 120 polymedicated patients (79 iDILI; 41 nonDILI) the MH test sensitivity was 96% and specificity was 98% for iDILI diagnosis, respectively. In polymedicated cases RUCAM showed a sensitivity of 73% and a sensitivity of 81%, respectively. In 32 polymedicated iDILI patients re-exposures occurred: of 11 drugs with inadvertent positive rechallenge 10 drugs were correctly identified by the MH cell test. All of the 69 drugs that showed negative re-exposure were negative in the MH cell test.

Conclusion: Polymedication is a very frequent issue in iDILI causality assessment. RUCAM has a low sensitivity and specificity in polymedicated iDILI cases. MH cell testing showed a high sensitivity and specificity for iDILI diagnosis and drug causality in polymedicated iDILI patients with rechallenge. Thus, the MH cell test seems to be a valuable tool for causality assessment in complex iDILI cases.

Disclosure of Interest: A. Benesic: Stakeholder MetaHeps GmbH Patent holder

D. Dragoi: Employee MetaHeps GmbH

A.L. Gerbes: Stakeholder MetaHeps GmbH Patent holder

All other authors have declared no conflicts of interest.

References

1. Chalasani NP. Hayashi PH. Bonkovsky HL et al. ACG Clinical Guideline: the diagnosis and management of idiosyncratic drug-induced liver injury. Am J Gastroenterol . 2014 Jul;109(7):950–66

2. Benesic A. Rahm NL. Ernst S et al. Human monocyte-derived cells with individual hepatocyte characteristics: a novel tool for personalized in vitro studies. Lab Invest . 2012 Jun; 92(6):926–36

3. Benesic A. Leitl A and Gerbes AL. Monocyte-derived hepatocyte-like cells for causality assessment of idiosyncratic drug-induced liver injury. Gut . 2016 Sep; 65(9):1555–63

OP090 SCREENING RATE FOR HEPATITIS B VIRUS AMONG CANCER PATIENTS RECEIVING CHEMOTHERAPY IN TAIWAN: A NATIONWIDE POPULATION-BASED STUDY

W.C. Sun 1 , K. Lin 1 , H. Yu 1 , W. Chen 1 , W. Tsai 1 , H. Chan 1 , P. Hsu 1 , H. Lin 1 , P. Tang 2 , J. Cheng 1

1 Division Of Gastroenterology And Hepatology, Department Of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung City/Taiwan

2 Research Center Of Medical Informatics, Kaohsiung Veterans General Hospital, Kaohsiung City/Taiwan

Contact E-mail Address: maudisun@gmail.com

Aims & Methods: The aim of this study was to evaluate the screening rate for HBV among cancer patients receiving chemotherapy in Taiwan. We collected data from National Health Insurance Research Database in Taiwan on cancer patients receiving chemotherapy from January 1, 2000 to December 31, 2012. The data were collected regarding age, gender, case-loading, department, and specialist of doctor administering chemotherapy, age, gender, and department of patient, type of cancer, and HBV testing (HBsAg, anti-HBc, and anti-HBs) within 2 years prior to chemotherapy. HBV screening was identified based on tests for HBsAg. Overall screening rates were compared between different types of cancer, departments of patient, and time periods before and after the announcement of Taiwanese guideline and the implementation of NHI regulation. Annual percentage change of screening rate and factors associated with screening were also investigated.

Introduction: Many clinical practice guidelines recommend that all cancer patients should be screened for HBV infection before chemotherapy, but the screening rate of 14% - 34% reported from previous studies remains unsatisfactory. In Taiwan, an endemic area of HBV infection, HBV testing (HBsAg/anti-HBc) for all cancer patients scheduled for chemotherapy and prophylactic antiviral therapy for those who are HBsAg-positive have been advised by our guideline and subsidized by National Health Insurance (NHI) since 2009.

Results: Of 379,639 cancer patients, 174,141 (45.9%) received pre-chemotherapy HBV screening. Of patients with screening, 73.2% were tested for HBsAg, 22.1% for HBsAg/anti-HBc, and 4.7% for HBsAg/anti-HBc/anti-HBs. The overall screening rate was 79.1% for hematological cancer and 43.6% for solid cancer; 55.3% for patients from medical departments and 30.9% for those from surgical departments; 38.1% during 2000–2008 and 57.5% during 2009–2012 (p < 0.0001). The annual screening rate for all patients increased from 31.5% in 2000 to 66.3% in 2012, from 64.5% to 90.7% for those with hematological cancer, and from 28.7% to 64.6% for those with solid cancer (p < 0.0001). There was a higher rise of screening rate by 35.9% for solid cancer than by 26.2% for hematological cancer (p < 0.0001). Factors significantly associated with HBV screening were treatment by younger doctor, female doctor, specialist, medical doctor, and doctor with higher-volume case-loading, younger patient, male patient, hematological cancer, and the time period during 2009–2012 (p < 0.0001).

Conclusion: The screening rate for HBV in cancer patients before chemotherapy is still suboptimal. Although the public policy can increase the screening rate, there are some barriers needed to be overcome to improve the awareness about HBV reactivation during chemotherapy.

Disclosure of Interest: All authors have declared no conflicts of interest.

References

1. Hwang P, et al. Low rates of hepatitis B virus screening at the onset of chemotherapy. J Oncol Pract 2012; 8:e32-e39.

2. Lee R, et al. Screening for hepatitis B surface antigen before chemotherapy: current practice and opportunities for improvement. Curr Oncol 2010; 17:32–38.

3. Wang Y, et al. Testing for hepatitis B infection in prospective chemotherapy patients: a retrospective study. World J Gastroenterology 2013; 19:923–930.

4. Chung-II Wi, et al. Low level of HBV screening Among patients receiving Chemotherapy . 2015; 13(5): 970-e51.

OP091 NODULAR REGENERATIVE HYPERPLASIA IN INFLAMMATORY BOWEL DISEASE: LOW IMPACT IN DAILY PRACTICE

M. Simsek , B. Meijer, K. H. N. De Boer, C.J. j. Mulder

Gastroenterology and Hepatology, VU Medical Center, Amsterdam/Netherlands

Contact E-mail Address: m.simsek@vumc.nl

Introduction: Nodular regenerative hyperplasia (NRH) of the liver is a poorly understood condition which has previously been related to, amongst others, the use of thiopurines in patients with inflammatory bowel disease (IBD). The diagnosis and management of NRH are challenging since the natural history of this disease is unknown, and the clinical presentation varies from asymptomatic to severe complications of portal hypertension, such as variceal bleeding or ascites.

Aims & Methods: In this nationwide study, we aimed to assess the clinical, biochemical, radiological and histological characteristics of NRH in order to identify risk parameters and the clinical course of this disease. We requested the departments of gastroenterology and hepatology from all Dutch hospitals (n = 81) to complete questionnaires. When NRH cases were present, subsequent questionnaires were sent in order to collect data on demographics, clinical presentation, blood counts, liver chemistry and abdominal imaging.

Results: In total, 72 hospitals (89%) responded to our primary questionnaire. Based on the completed questionnaires, approximately 22,500 IBD-patients are treated with thiopurines, annually. Out of a total of 85 identified cases of NRH, 54 were thiopurine using IBD-patients (64%; 38 men, mean age at NRH diagnosis 49 years [range: 17–74], mean disease duration 17 years [range: 3–44]). Of these, 35 patients were (historically) treated with azathioprine (65%), 18 with mercaptopurine (33%) and 25 with thioguanine (46%). Of the NRH patients exposed to thioguanine, 80% received azathioprine and/or mercaptopurine before. At the time of diagnosis, 58% of the patients had thrombocytopenia, 43% had elevated liver enzymes and 63% had liver-related abnormalities at abdominal imaging. Furthermore, 20 out of 54 patients (37%) presented with signs of portal hypertension (i.e. esophageal variceal bleeding in 45%, thrombocytopenia in 95%, splenomegaly in 55% and ascites in 10%).

Conclusion: In this largest NRH case series to date, the majority of the patients were men (70%) and had an asymptomatic clinical presentation (63%) at time of diagnosis, consistent with earlier literature reports.

Disclosure of Interest: All authors have declared no conflicts of interest.

References

1. Vernier-Massouille G, Cosnes J, Lemann M, et al. Nodular regenerative hyperplasia in patients with inflammatory bowel disease treated with azathioprine. Gut 2007; 56(10): 1404–9.

2. Shastri S, Dubinsky MC, Fred Poordad F, Vasiliauskas EA, Geller SA. Early nodular hyperplasia of the liver occurring with inflammatory bowel diseases in association with thioguanine therapy. Arch Pathol Lab Med 2004; 128(1): 49–53.

3. Musumba CO. Review article: the association between nodular regenerative hyperplasia, inflammatory bowel disease and thiopurine therapy. Aliment Pharmacol Ther 2013; 38(9): 1025–37.

4. De Boer NK, Tuynman H, Bloemena E, et al. Histopathology of liver biopsies from a thiopurine-naive inflammatory bowel disease cohort: prevalence of nodular regenerative hyperplasia. Scand J Gastroenterol 2008; 43(5): 604–8.

OP092 CAN MESALAZINE AFFECT THE PROGNOSIS OF ACUTE PANCREATITIS?––EVIDENCE FROM THE INTESTINE

L. Huang , W. Yang, J. Li, Y. Tai, C. Ye, S. Tang, C. Tang

Department Of Gastroenterology, West China Hospital, Sichuan University, Chengdu/China

Contact E-mail Address: melody224@163.com

Introduction: The intestine plays an important role in the development of acute pancreatitis (AP). Previous studies have indicated that controlling the intestinal inflammation, restoring the intestinal mucosal barrier function and improving intestinal micro-ecological environment may lessen the severity of AP and improve its prognosis. Mesalazine has been proved to effectively alleviate active intestinal inflammation and regulate intestinal flora. However, it is still unclear whether mesalazine has similar effect in AP. This study is to investigate whether mesalazine can affect the prognosis of AP and to find out its evidence from the intestine.

Aims & Methods: 70 patients with AP were randomly divided into conventional treatment group (n = 38) and mesalazine group (n = 32). Meanwhile, 20 healthy adults were recruited for the analysis of intestinal flora in the healthy control group. Histological score of duodenal inflammation was evaluated after hematoxylin-eosin staining. The expression of myeloperoxidase in the duodenal mucosa was semi-quantified by immunohistochemistry for evaluating the extent of neutrophil infiltration. Second-generation high-throughput sequencing was performed to detect intestinal flora. Circulating levels of proinflammatory cytokines (C-reactive protein, interleukin (IL)-6, tumor necrosis factor-α, IL-8) were measured by enzyme-linked immunosorbent assay on admission and the 9 th day after admission. During hospitalization, the incidence of organ failure, septic complications and death were recorded as well.

Results: 1) Mesalazine alleviated the inflammatory changes of duodenum. Histological scores of duodenal inflammation and neutrophil infiltration in duodenal mucosa were much lower in mesalazine group than that of in conventional treatment group (P < 0.05). 2) Compared with healthy control group, the proportion of aggressive bacteria of conventional treatment group were significantly elevated (P < 0.05), while that of protective bacteria were decreased significantly (P < 0.05). After mesalazine administration, the proportion of aggressive bacteria were decreased significantly (P < 0.05), while that of protective bacteria were increased significantly (P < 0.05). 3) Compared with conventional treatment, mesalazine markedly increased the degree of decline in circulating proinflammatory factors (P < 0.05). 4) Mesalazine significantly reduced the incidence of organ failure (P < 0.05).

Conclusion: Mesalazine could improve the prognosis of AP patients to a certain extent, possibly by rebalancing intestinal bacterial composition, alleviating duodenal and systemic inflammation.

Disclosure of Interest: All authors have declared no conflicts of interest.

References

1. Frossard JL, Steer ML, Pastor CM. Acute pancreatitis. Lancet , 2008, 371: 143–152.

2. Llopis M, Antolin M, Carol M, et al. Lactobacillus casei downregulates commensals' inflammatory signals in Crohn's disease mucosa. Inflamm Bowel Dis , 2009, 15: 275–283.

3. Sokol H, Pigneur B, Watterlot L, et al. Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients. Proc Natl Acad Sci , 2008, 105: 16731–16736.

4. Kaufman J, Griffiths TA, Surette MG, et al. Effects of mesalamine (5-aminosalicylic acid) on bacterial gene expression. Inflamm Bowel Dis , 2009, 15: 985–996.

5. Rajilić-Stojanović M, Smidt H, de Vos WM. Diversity of the human gastrointestinal tract microbiota revisited. Environ Microbiol , 2007, 9: 2125–2136.

OP093 STATINS AND RISK OF ACUTE PANCREATITIS - A META-ANALYSIS OF OBSERVATIONAL STUDIES

G. Poropat 1 , L. Archibugi 2 , T. Korpela 3 , K. Cardenas-Jaen 4 , E. De-Madaria 4 , G. Capurso 2

1 Department Of Gastroenterology, University Hospital Rijeka, Rijeka/Croatia

2 Digestive & Liver Disease Unit, Sant'Andrea Hospital, Faculty of Medicine and Psychology, University of Rome "La Sapienza", Rome/Italy

3 Department Of Surgery, Helsinki University Hospital, University of Helsinki, Helsinki/Finland

4 Gastroenterology Department, Alicante University General Hospital. ISABIAL-FISABIO Foundation, Alicante/Spain

Contact E-mail Address: goran_poropat@yahoo.com

Introduction: Existing reports on the association between statins administration and the risk of developing acute pancreatitis (AP) are contradictory. Statins are widely perceived as potential etiological factors for AP, but more recent evidence suggests the opposite. The mechanisms of their possible benefit is still unclear, with experimental studies showing potential specific anti-inflammatory aspects. The latest meta-analysis on this topic evaluted only clinical trials, excluding observational studies and found a reduced risk of AP in statin users.

Aims & Methods: The aim of this systematic review and meta-analysis was to evaluate the association between the use of statins and the risk of developing AP. Medline, Scopus, and Web of Science were searched for cohort (C) and case-control (C-C) studies in which statins are included as an intervention and AP as an outcome regardless of publication language. Two authors independently searched the literature and extracted data. Disagreements were solved by discussion and by decision of a third author. Eligible studies were selected according to the PRISMA statement. Pooled adjusted ORs with corresponding 95% CIs were calculated using random effects model. Publication bias was assessed through Begg and Mazumdar test. Heterogeneity was assessed by means of the I 2 value.

Results: A total of 13 studies (7 CC, 6 C) contributed to the analysis. A total of 34,899 AP patients and 5,377,894 controls were included. The pooled prevalence of statin use was 9.8% (3411/34,899) among AP patients and 25% (1,357,175/53,77,894) among controls. The pooled adjusted OR for the 13 studies was 1.00 (95% CI 0.63–1.59; p = 0.99) with considerable heterogeneity (I 2 = 98%). In a sensitivity analysis for study design, case-control studies were associated to an increased risk (OR 1.33; 95% CI 1.20–1.47; p < 0.0001), but cohort studies were not (OR 0.69; 95% CI 0.37–1.31; p = 0.26). Similarly, in a sensitivity analysis for country of origin no association with the risk was seen for Western countries (OR 0.90; 95% CI 0.52–1.56; p = 0.71) while there was an increased risk in studies conducted in Asia (OR 1.39; 95% CI 1.10–1.75; p = 0.006). There was evidence of publication bias (Begg and Mazudmar Kendall’s tau = −0.549; p = 0.006) suggesting that studies showing an increased risk of AP associated with statin use were more likely to be published than studies with negative results.

Conclusion: The results of the first meta-analysis of observational studies for the association between statins use and AP suggest the absence of an increased risk in statin users. Evidence for an increased risk is limited to case-control studies, while cohort studies showed no global effect, similarly to previous data from controlled trials. Further research on the topic is needed to clarify whether statin type, dosage, lenght of use or etiology of AP might account for this difference.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP094 CLINICAL SIGNIFICANCE OF PATHOGENIC CTRC, CFTR AND SPINK1 MUTATIONS IN CHILDHOOD-ONSET PANCREATITIS (DATA ANALYSIS FROM APPLE STUDY)

B. Nemeth 1 , A. Parniczky 2 , C. Pienar 3 , M. Sahin-Toth 4 , P. Hegyi 5

1 First Department Of Medicine, University of Szeged, Szeged/Hungary

2 Heim Pal Children’s Hospital, Budapest/Hungary

3 Pediatrics Department, "Victor Babes" University of Medicine and Pharmacy, Timisoara/Romania

4 Center For Exocrine Disorders, Department Of Molecular And Cell Biology, Boston University Henry M. Goldman School of Dental Medicine, Boston/United States of America/MA

5 Institute For Translational Medicine, University of Pecs, Pecs/Hungary

Contact E-mail Address: nemeth.balazs@med.u-szeged.hu

Introduction: Increasing incidence of pancreatitis was observed in children in the past years. Genetic risk is a significant etiological factor in pediatric cases. Specific genetic testing became relatively widely available after the discovery of susceptibility genes. Mutations in the CTRC, CFTR and SPINK1 genes are overrepresented in pediatric pancreatitis. It is still unclear whether these mutations change the clinical onset and outcome in these patients.

Aims & Methods: Our aim was to perform genetic testing and investigation of genotype-phenotype associations in childhood-onset pancreatitis. Patients with childhood-onset pancreatitis (n = 121) were recruited by the Hungarian Pancreatitis Study Group. The clinical data of patients who carried known pathogenic mutation(s) in the CTRC (n = 41) or CFTR (n = 15) or SPINK1 (n = 13) genes were compared to those patients who did not have any known genetic risk factor (n = 62).

Results: Patients with pancreatitis who carried pathogenic CTRC or SPINK1 mutations more likely developed recurrent acute or chronic pancreatitis than those patients who did not have any genetic risk factor (48.7% or 70% vs. 8.8%, respectively). Additionally, average number of documented acute episodes was higher in patients carrying CTRC or SPINK1 mutation(s) compared to the control group (4.5 or 3.4 vs. 1.5, respectively). Age of onset and days spent in the hospital did not differ significantly between groups of patients carrying pathogenic mutation(s) ( CTRC or CFTR or SPINK1 ) and patients without any known genetic risk factor.

Conclusion: Patients with childhood-onset pancreatitis more likely develop recurrent acute or chronic pancreatitis if they carry pathogenic CTRC or SPINK1 mutation(s). Moreover, they develop acute episodes more frequently compared to those patients who do not have genetic risk factor. Mutations in the CTRC or CFTR or SPINK1 genes do not influence the age of onset and the duration of hospitalization in children with pancreatitis.

Disclosure of Interest: All authors have declared no conflicts of interest.

Reference

Párniczky A, Mosztbacher D, Zsoldos F, Tóth A, Lásztity N, Hegyi P; Hungarian Pancreatic Study Group and the International Association of Pancreatology. Analysis of Pediatric Pancreatitis (APPLE Trial): Pre-Study Protocol of a Multinational Prospective Clinical Trial. Digestion . 2016;93(2):105–10. doi: 10.1159/000441353. Epub 2015 Nov 26.

MONDAY, OCTOBER 30, 201715:45-17:15

CLINICAL TRIALS IN ULCERATIVE COLITIS - ROOM F2____________________

OP095 TOFACITINIB, AN ORAL JANUS KINASE INHIBITOR, IN THE TREATMENT OF ULCERATIVE COLITIS: OPEN-LABEL, LONG-TERM EXTENSION STUDY

G. R. Lichtenstein 1 , E.V. Loftus Jr 2 , S. Bloom 3 , N. Lawendy 4 , G. Friedman 4 , H. Zhang 4 , W. Wang 4 , A. J. Thorpe 4 , C. Nduaka 4 , C. Su 4

1 Division Of Gastroenterology, Perelman School of Medicine of the University of Pennsylvania, Philadelphia/United States of America/PA

2 Division Of Gastroenterology And Hepatology, Mayo Clinic, Rochester/United States of America/MN

3 University College London Hospitals NHS Foundation Trust, London/United Kingdom

4 Pfizer Inc, Collegeville/United States of America/PA

Contact E-mail Address: stuart.bloom@uclh.nhs.uk

Introduction: Tofacitinib is an oral, small molecule Janus kinase inhibitor that is being investigated for ulcerative colitis (UC). The efficacy and safety of tofacitinib was demonstrated as induction and maintenance therapy in three Phase 3, randomised, placebo-controlled studies (OCTAVE Induction 1, NCT01465763 ; OCTAVE Induction 2, NCT01458951 ; OCTAVE Sustain, NCT01458574 ) in patients (pts) with moderate to severe UC. 1, 2

Aims & Methods: We present interim safety and efficacy data up to 3 years of treatment (as of 08 July 2016) from an ongoing Phase 3, multicentre, open-label, long-term extension study (OLE, NCT01470612 ) in pts who had completed or demonstrated treatment failure in OCTAVE Sustain, or who were non-responders after completing OCTAVE Induction 1 or 2. Eligibility for this study was determined based on Week (Wk) 8 data from OCTAVE Induction 1 & 2, or Wk 52 data (for completers) or early termination data from OCTAVE Sustain. Pts who were in remission at Wk 52 of OCTAVE Sustain were assigned to tofacitinib 5 mg twice daily (BID); all others were assigned 10 mg BID. At Month 2, all pts underwent endoscopy, and non-responders from induction were mandated to withdraw if they did not show evidence of clinical response. Remission was defined by a Mayo score ≤2 with no individual subscore >1, and rectal bleeding subscore of 0. Binary efficacy endpoints were derived from Mayo score based on local-read endoscopic subscore.

Results: A total of 914 pts (5 mg BID, N = 156 [17.1%]; 10 mg BID, N = 758 [82.9%]) received at least one dose of study drug, of whom 381 (41.7%) discontinued (reasons included adverse events [AEs]: 23 [2.5%] and insufficient clinical response: 283 [31.0%]). The most frequent AE leading to discontinuation was worsening of UC. Serious and severe AEs occurred in 10.4% and 7.8% of pts, respectively (5 and 10 mg BID groups combined). The two most frequent treatment-emergent AE (TEAE) system organ classes in both dose groups were ‘infections and infestations’ and ‘gastrointestinal disorders’. The two most frequent TEAEs by preferred term were nasopharyngitis and worsening of UC. Serious infections AEs were reported in four (2.6%) and 14 (1.8%) pts in the 5 and 10 mg BID groups, respectively. Malignancies excluding non-melanoma skin cancer were reported in nine (1.2%) pts in the 10 mg BID group (with no clustering of malignancy type); none were reported in the 5 mg BID group. No new safety risks were identified. The available data ‘as observed’ for remission and mucosal healing at Months 2, 12 and 24 are shown in the Table.

Disclosure of Interest: G.R. Lichtenstein: Consultant for Pfizer Pharmaceuticals E.V. Loftus Jr: Consulting for Takeda, Janssen, AbbVie, UCB, Pfizer, Amgen, Eli Lilly, CVS Caremark, Mesoblast, Salix. Research support from Takeda, Janssen, AbbVie, UCB, Pfizer, Amgen, Genentech, Receptos, Gilead, Celgene, Robarts Clinical Trials, Seres, MedImmune.

N. Lawendy: Employee and shareholder of Pfizer Inc

G. Friedman: Employee and shareholder of Pfizer Inc

H. Zhang: Employee and shareholder of Pfizer Inc

W. Wang: Employee and shareholder of Pfizer Inc

A.J. Thorpe: Employee and shareholder of Pfizer Inc

C. Nduaka: Employee and shareholder of Pfizer Inc

C. Su: Employee and shareholder of Pfizer Inc

All other authors have declared no conflicts of interest.

References

1. Sandborn WJ et al. J Crohns Colitis 2016;10(S1):S15, Abstract OP019

2. Sandborn WJ et al. J Crohns Colitis 2017:11(S1):S19–20, Abstract OP032

OP096 SAFETY AND EFFICACY OF LONG-TERM TREATMENT WITH OZANIMOD, AN ORAL S1P RECEPTOR MODULATOR, IN MODERATE TO SEVERE ULCERATIVE COLITIS: TOUCHSTONE EXTENSION 2-YEAR FOLLOW-UP

W. J. Sandborn 1 , B. G. Feagan 2 , G. D'Haens 3 , S. Hanauer 4 , D. C. Wolf 5 , S. Vermeire 6 , S. Ghosh 7 , C. Li 8 , D. Penenberg 8 , A. Petersen 8 , R. Aranda 8 , A. Olson 8

1 Division Of Gastroenterology, University of California, La Jolla, San Diego/United States of America/CA

2 Robarts Research Institute, Western University, London/Canada/ON

3 Academic Medical Center, Amsterdam/Netherlands

4 Northwestern University Feinberg School of Medicine, Chicago/United States of America/IL

5 Atlanta Gastroentereology Associates, Atlanta/United States of America/GA

6 Department Of Gastroenterology, University Hospitals Leuven, Leuven/Belgium

7 Division Of Gastroenterology, Department Of Medicine, University of Calgary, Calgary/Canada

8 Receptos, a wholly-owned subsidiary of Celgene, San Diego/United States of America/CA

Contact E-mail Address: wsandborn@ucsd.edu

Introduction: Ozanimod, an oral, once-daily immunomodulator designed to selectively target S1P 1R and S1P 5R , has demonstrated clinical efficacy in ulcerative colitis (UC) for induction and maintenance therapy in the TOUCHSTONE trial (Sandborn NEJM 2016). The objective of the open-label extension (OLE) of the TOUCHSTONE trial is to evaluate the long-term efficacy and safety of daily 1 mg ozanimod in patients with moderate to severe UC who had initially participated in the TOUCHSTONE trial for up to 32 weeks.

Aims & Methods: A total of 197 patients were randomized (1:1:1) and treated with daily ozanimod 0.5 mg (n = 65), 1 mg (n = 67), or placebo (n = 65) in the TOUCHSTONE trial. Of the initial 197 patients randomized, 170 (86%) entered the OLE and received daily ozanimod 1 mg. As of the data cut-off in March 2017, 100 (58.8%) had efficacy evaluations reported through Week 92; of these 100 patients, 94 (55.3%) had received ozanimod 1 mg/day in the OLE for ≥2 years. Efficacy data are reported as observed through Week 92 and safety includes all events through the data cut-off of March 2017.

Results: At entry into the OLE, the partial Mayo Score (pMS) for patients on placebo, ozanimod 0.5 mg, and 1.0 mg was 4.6, 4.5, and 3.3 respectively, which improved significantly by OLE Week 8 (−2.3, −1.9 and −1.1), with the greatest improvement reported in patients who had received placebo or ozanimod 0.5 mg in the TOUCHSTONE trial. At the Week 92 visit in the OLE, 91/100 (91.0%) had little or no active disease based on the physician global assessment (PGA 0 or 1), 97/100 (97.0%) had little or no blood in their stools (rectal bleeding subscore [RBS] 0 or 1), 86/100 (86.0%) had no blood in the stools (RBS 0). Adverse events (AEs) and serious AEs were reported in 85 (50.0%) and 20 (11.1%) of patients respectively. The most common AEs (>2.0%) during OLE were UC flare, anaemia, nausea, upper respiratory tract infection, nasopharyngitis, back pain, arthralgia, headache, alanine aminotransferase (ALT) or aspartate aminotransferase (AST) elevation and hypertension. The only serious AEs in ≥2 patients were anaemia, and ulcerative colitis flare. ALT and AST >3x upper limit of normal (ULN) occurred in 5 (2.9%) of the 170 patients in the OLE. All elevations were asymptomatic, <5xULN, transient, and resolving while receiving continued treatment.

Conclusion: Long-term treatment with ozanimod continues to be safe and well tolerated with good compliance and evidence of durable efficacy.

Disclosure of Interest: W.J. Sandborn: Financial support for research; Consultancy - Celgene.

B.G. Feagan: Consultancy: Celgene.

G. D'Haens: Consultancy or speaker fees: Celgene; Directorship(s): Robarts Clinical Trials; Shareholder: Engene.

S. Hanauer: Consultancy: Celgene.

D.C. Wolf: Financial support for research; Consultancy - Celgene.

S. Vermeire: Consultancy - Celgene.

S. Ghosh: Consultancy - Celgene.

C. Li: Shareholder - Celgene.

D. Penenberg: Shareholder - Celgene.

A. Petersen: Shareholder - Celgene.

R. Aranda: Shareholder - Celgene.

A. Olson: Shareholder - Celgene.

Reference

Sandborn WJ, Feagan BG, Wolf DC, D'Haens G, et al. Ozanimod Induction and Maintenance Treatment for Ulcerative Colitis. N Engl J Med . 2016 May 5; 374(18):1754–62.

OP097 VEDOLIZUMAB DEMONSTRATES EARLY SYMPTOMATIC IMPROVEMENT IN ULCERATIVE COLITIS: A GEMINI 1 POST HOC ANALYSIS

B. Feagan 1 , K. Lasch 2 , J. M. Khalid 3 , C. Cao 2 , A. M. Wojtowicz 2 , A. James 3 , J. Colombel 4

1 Robarts Research Institute, University of Western Ontario, London/Canada/ON

2 Takeda Pharmaceuticals USA, Inc., Deerfield/United States of America/IL

3 Takeda Development Centre Europe, London/United Kingdom

4 Department Of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York/United States of America/NY

Contact E-mail Address: brian.feagan@robartsinc.com

Introduction: Vedolizumab (VDZ) achieves long-term clinical remission and mucosal healing in patients with moderately to severely active ulcerative colitis (UC). 1 Rapid symptomatic relief of rectal bleeding (RB) and stool frequency (SF) remain important treatment goals for patients and key indicators of remission for physicians in clinical practice. We aimed to characterize early symptomatic response with VDZ, specifically evaluating the timing of RB and SF improvement.

Aims & Methods: We assessed symptomatic improvement with VDZ through post hoc analysis of GEMINI 1 data. Patients with active UC were randomised to receive double-blind placebo (PBO) or VDZ at weeks (wks) 0 and 2 during the 6-wk induction phase (intent-to-treat population). Mayo clinic subscores of SF and RB were evaluated at 0, 2, 4, and 6 wks. Mean subscores and mean percent change from baseline (BL) were reported for the overall population and in those who were tumour necrosis factor antagonist (anti-TNF) naïve. The percentages of patients who reached SF subscore ≤1 and/or RB subscore of 0 were also determined.

Results: In anti-TNF-naïve patients, greater percentage decreases in mean SF subscores from BL were observed with VDZ than with PBO, reaching statistical significance at wks 4 and 6 as indicated by the non-overlapping 95% confidence intervals (Table). The same trends were observed in the overall population without reaching statistical significance. Similarly, a numerically greater percentage decrease from BL in RB subscore was observed with VDZ than with PBO, reaching statistical significance at wk 6 in both anti-TNF-naïve and overall populations. Significantly larger percentages of patients overall achieved SF subscore ≤1 or RB subscore of 0 with VDZ than with PBO at wk 6 and as early as wk 2 among the anti-TNF-naïve population (Table). A composite of SF subscore ≤1 and RB subscore of 0 was achieved in a significantly greater percentage of patients with VDZ than PBO at all time points (Table).

Conclusion: Symptomatic improvements were achieved with VDZ as early as wk 2, with greater differences from PBO observed in anti-TNF-naïve patients. Taken together, these results highlight the rapid onset of VDZ in UC; however, assessing clinical efficacy at wk 14 and beyond for those who exhibit a more gradual response should be used to inform clinical practice.

Disclosure of Interest: B. Feagan: Dr. Feagan has received grant support, consultancy, speaker, and advisory board fees from Millenium/Takeda.

K. Lasch: Employment: Takeda Pharmaceuticals USA, Inc.

J.M. Khalid: Employment: Takeda Development Centre Europe Ltd.

C. Cao: Employment: Takeda Pharmaceuticals USA, Inc.

A.M. Wojtowicz: Employment: Takeda Pharmaceuticals US.A, Inc.

A. James: Employment: Takeda Development Centre Europe Ltd.

J. Colombel: Dr. Colombel has received research grant and consultancy fees from Takeda.

Reference

1. Feagan BG, et al. N Engl J Med . 2013;369:699–710; NCT00783718 . The clinical study was funded by Millennium Pharmaceuticals, Inc (d/b/a Takeda Pharmaceuticals International Co). Medical writing assistance was provided by inVentiv Medical Communications and supported by Takeda Pharmaceuticals U.S.A, Inc.

OP098 INDIGO NATURALIS IS EFFECTIVE FOR INDUCING CLINICAL REMISSION AND MUCOSAL HEALING IN PATIENTS WITH ULCERATIVE COLITIS (INDIGO STUDY)

M. Naganuma 1 , S. Sugimoto 1 , K. Mitsuyama 2 , T. Kobayashi 3 , N. Yoshimura 4 , K. Matsuoka 5 , T. Hisamatsu 6 , K. Watanabe 7 , T. Abe 8 , Y. Suzuki 9 , T. Hibi 3 , T. Kanai 1

1 Division Of Gastroenterology And Hepatology, Department Of Internal Medicine, Keio University, Tokyo/Japan

2 Division Of Gastroenterology, Kurume University, Kurume/Japan

3 Center For Advanced Ibd Research And Treatment, Kitasato University Kitasato Institute Hospital, Tokyo/Japan

4 Dept. Of Internal Medicine, Central General Hospital Dept. of Medicine, Tokyo/Japan

5 Gastroenterology And Hepatology, Tokyo Medical and Dental University, Tokyo/Japan

6 Kyorin University, Tokyo/Japan

7 Gastroenterology, Osaka City General Hospital, Osaka/Japan

8 Department Of Preventive Medicine And Public Health, Biostatistics Unit At Clinical And Translational Research Centre, Keio University, Tokyo/Japan

9 Internal Medicine, Toho Unversity Sakura Medical Centre Division of Gastroenterology, Sakura/Japan

Contact E-mail Address: maknaganuma@gmail.com

Introduction: By recent advances of immune-biological therapy for UC, the clinical outcomes of UC have been improved. However, intractable cases, in which mucosal regeneration is disturbed, cannot yet be treated well even by the most advanced anti-inflammatory biological therapies. Indigo naturalis (IN), contains highly concentrated aryl hydrocarbon receptor (AhR) ligands, which has the effect for mucosal regeneration via AhR/interleukin−22. Therefore, IN may be effective for inducing mucosal healing in ulcerative colitis (UC). More recently, we reported the efficacy of IN for UC patients who were refractory to conventional treatments in a prospective study, and approximately 70% of patients had clinical response within 8 weeks after the treatment. However, there have been no double-blind trials which demonstrate the efficacy of IN and its appropriate doses are unclear.

Aims & Methods: In this study, we have evaluated the efficacy and safety of IN in terms of the dose dependency. This multicenter, double-blind trial evaluated the safety and efficacy of IN in 86 patients with active UC. An independent centre randomly allocated UC patients (Mayo score of ≥6) to four treatment groups to receive IN (daily dose, 0·5 g, 1·0 g, 2·0 g) or placebo in a 1:1:1:1 ratio. The primary efficacy endpoint (the rate of clinical response) and key secondary endpoints (the rates of clinical remission and mucosal healing) at 8 weeks of treatment were assessed in the full analysis set (FAS). For a longitudinal profile of Mayo scores and partial Mayo score, changes from baseline over 8 weeks were compared between treatment groups by means of a mixed-effects model for repeated measuresThis study is registered with UMIN Clinical Trials Registry (UMIN000021439).

Results: A total of 86 patients were enrolled. The proportion of steroid-dependent patients was 36.4, 56.5, 60.0, and 52.4% in patients receiving placebo, 0.5, 1.0 and 2.0 g daily of IN, respectively. Mean Mayo score at the week 0 was comparable among the 4 groups (8.2, 8.1, 8.5, and 8.3 in patients receiving placebo, 0.5, 1.0 and 2.0 g daily of IN, respectively). In the FAS population (n = 81), significant linear trend for the dose-response in clinical response rates was confirmed (placebo (n = 21): 14.3%, IN 0.5 g (n = 20): 80·0%, 1.0 g (n = 19): 79·5%, 2.0 g (n = 19): 89·5%, vs. placebo, P < 0·001). The dose-response in clinical remission rates showed significant linear trend (placebo: 4.8%, IN 0.5 g: 26.1%, P < 0.05, 1.0 g: 57.9%, P < 0.001, 2.0 g: 42.1%, P < 0·01). The mucosal healing rates were 14.3%, 65.0%, 63.2%, and 52.6%, in placebo, IN 0.5 g (P < 0.01), 1.0 g (P < 0.001), 2.0 g (P < 0.05) group, respectively. Patients receiving 0.5, 1.0 and 2.0 g daily of IN had greater improvement in the Mayo score compared with patients receiving placebo at week 8 and partial Mayo score showed a gradual decrease in score in 2 weeks, 4 weeks, and 8 weeks in patients receiving IN. No serious adverse events were observed.

Conclusion: In this multi-centre, randomized, double-blind, placebo-controlled study, we demonstrated that IN is tolerated and the efficacy was confirmed in patients receiving 0.5–2.0 g daily doses. IN may be able to use as an alternative induction therapy to steroids and as a therapy for refractory cases including chronic persistent type, especially cases with insufficient mucosal regeneration by immunosuppressants and anti-TNFα treatments.

Disclosure of Interest: M. Naganuma: EA Pharma, Zeria Pharmaceutical, Mitsubishi Tanabe, Kyorin Pharmaceutical, JIMRO, Astellas Pharma, Mochida, outside the submitted work.

T. Kobayashi: Mitsubishi Tanabe, Eisai, Kyorin Pharmaceutical, AbbVie GK, Janssen Japan, JIMRO, Ajinomoto, EA Pharma, Astellas, Mochida, Asahi Kasei Medical, Takeda Pharmaceutical, Gilead Sciences, Eli Lilly Japan, Nihon Kayaku outside the submitted work.

N. Yoshimura: Ajinomoto Pharmaceuticals Co., Ltd., lecture fees from AbbVie GK, Eisai Co., Ltd., Kyowa Hakko Kirin Co., Ltd., and Mitsubishi Tanabe outside the submitted work.

K. Matsuoka: Eisai, Kyorin Pharmaceutical, AbbVie GK, Janssen Japan, JIMRO, Ajinomoto, Astellas Pharma Inc., Mochida Pharmaceutical, Kissei Pharmaceutical, Asahi Kasei Medical, Kyowa Hakko Kirin, Takeda, outside the submitted work.

T. Hisamatsu: AbbVie GK, EA pharma Co., Ltd., Eisai Co., Ltd., JIMRO Co., Ltd., Mitsubishi Tanabe Pharma Corp., Pfizer Japan Inc., Takeda Pharmaceutical Co., Ltd. outside the submitted work.

K. Watanabe: AbbVie GK, EA Pharma Co., Ltd., Takeda Pharmaceutical Co., Ltd., Kyorin Pharmaceutical Co., Ltd, Mitsubishi Tanabe Pharma Corp, Astellas Pharma Inc. outside the submitted work.

Y. Suzuki: Mitsubishi Tanabe Pharma Corp., AbbVie GK, Zeria Pharmaceutical co., Ltd., Eisai Co., Ltd., Kyorin Pharmaceutical Co., Ltd. and research grant from Mitsubishi Tanabe Pharma Corp. and AbbVie GK, outside the submitted work.

T. Hibi: AbbVie GK, Otsuka Pharmaceutical, AstraZeneca, Eisai, JIMRO Co., Ltd., Mitsubishi Tanabe Pharma, Zeria Pharmaceutical, Kyorin Pharmaceutical, Pfizer Japan, Janssen Pharmaceutical, outside the submitted work.

T. Kanai: Ajinomoto, Takeda Pharma, Mitsubishi Tanabe, AbbVie GK, Kyorin Pharma, Pfizer Japan, Zeria Pharma, Miyarisan Pharmaceutical, Astellas, Mochida Pharma, AstraZeneca, EA Pharma, outside the submitted work.

All other authors have declared no conflicts of interest.

OP099 SUBMUCOSAL INJECTION OF THE RNA OLIGONUCLEOTIDE STNM01 IN ACTIVE ULCERATIVE COLITIS INDUCES MUCOSAL HEALING AND REVERSES TISSUE REMODELING

R. Atreya 1 , T. Kühbacher 2 , M. J. Waldner 1 , S. Hirschmann 1 , O. Drvarov 2 , R.A. Hashem 2 , C. Maaser 3 , T. Kucharzik 4 , J. Dinter 5 , J. Mertens 6 , C. Schramm 5 , B. Holler 7 , J. Mössner 7 , K. Suzuki 8 , N. Yokoyama 8 , S. Terai 9 , H. Yoneyama 10 , H. Asakura 9 , T. Hibi 11 , M. F. Neurath 1

1 Medical Department, University Erlangen-Nuremberg, Erlangen/Germany

2 Asklepios Westklinikum, Hamburg/Germany

3 Ambulanzzentrum Gastroenterologie, University Teaching Hospital Lüneburg, Lüneburg/Germany

4 Department Of Internal Medicine And Gastroenterology, University Teaching Hospital Lüneburg, Lüneburg/Germany

5 Uniklinik Köln, Köln/Germany

6 Köln, Uniklinik Köln, Köln/Germany

7 Department of Internal Medicine, Neurology and Dermatology, Division of Gastroenterology, University of Leipzig, Leipzig, Germany, Leipzig/Germany

8 Niigata City General Hospital Dept. of Digestive Surgery, Niigata/Japan

9 Division Of Gastroenterology And Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata/Japan

10 Stelic Institute & Co., Inc., Tokyo/Japan

11 Center For Advanced IBD Research And Treatment, Kitasato University Kitasato Institute Hospital, Tokyo/Japan

Contact E-mail Address: raja.atreya@uk-erlangen.de

Introduction: Ulcerative colitis (UC) is characterized by mucosal inflammation and structural damage that is associated with matrix remodeling and tissue fibrosis. We had previously shown that carbohydrate sulfotransferase 15 (CHST15) that biosynthesizes sulfated matrix glycosaminoglycans is an important regulator of experimental colitis and gut fibrosis. Here, we evaluated the efficacy of the double-stranded RNA oligonucleotide STNM01, a specific blocker of CHST15, in refractory UC patients.

Aims & Methods: In this randomized, double-blind, placebo-controlled phase 2a trial, 24 patients with moderate-to-severe UC were randomized to receive a single endoscopic submucosal injection of 25 nM, 250 nM STNM01 or placebo.

Results: The primary endpoint, mucosal healing at weeks 2 or 4 was achieved by 62.5% in the STNM01 (250 nM) group compared to 28.6% in the placebo group (p = 0.018). Clinical remission at these time points was reached by 50.0% in the STNM01 (250 nM) and 14.3% in the placebo groups (p = 0.050). There was significant histological improvement according to the Geboes score in the STNM01 (250 nM) group (p < 0.01). There were no statistical differences between the lower dose STNM01 (25 nM) and placebo groups. STNM01 application was well tolerated. Immunostaining demonstrated significant inhibition of CHST15 expression in STNM01 (250 nM) treated patients. Functionally, STNM01 inhibited sulfation of L-selectin ligand on inflammation-associated high endothelial venule-like vessels, suppressed hydrogen sulfide-producing enzymes and inhibited pre-established fibrosis.

Conclusion: In conclusion, the present study demonstrates that targeting CHST15 by submucosal injection of the CHST15 blocker STNM01 could allow refractory UC patients to achieve mucosal healing and clinical remission. Local application of STNM01 would thus be a unique novel therapeutic approach for reversal of tissue remodeling in refractory UC.

Disclosure of Interest: H. Yoneyama: H.Y. founded Stelic Institute & Co., Inc. in 2004

All other authors have declared no conflicts of interest.

OP100 EARLY RELAPSE OF ULCERATIVE COLITIS AFTER DISCONTINUATION OF TREATMENT IN PATIENTS RESPONDING TO GOLIMUMAB

P. J. Hamlin 1 , S. Sebastian 2 , P. Irving 3 , D. R. Gaya 4 , C. Wheeler 5 , A. Rose 6 , G. Gillespie 6 , C. S. J. Probert 7

1 Department Of Gastroenterology, Leeds Teaching Hospitals Trust, Leeds/United Kingdom

2 Hull Royal Infirmary, Hull/United Kingdom

3 Dept. Of Gastroenterology, Guy's and St Thomas' Hospital, London/United Kingdom

4 Gastroenterology Unit, Glasgow Royal Infirmary, Glasgow/United Kingdom

5 Medical Affairs, MSD, Hoddesdon/United Kingdom

6 MSD Sharp & Dohme Division of Immunology, Hoddesdon/United Kingdom

7 Gastroenterology Research Unit, Cellular And Molecular Physiology, University of Liverpool, Liverpool/United Kingdom

Contact E-mail Address: chris.probert@liverpool.ac.uk

Introduction: GO-COLITIS ( NCT02092285 ; 2013−004583-56) is a phase 4, multicentre, open-label, single-arm trial in the UK assessing efficacy of golimumab (GLM) in induction and maintenance of clinical response in patients with moderate to severe ulcerative colitis (UC) despite conventional treatment. Data from the 12-week follow-up of patients in clinical response at week 54 is presented here.

Aims & Methods: 141/205 (68.8%) anti-TNF naive adults with UC ≥3 months responded to induction therapy with subcutaneous GLM at week 6, according to partial Mayo score (PMS) 1 and were eligible to receive GLM maintenance of 50 mg or 100 mg (based on body weight) every 4 weeks for a total of 54 weeks. At the end of 54 weeks, their physician reviewed their treatment choosing to either continue with GLM or discontinue GLM treatment. PMS response was assessed at week 30, 54 and 66 (defined as decrease in PMS of ≥2 points and ≥30% from baseline, plus a decrease in rectal bleeding subscore of ≥1 point or absolute rectal bleeding score ≤1). 52/140 (37.1%) responders were monitored for sustained efficacy and safety at week 66 (12 weeks after study end). During this period concomitant medications were permitted at the discretion of the treating physician.

Results: 60/140 patients continued GLM maintenance treatment through week 54; 52/140 were responders at week 54. Of these 21 continued GLM treatment while 31 discontinued GLM treatment at week 54 (Table). All patients continuing GLM treatment (21/21) remained in clinical response at week 66. Of the patients who discontinued GLM at week 54, 27/31 (87%) patients maintained clinical response at week 66.

Conclusion: 100% of patients who continued on GLM treatment between weeks 54 and 66 continued to respond; of the patients who discontinued GLM treatment at week 54, early relapse (i.e. relapsed within 12 weeks of stopping GLM treatment) was seen in 4/31 (13%). These are the first data on the effect of GLM withdrawal after 1 year in patients with moderate to severe UC responding to treatment. Further studies are required to evaluate the percentage of patients remaining in response at 6 months, or later, following anti-TNF treatment discontinuation in responding patients after 1 year of treatment.

Disclosure of Interest: P.J. Hamlin: P. John Hamlin: speaker for Abbvie, Ferring, Janssen, MSD, Takeda, Tillotts, Warner Chilcott.

S. Sebastian: Shaji Sebastian: research funding from and is a speaker or advisory board member for Abbvie, Dr Falk Pharma, Ferring, MSD, Takeda, Warner Chilcott and Vifor Pharma.

P. Irving: Peter Irving: research funding from and is a speaker or advisory board member for Abbvie, Dr Falk Pharma, Ferring, Genentech, Hospira, Janssen, Johnson and Johnson, MSD, Pharmacosmos, Shire, Takeda, Tillotts, Topivert, Vifor Pharma & Warner Chilcott.

D.R. Gaya: Daniel R. Gaya: speaker for Abbvie, Dr Falk Pharma, Ferring, MSD, Shire, Takeda, Vifor.

C. Wheeler: Colin Wheeler: consultant for Aegerion, Amryt Pharma, Astrazeneca, Daiichi Sankyo, GSK, MSD UK, Takeda, Sanofi and Shionogi; was an employee of MSD UK and owns stocks and shares in Clovis Oncology, Novelion, Shield Therapeutics and Tesaro.

A. Rose: Anita Rose: employee of MSD UK and owns stocks and shares in Merck & Co., Inc., Kenilworth, NJ USA.

G. Gillespie: Gillian Gillespie: employee of Merck & Co., Inc., Kenilworth, NJ USA and owns stocks and shares in Merck & Co., Inc., Kenilworth, NJ USA.

C.S.J. Probert: Christopher S.J. Probert: speaker and a consultant for Abbvie, Aventis, Dr Falk Pharma, Ferring, Janssen, MSD, Napp, Pfizer, Shield, Shire, Takeda and Vifor.

Reference

1. Probert C, et al. Poster DOP049, presented at ECCO 2016.

MONDAY, OCTOBER 30, 201715:45-17:15

ALCOHOLIC LIVER DISEASE: ANYTHING NEW? - ROOM A2____________________

OP101 TARGETING LIVER INFLAMMATION USING MINCLE-TARGETED LIPOSOMES AS A NOVEL DRUG DELIVERY SYSTEM

M. Szachniewicz 1 , M. Bartneck 2 , F. Tacke 3 , R. Bansal 1

1 Targeted Therapeutics, Department Of Biomaterials Science And Technology, MIRA Institute, University of Twente, Enschede/Netherlands

2 Department Of Medicine Iii, University Hospital RWTH Aachen, Aachen/Germany

3 Dept Of Medicine Iii, University Hospital Aachen - Dept of Medicine III, University Hospital Aachen; Aachen/DE, Aachen/Germany

Contact E-mail Address: r.bansal@utwente.nl

Introduction: Inflammatory macrophages (Mϕs) play a critical role in the development of liver inflammation. Hepatocellular damage, instigated by hepatitis viral infections, alcohol abuse or metabolic syndrome, results in the recruitment and activation of inflammatory cells mainly Mϕs in the liver. The inflammatory Mϕs initiates the process of liver injury progressing from liver fibrosis to cirrhosis and hepatocellular carcinoma. Therefore, selective targeted inhibition of the inflammatory macrophages would be a promising approach to attenuate liver inflammation or liver fibrosis. Anti-inflammatory therapies targeting Mϕs has shown to be highly efficacious in many disorders. Currently there is no therapy available for the treatment of liver fibrosis therefore there is an unmet need to develop a efficacious therapy with minimal side effects for the treatment of progressive disease. We identified Mincle receptor as a prospective target for pro-inflammatory subset (M1) of Mϕs for the development of effective inflammatory macrophage specific drug delivery system.

Aims & Methods: In this study, we developed a novel delivery system i.e. Mincle-targeted liposomes to achieve M1-specific uptake and to selectively deliver anti-inflammatory drugs to inhibit M1 Mϕs thereby ameliorating liver inflammation. Specificity and significance of Mincle receptor was evaluated in vitro in murine and human M1 Mϕs, in vivo in CCl 4 -induced acute liver inflammation using immunostainings and quantitative PCR. Diverse Mincle-targeted liposomes were synthesized and characterized using dynamic light scattering (DLS). M1-specific uptake in murine and primary human Mϕs was analyzed using fluorescence-activated cell sorting (FACS). We used prednisolone as an anti-inflammatory drug to inhibit inflammatory M1 macrophages. Prednisolone encapsulated mincle-targeted liposomes were generated, characterized and tested for efficacy in vitro in murine RAW macrophages, primary BMDMs, primary human Kupffer cells and in vivo in acute CCl 4 -induced liver injury mouse model.

Results: Significant up-regulation of Mincle receptor was confirmed in murine and human M1 Mϕs in vitro , in vivo in liver fibrosis mouse models and human fibrotic liver tissues. siRNA mediated knockdown (70% inhibition) of Mincle receptor in M1 Mϕ resulted in reduced inflammatory markers (TNFα and IL1β) and Mincle co-receptor. Mincle-targeted liposomes showed favorable size, stability and drug entrapment efficiency. We used prednisolone as an anti-inflammatory drug as a model drug to inhibit inflammatory M1 macrophages. We tested these liposomes in different mouse macrophage cell lines, primary bone marrow derived macrophages and in primary human macrophages for efficacy and M1-specific uptake. Significantly, targeted liposomes showed M1-specific uptake, while liposomes without targeting moiety showed comparatively reduced internalization at different time points. Furthermore, targeted liposomes demonstrated significantly reduced uptake in M2 restorative Mϕs. No significant uptake in other cells was observed. Antibody blocking of Mincle receptor significantly inhibited uptake in M1 Mϕ strongly suggesting Mincle-mediated mechanism of uptake. Prednisolone-encapsulated Mincle targeted liposomes showed significant reduction in M1-specific markers and inflammatory markers in vitro in RAW cells, in primary murine BMDMs and human kupffer cells. In vivo in acute CCl 4 -induced liver inflammation mouse model, prednisolone-encapsulated Mincle-targeted liposomes demonstrated specific liver uptake, highly significant attenuation in intra-hepatic inflammation, macrophage infiltration and reduction in fibrotic parameters as compared to free prednisolone and non-targeted liposomes.

Conclusion: This study presents a highly novel targeting approach of specifically targeting inflammatory macrophages with increased therapeutic efficacy while off-target effects on healthy tissues and other cell types can be avoided. These inflammatory macrophage targeted liposomes therefore holds great promise for diagnosis and therapeutic treatment of liver fibrosis and other inflammatory diseases.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP102 IGA ANTIBODIES AGAINST FILAMENTOUS-ACTIN ARE FREQUENTLY DETECTED IN PATIENTS WITH CIRRHOSIS AND INDICATE A PROGRESSIVE DISEASE COURSE

T. Tornai 1 , B. Balogh 1 , N. Sipeki 1 , Z. Vitalis 1 , I. Tornai 1 , P. Antal-Szalmas 1 , G.L. Norman 2 , T. Bruns 3 , M. Papp 1

1 Division Of Gastroenterology, University of Debrecen, Faculty of Medicine, Institute of Medicine, Debrecen/Hungary

2 Inova Diagnostics, San Diego/United States of America/CA

3 Department Of Internal Medicine IV, University Hospital Jena, Jena/Germany

Contact E-mail Address: papp.maria@med.unideb.hu

Introduction: Gut barrier failure and the consequential pathological bacterial translocation (BT) are characteristic features of cirrhosis and play an important role in the progression of liver disease. We hypothesized that serological hallmarks of gut barrier dysfunction are associated with accelerated progression of liver disease in cirrhosis and the development of specific complications and liver-related death.

Aims & Methods: Sera from 260 stable outpatients with cirrhosis (male: 129, age: 56 ± 11 yrs, alcohol: 167 [64.2%]) and from 155 healthy subjects were assayed for the presence of antibodies against filamentous-actin [AAA IgA and IgG] and gliadin [AGA IgA and IgG]) and for intestinal fatty acid-binding protein (I-FABP) by ELISA. Association of gut failure markers with disease specific characteristics was assessed at baseline and the course of liver disease was evaluated in a 5-year follow-up observational study for decompensating events (ascites, variceal bleeding, hepatic encephalopathy and/or bacterial infection) and liver-related death. BT was assessed based on the presence of anti-microbial antibodies (anti-OMP Plus IgA and/or endotoxin core IgA antibody [EndoCab]).

Results: Elevated concentrations of the gut failure markers IgA-AAA (62.7 vs. 4.4%) and IgA-AGA (27.7 vs. 2.6%) were more often observed in cirrhosis as compared to healthy controls (p < 0.001 for both). In addition, serum I-FABP was increased in cirrhosis as compared to controls (741 vs. 244 pg/mL, p < 0.001) and correlated with serum levels of IgA-AAA and IgA-AGA. IgA-AAA positivity was associated with alcoholic liver disease, liver disease scores and decompensated clinical stage (all p < 0.001). Serological markers of BT were more often found in patients with elevated IgA-AAA compared to those without (72.3 vs. 13.5 % for IgA-EndoCab and 85.2 vs. 20.5% for IgA-anti-OMP, p < 0.001 for both). In patients with compensated disease stage (n = 131) the risk of decompensation was higher in patients with elevated IgA-AAA (HR [95%CI]: 1.85 [1.06–3.24]), as was the risk of liver-related mortality (HR: 2.66 [1.27–5.56]). Such associations were not observed for IgG-AAA and IgA/IgG-AGAs. In the overall cohort, IgA-AAA remained an independent predictor of liver-related death (HR adj : 1.96 [1.08–3.55]) when adjusting for important clinical variables (MELD score, etiology, clinical stage, see Table 1 ).

Conclusion: Elevated serum concentrations of IgA antibodies against filamentous-actin indicate patients with an unfavourable outcome in cirrhosis, which may be related to intestinal damage beyond being related to bacterial translocation. IgA-AAA might be consider as a novel serologic marker of the disease progression.

Disclosure of Interest: G.L. Norman: Employee of INOVA

All other authors have declared no conflicts of interest.

MONDAY, OCTOBER 30, 201715:45-17:15

ERCP: WHEN THE GOING GETS TOUGH - ROOM B2____________________

OP103 SELF-CONFORMABLE COVERED VS SELF-CONFORMABLE UNCOVERED METALLIC STENTS IN THE PALLIATIVE TREATMENT OF MALIGNANT EXTRA-HEPATIC BILIARY STRICTURE: A MULTICENTRIC RANDOMIZED STUDY

B. Mangiavillano 1 , A. De Ceglie 2 , R. Filiberti 3 , A. Caruso 4 , L. De Luca 5 , S. Signorelli 6 , M. Marini 7 , P. Ravelli 6 , A. Parodi 8 , R. Conigliaro 9 , M. Conio 2

1 Gastrointestinal Endoscopy Unit, Humanitas - Mater Domini, Castellanza (VA)/Italy

2 Gastroenterology And Gastrointestinal Endoscopy, Borea Hospital, Sanremo (IM)/Italy

3 Clinical Epidemiology, IRCCS AOU San Martino, Genova/Italy

4 Aou Modena, Gastroenterology and Digestive Endoscopy Unit, Modena/Italy

5 Endoscopy Unit, Pesaro Hospital, Pesaro/Italy

6 Ospedali Riuniti di Bergamo, Bergamo/Italy

7 Gastroenterology, Santa Maria alle Scotte, Siena/Italy

8 Ospedale Galliera, Genova/Italy

9 Gastrointestinal Endoscopy, Baggiovara Hospital, Modena/Italy

Contact E-mail Address: b_mangiavillano@hotmail.com

Introduction: Cancer of the pancreas, gallbladder and bile ducts is the most common cause of malignant biliary obstruction (MBO). In case of unresectable cancer the survival at 5 years is less than 2%. We present preliminary results of a prospective RCT ( NCT 02930252 ) comparing covered (Niti-S Biliary ComVi) with uncovered (Niti-s D) self-conformable metal stent (SEMS) placed in patients with MBO conditioning jaundice. No RCTs are present in literature comparing these two types of stent.

Aims & Methods: Primary aim was to compare stent patency between the two groups. Secondary aims were to evaluate relationships between adverse events (AEs) rate and stent type (i.e. time to stent dysfunction and survival). 158 patients (76 M 82F, median age 78 ys) were randomized in two groups: 78 received a fully-covered SEMS (FCSEMS) and 78 an uncovered SEMS. Data from 148 (72 FCSEMS and 76 USEMS) out of 158 patients were analyzed. All patients received sphincterotomy before stent insertion.

Results: Placement was successful in 100% of patients with the uncovered and 98.7% patients with FCSEMS. Levels of conjugated bilirubin improved significantly (p < 0.001) in both groups during the first week, with a median variation of −70% for FCSEMS and −68% for SEMS. Normalization of bilirubin levels (≤1, 2 mg/dL) was observed in 42 patients (28.6%; 28.2% FCSEMS and 28.9% SEMS, p = 1.0). AEs occurred in 28 out of 147 patients [19.0%: 18 FCSEMS (25.4%) and 10 SEMS (13.1%), p = 0.092]. Stent occlusion occurred in 12 patients with FCSEMS and in 10 patients with SEMS. Cholangitis was observed in 6 patients for each group. In patients with SEMS, occlusion was due to in-growth and in 9 out of 10 patients, was reported as a late complication . In FCSEMS group, 6 out of 12 patients had stent occlusion within the first month. Cholecystitis was observed in a patient with FCSEMS. No stent migration occurred in SEMS group while it was observed in 5 (7%) of the FCSEMS group (p = 0.024). Median time of stent patency was lower for FCSEMS (9.5 months, 95%CI 7.2–11.8 months) vs 18.0 months (95% CI 10.7–25.4 months) for SEMS (p = 0.046). No differences were observed with regard of stent dysfunction in patient survival: 4.0 months (95%CI 2.5–5.5 months) for FCSEMS and 3.7 days (95%CI 2.3–5.0) for SEMS (p = 0.80). Median survival was 4.5 months (95%CI: 3.3–5.7 months) in FCSEMS group and 3.7 months (95%CI: 2.2–5.3 months) in the SEMS (p = 0.23).

Conclusion: No significant differences were observed in levels of bilirubin improvement, stent dysfunction-free and median survival between the two groups. AEs were higher, although not significantly, among FCSEMS group. FCSEMS had a significantly higher rate of migration. A significantly difference in patency was observed for SEMS group.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP104 CLINICAL EFFICACY OF ANTI-MIGRATION FEATURES IN FULLY-COVERED SELF-EXPANDABLE METALLIC STENTS FOR ANASTOMOTIC BILIARY STRICTURES AFTER LIVER TRANSPLANTATION: A RETROSPECTIVE COHORT COMPARISON OF STANDARD AND ANTI-MIGRATION STENTS

B. Bordacahar 1 , M. Barret 2 , M. Guillaumot 2 , O. Scatton 3 , F. Perdigao 3 , S. Leblanc 4 , S. Chaussade 5 , F. Prat 6

1 Endoscopy And Digestive Oncology Unit, Hopital Cochin, Paris/France

2 Gastroenterology, Cochin Hospital, Paris/France

3 Liver Transplant Unit, Pitié Salpétrière, paris/France

4 CHU Cochin Dept. of Gastroenterology, Paris/France

5 Service De Gastro-entérologie, CHU Cochin Dept. de Gastroenterologie, Paris/France

6 Hôpital Cochin Dept. of Gastroenterology, Paris/France

Contact E-mail Address: benoit.bordacahar@gmail.com

Introduction: Anastomotic biliary strictures (ABS) are one of the most frequent adverse effects occurring after orthotopic liver transplantation (OLT). Multiple plastic stents (MPS) have been validated in this indication. More recently, fully covered self-expandable metallic stents (FC-SEMS) have been used with positive outcomes but also a higher rate of migration which may limit success.

Aims & Methods: Our primary objective was to compare stent migration rates observed with commonly used FC-SEMS and so-called “anti-migration” FC-SEMS, newly designed with reversed proximal side flaps. Secondary objectives were to compare the rates of ABS recurrence, and sustained stricture resolution as well as procedure-related morbidity. We conducted a retrospective analysis of a subset of patients (FC-SEMS for post-OLT ABS) from 2 prospectively maintained databases of a) OLT patients, and b) ERCP and stenting. Between January 2008 and January 2016, consecutive patients presenting with ABS after OLT referred to Cochin Hospital (Paris, France) for ERCP and receiving an FC-SEMS were included. Exclusion criteria were any other cause of biliary stricture (i.e malignant stricture, ischemic origin), and biliary fistulae.

Results: One hundred and twenty-five FC-SEMS (57 anti-migration stents, 52 conventional stents type 1 and 16 conventional stents type 2) were used in 75 patients for ABS after OLT. The rate of FC-SEMS complete migration was 16% (20/125), respectively 1.7% (1/57) for anti-migration stents, 17.3% (9/52) for type 1 conventional stents and 62.5% (10/16) for type 2 conventional stents (p < 0.0001). An early endoscopic revision for cholestasis or acute cholangitis was necessary in 24.8% (31/125) of cases, 12.2% (7/57) for anti-migration stents, 26.9% (14/52) for type 1 conventional stents and 62.5% (10/16) for type 2 conventional stents (p < 0.0002). First ERCP follow-up after each FC-SEMS highlighted a stricture resolution in 80% (100/125) of cases, 93% (53/57) for anti-migration stents, 77% (40/52) for type 1 conventional stents and 37.5% (6/16) for type 2 conventional stents. There was no difference for patient characteristics (i.e previous endoscopic treatment, timing of ABS occurrence after OLT) or procedure-related morbidity between each type of FC-SEMS.

Conclusion: In patients with ABS after OLT, the use of anti-migration FC-SEMS significantly decreased the risk of stent migration and improved sustained stricture resolution. Endoscopic removal success and procedure-related morbidity were similar for both usual and anti-migration stents.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP105 UTILITY OF NEWLY DEVELOPED SHORT TYPE DOUBLE BALLOON ENDOSCOPY FOR ERCP IN POSTOPERATIVE PATIENTS WITH SURGICAL ANATOMIC VARIATIONS; A LARGE CASE SERIES

M. Shimatani 1 , M. Tokuhara 1 , M. Masuda 1 , S. Miyamoto 1 , M. Sakao 1 , H. Miyoshi 1 , T. Ikeura 2 , M. Takaoka 1 , K. Uchida 1 , K. Okazaki 1

1 The Third Department Of Internal Medicine, Kansai Medical University, Hirakata/Japan

2 Kansai Medical University, Hirakata/Japan

Contact E-mail Address: shimatam@hirakata.kmu.ac.jp

Introduction: The utility of conventional short-type DBE for pancreatobiliary disease in postoperative patients had been widely accepted 1–4 . However, some technical problems yet remained, and the new short-type DBE that was specially designed for therapeutic endoscopic retrograde cholangiopancreatography (ERCP) in postoperative patients solved these problems.

Aims & Methods: The aim of this study was to evaluate the usefulness of new short DBE for ERCP in postoperative patients. From August 2015 to May 2017, ERCP using new short DBE (DB-ERCP) was performed in 222 postoperative patients (280 procedures). We retrospectively studied the success rate of reaching the blind end, the mean time to reach the blind end, the diagnostic success rate, the therapeutic success rate, the mean time to complete ERCP related interventions, the overall success rate, the mean time to complete DB-ERCP, and adverse events.

Results: The success rate of reaching the blind end was 98.6% (276/280). By type of reconstruction methods, the success rate of reaching the blind end was 95.6% (87/91) in Roux-en-Y (R-Y) hepaticojejunostomy, 100% (36/36) in R-Y partial gastrectomy, 100% (42/42) in R-Y total gastrectomy, 100% (19/19) in Billroth II gastrectomy (B-II), 100% (45/45) in pancreatoduoderectomy (PD), 100% (40/40) in pylorus preserving pancreaticoduodenectomy (PpPD) and 100% (7/7) in others. The mean time to reach the blind end was 14.4 min. (1–105). By type of reconstruction methods, the mean time to reach the blind end was 20.9 min. (3–74) in R-Y hepaticojejunostomy, 16.9 min. (1–105) in R-Y partial gastrectomy, 13.4 min. (2–57) in R-Y total gastrectomy, 6.4 min. (1–22) in B-II, 8.4 min. (1–39) in PD, 20.9 min. (2–41) in PpPD and 11.0 min. (2–32) in others. The diagnostic success rate was 97.5% (269/276). By type of reconstruction methods, the diagnostic success rate was 100% (87/87) in R-Y hepaticojejunostomy, 100% (34/36) in R-Y partial gastrectomy, 95.2% (40/42) in R-Y total gastrectomy, 89.5% (17/19) in B-II, 100% (45/45) in PD, 97.5% (39/40) in PpPD and 100% (7/7) in others. Therapeutic intervention was achieved in all of the 269 procedures of successful deep cannulation (100%). The overall DB-ERCP success rate was 96.1% (269/280). By type of reconstruction methods, the overall DB-ERCP success rate was 95.6% (87/91) in R-Y hepaticojejunostomy, 94.4% (34/36) in R-Y partial gastrectomy, 95.2% (40/42) in R-Y total gastrectomy, 89.5%(17/19) in B-II, 100% (45/45) in PD, 97.7% (39/40) in PpPD and 100% (7/7) in others. The mean time to complete DB-ERCP was 61.0 min. (12–252). By type of reconstruction methods, the mean time required to complete DB-ERCP was 71.7 min. (18–228) in R-Y hepaticojejunostomy, 69.4 min. (21–170) in R-Y partial gastrectomy, 78.5 min. (16–252) in R-Y total gastrectomy, 51.9 min. (21–105) in B-II, 39.6 min. (12–107) in PD, 45.1 min. (15–144) in PpPD and 47.2 min. (17–86) in others. The occurrence of adverse events was 1.1% (3/280).

Conclusion: The newly developed short DBE for ERCP in postoperative patients is useful and safe. DB-ERCP is a promising therapeutic modality in such patients and should be selected as the first-line policy.

Disclosure of Interest: All authors have declared no conflicts of interest.

References

1. Shimatani M, Hatanaka H, Kogure H, et al. Diagnostic and Therapeutic Endoscopic Retrograde Cholangiography Using a Short-Type Double-Balloon Endoscope in Patients With Altered Gastrointestinal Anatomy: A Multicenter Prospective Study in Japan. Am J Gastroenterol . 111(12):1750–1758, 2016

2. Shimatani M, Matsushita M, Takaoka M, et al. Effective “short” double-balloon enteroscope for diagnostic and therapeutic ERCP in patients with altered gastrointestinal anatomy: a large case series. Endoscopy . 41(10):849–854, 2009

3. Shimatani M, Takaoka M, Matsushita M, et al. Endoscopic approaches for pancreatobiliary diseases in patients with altered gastrointestinal anatomy. Dig Endosc . 26 Suppl 1:70–78, 2014

4. Shimatani M, Takaoka M, Okazaki K. Tips for double balloon enteroscopy in patients with Roux-en-Y reconstruction and modified child surgery. J Hepatpbiliary Pancreat Sci . 21(4):E22–28, 2014

OP106 AN INTERNATIONAL, MULTICENTER, COMPARATIVE TRIAL OF EUS-GUIDED GASTROGASTROSTOMY-ASSISTED ERCP VERSUS ENTEROSCOPY-ASSISTED ERCP IN PATIENTS WITH ROUX-EN-Y GASTRIC BYPASS ANATOMY

M. Bukhari 1 , A. A. Siddiqui 2 , J. Nieto 3 , R. Kunda 4 , N. K. Ahuja 1 , S.S. Irani 5 , A. Shah 2 , T. Kowalski 2 , D. Loren 2 , O.I. Brewer Gutierrez 1 , O. Sanaei 1 , L. Fayad 1 , Y. Chen 1 , S. Ngamruengphong 1 , V. Kumbhari 1 , Y. Haito-Chavez 1 , V. Singh 1 , H. Dakour Aridi 1 , M. A. Khashab 1

1 Division Of Gastroenterology And Hepatology, Johns Hopkins Medical Institutions, Baltimore/United States of America

2 Division Of Gastroenterology And Hepatology, Thomas Jefferson University, Philadelphia/United States of America

3 Borland-Groover Clinic, Jacksonville/United States of America/FL

4 Department Of Surgical Gastroenterology, Arhus University Hospital, Aarhus/Denmark

5 Division Of Gastroenterology And Hepatology, Virginia Mason Medical Center, Seattle/United States of America

Contact E-mail Address: bukhari.majidah@gmail.com

Introduction: Endoscopic retrograde cholangiopancreatography (ERCP) is challenging in patients with Roux-en-Y gastric bypass (RYGB) anatomy. EUS-guided gastrogastrostomy (GG) creation is a promising novel technique by which to access the excluded stomach in order to facilitate conventional ERCP.

Aims & Methods: We aimed to compare procedural outcomes and adverse events (AEs) between EUS-guided gastrogastrostomy-assisted ERCP (EUS-GG-ERCP) and enteroscoy assisted ERCP (e-ERCP) in patients with RYGB. Patients with RYGB anatomy who underwent EUS-GG-ERCP or e-ERCP between 2014 and 2016 at 5 tertiary centers were included. The primary outcome was technical success of ERCP, defined as successful cannulation of the selected duct with successful intervention as intended. Secondary outcomes included: (1) total procedural time (in the EUS-GG group, total procedural time included EUS-GG creation plus ERCP procedure time); (2) length of hospital stay; and (3) rate/severity of AEs graded according to the ASGE lexicon.

Results: A total of 160 patients (mean age 58, 53.8% female) were included, of whom 53 (33.1%) underwent EUS-GG-ERCP and 107 (66.9%) underwent e-ERCP (DBE-ERCP 79, SBE-ERCP 25, other 3). The technical success rate was significantly higher in the EUS-GG-ERCP versus the e-ERCP group (88.7% vs. 60.8%, p < 0.001). Total procedure time was significantly shorter in patients who underwent EUS-GG-ERCP (50.1 min vs. 86.1 min, p < 0.001). Post-procedure median length of hospitalization was shorter in the EUS-GG group (2 vs. 7 days, p = 0.0001). Rate of AEs was similar in both groups (7.5% vs. 5.6%, p = 0.73).

Conclusion: EUS-GG-ERCP is superior to e-ERCP in patients with RYGB anatomy in terms of technical success with a similar safety profile.

Disclosure of Interest: R. Kunda: Consultant, speaker, and medical advisory board for Boston Scientific. Consultant for Omega Imaging. Consultant and speaker for Olympus.

T. Kowalski: Consultant for Boston Scientific and Medtronics

M.A. Khashab: Consultant for Boston Scientific

All other authors have declared no conflicts of interest.

References

1. Tyberg A, Nieto J, Salgado S, et al. Endoscopic Ultrasound (EUS)-Directed Transgastric Endoscopic Retrograde Cholangiopancreatography or EUS: Mid-Term Analysis of an Emerging Procedure. Clin Endosc 2016.

2. Kedia P, Tyberg A, Kumta NA, et al. EUS-directed transgastric ERCP for Roux-en-Y gastric bypass anatomy: a minimally invasive approach. Gastrointest Endosc 2015;82:560–5.

3. Kedia P, Sharaiha RZ, Kumta NA, et al. Internal EUS-directed transgastric ERCP (EDGE): game over. Gastroenterology 2014;147:566–8

OP107 AN INTERNATIONAL MULTICENTER STUDY ON DIGITAL SINGLE OPERATOR CHOLANGIOSCOPY FOR THE MANAGEMENT OF DIFFICULT BILE DUCT STONES IN 407 PATIENTS

O.I. Brewer Gutierrez 1 , S. Ngamruengphong 1 , N. Bekkali 2 , I. Raijman 3 , R. Sturgess 4 , D.V. Sejpal 5 , H. D. Aridi 1 , S. Sherman 6 , R. J. Shah 7 , R. Kwon 8 , J. L. Buxbaum 9 , C. Zulli 10 , W. Wassef 11 , D. G. Adler 12 , V. Kushnir 13 , A. Y. Wang 14 , K. Krishnan 15 , V. Kaul 16 , D. Tzimas 17 , C. J. Dimaio 18 , S. Ho 19 , B. T. Petersen 20 , M.S. Lee 21 , B. J. Elmunzer 22 , G. Webster 2 , Y.I. Chen 1 , L. K. Dwyer 4 , S. Inamdar 5 , V. B. Patrick 6 , A. Attwell 7 , A. Hosmer 8 , C. Ko 9 , A. Maurano 10 , A. Sarkar 11 , L. J. Taylor 12 , M. H. Gregory 13 , D. S. Strand 14 , A. Raza 15 , S. Kothari 16 , J. P. Harris 17 , N. Kumta 18 , A. Manvar 19 , M. Topazian 20 , Y.N. Lee 21 , C. M. Spiceland 22 , M. A. Bukhari 1 , O. Sanaei 1 , M. A. Khashab 1

1 Gastroenterology And Hepatology, Johns Hopkins Hospital, Baltimore/United States of America/MD

2 Gastroenterology And Hepatology, University College London Hospitals, London/United Kingdom

3 Greater Houston Gastroenterology, Houston/United States of America/TX

4 Aintree University Hospital, Liverpool/United Kingdom

5 Hofstra-Northwell School of Medicine, Manhasset/United States of America/NY

6 Indiana University Medical Center, Indiana/United States of America

7 University of Colorado Denver, Denver/United States of America

8 University of Michigan, Ann Arbor/United States of America

9 University of Southern California Keck School of Medicine, Los Angeles/United States of America

10 Hospital of Salerno, Mercato San Severino/Italy

11 UMassMemorial Health Center, Worcester/United States of America

12 University of Utah School of Medicine, Salt Lake City/United States of America

13 Washington University in St. Louis School of Medicine, St. Louis/United States of America

14 University of Virginia Health System, Charlottesville/United States of America

15 Houston Methodist Hospital, Houston, Houston/United States of America

16 University of Rochester Medical Center - Strong Memorial Hospital, Rochester, New York/United States of America

17 Stony Brook University School of Medicine, New York/United States of America

18 Icahn School of Medicine at Mount Sinai, New York/United States of America

19 Montefiore Medical Center, New York/United States of America

20 Mayo clinic, Rochester/United States of America

21 SoonChunHyang University School of Medicine, Seoul/Korea, Democratic People's Republic of

22 Medical University of South Carolina, Charleston/United States of America

Contact E-mail Address: obrewer1@jhmi.edu

Introduction: Background: The role of the recently developed digital single-operator cholangioscopy (D-SOC) for the treatment of difficult biliary stones using electrohydraulic (EHL) and laser lithotripsy (LL) is not well known.

Aims & Methods: (1) To study the technical success (complete ductal clearance) and safety (rate/severity of adverse events (AE) per ASGE lexicon) of D-SOC with EHL/LL in the treatment of difficult biliary stones; (2) To compare the performance of EHL vs. LL. This is an international, multicenter, retrospective study at 22 tertiary centers between 02/2015 and 12/2016. Difficult bile duct stones were defined as large (≥15 mm), multiple (>3), impacted, intrahepatic/cystic duct location, associated with a stricture, difficult anatomic access, or Mirizzi’s syndrome. Logistic regression analysis was performed to identify factors associated with technical failure and more than one EHL/LL session

Results: A total of 407 patients (60% F, mean age 64 yr) underwent D-SOC for difficult bile duct stones and 74.5% had more than one indication which included: large stones (223), multiple (219), impacted stones (155), intrahepatic stones (72), cystic duct stones (50), stones above biliary stricture (80), difficult anatomic access (57) and Mirizzi’s syndrome (35). Of these, 85.8% had previous failed ERCP to clear the bile duct and 75.9% had a prior stent placed. Location of stones was CBD 59.7%, CHD 9.6%, intrahepatic ducts 15.2%, cystic duct 11.3%, hilar 1.5% and more than one location 2.6%. The mean stone size was 16.01 mm ± 7.14 mm. A total of 306 were treated with EHL and 101 with LL. Mean procedure time was 67 min±34.9 min. Complete ductal clearance using EHL/LL (technical success) was achieved in 396 (97.3%) patients, with a median number of lithotripsy sessions of 1 (range 1–4). Successful ductal clearance in a single session of EHL/LL was achieved in 328 (80.6%) cases. A total of 11 (2.7%) patients failed EHL/LL and were treated with surgery (n = 8), ESWL (n = 2) or both (n = 1). Fifteen (3.7%) AEs occurred, including 6 cholangitis, 5 abdominal pain, 1 pancreatitis, 1 transient bacteremia, 1 bleeding and 1 bile duct perforation (10 mild, 3 moderate, and 2 severe). Recurrent bile duct stones occurred in 17 (6.1%) patients during a median follow up of 83.5 days [IQR 33–155]. Technical success (96.7% vs 99%, p = 0.31), median number of lithotripsy sessions to achieve bile duct clearance (1 vs 1, p = 0.16), and rate of AEs (3.3% vs 5%, p = 0.44) were similar between EHL and LL groups, respectively. Mean procedure time (73.9 vs 49.9, p = <0.001) was significantly shorter in the LL group. Difficult anatomy/cannulation was significantly correlated with technical failure [aOR(95%CI):5.18(1.26–21.2), p = 0.02] while duration of procedure [aOR(95%CI):1.02(1.01–1.03), p = <0.001] was a significant predictor of the need for more than one session of D-SOC EHL/LL .

Conclusion: D-SOC with EHL or LL is effective and safe in treating difficult bile duct stones. Few patients will require surgery or ESWL to achieve ductal clearance. Procedure time is significantly lower in the LL group as compared to EHL group.

Disclosure of Interest: I. Raijman: consultant and speaker for Boston Scientific and Covidien. Co-owner of EndoRx

R. Sturgess: Consultant for Boston Scientific

S. Sherman: Consultant for Boston Scientific

R.J. Shah: Raj J. Shah is consultant for Cook and for Boston Scientific

W. Wassef: Consultant to Boston Scientific Consultant to Abbvie

D.G. Adler: Consultant for Boston Scientific

V. Kushnir: BSCI: consultant and speakers bureau

A.Y. Wang: has received research support from Cook Medical

K. Krishnan: BSCI: Speaker Olympus: Consulting

C.J. DiMaio: consultant for Boston Scientific

B.T. Petersen: Consultant for Boston Scientific

G. Webster: received honoraria from Boston scientific for an advisory board, consultancy and lecture invitations

M.A. Khashab: Consultant for Boston Scientific

All other authors have declared no conflicts of interest.

OP108 ERCP WITH PANCREATOSCOPY-GUIDED LASER LITHOTRIPSY FOR CHRONIC PANCREATITIS COMPLICATED BY PANCREATIC DUCT STONES: A FIVE YEAR SINGLE CENTER EXPERIENCE

A. Malachias , D. Kypraios, S. Stavrinidis, S.L. Hatzinicolaou, D. Dimitroulopoulos, G. Sofianidis, D. Xinopoulos

Department Of Gastroenterology, ST. Savvas Athens Cancer Hospital, Athens/Greece

Contact E-mail Address: aposm@yahoo.gr

Introduction: Pancreatoscopy-guided laser lithotripsy is being increasingly used for pancreatic stone extraction, after unsuccessful conventional ERCP, with possible advantages over surgery, or extracorporeal shock wave lithotripsy. We report our experience in the management of pancreatic duct stones over the past five years.

Aims & Methods: To evaluate the safety, feasibility and technical success of intracorporeal laser lithotripsy. In a five-year period a total of 19 patients (13 men, 6 women, aged 38 to 79 years) were referred with chronic pancreatitis, complicated with pancreatic duct stones. Treatment with conventional ERCP was unsuccessfully attempted for all patients. Laser lithotripsy was performed using a 10 Fr direct visualization system. For stone fragmentation a Holmium-YAG laser lithotripsy device was used. A 230μm or 365μm fiber with energy output settings at 800–1500 mJ and pulse rates of 8–10 Hz was used.

Results: Chronic calcific pancreatitis was the result of chronic ethanol abuse in 15 patients. Idiopathic pancreatitis was diagnosed in 4 patients. Presenting symptoms included chronic or recurrent pain, weight loss, use of opioids and multiple hospitalizations. Nine (9) patients had single stone located in the pancreatic head, while 10 had multiple stones (up to 4) in the head, neck and body of pancreas. The average stone size was 0.9 cm (0.4–1.2 cm). Successful treatment, defined as complete stone extraction, was achieved in 10 patients after a single laser lithotripsy procedure. In 8 patients a second lithotripsy session was performed to ensure total stone removal. In a single patient pancreatic duct cannulation with the pancreatoscope was not achieved. Dilation with a 3 cm long and 10 mm diameter balloon was necessary in 12 cases for associated main pancreatic duct strictures. Extraction of the fragments was performed using balloon catheter (up to 15 mm diameter) and in 7 patients a 10 mm diameter dormia basket was used. In all cases a 7 Fr pancreatic stent was placed. In 11 patients increased serum pancreatic enzyme levels were noted following laser lithotripsy. None of the patients showed clinical signs of acute pancreatitis. No other clinical adverse events were noted. Follow up was achieved by EUS, having the first appointment four months after lithotripsy. Fourteen patients have already been evaluated, with no stone recurrence. All patients report clinical improvement.

Conclusion: Pancreatoscopy-guided laser lithotripsy is a safe, effective and self-reliant treatment, compared to extracorporeal shock wave lithotripsy, for patients with difficult pancreatic duct stones. It is technically challenging but is a promising and viable method in experienced centers. Further research and clinical studies are necessary to evaluate and standardize the technique.

Disclosure of Interest: All authors have declared no conflicts of interest.

References

1. ERCP with per-oral pancreatoscopy-guided laser lithotripsy for calcific chronic pancreatitis: a multicenter U.S. experience. Attwell AR, Patel S, Kahaleh M, Raijman IL, Yen R, Shah RJ. Gastrointestinal Endoscopy 2015 August 82(2)

2. Endoscopic retrograde cholangiopancreatography with per oral pancreatoscopy for calcific chronic pancreatitis using endoscope and catheter-based pancreatoscopes: a 10-year single-center experience. Attwell AR, Brauer BC, Chen YK, Yen RD, Fukami N, Shah RJ. Pancreas 2014 March 43(2)

3. Pancreatoscopy-guided intracorporeal laser lithotripsy for difficult pancreatic duct stones: a case series with prospective follow-up (with video). Alatawi A, Leblanc S, Vienne A, Pratico CA, Gaudric M, Duchmann JC, Boyer J, Mangialavori L, Chaussade S, Prat F. Gastrointestinal Endoscopy 2013 July 78(1)

4. Single-operator cholangioscopy-guided laser lithotripsy in patients with difficult biliary and pancreatic ductal stones (with videos). Maydeo A, Kwek BE, Bhandari S, Bapat M, Dhir V. Gastrointestinal Endoscopy 2011 December 74(6)

5. Intraductal biliopancreatic imaging: European Society of Gastrointestinal Endoscopy (ESGE) technology review. Tringali A, Lemmers A, Meves V, Terheggen G, Pohl J, Manfredi G, Häfner M, Costamagna G, Devière J, Neuhaus H, Caillol F, Giovannini M, Hassan C, Dumonceau JM. Endoscopy 2015 August 47(8)

MONDAY, OCTOBER 30, 201715:45-17:15

SPORADIC AND HEREDITARY COLON CANCER - ROOM 7.1____________________

OP109 LONG-TERM USE OF ASPIRIN IS MORE EFFECTIVE TO REDUCE THE INCIDENCES OF GASTROINTESTINAL CANCERS THAN NON-GASTROINTESTINAL CANCERS: A 10-YEAR POPULATION-BASED STUDY IN HONG KONG

K. Kf Tsoi 1 , F.C. Chan 1 , H.W. Hirai 1 , J.J.Y. Sung 2

1 The Chinese University of Hong Kong, Hong Kong/Hong Kong PRC

2 Institute Of Digestive Disease And Department Of Medicine And Therapeutics, State Key Laboratory Of Digestive Disease, The Chinese University of Hong Kong, Hong Kong/Hong Kong PRC

Contact E-mail Address: kelvintsoi@cuhk.edu.hk

Introduction: Aspirin has been shown to be a chemopreventive agent for colorectal cancer (CRC), and recent publications have also suggested chemopreventive effect of aspirin on other cancers.

Aims & Methods: The aim of this study is to compare the benefits of long-term aspirin use to reduce the incidences of gastrointestinal (GI) cancers and non-gastrointestinal cancers. This is a matched-cohort study of a territory-wide database from all public hospitals in Hong Kong. Patients with aspirin prescribed for at least 6 months between 2000 and 2004 were extracted and matched with non-users in 1:2 ratios. Immortal time bias was further adjusted for the non-users who died in 6 months after matching. The incidences of GI cancers which referred to colorectum, liver, oesophageal, pancreas or stomach cancers, and the incidences of non-GI cancers which referred to breast, bladder, kidney, leukaemia, lung, multiple myeloma, or prostate cancers were the study outcomes. Patients' outcomes were documented for up to 14 years until 2013. Odds ratio (OR) with it associated 95% confidence intervals (95% CI) were used to measure the association of long-term aspirin use and the cancer incidences.

Results: A total of 618,884 subjects were extracted and matched from the database, including 206,295 aspirin users and 412,589 non-aspirin users. The mean ages of patients in aspirin and non-aspirin group were 67.5 years and 67.6 years respectively. In the aspirin users, the average duration of aspirin prescribed was 7.7 years, and the median dose of aspirin prescribed was 80 mg with the inter-quartile range between 80 mg and 100 mg. Cancer incidences were found in 98, 533 (15.9%) out of 618, 884 subjects, and the lung cancer was the most common cancer. Long-term use of aspirin showed 24% to 47% significant reduction on major cancers in the GI tract including colorectal (OR: 0.76, 95% CI: 0.73 to 0.78), liver (OR: 0.53, 95% CI: 0.51 to 0.56), oesophagus (OR: 0.53, 95% CI 0.49 to 0.59), pancreas (OR: 0.66, 95% CI 0.60 to 0.71) and stomach (OR: 0.62, 95% CI: 0.58 to 0.65). For non-GI cancers, long-term use of aspirin only showed significant reduction on leukaemia, lung, and prostate cancers, but not breast, bladder, kidney and multiple myeloma cancers (Table 1). Table 1 . Comparison between Aspirin Users and Non-users for Major Cancers Incidence.

Conclusion: Long-term use of aspirin can reduce the major types of GI cancers, but the benefits are limited to some other non-GI cancers, such as breast and kidney.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP110 USE OF ASPIRIN AFTER CURATIVE SURGERY CAN REDUCE MORTALITY DUE TO COLORECTAL CANCER: A 10-YEAR POPULATION-BASED STUDY IN HONG KONG

J. Jy Sung 1 , F.C. Chan 1 , H.W. Hirai 1 , K. Kf Tsoi 1

1 Institute Of Digestive Disease, The Chinese University of Hong Kong, Hong Kong/Hong Kong PRC

Contact E-mail Address: joesung@cuhk.edu.hk

Introduction: Aspirin was shown to be effective to reduce the risk of colorectal cancer (CRC) and mortality. However, the use of aspirin after curative colorectal surgery was uncertain.

Aims & Methods: This study aims to demonstrate if aspirin can also reduce colorectal cancer mortality after diagnosis and surgical resection. A cohort with long-term use of aspirin and a matched cohort of non-users were extracted from the electronic healthcare records in all public hospitals in Hong Kong. Patients with curative resection for CRC since 2000 were extracted according to the ICD-9 and procedure codes, such as resection of colon/rectum. Patients were categorized into two groups: (a) Patients with continuous use of aspirin after surgery were compared with those who stopped; (b) Patients with aspirin started after surgeries were compared with those who remained not taking aspirin. The primary outcome was CRC related mortality and the secondary outcome was overall mortality. Cox-proportional Hazard Models were fitted with the control of confounding factors including history of cardiovascular or cerebrovascular diseases. Sub-distribution Hazard Ratio (SHR) for competing risk mortality on CRC was fitted, and Hazard Ratio (HR) was used to measure all-cause mortality. Subgroup analyses on gender were performed.

Results: From the healthcare records between 2000 and 2013, a total of 13,552 subjects were included: 3,301 of them (24.4%) were aspirin users and 10,251 (75.6%) were non-users before CRC diagnosis. The median dose of aspirin used was 80 mg. Patients in group (a) with aspirin use before CRC diagnosis, 2,665 (80.7%) continued aspirin and 636 (19.3%) discontinued aspirin after curative surgery. Continuous use of aspirin significantly reduced 31% risk of CRC-caused mortality with SHR: 0.69 (95% CI: 0.59 – 0.81) and 42% risk of all-cause mortality with HR: 0.58 (95% CI: 0.49 – 0.68). Patients in group (b) who never use aspirin before CRC diagnosis, 1055 patients (10.3%) initiated aspirin after curative surgery and 9196 (89.7%) patients remained not to have aspirin. Initiating aspirin after surgery significantly reduced 12% risk of CRC-caused mortality with SHR: 0.88 (95% CI: 0.80 – 0.98) and 18% risk of all-cause mortality with HR: 0.82 (95% CI: 0.73 – 0.91). Subgroup analyses did not show significant different between male and female (Table 1). Table 1. The Sub-distribution Hazard Ratio (95% CI) and Hazard Ratio (95% CI) for Continuing and Initiating Aspirin after Curative Surgery

1 Presented by sub-distribution hazard ratio (SHR) for competing risk mortality on CRC 2 Presented by hazard ratio (HR) for all-cause mortality

Conclusion: Aspirin initiated after the curative surgery leads to significantly lower risks on both CRC-related and overall mortalities. Patients with regular use of aspirin even showed higher benefits.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP111 COLORECTAL CANCER INCIDENCE IN PATIENTS WITH LYNCH SYNDROME: FIRST REPORT OF A MULTICENTER NATION-WIDE STUDY

A. Sánchez García 1 , M. Navarro 2 , T. Ocaña 3 , M. Pineda 2 , L. Moreno 1 , F. Rodriguez Moranta 4 , A. Soriano Izquierdo 4 , T. Ramon, Y Cajal 5 , G. Llort 6 , C. Yagüe 6 , M.D. Pico Sala 7 , R. Jover 7 , A. Lopez Fernandez 8 , E. Martinez De Castro 9 , C. Alvarez Urturi 10 , X. Bessa Casserras 10 , L. Rivas 11 , D. Rodríguez-Alcalde 12 , A. Dacal Rivas 13 , M. Herraiz 14 , C. Garau Colom 15 , L. Bujanda Fernández De Piérola 16 , L. Cid Gómez 17 , C. Poves 18 , M. Garzon-Benavides 19 , Á.E. Pizarro Moreno 19 , I. Salces 20 , M. Ponce 21 , M. Carrillo Palau 22 , E. Aguirre 23 , E. Saperas Franch 24 , A. Virgili 5 , D. Fisas 5 , V. Piñol 25 , G. Jung 1 , S. Carballal 1 , L. Rivero Sánchez 1 , M. Pellisé Urquiza 1 , M. Serra 26 , J. Balmana 8 , G. Capella 2 , J. Brunet 27 , A. Castells 1 , L. Moreira 1 , F. Balaguer 1

1 Gastroenterology, Hospital Clinic Barcelona, Barcelona/Spain

2 Institut Català d'Oncologia, Barcelona/Spain

3 Hospital Clinic Barcelona, Barcelona/Spain

4 University Hospital of Bellvitge (HUB-IDIBELL), Barcelona/Spain

5 Hospital de la Santa Creu i Sant Pau, Barcelona/Spain

6 Corporació Sanitària Parc Taulí-Consorci Sanitari Terrasa, Sabadell - Terrassa/Spain

7 Hospital General Universitario de Alicante, Alicante/Spain

8 Hospital Universitari Vall d'Hebron, Barcelona/Spain

9 Hospital Universitario Marques de Valdecilla, Santander/Spain

10 Hospital del Mar - Parc de Salut Mar, Barcelona/Spain

11 Complexo Universitario Hospitalario de Ourense, Ourense/Spain

12 Hospital Universitario de Móstoles, Madrid/Spain

13 Hospital Universitario Lucus Aungusti, Lugo/Spain

14 Clinica Universitaria de Navarra, Pamplona/Spain

15 Hospital de Son Llàtzer, Palma de Mallorca/Spain

16 Hospital de Donostia, Donostia/Spain

17 Complejo Hospitalario Universitario de Vigo, Vigo/Spain

18 Hospital Clínico San Carlos, Madrid/Spain

19 Gastroenterology, Hospital Virgen del Rocio, Sevilla/Spain

20 Hospital 12 de Octubre, Madrid/Spain

21 Hospital Universitari i Politecnic de la Fe, Valencia/Spain

22 University Hospital of Canary Islands, Tenerife/Spain

23 Hospital Quiron, Zaragoza/Spain

24 Hospital General de Catalunya, Barcelona/Spain

25 Hospital Josep Trueta, Girona, Girona/Spain

26 Universitat de Barcelona & Centre de Recerca en Economia i Salut (CRES-UPF), Barcelona/Spain

27 Institut Català d'Oncologia, Girona/Spain

Contact E-mail Address: asanchezg@clinic.ub.es

Aims & Methods: We set up a multicenter nation-wide study in Spain with the following aims: 1) establishing the prevalence and cumulative incidence of colorectal cancer and other tumors in Lynch syndrome; 2) evaluating the effect of screening-surveillance on cancer incidence; and 3) assessing the cancer-specific survival. Herein we report the first preliminary analysis focused on the prevalence and the incidence of colorectal cancer. We designed a retrospective collection study of prospectively observed data in the setting of organized high-risk clinics. A centralized online database was used, including demographic, genetic, family and personal cancer history, and surveillance protocol and treatments. First prospectively colonoscopy planned as Lynch syndrome screening-surveillance was considered as date of inclusion. Cumulative incidence of the first colorectal cancer diagnosed under screening was calculated by mutated gene. For this analysis, colorectal cancers diagnosed prior or within 6-months of the beginning of follow-up (prevalent cancers) were excluded. Additionally, we calculated the cumulative incidence of subsequent colorectal cancers in patients with a prior colorectal cancer by mutated gene. Preliminary statistical analysis has been performed by Kaplan-Meier.

Introduction: Lynch syndrome is caused by germline mutations in the mismatch DNA repair system ( MLH1, MSH2, MSH6, PMS2, EPCAM ) and predisposes to colorectal, endometrial and other tumors. Estimates of cancer risk in Lynch syndrome have been frequently biased due to retrospective designed studies and small cohorts.

Results: One thousand one hundred eight patients with Lynch syndrome from 25 centers were included [MLH1, 449 (40.5%); MSH2, 371 (33.5%); MSH6, 197 (17.8%); PMS2, 68 (6.1%); EPCAM, 23 (2.1%)] and followed-up for a mean of 67.5 + 57.8 months. Mean age was 52.4 + 15.4, and 630 (56.9%) were female. Mean age at inclusion was 45.2 + 15. Colorectal cancer was present in 426 (38.4%) patients with Lynch syndrome and 114 where diagnosed of more than 1 colorectal cancer. The distribution per gene was: MLH1, 204 (48%); MSH2, 140 (33%); MSH6, 47 (11%); PMS2, 23 (5%); EPCAM, 12 (3%). First colorectal cancer under screening with colonoscopy was found in 49/713 (6.7%) patients with the following distibution per gene: MLH1, n = 23/268; MSH2, n = 18/249; MSH6, n = 4/154; PMS2, n = 2/47; EPCAM, n = 2/13. The cumulative incidences of the first colorectal cancer at 70 years by gene were 25.6% (95%CI = 13.2–38.2), 22.1% (95%CI = 11.3–35.1), 6.3% (95%CI = 0–12.8) and 25.9% (95%CI = 7–71) for MLH1, MSH2, MSH6 and PMS2 mutation carriers, respectively. Tumor stages of first colorectal cancer under surveillence were: stage I (45.7%), stage II (28.6%), stage III (22.9%) and stage IV (2.9%). The 10-year cumulative incidences for subsequent colorectal cancers for patients with a prior colorectal cancer were 9.4% (95%CI = 5–17) for MLH1, 12.6% (95%CI = 5.6–27.6) for MSH2, and 17.2% (95%CI = 6.6–40) for MSH6, respectively. Two-hundred-sixteen (19.5%) patients with Lynch syndrome presented cancer in other locations: 119 endometrium (18.8% woman) [MLH1, 39 (32.8%); MSH2, 47 (39.5%); MSH6, 31 (26.1%); PMS2, 1 (0.8%); EPCAM, 1 (0.8%)], 26 ovarium (4.12% of woman), 12 stomach (1%), 17 urinary bladder (1.5%), 20 ureter (1.8%), 21 skin (1.9%), 19 breast (1.7%) and 9 prostate cancer (0.8%).

Conclusion: In this large multicenter study, a preliminary analysis shows that cumulative incidence of first colorectal cancer under screening colonoscopy is lower than in previous published series. This observation reinforces the importance of screening colonoscopy in patients with Lynch syndrome and may suggest differences in the penetrance of the syndrome in our environment. The results of this study will be key for the further improvement on the management of families with Lynch syndrome.

Disclosure of Interest: All authors have declared no conflicts of interest.

Reference

Pal Moller, Toni Seppala, Inge Bernstein, Elke Hollinski-Feder et al. Cancer incidence and survival in Lynch syndrome patients receiving colonoscopic and gynaecological surveillance: first report from the prospective Lynch syndrome database. Gut 2015 Dec 9. pii: gutjnl-2015-309675

OP112 CLINICAL AND MOLECULAR CHARACTERIZATION OF LYNCH-LIKE SYNDROME

M.D. Pico Sala 1 , R. Jover 2 , M. Giner-Calabuig 2 , M. Alustiza 2 , J.L. Soto 3 , A. Castillejo 1 , A.B. Sánchez 1 , A. Sánchez García 4 , F. Balaguer 4 , L. Moreira 4 , A. Castells 4 , M. Pellisé Urquiza 4 , T. Ramon, Y Cajal 5 , M. Carrillo Palau 6 , G. Llort 7 , C. Yagüe 8 , A. Lopez Fernandez 9 , J. Balmana 10 , E. Martinez De Castro 11 , C. Alvarez Urturi 12 , X. Bessa Casserras 13 , L. Rivas 14 , D. Rodríguez-Alcalde 15 , A. Dacal Rivas 16 , M. Herraiz 17 , C. Garau Colom 18 , L. Bujanda Fernández De Piérola 19 , L. Cid Gómez 20 , C. Poves 21 , M. Garzon-Benavides 22 , Á.E. Pizarro Moreno 21 , A. Gomez 1 , I. Salces 22 , M. Ponce 23 , E. Aguirre 24 , E. Saperas Franch 25 , V. Piñol 26 , M. Serra 27

1 Gastroenterology, Hospital General Elche, Elche/Spain

2 Gastroenterology, Hospital General Alicante, Elche/Spain

3 Hospital General Universitario de Elche, Alicante/Spain

4 Gastroenterology, Hospital Clinic de Barcelona, Barcelona/Spain

5 Hospital de la Santa Creu i Sant Pau, Barcelona/Spain

6 University Hospital of Canary Islands, Tenerife/Spain

7 Corporació Sanitària Parc Taulí-Consorci Sanitari Terrasa, Sabadell - Terrassa/Spain

8 Hospital Universitari Vall d'Hebron, Barcelona/Spain

9 Institute Of Oncology, Vall d'Hebron University Hospital, Barcelona/Spain

10 Hospital Universitario Marques de Valdecilla, Santander/Spain

11 H. Del Mar - Parc de Salut Mar, Barcelona/Spain

12 Hospital del Mar - Parc de Salut Mar, Barcelona/Spain

13 Complexo Universitario Hospitalario de Ourense, Ourense/Spain

14 Hospital Universitario de Móstoles, Madrid/Spain

15 Hospital Universitario Lucus Aungusti, Lugo/Spain

16 Clinica Universitaria de Navarra, Pamplona/Spain

17 Hospital de Son Llàtzer, Palma de Mallorca/Spain

18 Hospital de Donostia, Donostia/Spain

19 Complejo Hospitalario Universitario de Vigo, Vigo/Spain

20 Hospital Clínico San Carlos, Madrid/Spain

21 Gastroenterology, Hospital Virgen del Rocio, Sevilla/Spain

22 Hospital 12 de Octubre, Madrid/Spain

23 Hospital Universitari i Politecnic de la Fe, Valencia/Spain

24 Hospital Quiron, Zaragoza/Spain

25 Hospital General de Catalunya, Barcelona/Spain

26 Hospital Josep Trueta, Girona, Girona/Spain

27 Universitat de Barcelona & Centre de Recerca en Economia i Salut (CRES-UPF), Barcelona/Spain

Contact E-mail Address: madopisa@hotmail.com

Introduction: Lynch syndrome (LS) is the most common cause of inherited colorectal cancer (CRC). However, there is a group of patients that develop CRC or LS-related tumors in which the presence of microsatellite instability or loss of expression of the mismatch repair proteins is observed in the tumor, but no germinal pathogenic mutation is found in these genes. This group of patients is known as Lynch-like syndrome (LLS) and represents approximately 30% of all patients with unstable tumors (1). These cases and their relatives show high risk for CRC and there is no consensus about their management (2, 3).

Aims & Methods: The aim of this study is to know the clinical and molecular characteristics of these patients in a large nation-wide cohort and to analyze if there are clinical, pathology or molecular characteristics that could suggest a probably hereditary or sporadic origin. This is a multicenter nation-wide study, involving 25 Spanish hospitals. Patients with CRC were included when their tumors show immunochemical loss of MSH2, MSH6, PMS2 or loss of MLH1 with BRAF-wild type and/or no MLH1 methylation and absence of pathogenic mutation in these genes. Immunochemical study of the tumors was performed because of fulfilment of revised Bethesda Guidelines (4) or because of universal molecular screening for LS (5). These patients were included in a national registry (EPICOLON-III) and demographic, clinical and pathological variables, as well as family history of neoplasms were registered.

Results: Our study included 85 patients with LLS. Mean age at diagnosis of CRC was 55 years (SD 14). A total of 39 patients were female (46%). Loss of MLH1/PMS2 was found in 46% of CRC, loss of MSH2/MSH6 in 34%, isolated loss of MSH6 was found in 12% and isolated loss of PMS2 in a 6%. Revised Bethesda guidelines were fulfilled by 78% of cases, whereas Amsterdam I criteria were fulfilled by 10% and Amsterdam II in 13%. A total of 56 patients (66%) had CRC located in the right colon. Regarding TNM, 19% of tumors were in stage I, 32% in stage II, 28% in stage III and 8% in stage IV. None of the patients showed personal history of previous CRC. A total of 12 patients (14%) had personal history of non-colorectal cancer, and only 3 (3.5%) patients had previous history of LS-related cancer. Regarding family history, a total of 46 patients (54%) had at least one relative with CRC, and 38 patients (45%) showed familial history of LS-related cancer. Comparison of clinical and molecular characteristics of patients depending on age at diagnosis of CRC or family history can be seen in Table 1. *p < 0.05 for comparison

Conclusion: In this cohort of LLS patients, the largest collected until now, there are no clinical, molecular or pathological characteristics that could be of help to distinguish between probably sporadic and hereditary patients. These results support the need of homogeneous follow-up for this group of patients.

Disclosure of Interest: All authors have declared no conflicts of interest.

References

1. Perez-Carbonell, L., Ruiz-Ponte C, Guarinos C, Jover R et al . Comparison between universal molecular screening for Lynch syndrome and revised Bethesda guidelines in a large population-based cohort of patients with colorectal cancer. Gut 2011; 61, 865–872.

2. Lynch, H. T., Boland C. R., Rodriguez-Bigas M.A. et al. Who should be sent for genetic testing in hereditary colorectal cancer syndromes? J Clin Oncol 2007; 25, 3534–3542.

3. Rodriguez-Soler M, Pérez-Carbonell L, Guarinós C et al. Risk of cancer in cases of suspected lynch syndrome without germline mutation. 2013;144(5):926–932.

4. Umar A, Boland CR, Terdiman JP, Syngal S, de la Chapelle A, Rüschoff J et al. Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (lynch syndrome) and microsatellite instability. J Natl Cancer Inst . 2004:18;96:261–8.

5. Boland CR, Shike M. Report from the Jerusalem workshop on Lynch syndrome-hereditary nonpolyposis colorectal cancer. Gastroenterology . 2010;138:2197 e1–7.

MONDAY, OCTOBER 30, 201715:45-17:15

GLUTEN-RELATED DISORDERS - ROOM E2____________________

OP113 THE PREVALENCE OF NON-CELIAC GLUTEN SENSITIVITY IN PATIENTS WITH ABDOMINAL PAIN AND BLOATING

M. Di Stefano 1 , G. Di Fede 2 , I. Benedetti 3 , M. Bresciani 1 , C. Pedroni 2 , A. Gabriele 2 , M. Bergonzi 3 , E.V. Pesatori 3 , G.F. Manfredi 3 , G.R. Corazza 4

1 IRCCS Policlinico San Matteo, Pavia/Italy

2 istituto di medicina biologica, Milano/Italy

3 First Department Of Internal Medicine, IRCCS Policlinico San Matteo, Pavia/Italy

4 Cattedra Di Gastroenterologia - Dip. Di Med. Interna E Terapia Medica 1st Department of Medicine, University of Pavia, IRCCS, San Matteo? Hospital, Pavia, Italy, Pavia/Italy

Contact E-mail Address: irene.benedetti89@gmail.com

Introduction: A new entity, called Non-Celiac Gluten Sensitivity (NCGS), was recently proposed to categorize patients suffering from a wide range of both intestinal and extra-intestinal symptoms after gluten ingestion (Sapone A, et al, BMC Medicine 2012). A very high prevalence of this condition was reported (Sapone A, et al, BMC Medicine 2012), but in our experience such a high figure was not confirmed (Di Sabatino A, et al, CGH 2015). We have recently shown that the ingestion of gluten may hamper colonic fermentation (DLD) in healthy volunteers. Accordingly, it is possible that a high prevalence of NCGS could be present in patients with bloating.

Aims & Methods: Our aim was to detect the prevalence of non-celiac gluten sensitivity in functional patients with a long history of abdominal pain and bloating, claiming a relationship between gluten intake and symptom occurrence, and referred to an outpatient clinic for functional gastrointestinal disorders of a tertiary medical center. In accordance with the Salerno Criteria (Catassi C, et al, Nutrients 2015), we conducted a double-blind, placebo controlled trial with gluten vs placebo in thirty-two non-celiac patients with moderate to severe abdominal bloating and pain, enrolled in an outpatient clinic (M/F 3/29, mean age 31 ± 5). Symptoms were present for a mean period of 10 ± 3 years and were judged by patients as poorly responsive to all previous treatments. The presence of allergic, organic gastrointestinal and systemic disorders was ruled out in all patients. All subjects reported abdominal pain, bloating, flatulence, borborygmi, bowel habit alterations, dyspeptic symptoms on gluten-containing diet (GCD) and, considering gluten as the causal agent, had been spontaneously following a non-blinded gluten-free diet (GFD) for at least a 6-week period, reporting an improvement of symptoms. They then started a rigorous GFD and entered this trial. In a double-blind, crossover protocol, ten capsules, containing 475 mg of gluten or 475 mg of rice starch, were administered randomly, each day for a 1-week period, with a 1-week wash-out interval. The patients completed a diary of symptoms, every evening at the same time for the duration of the study. The two main symptoms recorded by all patients were bloating and abdominal pain: a mean value during gluten ingestion over 30% higher than the value during placebo was considered as indicative of gluten sensitivity (Catassi C, et al, Nutrients 2015).

Results: In seventeen out of 32 patients (53%), the severity of abdominal pain was significantly higher during the week of gluten capsule ingestion than during the week of placebo capsule ingestion: the severity of abdominal pain in the group of patients with NCGS was 2.8 ± 2.4 during gluten and 1.5 ± 2.0 during placebo (p = 0.00001), on the contrary, in the group of non-sensitive patients it was 0.7 ± 1.8 during gluten and 1.2 ± 1.9 during placebo (p = 0.013). In fifteen out of 32 patients (47%), the severity of bloating was significantly higher during gluten than during placebo: the severity of bloating in the group of patients with NCGS was 3.7 ± 2.5 during gluten and 2.2 ± 2.0 during placebo (p = 0.0001), while in the group of non-sensitive patients it was 2.1 ± 1.5 during gluten and 3.5 ± 2.3 during placebo (p = 0.00001). Considering the modification of at least one of the two main symptoms, the diagnosis of NCGS was possible in 22 out of 32 patients (68.7%).

Conclusion: Around half of the patients with a long history of abdominal pain and bloating, claiming a relationship with gluten ingestion, resistant to previous treatments and referred to a tertiary clinic, show a positive result at the double blind test for the diagnosis of NCGS.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP114 PROSPECTIVE EVALUATION OF TRANSGLUTAMINASE ANTIBODY CUT-OFF LIMITS TO PREDICT SCREEN-DETECTED COELIAC DISEASE

I.R. Korponay-Szabo 1 , J. Gyimesi 1 , G. Castillejo 2 , S. Vriezinga 3 , R. Auricchio 4 , A. Chmielewska 5 , K. Werkstetter 6 , P. Crespo 7 , C. Hartman 8 , E. Martinez 9 , P. Szillat 10 , H. Szajewska 11 , I. Polanco 9 , R. Shamir 8 , S. Koletzko 6 , C. Ribes Koninckx 7 , R. Troncone 12 , M.L. Mearin Manrique 3

1 Heim Pal Children's Hospital, Budapest and University of Debrecen MHSC, Debrecen/Hungary

2 Hospital Universitari Sant Joan, Reus/Spain

3 University Medical Center, Leiden/Netherlands

4 University Federico II, Naples/Italy

5 The Medical University of Warsaw, Warsaw/Poland

6 Dr. von Hauner Children’s Hospital, München/Germany

7 La Fe University Hospital, Valencia/Spain

8 Institute Of Gastroenterology, Nutrition And Liver Diseases, Tel-Aviv University Schneider Childrens Hospital Gastroenterology and Nutrition, Petach-Tikva/Israel

9 La Paz University Hospital, Madrid/Spain

10 Thermofisher, Freiburg/Germany

11 The Medical University of Warsaw, Warszawa/Poland

12 Pediatrics, University Federico II Naples Dept. of Pediatrics, Naples/Italy

Contact E-mail Address: loilko@uta.fi

Introduction: Current ESPGHAN guidelines allow the non-invasive diagnosis of paediatric coeliac disease (CD) in clinical patients with relevant symptoms, serum transglutaminase 2 antibody levels above 10 times of the upper limit of normal (ULN), endomysial antibody positivity (EMA) and an HLA-DQ2 or DQ8 background.

Aims & Methods: In this study we evaluated whether high serum antibody concentrations also predict CD in prospectively followed, regularly screened family members. The PREVENTCD multicenter FP6 study ( www.preventcd.com ) enrolled in 8 European countries 1002 DQ2- and/or DQ8-positive newborns with at least one family member diagnosed with CD for a prospective dietary intervention consisting of 100 mg of gluten per day or placebo between the age of 4–6 months. IgA antibodies against transglutaminase 2 (TGA) were determined 7 times until 3 years of age and then annually. TGA was measured in years 2007–2014 by the Celikey Varelisa test, in years 2015–2016 by Celikey ELIA method (both from Phadia and utilising the same TG2 antigen but having 5 U/ml and 7 U/ml positivity cut-offs as declared by the manufacturer), respectively. EMA tests were performed locally as needed. A small bowel biopsy was offered to asymptomatic children with persistent seropositivity or when symptoms appeared. CD was diagnosed in children with Marsh III histology lesions according to central evaluation by a reference pathologist blinded to the clinical and antibody results. In case of decreasing or increasing TGA concentrations, the highest value before biopsy was taken into account for the calculations. IgA-deficient subjects were excluded from the present analysis .

Results: During follow-up, small bowel biopsy was performed in altogether 144 children and 124 children were diagnosed with CD by histology of whom 67 (54%) were asymptomatic. Of the 149 TGA+ children, 71 (48%) had values >100U/ml, 36 (24%) had values between 30–100U/ml and 42 had values <30 U/ml of which 14/42 had transient seropositivity. TGA+ values >6.0xULN or higher were associated with 100% positive predictive value for CD (Table). There was no statistical difference for disease prediction between symptomatic and asymptomatic children with TGA+ levels >4.0xULN.

Conclusion: TGA+ levels >6xULN measured by the utilised test kits safely predicted CD both in symptomatic and asymptomatic children. Predictive cut-off levels of other TGA measuring kits may substantially differ, and such differences should be carefully considered when applying ESPGHAN guidance for omitting biopsy. Test-specific predictive values are to be systematically established in similar prospective studies.

Disclosure of Interest: P. Szillat: Employee of Phadia Thermofisher

All other authors have declared no conflicts of interest.

OP115 RECTO-SIGMOID SENSORIMOTOR ACTIVITY IN SELF-REPORTED NON-CELIAC GLUTEN SENSITIVITY: A COMPARISON WITH IRRITABLE BOWEL SYNDROME AND HEALTHY VOLUNTEERS

M. Di Stefano 1 , I. Benedetti 1 , E.V. Pesatori 1 , G.F. Manfredi 1 , M. Bergonzi 1 , E. Pagani 1 , B. Valvo 1 , E. Miceli 1 , G.R. Corazza 1

1 IRCCS Policlinico San Matteo, Pavia/Italy

Contact E-mail Address: manuela.bergonzi@libero.it

Introduction: The ingestion of gluten may be responsible for symptom onset in non-celiac patients (Cooper BT, et al Gastroenterology 1980), and a new entity, called Non Celiac Gluten Sensitivity (NCGS), was recently proposed (Sapone A, et al, BMC Medicine 2012). In the general population, a very high prevalence of this condition was also suggested (Sapone A, et al, BMC Medicine 2012) but many doubts on its pathophysiology and diagnostic algorithm were raised (Di Sabatino A, et al, CGH 2015). In particular, the oral administration of gluten in a double-blind, crossover, placebo-controlled protocol in non-celiac patients claiming gluten-related symptoms showed a very low prevalence of this condition (Di Sabatino A, et al, CGH 2015). Many aspects of the clinical presentation of NCGS resemble those of irritable bowel syndrome (IBS), characterized by an impairment of intestinal sensorimotor activity. In particular, symptoms like bloating, flatulence, alterations of bowel habit and abdominal pain could share same pathophysiological mechanisms with IBS.

Aims & Methods: Our aim was the study of intestinal sensitivity thresholds and the meal-induced modification of intestinal tone in NCGS in comparison to a group of IBS patients and healthy volunteers (HV). Sixteen consecutive non-celiac patients (14 F, 2 M, mean age 38 ± 4) complaining of severe symptoms after gluten ingestion took part in the study. In all subjects the presence of allergic, organic gastrointestinal and systemic disorders was ruled out. A group of 35 IBS patients diagnosed according to Rome IV criteria (23 IBS-C e 12 IBS-D) and a group of 20 HV, both matched for gender and age, were recruited. The recto-sigmoid barostat test was performed in all subjects (Di Stefano M, et al, Gut 2006; Di Stefano M, et al, AJG 2007). Basal recto-sigmoid sensitivity thresholds were determined by sequential ramp distentions and the subjects were instructed to score their perception on a 0–6 scale. The perception threshold was defined as a perception score of 1 or more and the discomfort as a perception score of 5. Fasting and post-prandial intestinal tone were measured by monitoring recto-sigmoid volume during a 30-min fasting period and a 60-min period after liquid meal consumption (200 Kcal, 200 mL liquid meal), and the modification of recto-sigmoid volume was calculated (Di Stefano M, et al, AJG 2007).

Results: In comparison with HV, the mean perception threshold was similar in NCGS and IBS patients (perception; NCGS patients 4.7 ± 3.8 mmHg, IBS patients 4.6 ± 4.4 mmHg, HV 5.4 ± 1.3 mmHg, ANOVA = NS). The mean discomfort threshold was similar in NCGS and IBS patients (NCGS patients 15.6 ± 6.8 mmHg, IBS 13.4 ± 6.2), but significantly lower than in HV (20.2 ± 2.3 mmHg, ANOVA p < 0.001). The mean fasting recto-sigmoid volume was similar in the three groups of subjects (NCGS 138 ± 50 mL, IBS 142 ± 60 mL, HV 124 ± 23 mL; ANOVA p = NS) but in comparison with HV both mean post-prandial recto-sigmoid volume and mean percent modification of recto-sigmoid volume were significantly different in NCGS and IBS patients (mean post-prandial volume: self-reported NCGS patients 171 ± 84 mL, IBS 165 ± 86 mL, HV 75 ± 14 mL; ANOVA p = 0.001; mean percent volume modification: NCGS patients +22 ± 26%, IBS +19 ± 40%, HV −39 ± 7%; ANOVA p = 0.0001). The mean percent modification of recto-sigmoid volume was similar in NCGS and IBS patients.

Conclusion: No difference was detected in recto-sigmoid sensorimotor activity between self-reported NCGS and IBS. Self-reported NCGS overlaps IBS both in clinical presentation and pathophysiological aspects. Accordingly, NCGS diagnosis should be not performed on the basis of a mere anamnestic evaluation.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP116 RISK OF LYMPHOMAS AND GASTROINTESTINAL CARCINOMAS AFTER A DIAGNOSIS OF CELIAC DISEASE BASED ON A NATIONWIDE POPULATION-BASED CASE-CONTROL STUDY

T. Van Gils 1 , P. Nijeboer 1 , L.I. h. Overbeek 2 , M. Hauptmann 3 , D. A. r. Castelijn 1 , G. Bouma 1 , C.J. j. Mulder 1 , F. E. Van Leeuwen 3 , D. De Jong 4

1 Celiac Center Amsterdam, Department Of Gastroenterology And Hepatology, VU University Medical Center, Amsterdam/Netherlands

2 Foundation PALGA (The Nationwide Network and Registry of Histo- and Cytopathology in the Netherlands), Houten/Netherlands

3 Department Of Epidemiology And Biostatistics, Netherlands Cancer Institute/Antoni van Leeuwenhoek, Amsterdam/Netherlands

4 Department Of Pathology, VU University Medical Center, Amsterdam/Netherlands

Contact E-mail Address: t.vangils@vumc.nl

Introduction: Celiac disease (CD) patients are likely at increased risk to develop various malignancies. Relative and absolute risk estimates are essential to provide follow-up recommendations to newly diagnosed CD patients.

Aims & Methods: The aim of this study was to assess the subsequent relative and absolute risk for malignant lymphoma and gastro-intestinal (GI) carcinoma after CD diagnosis in a population-based study. All patients with lymphoma or GI carcinoma (cases) and melanoma or basal cell carcinoma (controls) diagnosed in the Netherlands between 1994 and 2014 were retrieved through the Dutch nationwide population-based pathology database (PALGA). Within this series, all individuals with histologically confirmed CD before or within 3 months after the diagnosis of malignancy were identified through PALGA. Odds ratios (OR) were determined using logistic regression analysis with corrections for age and gender.

Results: Of 301,424 cases and 576,971 controls, 349 (0.1%) and 282 (0.05%), respectively, were diagnosed with CD. ORs for small bowel adenocarcinoma and esophageal squamous cell carcinoma (SCC) after prior CD diagnosis were 11.9 [95% CI, 8.2–17.2] and 3.5 [95% CI 2.1–5.8]. Adenocarcinoma of the colon, esophagus and stomach and SCC of the anus were not associated with CD history. The OR for T-cell lymphoma after prior CD diagnosis was 35.8 [95% CI, 27.1–47.4], whereas B-cell lymphomas were not associated with CD history. Absolute cumulative risks of T-cell lymphoma reaches the risk of colorectal carcinoma in the general population. However, the most common T-cell lymphoma in CD, enteropathy associated T-cell lymphoma (101 of all 131 T-cell lymphomas in the CD group), was preferentially diagnosed at time of CD diagnosis.

Conclusion: This population-based study is unique by including pathologically confirmed CD. The data suggest strongly increased risk for specific malignancies after CD diagnosis. These results provide a strong motivation and detailed information to develop follow-up guidelines for newly diagnosed CD patients.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP117 THE ROLE OF TMPRSS6 VARIANT RS855791 IN IRON-REFRACTORY IRON DEFICIENCY ANAEMIA (IRIDA) IN CELIAC DISEASE

N. Imperatore 1 , R. Tortora 2 , L. De Falco 3 , A. Iolascon 3 , N. Gerbino 1 , D. Nudo 1 , L. Montesano 1 , F. Nastro 1 , N. Caporaso 4 , A. Rispo 5

1 Gastroenterology, Department of Clinical Medicine and Surgery, School of Medicine Federico II of Naples, Naples/Italy

2 Hepatology Unit, Cardarelli Hospital, Naples/Italy

3 Department of Molecular Medicine and Medical Biotechnologies, University “Federico II” of Naples, Ceinge, Advanced Biotechnologies, Naples/Italy

4 Department Of Clinical Medicine And Surgery, Gastroenterology Unit Aou Federico II, Naples/Italy

5 Dept. Clinical Medicine And Surgery, University ´´Federico II´´of Naples, Naples/Italy

Contact E-mail Address: nicola.imperatore@alice.it

Introduction: Iron deficiency anaemia (IDA) is very common in celiac disease (CD) and has been reported in up to 46% of cases of subclinical CD. Even though the link between malabsorption and anaemia is well known, the role of genetic factors remain unexplored. Iron-refractory IDA (IRIDA) has recently been described as an inherited cause of IDA due to loss-of-function mutations in TMPRSS6 gene.

Aims & Methods: We investigated the prevalence of TMPRSS6 in CD and its role in iron absorption in CD patients treated for IDA. From October 2011 to July 2015 we prospectively assessed the frequency of TMPRSS6 variant rs855791 in both anemic and non-anemic CD patients at time of CD diagnosis. We also estimated the association of this variant with some hematological and iron parameters (hemoglobin, MCV, serum iron and serum ferritin) at time of CD diagnosis and after 1-year of gluten-free diet. The prescribed treatment for IDA, both oral or parenteral iron, was recorded in all patients. Statistical analysis was performed by using T-student and X-square test when indicated; all differences were considered significant when p < 0.05.

Results: Finally, 505 CD patients were enrolled: 229 with IDA (45%; mean age 31.2; females 88%), 276 with non-IDA (55%; mean age 32.4; females 65%). The allelic frequencies for A736V mutation of TMPRSS6 variant rs855791 did not differ significantly between anemic (45.4%) and non-anemic CD patients (52.2%) at time of CD diagnosis. At follow-up, TMPRSS6 variant rs855791 was present in 88 out of 104 patients with persistent IDA, being significantly higher than in 125 non-IDA persistent patients (84.6% vs 56%, p < 0.01). In IDA patients, the presence of one or the other TMPRSS6 genotype (wild type, heterozygosis, homozygosis) did not influence iron parameters at diagnosis while CD patients with homozygous genotype presented lower hemoglobin, serum iron and ferritin levels than patients with wild type genotype (Hb: 11.5 ± 1.2 vs 12.4 ± 1.0, p < 0.01; serum iron: 51.1 ± 27.7 vs 70.4 ± 37.5, p < 0.01; ferritin: 18.7 ± 25.1 vs 40.4 ± 30.5, p < 0.01) despite their rigorous GFD.

Conclusion: TMPRSS6 variant rs855791 plays a central role in most of CD cases with iron-refractory IDA. TMPRSS6 genotyping appears useful to personalize the management and follow-up of IRIDA patients.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP118 SAFETY AND TOLERABILITY, IMMUNOLOGICAL AND INTESTINAL EFFECTS, AND PHARMACOKINETICS (PK) OF DOSE TITRATION PRECEDING MAINTENANCE DOSES OF NEXVAX2® IN HLA-DQ2.5+ CELIAC DISEASE (CED)

A. J. Daveson 1 , H. Ee 2 , J. M. Andrews 3 , T. King 4 , K. E. Goldstein 5 , L. J. Williams 5 , A. Treohan 5 , M. P. Cooreman 5 , R. P. Anderson 5

1 School of Medicine, University of Queensland, Brisbane/Australia/QLD

2 Sir Charles Gairdner Hospital, Nedlands/Australia/WA

3 Royal Adelaide Hospital, Adelaide/Australia/SA

4 Gastroenterology, Auckland City Hospital, Auckland/New Zealand

5 ImmusanT, Inc., Cambridge/United States of America/MA

Contact E-mail Address: bob@immusant.com

Introduction: Nexvax2 is a therapeutic vaccine under investigation to protect against effects of gluten in HLA-DQ2.5+ CeD. Nexvax2 includes 3 peptides with dominant HLA-DQ2.5 restricted gluten epitopes. Dose-dependent gastrointestinal symptoms and immune activation reflected by increased plasma cytokines occur 4 h after the 1 st dose especially in HLA-DQ2.5 homozygous CeD (Goel G. et al. 2017). However, after repeated fixed doses, Nexvax2 is well tolerated and does not cause immune activation. Higher maintenance doses of Nexvax2 are predicted to be more effective.

Aims & Methods: The aim was to test the clinical and immunological effects of Nexvax2 with up-dosing and maintenance dose levels above the previously tolerated maximum dose of 150 μg. A double-blind, placebo-controlled study was performed in HLA-DQ2.5+ adults with CeD on a gluten-free diet. Subjects were enrolled according to HLA-DQA1*05 and HLA-DQB1*02 gene dose (homozygotes in Cohort 1, non-homozygotes in Cohort 2 and Cohort 3). Twice weekly intradermal, escalating doses of Nexvax2 were administered followed by 8x 300 μg. After completion of Cohort 2, a third cohort of HLA-DQ2.5 non-homozygotes received escalating doses from 3 μg and then 8x 900 μg. The primary endpoint was treatment emergent adverse events (TEAEs). Secondary endpoints were weekly Gastrointestinal Symptom Rating Scale (GSRS) scores, and relative change from pre-dose in plasma cytokine levels 4 h after 150 μg and higher doses. PK pre- and 45 min post-dose, and villous height to crypt depth ratio (VH:CrD) in 2 nd part duodenal biopsies were assessed in Cohort 3.

Results: 38 subjects (mean age 42 yr) were randomized 8:3, 10:5, or 10:2 to Nexvax2 or placebo in Cohorts 1, 2 and 3, respectively. The 2 nd subject enrolled in Cohort 1 withdrew after 2 doses (30 μg & 60 μg) with severe abdominal pain, which led to a reduction in starting dose (3 μg). TEAEs with up-dosing from 3 μg and maintenance at 300 μg or 900 μg were mild or moderate apart from 1 subject in Cohort 2 who experienced a severe headache. Subjects who received placebo (n = 9) had TEAEs similar to Nexvax2 treated subjects whose dosing started at 3 μg in Cohorts 1 (n = 6) and 3 (n = 10). Mean GSRS was significantly less than baseline each week after Week 3 of Nexvax2 treatment in Cohort 3 (p < 0.05, Wilcoxon paired rank sum test). Nexvax2 150 μg preceded by 4 escalating doses starting at 3 μg, and subsequent dose levels up to 900 μg, did not increase any of the 38 cytokines assessed 4 h post-dose. All Nexvax2-treated subjects in Cohort 3 had quantifiable PK with dose-dependent plasma levels of each of the peptides (∼9 ng/mL after 900 μg). Mean duodenal VH:CrD was unaffected by Nexvax2 treatment (1.7, 95% CI 1.3–2.1 vs 1.7, 1.4–1.9).

Conclusion: Gradual dose escalation of Nexvax2 allows higher maintenance doses without mucosal injury. These findings support the safety and tolerability of higher maintenance doses in future studies of Nexvax2.

Disclosure of Interest: J.M. Andrews: Consultant to Abbvie, Abbott, Ferring, Janssen, MSD, Hospira, Pfizer, Takeda, and Shire

K.E. Goldstein: Employee of ImmusanT, Inc.

L.J. Williams: Chief Executive Officer of ImmusanT, Inc.

A. Treohan: Employee of ImmusanT, Inc.

M.P. Cooreman: Former employee of ImmusanT, Inc.

R.P. Anderson: I am Chief Scientific Officer, and shareholder in ImmusanT, Inc.

All other authors have declared no conflicts of interest.

Reference

Goel G., King T., Daveson A.J., Andrews J.M., Krishnarajah J., Krause R., Brown G., Fogel R., Barish C.F., Epstein R., Kinney T.P., Miner P.B. Jr, Tye-Din J.A., Girardin A., Taavela J., Popp A., Sidney J., Mäki M, Goldstein K.E., Griffin P.H., Wang S., Dzuris J.L., Williams L.J., Sette A., Xavier R.J., Sollid L.M., Jabri B., Anderson R.P. Epitope-specific immunotherapy targeting CD4+ T cells in celiac 1 disease: evaluation in randomized, double-blind, placebo-controlled phase 1 studies. Accepted for publication Lancet Gast Hepatol

MONDAY, OCTOBER 30, 201715:45-17:15

GENERAL HEPATOLOGY - ROOM E3____________________

OP119 HIGH TUMOR RECURRENCE AFTER HEPATITIS C TREATMENT WITH ORAL DIRECT ACTING ANTIVIRALS IN PATIENTS WITH HISTORY OF HEPATOCELLULAR CARCINOMA IN COMPLETE REMISSION

B. Merchan Gomez 1 , M. Maroto Castellanos 1 , M.J. Devesa Medina 2 , L. Redero Brioso 2 , S. Izquierdo Rubio 1 , E. Rey 1

1 Aparato Digestivo, Hospital Clínico San Carlos, Madrid/Spain

2 Gastroenterology And Hepatology, Hospital Clinico San Carlos, Madrid/Spain

Contact E-mail Address: beamerchan_89@hotmail.com

Introduction: Hepatocellular carcinoma (HCC) represents a serious complication of HCV-related cirrhosis. New direct acting antivirals (DAA) obtain an HCV erradication rate higher than 90%. However, there is increasing evidence according to recent studies of unexpected high rate of tumor recurrence after treatment with DAA.

Aims & Methods: The aim of this study is to evaluate the early recurrence of HCC in cirrhotic patients treated with DAAs and the risk factors associated. We analyzed 154 patients with chronic liver disease and HCC, of which 27 were due to HCV infection and were in complete radiologic tumor remission after treatment. All of them were treated with DAAs, and followed up for an average of 20 months since remission. The inclusion criteria were: 1. HCC diagnosed by pathology or non-invasive criteria according to American Association for the Study of Liver Diseases (AASLD) guidelines; 2. Complete response following treatment; 3. Treatment with DAA with confirmed sustained virological response; 4. At least one tumor status assessment after starting antiviral therapy. Control computed tomography (CT) and blood tests were performed every three months according to the protocol of our centre.

Results: Recurrence of HCC was detected in 51.9% of patients (14 of 27 patients) during a median follow-up of 20 months. All of them achieved sustained virological response. Having less than 1 cm size, non-specific nodules in control CTs is associated with a higher recurrence (p = 0.001; OR 15. 95% CI: 2.02–111.17). The recurrence rate in the group of patients without non-specific nodules was 17%. The median time to recurrence was 17.3 months since tumor remission. Previous HCV treatment with therapies based on interferon was associated with lower risk of recurrence; although these results are not statistically significant, they tend to be significant (p = 0.18; OR 0.347, 95% CI: 1.07–1.65). Regarding the type of antiviral treatment, there were no recurrences in the sofosbuvir plus simeprevir group. On the other hand, all patients treated with the combination of sofosbuvir and daclatasvir experienced tumor recurrence during the follow-up period, and this was statistically significant in the univariate analysis (p = 0.005). However, age, sex, Child-Pugh class, cardiovascular risk factors, HCC treatment, single tumor and HCV genotype were not significantly associated with HCC development. The main characteristics of the cohort are described in table 1.

Conclusion: The rate of HCC recurrence in our study was 51.4% which is significantly higher than the results previously published by Reig et al (1) and Conti et al (2). Having less than 1 cm size non-specific nodules in control CTs may increase the risk of recurrence. If we exclude the presence of these nodules the recurrence rate is 17%, resembling other studies. Although significant differences have been found according to the type of antiviral treatment, we cannot conclude that treatment with sofosbuvir and daclatasvir is a risk factor for recurrence, given the small number of patients included in this study. Previous treatment with interferon is related to a lower risk of recurrence; however, these results need to be confirmed. In summary, in patients with previous history of HCC in complete remission and HCV-related cirrhosis, DAA-induced resolution of HCV infection seems to increase the risk of HCC recurrence, especially in patients with small, non-specific nodules in control CTs, during the follow-up period. Thus, it would be advisable to delay the HCV treatment until having more certainty about the benign evolution of these nodules and the potential risk of HCC reactivation due to DAAs use. However, these results should be confirmed in further studies.

Disclosure of Interest: All authors have declared no conflicts of interest.

References

1. Reig M, Mariño Z, et al. Unexpected early tumor recurrence in patients with hepatitis C virus –relatedhepatocellular carcinoma undergoing interferon-free therapy: a note of caution. J Hepatol 2016; 65:719–726.

2. Conti F, Buonfiglioli F, et al. Earlyoccurrence of hepatocellular carcinoma in HCV-related cirrhosis treated withdirect acting antivirals. J Hepatol 2016; 65:727–733.

OP120 BRG1 POSITIVELY REGULATES LIVER REGENERATION AFTER PARTIAL HEPATECTOMY IN MICE

B. Wang 1 , M. Lu 1 , K. Benedikt 1 , N. Hüser 1 , S. Zhong 2 , G. Von Figura 2 , D. Hartmann 1

1 Department Of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich/Germany

2 Ii.medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Munich/Germany

Contact E-mail Address: baocai.wang@tum.de

Introduction: The SWI/SNF complex is a chromatin-remodelling complex that modifies chromatin structure in order to regulate gene expression. Brahma-related gene-1 (Brg1), a catalytic subunit of the SWI/SNF complex, is known to be involved in proliferative cell processes. Liver regeneration is activated spontaneously after injury and organized based on a strong proliferation rate. Up to the present, little is known on how Brg1 orchestrates liver regeneration.

Aims & Methods: The aim of the study was to investigate the role of Brg1 in liver regeneration following partial liver resection in mice. We used a hepatocyte-specific Brg1 gene knockout mouse model performing a 70% partial hepatectomy (PH) to analyse the role of Brg1 in liver regeneration. Liver regeneration was estimated by liver/body weight ratio, cell proliferation, and the related cellular signals were analysed.

Results: We found that the expression of Brg1 was markedly upregulated after PH in wildtype mice. Brg1 inactivation dramatically impaired liver regeneration and blocked proliferating hepatocytes. Liver/body ratio was lower for Brg1 liver-specific knockout mice 48 h post operation. A highly active proliferation was observed in the hepatocytes of wildtype mice post PH while fewer was observed in Brg1 liver-specific knockout mice. Cyclin D1 expression was lower in Brg1 liver-specific knockout mice 40 h post PH compared to the wildtype mice.

Conclusion: These results underline the important role of Brg1 on hepatic regeneration by promoting proliferation after liver injury. This study has led to new molecular insights and might potentially improve our understanding on potential interventions of this complex for promoting liver repair and regeneration.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP121 HVPG AND TRANSIENT ELASTOGRAPHY ARE THE BEST PROGNOSTIC FACTOR IN PATIENTS WITH HEPATOCELLULAR CARCINOMA SUBMITTED TO HEPATIC RESECTION

B.D. Procopet 1 , E. Mois 2 , A. Horhat 1 , A. Bugariu 1 , H. Stefanescu 1 , F. Graur 3 , M. Tantau 1 , N. Al Hajjar 2

1 3rd Medical Clinic, University of Medicine and Pharmacy “Iuliu Hatieganu”, Cluj-Napoca/Romania

2 Surgery Department, University of Medicine and Pharmacy “Iuliu Hatieganu”, Cluj-Napoca/Romania

3 Surgery, Institute of Gastroenterology and Hepatology, Cluj Napoca, Romania, Cluj-Napoca/Romania

Contact E-mail Address: bogdan.procopet@umfcluj.ro

Introduction: Hepatic resection is one of the best curative treatments in well-selected patients with hepatocellular carcinoma (HCC) and cirrhosis. The risk of decompensation after resection has major impact over the outcome of these patients. Portal hypertension is the main risk factor for decompensation and it is still a matter of debate which is the best method to identify patients at risk.

Aims & Methods: The aim of the study was to compare different methods for risk assessment in patients with HCC submitted to hepatic resection. Since January 2016 94 consecutive patients were diagnosed with HCC and were prospectively registered. Thirty-three patients were submitted to hepatic resection and among them: 22 were screened for esophageal varices (EV), 13 patients were evaluated by hepatic venous pressure gradient (HVPG) and 18 by transient elastography.

Results: Among the 33 included patients, 8/22 (35%) had EV, 6/13 (46%) had clinical significant portal hypertension (HVPG > 10 mmHg) and 9 (30%) had platelet count <100.000/mmc. During follow-up 12 (36%) patiens presented decompensation (3 variceal bleeding, 7 ascites, 6 renal dysfunction and 1 jaundice). In univariate analysis HVPG, liver stiffness, platelet count, ALT and AST were associated with decompensation. Neither presence of EV (40% correctly classified, p = 0.13) or platelet count <100.000/mmc (64% correctly classified, p = 0.08) were accurate enough to predict decompensation. Presence of CSPH assessed by HVPG correctly classified 92% of patients (p = 0.002). There was no difference between HVPG and transient elastography regarding the performances (AUROC) for predicting decompensation, 0.91 (95%CI: 0.74–1, p = 0.012) and 0.93 (95%CI: 0.80–1, p = 0.007), respectively.

Conclusion: HVPG is the best prognostic factor for the risk of decompensation after hepatic resection in patient with HCC and cirrhosis, while surrogate markers, as presence of EV of low platelet count, is not accurate enough. Liver stiffness measurement with transient elastography is a promising prognostic tool.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP122 INNOVATIVE THERAPEUTIC EFFICACY OF A NOVEL REIC/DKK-3 EXPRESSING ADENOVIRAL VECTOR FOR HEPATOCELLULAR CARCINOMA

H. Sawahara 1 , H. Shiraha 1 , D. Uchida 1 , H. Kato 1 , A. Oyama 1 , M. Mandai 2 , T. Mimura 3 , M. Watanabe 4 , M. Sakaguchi 5 , T. Yagi 6 , Y. Nasu 4 , H. Kumon 7 , H. Okada 1

1 Departments Of Gastroenterology And Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama/Japan

2 Department Of Internal Medicine, Okayama Saiseikai General Hospital, Okayama/Japan

3 Department Of Surgery, Okayama Saiseikai General Hospital, Okayama/Japan

4 Center For Innovative Clinical Medicine, Okayama University Hospital, Okayama/Japan

5 Department Of Cell Biology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama/Japan

6 Departments Of Gastroenterological Surgery, Transplant, And Surgical Oncology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama/Japan

7 Department Of Innovation Center Okayama For Nanobio-targeted Therapy, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama/Japan

Contact E-mail Address: yamairo@hotmail.com

Introduction: Reduced expression in immortalized cells (REIC)/dickkopf 3 (Dkk-3) is a tumor suppressor gene that is downregulated in various cancers. In our previous study, the REIC/Dkk-3-expressing adenoviral vector (Ad-REIC) was found to induce cancer-selective apoptosis by mediating the unfolded protein response in the endoplasmic reticulum (ER) stress and activation of the c-Jun-NH2-terminal kinase (JNK). A phase I/IIa study of Ad-REIC gene therapy in patients with prostate cancer, conducted at Okayama University Hospital from January 2011 to November 2014, demonstrating the feasibility of Ad-REIC gene therapy as a therapeutic cancer vaccine. More recently, we have developed a novel super gene expression (SGE) system and used this system to re-construct an Ad-REIC vector, termed the Ad-SGE-REIC, to achieve more effective therapeutic outcomes.

Aims & Methods: In the current study, we assessed the therapeutic potential of REIC/Dkk-3 gene therapy using Ad-SGE-REIC in hepatocellular carcinoma (HCC). Human HCC cell lines (HLE, Huh7, and HepG2), human HCC tissues, and mouse HCC cell line (Hepa1-6) were used in this study. REIC/Dkk-3 expression was assessed by immunoblotting and immunohistochemistry. The relative cell viability and the apoptotic effect were examined by MTT assay and Hoechst staining, respectively. The protein expression of IRE1α, JNK, c-Jun, and caspase-3 was assessed by immunoblotting using specific antibodies. The anti-tumor effects of Ad-SGE-REIC treatment were analyzed in the mouse xenograft model with Huh7 cells. Furthermore, we assessed anti-tumor immunological effects in the immunocompetent mice.

Results: REIC/Dkk-3 expression was decreased in HCC cell lines and HCC tissues. Ad-SGE-REIC treatment markedly reduced cell viability in HCC cell lines; the reduction rate for HLE, Huh7, and HepG2 were 87.2%, 76.3%, and 36.4%, respectively. Hoechst 33342 staining demonstrated the rate of apoptosis in the cells treated with Ad-SGE-REIC (HLE; 69.4%, Huh7; 66.0%, HepG2; 40.1%). Ad-SGE-REIC treatment mediated cancer selective apoptosis due to ER stress mainly through the activation of JNK pathway. Ad-SGE-REIC treatment suppressed tumor growth by 68.7% in comparison with the control in the mouse xenograft model. Moreover, the lymphocytes isolated from immunocompetent mice treated with Ad-SGE-REIC demonstrated higher cytotoxicity against the target cancer cells than those from the control mice (253.5%).

Conclusion: Ad-SGE-REIC treatment not only enhanced cell-killing effects in vitro but also elicited significant therapeutic effects in vivo . REIC/Dkk-3 gene therapy using Ad-SGE-REIC potentially represents an innovative new therapeutic tool for HCC.

Disclosure of Interest: M. Watanabe: Okayama University and Momotaro-Gene Inc., a startup biotech company from the Okayama University, holds the patents of the Ad-REIC agent and develops the agent as a cancer therapeutic medicine. M.W. own stocks in Momotaro-Gene, Inc.

M. Sakaguchi: Okayama University and Momotaro-Gene Inc., a startup biotech company from the Okayama University, holds the patents of the Ad-REIC agent and develops the agent as a cancer therapeutic medicine. M.S. own stocks in Momotaro-Gene, Inc.

Y. Nasu: Okayama University and Momotaro-Gene Inc., a startup biotech company from the Okayama University, holds the patents of the Ad-REIC agent and develops the agent as a cancer therapeutic medicine. Y.N., and own stocks in Momotaro-Gene, Inc.

H. Kumon: Okayama University and Momotaro-Gene Inc., a startup biotech company from the Okayama University, holds the patents of the Ad-REIC agent and develops the agent as a cancer therapeutic medicine. H.K. own stocks in Momotaro-Gene, Inc.

All other authors have declared no conflicts of interest.

OP123 EFFECT OF INTERFERON-FREE DIRECT-ACTING ANTIVIRAL THERAPY FOR HEPATITIS C VIRUS IN THE CARDIAC CONDUCTION SYSTEM

O.N. López-García 1 , D. García-Arribas 2 , M.J. Devesa Medina 1 , C. Olmos 2 , J. Higueras Nafría 2 , B. Merchan Gomez 1 , S. Izquierdo Rubio 1 , F. Cuenca Alarcón 1 , M. Maroto Castellanos 1 , E. Rey 1

1 Gastroenterology And Hepatology, Hospital Clinico San Carlos, Madrid/Spain

2 Cardiology, Hospital Clinico San Carlos, Madrid/Spain

Contact E-mail Address: oliapunto@gmail.com

Introduction: Concomitant use of sofosbuvir and Amiodarone has been associated with cases of atrioventricular block and symptomatic bradycardia (1–2), therefore such combination is not recommended. In addition, it has been recently suggested that there is QT interval prolongation in the first weeks of treatment without the combination with Amiodarone (3).

Aims & Methods: Our study aims to confirm if there is a prolongation of QT interval during treatment with Sofosbuvir and other antivirals, to study whether this alteration persists after treatment and to investigate other possible alterations in the cardiac conduction system. We accomplished a prospective study in which a baseline electrocardiogram (ECG), before starting treatment, and another one during treatment (at the fourth week) were performed on hepatitis C patients undergoing Interferon-free antiviral therapy between April 2016 and April 2017 in Hospital Clinico San Carlos (Madrid). Moreover, in some patients a third ECG was performed in the twelfth week after treatment. Heart rate and duration of PR, QRS, QT and corrected QT intervals (QTc) were measured. A paired Student's T test was applied to compare the variables before and during treatment, and before and after treatment in the subgroup of patients with the third ECG.

Results: We included 100 patients with an average age of 64 years old. 50 % were males. Most of them were 1 b genotype. 37 % had a grade 0–1 of fibrosis (F) in the Fibroscan, 35% F2 and 28% F 3–4. 66 % received treatment with Sofosbuvir in every combination (3% with ribavirina, 55% with Ledipasvir, 7% with Daclatasvir, and 1% with Ombitasvir, Paritaprevir, Ritonavir and Dasabuvir). 32 % were treated with Ombitasvir, Paritaprevir, Ritonavir and Dasabuvir and finally 3% received Elbasvir, Grazoprevir. Differences between ECG measurements before and during treatment are shown in Table 1. There were no significant differences in heart rate, PR interval nor QRS interval between patients before and during treatment. QTc was 4.14 ms longer in the ECG done during the treatment than the one done before (p = 0.02). This difference depended on patients taking sofosbuvir (5.71 ms, p = 0.01). In patients who did not take sofosbuvir, there were no significant differences (1.3 ms, p = 0.68). Moreover, in 54 patients a third ECG was performed in the twelfth week after treatment. 32 of them had received treatment with Sofosbuvir. There were no significant differences in heart rate, PR interval, QRS interval, nor QTc (1.84 ms p = 0, 55) between measurements before and after treatment Table 1. In the subgroup of patients taking sofosbuvir there were neither significant differences in the QTc before and after treatment (2.43 ms, p = 0, 55).

Conclusion: In patients on treatment with sofosbuvir a statistically significant prolongation of the QTc interval was observed after 4 weeks of treatment. In addition, in the subgroup with ECG before, during and after treatment, the QTc prolonged during treatment had reverted at the twelfth week after treatment. This elongation was not clinically relevant in most cases.

Disclosure of Interest: All authors have declared no conflicts of interest.

References

1. Renet S, Chaumais M-C, Antonini T, et al. Extreme bradycardia after first doses of sofosbuvir and daclatasvir in patients receiving amiodarone: 2 cases including a rechallenge. Gastroenterology 2015;149:1378–1380.

2. Armando Lagrutta, Haoyu Zeng, John Imredy, et al. Interaction between Amiodarone and Hepatitis-C Virus Nucleoside Inhibitors in Human Induced Pluripotent Stem Cell Derived-Cardiomyocytes and HEK-293 Cav1.2 Over-expressing Cells. Toxicology and Applied Pharmacology 2016; 308: 66–76.

3. Satoru Hagiwara Naoshi Nishida Tomohiro Watanabe et al. Outcome of Combination Therapy with Sofosbuvir and Ledipasvir for Chronic Type C Liver Disease. Clinical Study 2017;92 Suppl 1:3–9.

OP124 NON-ALCOHOLIC STEATOHEPATITIS IS THE MOST RAPIDLY GROWING INDICATION FOR LIVER TRANSPLANTATION IN IRANIAN PATIENTS

A. Eshraghian 1 , S. Nikeghbalian 2 , S.A. Taghavi 3 , M.R. Fattahi 4 , S. Ali Malek-Hosseini 2

1 Gastroenterohepatology Research Center, Shiraz University of Medical Sciences, Shiraz/Iran

2 Transplant Research Center, Shiraz/Iran

3 Gastroenterology, Shiraz University of medical sciencez, shiraz/Iran

4 Endoscopy Ward, Namazi Hospital, Fars-Shiraz/Iran

Contact E-mail Address: eshraghiana@yahoo.com

Introduction: Non-alcoholic fatty liver disease (NAFLD) is a rapidly growing disease and is supposed to be the most common cause of abnormal liver enzymes worldwide. A considerable proportion of NAFL patients will progress to non-alcoholic steatohepatitis (NASH) that is anticipated to become the most common cause of liver cirrhosis and liver transplantation in next 20 years. Iran has been located in the Middle East with a high prevalence of NAFLD.

Aims & Methods: This study aimed to investigate the incidence and trend of NASH as an indication for liver transplantation in Iranian patients. The liver transplant data of all patients who had undergone liver transplantation between 1993 and 2016 at Shiraz Organ Transplant Center, Shiraz, Iran were reviewed. The underlying liver diseases leading to liver transplantation were stratified according to the years of transplantation and trend of increase or decline were calculated. Data regarding post-transplant mortality of patients with biopsy proven NASH were recorded. Patients with cryptogenic liver cirrhosis with body mass index ≥30 kg/m 2 was defined as modified NASH. Kaplan-Meier curve was used for analysis of post-transplant survival of patients with NASH and patients with modified NASH.

Results: Totally 3727 liver transplantations were performed between May 1993 and December 2016. The first patient with NASH has undergone liver transplantation in 2011. Afterwards 64 patients with biopsy proven NASH underwent liver transplantation at our center. Mean age of patients was 52.86 ± 9.01 years in those with NASH and 51.73 ± 7.91 years in patients with modified NASH (P > 0.05). Mean model for end stage liver disease (MELD) was 24.27 ± 7.42 in patients with NASH and 23.82 ± 5.66 in those with modified NASH (P > 0.05). The prevalence of NASH as an indication for liver transplantation in 2011 was 0.59 %, in 2012 was 0.25 %, in 2013 was 1.49 %, in 2014 was 3.07 %, in 2015 was 2.26 % and in 2016 was 5.4 %. The prevalence of modified NASH (cryptogenic cirrhosis with BMI ≥ 30 kg/m 2 ) was 2.08 % in 2011, 1.81 % in 2012, 2.34 % in 2013, 1.97 % in 2014, 1.89 % in 2015, and 1.86 % in 2016. Using Kaplan-Meier curve, mean post-liver transplant survival was 42.38 ± 2.35 months in NASH patients and 47.71 ± 2.98 in modified NASH patients (P = 0.558). Post-liver transplant survivals at 6 months, 1 year and 4 years in patients with NASH and those with modified NASH were outlined in Table. Table: Post-liver transplant survivals at 6 months, 1 year and 4 years in our patients

Conclusion: NASH is a rapidly growing indication for liver transplantation in Iranian patients. Since considerable proportion of NASH patients result from progression from simple steatosis, health care providers should consider programs for prevention and early diagnosis of patients with NASH for proper treatment.

Disclosure of Interest: All authors have declared no conflicts of interest.

References

1. Wong RJ, Aguilar M, Cheung R, Perumpail RB, Harrison SA, Younossi ZM, Ahmed A. Nonalcoholic steatohepatitis is the second leading etiology of liver disease among adults awaiting liver transplantation in the United States. Gastroenterology 2015; 148(3):547–55.

2. Goldberg D, Ditah IC, Saeian K, Lalehzari M, Aronsohn A, Gorospe EC, Charlton M. Changes in the Prevalence of hepatitis C virus infection, nonalcoholic steatohepatitis, and alcoholic liver disease among patients with cirrhosis or liver failure on the waitlist for liver transplantation. Gastroenterology 2017; 152(5):1090–1099.e1

MONDAY, OCTOBER 30, 201715:45-17:15

UPPER GI MOTILITY AND BRAIN-GUT INTERACTIONS - ROOM B5____________________

OP125 RESPONSES TO GASTRIC GAS IN PATIENTS WITH FUNCTIONAL GASTRODUODENAL DISORDERS

E.N. Caballero De Garcia , B. Benslaiman Seyid-Jebari, J. Serra Pueyo

Motility And Functional Gut Disorders Unit, Hospital Unversitary Germans Trias i Pujol, Badalona/Spain

Contact E-mail Address: noecaballerosuarez@gmail.com

Introduction: Belching from gastric origin is a reflex response that is triggered by distension of the gastric fundus, and has largely been recognized as a protective venting mechanism to avoid symptomatic pooling of gas into the stomach. However, despite patients with functional gut disorders often referring worsening of symptoms after meals, the role of belching reflexes in symptom generation in patients with functional gut disorders has been poorly investigated.

Aims & Methods: Our aim was to compare the responses to gastric gas in patients with belching disorders and functional dyspepsia, and a cohort of healthy controls. In 8 healthy volunteers without gastrointestinal symptoms, 8 patients with belching disorder, and 8 patients with functional dyspepsia according to Rome IV criteria, 1500 ml of a mixture of non-absorbable gases was infused into the stomach, 5-cm caudal to the lower margin of the LES, at 25 ml/min during 60 min. Belching, by an esophageal multilumen impedance manometry catheter and rectal gas evacuation, via a rectal tube connected to a barostat, were continuously recorded for 90 min. Epigastric perception was recorded at 10 min intervals using a graded (0–6) questionnaire.

Results: Healthy controls evacuated virtually all the infused gas via the rectum (1560 ± 102 ml) without an increment in belching (0.2 ± 0.2 belches). Patients with functional dyspepsia had a similar rectal gas evacuation (1469 ± 45 ml) and belching (0.1 ± 0.1 belches) as controls. By contrast, patients with a belching disorder had a significantly smaller rectal evacuation of gastric gas (1208 ± 78 ml; p < 0.05 vs controls and dyspepsia) that was associated to a greater number of belches during gas infusion (33 ± 13 belches; p < 0.05 vs controls and dyspepsia). Gastric gas infusion was associated to a minor increment in abdominal perception in healthy controls (1.0 ± 0.4 score increment). By contrast, patients with functional dyspepsia developed significant perception of epigastric symptoms during gas infusion (2.5 ± 0.6 score increment; p < 0.05 vs controls) whereas patients with a belching disorder develop no epigastric perception (0.9 ± 0.2 score increment; NS vs sham and p < 0.05 vs functional dyspepsia) despite the lower rectal gas evacuation associated to increased belching.

Conclusion: Patients with specific gastroduodenal disorders exhibit different responses to increments in gastric gas. Whereas in patients with functional dyspepsia belching is exceptional and gastric gas may induce epigastric symptoms, increased belching in response to gastric gas seems to prevent epigastric symptoms in patients with a belching disorder.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP126 INTRAGASTRIC FRUCTOSE INFUSION AND EMOTIONAL STATE INTERACT IN HOMEOSTATIC AND HEDONIC BRAIN REGIONS

J. Iven , J. Biesiekierski, D. Zhao, E. Deloose, L. Van Oudenhove, J. Tack

Translational Research Center For Gastrointestinal Disorders, Katholieke Universiteit Leuven, Leuven/Belgium

Contact E-mail Address: julie.iven@kuleuven.be

Introduction: Exteroceptive properties of food such as taste or smell can influence a person’s emotional state and its neural basis. However, purely interoceptive properties of food can also effect emotional state, since behavioral and neural responses to sad emotion induction were attenuated by fatty acid infusion (Van Oudenhove et al., 2011). Whether this also applies to other nutrients, including carbohydrates, remains unknown.

Aims & Methods: We aimed to study the effect of intragastric fructose administration compared to placebo, and its interaction with the effect of sad emotion induction, on brain activity in homeostatic and hedonic regions and on circulating levels of the anorexigenic hormone GLP-1. Fifteen healthy subjects were studied after an overnight fast. Brain activity before and up to 40 min after intragastric infusion of fructose (25 g) or distilled water (placebo) was recorded using functional magnetic resonance imaging. Sad or neutral emotional states were induced using a combination of playback of validated classical music pieces and projection of emotional facial expressions. Emotional state was assessed every 10 min using the Self-Assessment Manikin. Blood samples were taken at the same time points. Plasma levels of GLP-1 were analyzed using Meso Scale Discovery immunoassay kits. Brain responses to fructose versus placebo, sad versus neutral emotion, and their interaction were analyzed over time in a priori defined regions of interest (ROI) at a voxel-level threshold of p FWEcorrected <0.05. Similar effects on emotional ratings and GLP-1 levels were tested using linear mixed models.

Results: We did not observe significant main effects of nutrient and emotion, and no significant nutrient-by-emotion interaction effect, on emotional ratings. However, significant main effects of fructose, emotional state, and a significant nutrient-by-emotion interaction effect on brain responses in pre-hypothesized ROIs, including the medulla, midbrain, hypothalamus, basal ganglia, anterior insula, orbitofrontal cortex and amygdala were found (see Table 1). A trend towards an interaction between emotional state and nutrient was also observed on GLP-1 levels. Specifically, the increase in circulating levels of GLP-1 after fructose administration in the neutral emotion condition was abolished in the sad emotional state (p = 0.06).

Table 1 . Regions of interest where significant main effects of emotion and nutrient and a significant nutrient-by-emotion interaction were observed

Conclusion: Emotional state interacts with brain and endocrine responses to intragastric infusion of 25 g of fructose; however, such an effect was not found at the behavioural level.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP127 DDP-4 INHIBITOR, VILDAGLIPTIN INHIBITS GASTRIC ACCOMMODATION AND FOOD INTAKE IN HUMANS

A. Rotondo 1 , J. Biesiekierski 1 , I. Masuy 1 , J. Tack 1

1 Targid, Katholieke Universiteit Leuven, Leuven/Belgium

Contact E-mail Address: alerotondo83@libero.it

Introduction: Glucagon-like peptide 1 (GLP-1), an endogenous modulator of gastrointestinal motility and food intake, is inactivated by dipeptidyl peptidase-4 (DPP-4). Administration of DPP-4 inhibitor vildagliptin can amplify endogenous GLP-1 effects.

Aims & Methods: The objectives were to assess the effect of vildagliptin on gastric accommodation, measured as the intragastric pressure (IGP) during intragastric nutrient infusion and food intake in humans in 2 protocols, each including 10 healthy volunteers (HVs). Hunger, satiation and epigastric symptoms (fullness, nausea, bloating, belching, pain, cramps) were assessed using a visual analogue scale (VAS). In Protocol 1, an infusion catheter and a high-resolution manometry probe were positioned in the proximal stomach. HVs took vildagliptin (50 mg) or placebo orally in a randomized single-blinded fashion, followed by an intragastric nutrient drink (ND, Nutricia, 1.5Kcal*ml −1 ) infusion (60 ml/min for 3 min). In Protocol 2, a forearm vein was cannulated to allow blood collection and vildagliptin (50 mg) or placebo were administered. One hour later, HVs consumed 200 ml of a ND and after 30 min, HVs ate ad libitum from an excess free-choice buffet (2330 kcal) for the duration of 30 min. Blood was collected before the drug administration, before and after the ND and before the buffet. All values are presented as mean ± SEM. IGP recovery time, maximum IGP drop, area above the curve (AAC) of IGP during ND infusion, area under the curve (AUC) of VAS score, kcal and grams of food eaten were compared using a Wilcoxon paired t-test. GLP-1(7–36) data was log-transformed and analyzed using mix-model analysis. p < 0.05 was considered significant.

Results: Vildagliptin was well tolerated and no side effects were reported. Protocol 1: During intragastric ND infusion, IGP decreased initially and increased thereafter. The IGP recovery time was 20 ± 2 min after placebo and 12 ± 4 min after vildagliptin, from the start of ND infusion (p = 0.09). The maximum IGP drop was significantly smaller after vildagliptin (3 ± 0.4 vs 1.7 ± 0.4 mmHg for placebo and vildagliptin, respectively, p = 0.003). The AAC during the intragastric ND infusion was significantly lower after vildagliptin (1.3 ± 0.4 vs 0.04 ± 0.7 mmHg*min −1 for placebo and vildagliptin, respectively, p = 0.03). Protocol 2: Total food intake in weight was significantly higher for placebo (401 ± 63 gr) compared to vildagliptin (299 ± 55 gr, p = 0.002). Total energy content consumed was also higher after placebo (761 ± 111 kcal) compared to vildagliptin (580 ± 110 kcal, p = 0.06). Post-hoc analyses showed significantly higher GLP-1(7–36) plasma concentrations after ND ingestion for vildagliptin compared to placebo (see Table). Hunger or satiation were not affected by the treatment.

Conclusion: Vildagliptin inhibits gastric accommodation and decreases food intake in healthy lean volunteers. The observed effect could be due to the inhibition of GLP-1 degradation.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP128 RELAMORELIN IN PATIENTS WITH DIABETIC GASTROPARESIS: EFFICACY AND SAFETY RESULTS FROM A PHASE 2B RANDOMISED, DOUBLE-BLIND, PLACEBO-CONTROLLED, 12-WEEK STUDY (RM-131-009)

M. Camilleri 1 , R. W. Mccallum 2 , J. Tack 3 , S. C. Spence 4 , K. Gottesdiener 5 , F. T. Fiedorek 5

1 Mayo Clinic, Mayo Clinic Dept. of Gastroenterology Charlton Bldg., Rm. 8-110, Rochester, MN/United States of America

2 Texas Tech University Health Sciences University, El Paso/United States Minor Outlying Islands

3 K U Leuven, Leuven/Belgium

4 S. C. Spence Consulting, LLC, Westwood/United States of America

5 Rhythm, Boston/United States of America

Contact E-mail Address: camilleri.michael@mayo.edu

Introduction: Gastroparesis is a serious complication of diabetes mellitus (DM) with few treatment options. Relamorelin (RM) is a selective ghrelin agonist with potent prokinetic properties.

Aims & Methods: The aim was to evaluate the efficacy of RM on symptoms and gastric emptying (GE) in patients with moderate-to-severe diabetic gastroparesis in a 12-week, randomised, double-blind, placebo (PBO)-controlled, parallel-group study, with a 2-week single-blind PBO run-in. Eligible DG patients had 13 C-spirulina GE breath test (GEBT) T 1/2 values ≥79 min, a history of recent vomiting and a Gastroparesis Cardinal Symptom Index score ≥2.6. Patients were randomised to twice daily subcutaneous injections of PBO or RM: 10 µg, 30 µg or 100 µg. Patients completed the Diabetic Gastroparesis Symptom Severity Diary (DGSSD), a daily e-diary designed to collect patient-reported vomiting frequency and symptoms of nausea, abdominal pain, satiety, post-prandial fullness (PPF) and bloating on a 0–10 severity scale. The primary endpoint was change from baseline in vomiting frequency; a key secondary endpoint was change from baseline in the four-symptom DGSSD composite of nausea, abdominal pain, PPF and bloating. Weekly vomiting frequency (on log scale and normalised to account for number of days) and DGSSD composite scores (normalised to account for missing items) were analysed for change from baseline through to Week 12. A longitudinal, mixed-effects model using repeated measures, with baseline, weekly and baseline-by-week and week-by-treatment interaction values as covariates, was used to assess treatment effects over time. Safety was evaluated by vital signs, adverse events and laboratory assessments.

Results: A total of 393 DG patients (male: 37.7%; age: 57.0 ± 11.3 years; body mass index: 32.4 ± 7.3 kg/m 2 ; mean HbA1c: 7.7 ± 1.4%; Type 1 DM: 9.9%) were randomised at clinic sites in the US, Israel and Europe. RM led to ∼75% reduction in vomiting frequency compared to baseline (primary endpoint) across all doses tested; however, no significant difference was observed due to a high PBO response (∼70% reduction from baseline). RM demonstrated substantial efficacy: DG symptoms improved vs placebo for all three RM doses for the overall 12-week study period, indicated by the reduction in the composite score (Table). All three doses of RM tested also accelerated GE compared to PBO (Table). (GEBT) T 1/2 scores improved by a mean of ∼13 ± 38 min with RM compared to placebo (0 ± 38 min). RM was generally safe and well tolerated with high compliance and study completion rates. Worsening of glycaemic control was noted as an adverse event in 14.5% of RM patients, with some patients requiring adjustment of insulin dosage.

Conclusion: RM demonstrated clinically meaningful reductions in core DG symptoms and overall composite score, accelerated GE, and was generally safe and well tolerated. A high PBO response limited the ability to show efficacy of RM vs PBO for the vomiting frequency endpoint.

Disclosure of Interest: M. Camilleri: Received research grant to study pharmacology of relamorelin

R.W. McCallum: Received research funding to study relamorelin, consulted with Allergan plc, Salix Pharma, Evoke Pharma and Synergy Pharm, and received funding for clinical research trials from Salix Pharmaceuticals, Evoke Pharma, Theravance Biopharma and Vanda Pharma.

J. Tack: Abide, Abbott, AlfaWassermann, Allergan, AstraZeneca, Christian Hansen, Danone, Genfit, Ironwood, Janssen, Kiowa Kirin, Menarini, Mylan, Novartis, Nutricia, Ono, Rhythm, Shionogi, Shire, SK Life, Takeda, Theravance, Tsumura, Yuhan, Zealand, Zeria

S.C. Spence: My relationship with Motus is as a contractor/consultant to the relamorelin program

K. Gottesdiener: Employee of Motus

F.T. Fiedorek: Employee of and equity interest in Motus, a subsidiary of Rhythm Pharmaceuticals.

OP129 THE ACCURACY OF ALCAT 5 IN DIAGNOSING NON-CELIAC GLUTEN SENSITIVITY IN FUNCTIONAL PATIENTS WITH ABDOMINAL PAIN AND BLOATING

M. Di Stefano 1 , I. Benedetti 1 , M. Bresciani 1 , A. Gabriele 2 , M. Deamici 1 , E.V. Pesatori 1 , G.F. Manfredi 1 , M. Bergonzi 1 , C. Torre 1 , C. Pedroni 2 , D. Iozzi 2 , G.L. Marseglia 3 , G. Di Fede 2

1 IRCCS Policlinico San Matteo, Pavia/Italy

2 istituto di medicina biologica, Milano/Italy

3 Department Of Pediatrics, IRCCS Policlinico San Matteo, Pavia/Italy

Contact E-mail Address: irene.benedetti89@gmail.com

Introduction: Non-Celiac Gluten Sensitivity (NCGS) is a recently proposed condition causing intestinal and extra-intestinal symptoms without intestinal lesions after gluten ingestion. The Salerno Expert’s Criteria (Catassi C, et al, Nutrients 2015) suggested a double-blind, placebo-controlled trial with gluten vs placebo to diagnose this condition. Unfortunately, this is an accurate but very lengthy and cumbersome procedure, theoretically burdened by a significant number of drop-outs. ALCAT 5 is an automatized test evaluating the toxic effect in vitro of gluten on neutrophils by the exposure of these cells to a gluten-containing extract of gluten-containing cereals (wheat, rye, barley, oat).

Aims & Methods: The aim of this study was the evaluation of the accuracy of ALCAT 5 in the diagnosis of NCGS. Twenty-five non-celiac patients (M/F 3/22, mean age 32 ± 4 yrs) with a long history of refractory abdominal symptoms (abdominal pain, bloating, flatulence, borborygmi, bowel habit alterations, dyspeptic symptoms) were enrolled. The mean duration of symptoms was 10 ± 4 yrs. All the subjects reported their symptoms on a gluten-containing diet (GCD), considered gluten as the causal agent and judged abdominal pain and bloating as the main symptoms. According to Salerno Criteria (Catassi C, et al, Nutrients 2015), they underwent a double-blind, crossover, placebo controlled trial with gluten vs placebo. A mean value during gluten ingestion >30% the value during placebo was considered as indicative of gluten sensitivity (Catassi, et al, Nutrients 2015). Twenty-one patients proved to be gluten-sensitive according to this criterion, considering abdominal pain and bloating as the main symptoms. In the group of 25 enrolled patients, a blood sample was taken in order to perform ALCAT 5. The test was considered as positive when the automatized analysis revealed, in comparison with a basal value, a change in volume and number of PMN after exposure to a food test substance. The test data are expressed as a volume distribution curve and the area change under the curve compared to the basal volume is considered positive based on the mean change and SD. An area change between the mean value and 1 SD is considered positive.

Results: In sixteen patients out of 25 the result of ALCAT 5 was concordant with the double-blind trial (64%). In particular, in 14 patients both tests were positive and in 2 both were negative.

Conclusion: In functional patients with abdominal pain and bloating, claiming the association between symptoms and gluten intake, referred at a tertiary care center and resistant to previous treatments, ALCAT 5 is a useful screening test to select those patients requiring further investigation aimed at the confirmation of NCGS.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP130 CHRONIC INTESTINAL PSEUDO-OBSTRUCTION IN CHILDREN: THE EARLY OUTCOMES OF THE NATIONAL PAEDIATRIC PSEUDOOBSTRUCTION DIAGNOSTIC SERVICE IN QUATERNARY CARE SETTING

A. Rybak , K. Larmour, E. Saliakellis, J. Brind, K. Lindley, F. Valitutti, O. Borrelli, N. Thapar

Neurogastroenterology And Motility Division, Great Ormond Street Hospital, London/United Kingdom

Contact E-mail Address: aniarybak@hotmail.com

Introduction: Chronic intestinal pseudo-obstruction in children (CIPO) is a rare, complex and disabling disorder with poorly defined incidence and prevalence in pediatric populations. In April 2012, the National Paediatric Pseudo-obstruction Diagnostic Service (PPOD) was set up in The Great Ormond Street Hospital in United Kingdom (UK) to provide a service for the diagnosis and management of CIPO disorders in children.

Aims & Methods: This study presents a four-year experience of the PPOD service, including a clinical description of the paediatric CIPO population captured by it. This is a retrospective analysis of patients admitted within the PPOD service, between 04.2012 and 12.2016, with a suspected diagnosis of CIPO. The ultimate diagnosis of CIPO was confirmed on the presence of at least 2 out of 4 of the following criteria namely: (1) Manometric (antroduodenal - ADM) evidence of small intestinal neuromuscular involvement; (2) radiological evidence of recurrent and/or persistently dilated loops of small intestine with air fluid levels; (3) presence of the genetic, metabolic or other conditions definitively associated with paediatric CIPO; and (4) inability to maintain adequate nutrition and/or growth on oral feeding alone (need for specialized feeds and/or enteral/intravenous route for feeding). Clinical data, including age of onset of symptoms, dominant symptoms, results of the ADM investigations, surgical procedures, feeding history, need for gastric drainage and histology results of full thickness biopsies from the small intestine, were analyzed.

Results: Out of 113 children referred to the PPOD Service, 50 were definitively diagnosed with CIPO (26 girls), with median age at symptoms’ onset of 5 months (range: from birth to 168 months); 58% of patients were born prematurely. 40 children (83.3%) presented with first symptoms below first year of life. Median age at assessment was 45 months in the first half-time of service (32/50) and 35.5 months in the second half (18/50). Based on the ADM results, the majority of patients diagnosed with CIPO had patterns consistent with neuropathic involvement (n = 35), 2 with myopathy and 4 with both, neuropathy and myopathy. In 10 patients diagnosis of CIPO was based on clinical criteria. 46% of children had dominant upper gastro-intestinal (GI) tract presentation (nausea, vomiting, gastro-oesophageal reflux, feeding intolerance), 40% presented with lower GI tract symptoms (abdominal pain, abdominal distension, constipation). 29 children (58%) underwent colonic manometry, and majority of them (55%) showed colonic neuropathy. Out of 50 children with CIPO, 34 patients (68%) had an ileostomy performed, 9 (18%) had partial or total colectomy and 1 patient ultimately underwent multi-visceral transplantation. 35/50 patients had full thickness biopsy of small bowel. In 20/35 cases (57%) no histological abnormalities could be identified. Total parenteral nutrition (TPN) was required by 48% of children (23/48), 10 patients were on full enteral feeds; 4 patients remained on oral feeding.

Conclusion: Over the first four years of the UK national PPOD Service, we diagnosed an average of 12 patients a year, 5-fold higher than before the national UK service was established (2.4 patients/year; Henyeke et al 1999) with a trend towards decreasing age at first assessment (3.3 vs 11.3 years pre-2012, data not shown). This suggests that the national service not only appears effective in capturing more of the UK CIPO population but is making the definitive diagnosis earlier. The latter is especially important given the majority of patients presented with the onset of the first symptoms under 1 year of age and progress quickly to dependence on total parenteral nutrition. The majority of our patients underwent ileostomy formation soon after diagnosis and also showed large bowel dysmotility. We are now assessing whether early diagnosis and definitive intervention improves mid and long-term outcomes, including reduced morbidity, mortality, healthcare utilization costs and better tolerance of enteral feeding. The development of national CIPO registries and services is likely to be of benefit to improving early definitive diagnosis, expertise in management and ultimately outcomes of CIPO.

Disclosure of Interest: All authors have declared no conflicts of interest.

TUESDAY, OCTOBER 31, 201708:30-10:00

RECURRENCES AFTER COLORECTAL ENDOSCOPIC MUCOSAL RESECTION (EMR)/ENDOSCOPIC SUBMUCOSAL DISSECTION (ESD): HOW TO AVOID, HOW TO TREAT? - ROOM A1____________________

OP131 OUTCOMES OF ENDOSCOPIC SUBMUCOSAL DISSECTION FOR SUPERFICIAL ESOPHAGEAL CANCER IN AN ELDERLY POPULATION

T. Iizuka , D. Kikuchi, Y. Ochiai, S. Hoteya

Dept. Of Gastroenterology, Toranomon Hospital, Tokyo/Japan

Contact E-mail Address: t-iizuka@toranomon.gr.jp

Introduction: With population aging, there is increasing interest in the optimal treatment for esophageal cancer in older patients. Endoscopic submucosal dissection (ESD) is widely used to treat superficial cancers, but there are few reports on its use in elderly patients. The aim of this study was to determine the safety and efficacy of ESD for superficial esophageal cancer in an older population.

Aims & Methods: The study involved 162 elderly patients (>75 years; 209 lesions) and 502 younger patients (691 lesions) with a histologic diagnosis of squamous cell carcinoma or high-grade intraepithelial neoplasia who were treated by ESD between April 2008 and March 2016. The safety of ESD and its short-term and medium-term outcomes were compared between the two groups. Comorbidity was compared between the groups using the Charlson Comorbidity Index (CCI). Survival in patients with metachronous cancers was based on the deepest lesion.

Results: Ninety-nine patients (61%) in the elderly group and 344 (68.5%) in the younger group had a CCI <1 (p = 0.051). The mean tumor size was 24.1 mm in the elderly group and 23.2 mm in the younger group. The proportion of ESD procedures performed under general anesthesia was 14.8% and 20.8%, respectively (p = 0.055), and the incidence of bleeding, perforation, or local recurrence after ESD was not significantly different between the groups. The frequency of esophageal stricture was 11% in the elderly group and 20.8% in the younger group (p = 0.036); 43 lesions (20.6%) and 153 lesions (22.1%), respectively, were T1a-MM or deeper. Additional treatment was received by significantly more younger patients than elderly patients (72.2% vs 32.6%; p < 0.0001). There were 17 deaths in the elderly group and 36 in the younger group; 3 and 10 deaths, respectively, were from the primary cancer and 8 and 20 were from other malignant disease. The 3-year and 5-year survival rates were 60.9% and 24.7%, respectively, in the elderly group and 67% and 43.5% in the younger group (p < 0.0001); the respective survival rates in patients with a CCI < 1 were 65.0% and 25.2% in the elderly group and 67.1% and 44.2% in the younger group (p = 0.0004). The survival curves were similar between the two age groups until 3 years, but survival in the elderly group decreased dramatically thereafter. Three-year survival in the elderly group did not differ significantly between patients with a CCI score <1 or >2 (65% vs 54.7%).

Conclusion: ESD for superficial esophageal cancer can be performed safely in older patients. Additional treatment for T1a-MM or deeper lesions, which have a potential risk of metastasis to lymph nodes, was undertaken less often in the elderly group, but the rate of recurrence or death from primary cancer was not high. Survival was similar between older patients with low comorbidity and the younger patients until 3 years. These findings demonstrate that ESD is an effective treatment for elderly patients with superficial esophageal cancer, at least in the short-term.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP132 BALLOON-ASSISTED ENDOSCOPY FACILITATES ENDOSCOPIC SUBMUCOSAL DISSECTION OF COLONOSCOPICALLY DIFFICULT SUPERFICIAL RIGHT COLON TUMORS

T. Yamashina 1 , Y. Hayashi 1 , H. Sakamoto 1 , Y. Miura 1 , S. Shinozaki 2 , T. Yano 1 , K. Sunada 1 , A. K. Lefor 3 , H. Yamamoto 4

1 Division Of Gastroenterology, Department Of Medicine, Jichi Medical University, Tochigi/Japan

2 Shinozaki Medical Clinic, Tochigi/Japan

3 Surgery, Jichi Medical University, Shimotsuke, Japan, Yakushiji/Japan

4 Dept. Of Gastroenterology, Jichi Medical University, Shimotsuke/Japan

Contact E-mail Address: take8047@hotmail.com

Introduction: Colorectal endoscopic submucosal dissection (ESD) is a standard technique in Japan. However, colorectal ESD can be technically difficult in some situations such as paradoxical movement of the right colon. The double-balloon endoscope was introduced here, as a pioneering technique for balloon-assisted endoscopy, which provides stable endoscopic maneuvering even in the small intestine. Stable maneuverability can overcome the difficulties of colorectal ESD in the right colon.

Aims & Methods: The aim of this study is to assess the outcomes of balloon-assisted endoscopic submucosal dissection (BAESD) of colonoscopically difficult superficial right colon tumors. We retrospectively reviewed the records of patients who underwent BAESD of superficial right colon tumors where colonoscopic difficulties were encountered, from January 2011 to September 2016. Difficulties were defined as a previous incomplete colonoscopy using a conventional colonoscope or unstable endoscopic maneuverability around the tumor with conventional colonoscopy. A propensity score model was used as a secondary analysis to compare outcomes of the BAESD group to a group without difficulties.

Results: BAESD was performed on 67 tumors in 63 patients. There were 10, 22, and 35 tumors in the cecum, ascending colon and transverse colon, respectively. The median tumor size (range) was 31 (20–123) mm. The median (range) procedure time was 65 (15–382) minutes, and the median (range) dissection speed was 18.0 (4.4–71.4) mm 2 /minutes. En bloc resection was achieved for 66 tumors (99%) and an R0 resection was achieved for 58 tumors (87%). No perforations occurred. Two patients (3.0%) had delayed postoperative bleeding treated by endoscopic hemostasis. Propensity score-matching analysis created 65 matched pairs from the BAESD group and the conventional group. There were no significant differences in the en bloc resection rate (99% vs 99%, P = 1.0, Fisher's exact test), R0 resection (86% vs 91%, P = 0.58, Fisher's exact test), perforation (0% vs 1.5%, P = 1.0, Fisher's exact test) or postoperative bleeding rates (3.1% vs 3.1%, P = 1.0, Fisher's exact test) comparing the two groups. Although the ESD procedure time (64 vs 55 minutes, P = 0.09, Mann–Whitney U test) and dissection speed (16.7 vs. 19.7 mm 2 /minutes, P = 0.07, Mann–Whitney U test) in the BAESD group were slightly inferior to the conventional group, there were no significant differences.

Conclusion: Balloon-assisted endoscopy achieves safe and reliable ESD of colonoscopically difficult superficial right colon tumors.

Disclosure of Interest: All authors have declared no conflicts of interest.

TUESDAY, OCTOBER 31, 201708:30-10:00

DETECTION AND REMOVAL OF COLORECTAL POLYPS: LATEST TECHNIQUES - ROOM A3____________________

OP133 AUTOMATIC POLYP DETECTION IN COLONOSCOPY PROCEDURE USING DEEP LEARNING AND IMAGE PROCESSING TECHNIQUES

D. Zur , M. Zaltzhendler

Magnetiq Eye, Haifa/Israel

Contact E-mail Address: dror@magentiq.com

Introduction: It is estimated that 40 million colonoscopy procedures are performed every year (almost 40% in the US alone). The ability of colonoscopy procedures to decrease the number of colon cancer cases has been proven without a doubt and their number is expected to grow. However, research has shown that there is about 25% of misses (undetected polyps) in these procedures, misses which can, unfortunately, cause interval cancer. At Magnetiq Eye we put the growing power of Deep Learning, and of Image and Video Processing, to the help of doctors to reduce the miss rate in the colonoscopy procedures. Our first product the APDS is an Automatic Polyp Detection System, developed to be used in online and offline colonoscopies. The APDS-RT runs on the video feed from the endoscopic camera used by the physician in real time during the colonoscopy procedure and signs the polyp location as a contour in an overlay on the video at which the physician is looking during the procedure.

Aims & Methods: The APDS Prototype is aimed to detect polyps in recorded colonoscopy tests videos and to sign the polyp location on each frame of the played video either online while the played frames are presented or on a recorded video which is produced from the played video with the addition of the sign (colored contour) of the polyp location in each frame. We aimed at this phase to measure the performance of the prototype when running over the recorded videos. We used 63 video sequences of about half minute each to train the system, and about 23 video sequences of about half minute each to validate the training process, and tested the system which includes the trained model and additional image processing analysis techniques over 10 sequences of half minute each. The total database (training, validation and testing) included 46, 531 video frames and about 90 different polyps. We have measured, over the test videos, the FROC curve (True Positive Rate vs False Positive Per Frame) which was produced by changing a threshold parameter in the system, and the IoU (Intersection over Union ratio of the system prediction regions with the ground truth region) against changing he same threshold parameter of the system. The FROC was calculated over all the frames of the test database, and over subset of it which is all the frames from the test database which included polyps’ (ground truth polyps). In addition, the change of the False Positive Per Frame value against the system threshold parameter over a subset of the test frames (all the frames which didn't include polyps) was calculated. The IoU was calculated mainly over a subset which is all the frames which included polyps or predication of polyps.

Results: The best point of the FROC was 74% Detection Rate (TPR) vs. 0.07 False Positive Per Frame (FPPF) when calculated over all the frames, and 74% TPR vs. 0.05 FPPF when calculated over the subset of all the frames with ground truth polyps. For the system threshold which was used to select this working point, the FPPF over the subset of all frames without ground truth polyps was 0.05, and the average IoU value over all frames with ground truth or predicted polyps was 0.3. Increasing the system threshold would decrease the TPR, the FPPF, and the IoU, but would also decrease dramatically the FPPF over the subset of all frames without ground truth polyps.

Conclusion: We expect the system performance to be improved as it is exposed to more data in the training phase, in the sense that it would be able to choose a better working point (TPR vs. FPPF) on the same testing dataset, as well as to keep this working point as the testing dataset is increased, and also to get a better IoU value which is a quite good reference to the quality of the segmentation (depicting the polyp region) of the polyps. We can also see that we always have the possibility to increase the system threshold, and thus getting somewhat worse working point for all the frames or the frames with ground truth polyps, but earning dramatically less FPPF in the frames without ground truth polyps, and this is an important advantage since it would reduce the physician distraction during those frames.

Disclosure of Interest: D. Zur: CEO and R&D manager of my affiliation (Magnetiq Eye LTD)

M. Zaltzhendler: Senior Researcher and Developer in my affiliation (Magnetiq Eye LTD)

Reference

1. Van Rijn, Jeroen C., et al. "Polyp miss rate determined by tandem colonoscopy: a systematic review." The American journal of gastroenterology 101.2 (2006): 343–350.

OP134 IMPROVED DETECTION OF RIGHT-SIDED ADENOMAS BY G-EYE® COLONOSCOPY IN PATIENTS UNDERGOING COLORECTAL CANCER SCREENING-A PROSPECTIVE, RANDOMIZED, MULTICENTRE STUDY

H. Shirin 1 , B. Shpak 2 , J. Epshtein 3 , P. Vilmann 4 , A. Hoffman 5 , S. Sanduleanu 6 , P.A. Testoni 7 , S. Ishaq 8 , D. N. Reddy 9 , S.A. Gross 10 , P.D. Siersema 11 , H. Neumann 12 , M. Goetz 13 , D. Abramowich 1 , M. Moshkowitz 2 , M. Mizrahi 14 , J. Hendel 4 , J.W. Rey 5 , R. De Ridder 6 , E. Viale 7 , H. Chaudhari 9 , M.B. Pochapin 10 , M. Yair 1 , M. Shnell 2 , S. Yaari 3 , T. Stigaard 4 , R. Simantov 1 , N. Gluck 2 , E. Israeli 3 , S. Sloth 4 , S. Matalon 1 , A. Vilkin 2 , A. Benson 3 , A. Maliar 1 , A. Waizbard 2 , T. Hershcovici 3 , E. Shachar 1 , S. Rochberger 2 , E. Tsvang 3 , M. Braverman 1 , H. Jacob 3 , Y. Brachman 1 , J.G. Karstensen 4 , D. Teubner 5 , R. Bogie 6 , R. Kiesslich 5

1 Assaf Harofeh Medical Center, Tzrifin/Israel

2 Laniado Hospital, Netanya/Israel

3 Hadassah Medical Center, Jerusalem/Israel

4 Copenhagen University Hospital Herlev, Herlev/Denmark

5 HSK, Dr. Horst-Schmidt-Kliniken, Wiesbaden/Germany

6 UMC Maastricht, Maastricht/Netherlands

7 San Raffaele Hospital, Milano/Italy

8 Russells Hall, Dudley/United Kingdom

9 Asian Institute of Gastroenterology, Hyderabad/India

10 NYU Langone Medical Center, New York/United States of America

11 UMC Radboud, Nijmegen/Netherlands

12 Universitätsmedizin Johannes Gutenberg University Mainz, Mainz/Germany

13 Interdisziplinäre Endoskopie, Universitätsklinikum Tübingen, Tübingen/Germany

14 Beth Israel Deaconess Medical Center, Harvard Medical School, Boston/United States of America

Contact E-mail Address: info@ralf-kiesslich.de

Introduction: Colorectal Cancer (CRC) prevention has resulted in the implementation of screening programs worldwide in hopes to reduce the number of CRC incidences. Despite these programs’ best efforts, interval cancers continue to arise from lesions missed during standard procedures. Interval cancers have been found to occur more frequently in the right colon, often developing from flat and sessile lesions. These lesions have had reported miss rates of up to 60% compared to reported miss rates of 20%−30% for polyps and adenomas. The innovative G-EYE® endoscope (SMART Medical Systems Ltd, Ra’anana, Israel) includes an integral, reusable balloon that is permanently installed on the distal end of a standard endoscope. Upon withdrawal, inflation of the G-EYE® balloon to a partial pressure results in the centralization of endoscope optics, reduction in bowel slippage, and flattening of colon topography. The enhanced visualization provided by the G-EYE® balloon can result in an increase detection of lesions.

Aims & Methods: In this prospective, randomized, multicentre study, patients (age >50) referred to colonoscopy as a result of screening, surveillance, positive FOBT or change in bowel habits were randomized to either standard colonoscopy (SC) or G-EYE® colonoscopy. Detected lesions were removed and sent for pathology. We compared the detection rates of G-EYE® colonoscopy with that of SC in the right colon.

Results: 1000 patients were enrolled in the study, of which 498 underwent SC and 502 underwent G-EYE® colonoscopy. Baseline parameters were similar in both groups. The right colon was defined as the cecum, ascending colon, and hepatic flexure. Results are presented in Table 1. In addition, the G-EYE®increased the detection of both advanced and large-size adenomas by 40% in the right colon.

Conclusion: Our study shows that G-EYE® colonoscopy has the potential to significantly improve the quality of CRC screening through improved adenoma detection rates. Special attention should be given to the significant increase in right-sided flat lesions and sessile serrated adenomas by the G-EYE®, as these lesions are strongly attributed to CRC. Through increased detection of these right-sided lesions, G-EYE® colonoscopy can impact the quality of CRC screening by reducing miss rates and consequently reduce the incidents of interval cancers.

Disclosure of Interest: H. Jacob: Board member

All other authors have declared no conflicts of interest.

OP135 A STANDARDIZED IMAGING PROTOCOL IS ACCURATE FOR THE ENDOSCOPIC PREDICTION OF DYSPLASIA WITHIN SESSILE SERRATED POLYPS

D. J. Tate 1 , H. Awadie 1 , M. Jayanna 1 , L. Desomer 1 , R. Lee 1 , S. Heitman 1 , K. Goodrick 1 , D. Mcleod 2 , H. Mahajan 2 , M.J. Bourke 3

1 Department Of Gastroenterology And Hepatology, Westmead Hospital, Sydney/Australia/NSW

2 Institute Of Clinical Pathology And Medical Research, Westmead Hospital, Sydney/Australia/NSW

3 Westmead Clinical School, University of Sydney, Sydney/Australia/NSW

Contact E-mail Address: djtate@gmail.com

Introduction: Dysplasia within sessile serrated polyps (SSP) is difficult to detect, may be mistaken for an adenoma, risking incomplete resection of the background serrated tissue and is strongly implicated in interval cancer after colonoscopy. The use of endoscopic imaging to detect dysplasia within SSP has not been systematically studied.

Aims & Methods: We aimed to establish whether a standardized imaging protocol was accurate for the endoscopic prediction of dysplasia within sessile serrated polyps. Consecutively detected SSP ≥8 mm in size were evaluated using a standardized imaging protocol at a tertiary endoscopy centre over 3 years. Lesions suspected as SSP were analysed with high-definition white light (HDWL) then narrow band imaging (NBI). Lesions were considered as SSP when the following features were identified: mucous cap, cloud-like or finely nodular surface, indistinct border, irregular shape and lesion paler than the surrounding mucosa (under NBI). A demarcated area of neoplastic pit pattern (Kudo type III/IV, NICE type II) was sought amongst the serrated tissue. If this was detected the lesion was labelled dysplastic (SSP-D), if not it was labelled non-dysplastic (SSP-ND). Histopathology was reviewed by two blinded specialist gastrointestinal pathologists. Since histopathology is an imperfect gold standard to determine dysplasia within SSP (dysplastic areas can be small and may be missed between tissue sections, destroyed in tissue processing or not retrieved), at the end of the study a structured discussion between endoscopists and histopathologists was undertaken to assign the final determination of dysplasia. Agreement of all parties was required on the final determination.

Results: 141 suspected SSP were assessed in 83 patients. Median lesion size was 15.0 mm (interquartile range 10–20) and 54.6% were in the right colon. All 141 lesions suspected as SSP were confirmed as sessile serrated adenoma at histopathology. Endoscopic evidence of dysplasia was detected in 36/141 (25.5%) SSP. 2/105 (1.9%) endoscopically designated SSP-ND had dysplasia at histopathology. 10/36 (27.8%) endoscopically designated SSP-D had no dysplasia at histopathology. After discussion with the specialist gastrointestinal pathologists, agreement was reached that in 5/10 (50%) endoscopically designated SSP-D previously determined to be without dysplasia at histopathology, there was infact evidence for dysplasia. Endoscopic imaging therefore had an accuracy of 95.0% (95% confidence interval [CI] 90.1–97.6%) and a negative predictive value of 98.1% (95% CI 92.6–99.7%) for detection of dysplasia within SSP (table 1).

Conclusion: Dysplasia within SSP can be accurately detected using a simple, broadly applicable endoscopic imaging protocol allowing their complete resection. Independent validation of this protocol and its dissemination to the wider endoscopic community may have a significant impact on rates of interval cancer. Clinicaltrials.gov NCT03100552 .

Disclosure of Interest: All authors have declared no conflicts of interest.

OP136 RANDOMIZED CONTROLLED TRIAL OF THE USEFULNESS OF COLD SNARE POLYPECTOMY (CSP) FOR OUTPATIENTS

K. Ohtsu 1 , S. Sou 1 , T. Noda 1 , T. Karashima 1 , T. Takeda 1 , K. Imamura 1 , R. Sakemi 1 , H. Terabe 1 , Y. Morimitsu 2

1 Gastroenterology, Tobata Kyoritsu Hospital, kitakyushu/Japan

2 Pathology, Tobata Kyoritsu Hospital, Kitakyushu/Japan

Contact E-mail Address: k.ohtsu0120@gmail.com

Introduction: There have been few reports of the safety and usefulness of cold snare polypectomy (CSP) for colorectal polyps of 10 mm or less. This study examined the usefulness and safety of CSP for outpatient same-day treatment.

Aims & Methods: During the period from December 2015 to October 2016, informed consent was obtained before examining outpatients scheduled for colonoscopy of the entire large intestine. Patients found to have colorectal polyps (excluding Ip polyps) of 10 mm or less were included in this study. Patients on oral antithrombotic therapy, which was a stratifying factor, were randomly assigned to a CSP group and an endoscopic mucosal resection (EMR) group. The two groups were compared for the following treatment endpoints: (1) postoperative hemorrhage rate, (2) polyp resection time, (3) en bloc resection rate, (4) postoperative hemorrhage rate with and without oral antithrombotic administration, and the (5) rate of retrieval of tissue from resected lesions.

Results: 300 patients were enrolled in the study. After exclusion of one patient who did not complete CSP, 149 CSP group cases and 150 EMR group cases were analyzed. The values for the treatment endpoints were (1) 0.67% (1/149), (2) 92.2 ± 9.2 sec, (3) 99.1% (348/351), (4) 0% (0/21) and (5) 96.6% (339/351) in the CSP group, and (1) 0.67% (1/150), (2) 144.6 ± 18.9 sec, (3) 100% (322/322), (4) 0% (0/21) and (5) 99.1% (319/322) in the EMR group. Although there were no significant differences between the groups in regard to (1), (3), or (4), the (2) polyp resection time was significantly shorter in the CSP group (p < 0.001), and the (5) rate of collection of tissue from resected lesions was lower in the CSP group (p = 0.029).

Conclusion: Resection of colorectal polyps in outpatients showed a low incidence of complications in both the CSP and EMR groups and was performed safely. The polyp resection time was significantly shorter with CSP than with EMR, and shortening of the examination time can be expected.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP137 IS COLD-SNARE POLYPECTOMY ALWAYS ADEQUATE FOR REMOVAL OF SMALL COLORECTAL POLYPS WITH ADVANCED HISTOLOGY?

Y. Shimodate 1 , M. Mizuno 1 , J. Itakura 2 , R. Takezawa 1 , M. Kobayashi 1 , T. Yamazaki 1 , A. Doi 1 , N. Nishimura 1 , H. Mouri 1 , K. Matsueda 1 , H. Yamamoto 1

1 Gastroenterology And Hepatology, Kurashiki Central Hospital, Kurashiki/Japan

2 Pathology, Kurashiki Central Hospital, Kurashiki/Japan

Contact E-mail Address: ys13544@kchnet.or.jp

Introduction: The new European Society of Gastrointestinal Endoscopy clinical guidelines recommend cold-snare polypectomy (CSP) for removal of small colorectal polyps. The recommendation is based on the efficacy and safety of the technique and the assumption that most small polys have only low-grade histology. However, advanced neoplasia may be unexpectedly removed with CSP, raising concern about possible residual tumor and local recurrence in such cases. For accurate microscopic assessment of CSP-removed polyps, wide horizontal excision and adequate depth is necessary.

Aims & Methods: In this study, we prospectively investigated the efficacy of CSP from the aspects of depth of excised tumors and their vertical margins. Two hundred and seventy-six consecutive sessile or slightly elevated colorectal polyps, removed with CSP by an experienced endoscopist (more than 500 CSPs performed), were enrolled between May 2016 and January 2017. Three of the polyps were excluded because of retrieval failure. Devices used were the Profile/Captivator (Boston scientific) and Exacto (US Endoscopy). Excised polyps were retrieved by suctioning them through the colonoscope’s biopsy channel. All unfragmented retrieved specimens were mounted on plates with pins to facilitate pathological assessment and were evaluated blindly without pathologists having clinical information of the lesions. Evaluated items included resection into the muscularis mucosa (MM) and histology of the tumor’s vertical margins. Resection was considered complete when MM was present under the tumor along more than 80% of its horizontal axis. Gross morphology of polyps was classified according to the Paris classification system (sessile, Is; or slightly elevated, IIa).

Results: Mean size of 273 polyps was 4.9 mm. Twenty-one lesions (7.7%) were fragmented during their retrieval and were excluded from the analysis of the MM resection rate. The rate of complete MM resection was 78.6% (198/252), and negative vertical margins were identified in 217 of 273 polyps (79.5%). Pathologically, 16 polyps (5.9%) had advanced histology: 13 high-grade adenomas and 3 intramucosal carcinomas. Mean size of the polyps with advanced histology was 5.3 mm. In 4 of these16 polyps, vertical margins could not be adequately evaluated. 72 polyps (28.6%) were sessile, and this morphology was associated with incomplete MM resection (odds ratio = 2.3; 95% confidential interval, 1.2–4.4 by multivariate analysis). Limitation: CSP was performed by only one endoscopist.

Conclusion: CSP achieved proper resection depth in only about 80% of lesions even when performed by an experienced endoscopist. Given that a few small polyps with advanced histology may be unexpectedly resected with CSP, this procedure should be evaluated further, especially for sessile polyps with advanced histology, before it becomes standard of care for excision of small colorectal polyps.

Disclosure of Interest: All authors have declared no conflicts of interest.

Reference

Ferlitsch M, Moss A, Hassan C, et al. Colorectal polypectomy and endoscopic mucosal resection (EMR): European Society of Gastrointestinal Endoscopy (ESGE) Clinical Guideline. Endoscopy 2017; 49: 270–297.

OP138 MANAGEMENT AND RISK FACTORS FOR INCOMPLETE RESECTION ASSOCIATED WITH COLD FORCEPS POLYPECTOMY FOR DIMINUTIVE COLORECTAL POLYPS: A SINGLE-INSTITUTION RETROSPECTIVE COHORT STUDY

N. Asayama 1 , S. Nagata 1 , Y. Ogawa 1 , H. Tamari 1 , Y. Shimohara 1 , T. Aoyama 1 , A. Fukumoto 1 , S. Mukai 1 , M. Kaneko 2

1 Department Of Gastroenterology, Hiroshima City Asa Citizens Hospital, Hiroshima/Japan

2 Department Of Pathology, Hiroshima City Asa Citizens Hospital, Hiroshima/Japan

Contact E-mail Address: a-s-ayama@hotmail.co.jp

Introduction: Adequate polypectomy is important during screening colonoscopy to prevent progression of colorectal carcinoma and decrease mortality. Cold polypectomy, which involves no electrocautery, is reported to be safe and effective for removal of diminutive polyps (DPs) and is now widely performed. Cold forceps polypectomy (CFP) is a simple and quick technique allowing complete resection of most DPs. However, evidence for its efficacy is lacking, precise histopathological diagnosis may be difficult, and little is known about the risk factors for histologically incomplete resection.

Aims & Methods: The aim of this retrospective cohort study is to evaluate the clinicopathological characteristics and clinical outcomes of patients who underwent removal of DPs by CFP as well as predictors of incomplete resection. We retrospectively investigated 1129 DPs resected by CFP with jumbo biopsy forceps (Radial Jaw™ 4; Boston Scientific, Marlborough, MA) in 587 patients (392 men, 189 women; mean age 66 ± 9.4 years) at Hiroshima City Asa Citizens Hospital between November 2015 and December 2016. We evaluated the clinical outcomes of 999 tumours for which a precise histopathological analysis was made and investigated the relationship between incomplete resection and clinicopathological factors. Complete resection was defined as when additional bites for resection were not needed and both the lateral and vertical margins of the specimen were tumour-free resection margins.

Results: Lesions were mainly located in the transverse colon (336 lesions, 30%), ascending colon (252 lesions, 22%) and sigmoid colon (228 lesions, 20%). Of the lesions, 1013 (94%) were protruding/sessile and 65 (6%) were flat/elevated. Most lesions (985 [87%]) were low-grade (n = 783) or high-grade (n = 202) adenomas and 14 (1%) were well-differentiated adenocarcinomas. The en bloc resection rate was 92% (918/999) and the histological en bloc resection rate was 78% (777/999). Precise histopathological diagnosis was difficult in 22% of cases. The lateral margins could not be assessed histologically for tumour involvement in 155 (16%) lesions, additional bites for resection were needed for 81 (8%) lesions, and involvement of the vertical margin could not be histologically assessed in 58 (6%) lesions. Multivariate analysis showed tumour size ≥4 mm (odds ratio [OR] 3.8; 95% confidence interval [CI] 2.65–5.37; p < 0.01), non-tangential direction of forceps in relation to the tumour (OR 1.73; 95% CI 1.21–2.45; p < 0.01), and lack of muscularis mucosae in the pathological specimen (OR 15.7; 95% CI 9.16–27.7; p < 0.01) to be significant independent predictors of incomplete resection. One (0.1%) of the 999 patients had delayed bleeding that was easily managed by endoscopic clipping. There were no cases of perforation.

Conclusion: This study identified significant independent predictors of incomplete resection of diminutive colorectal polyps and may provide helpful information when planning CFP.

Disclosure of Interest: All authors have declared no conflicts of interest.

References

1. Raad D, Tripathi P, Cooper G et al. Role of the cold biopsy technique in diminutive and small colonic polyp removal: a systematicreview and meta-analysis. Gastrointest Endosc 2016;83:508–15.

2. Park SK, Ko BM, Han JP et al. A prospective randomized comparative study of cold forceps polypectomy by using narrow-bandimaging endoscopy versus cold snare polypectomy in patients with diminutive colorectal polyps. Gastrointest Endosc . 2016;83:527–32.

3. Matsuda T, Kawano H, Hisabe T et al. Current status and future perspectives of endoscopic diagnosis and treatment of diminutive colorectal polyps. Dig Endosc 2014;26:104–8.

4. Uraoka T, Ramberan H, Matsuda T et al. Cold polypectomy techniques for diminutive polyps in the colorectum. Dig Endosc 2014;26:98–103.

5. Jung YS, Park JH, Kim HJ et al. Complete biopsy resection of diminutive polyps. Endoscopy 2013;45:1024–9.

6. Draganov PV, Chang MN, Alkhasawneh A et al. Randomized, controlled trial of standard, large-capacity versus jumbo biopsy forceps for polypectomy of small, sessile, colorectal polyps. Gastrointest Endosc 2012;75:118–26.

TUESDAY, OCTOBER 31, 201708:30-10:00

DIAGNOSIS AND TREATMENT OF GORD - ROOM B2____________________

OP139 COMPREHENSIVE QUANTITATIVE ANALYSIS OF RELATIONSHIP BETWEEN ACIDIC LARYNGOPHARYNGEAL REFLUX (LPR) AND SYMPTOMS AND SIGNS OF LARYNGEAL INJURY BY DUAL PHARYNGEAL AND ESOPHAGEAL 24-HOUR PH/IMPEDANCE MONITORING

M. Ďuriček 1 , P. Banovcin 1 , T. Haličková 2 , R. Hyrdel 1 , M. Kollarik 3

1 Internal Gastroenterological Clinic, Jessenius Faculty of Medicine, Martin/Slovak Republic

2 Clinic Of ENT And Head And Neck Surgery, Central Military Hospital, Ružomberok/Slovak Republic

3 Asthma And Allergy Center, The Johns Hopkins University School of Medicine, Baltimore/United States of America/MD

Contact E-mail Address: martin.duricek@gmail.com

Introduction: Understanding of the relationship between LPR and symptoms and signs of laryngeal injury would greatly aid diagnosis of LPR, but it has proven elusive. Here we aimed to perform comprehensive quantitative analysis of the relationship between acidic LPR and symptoms and signs of laryngeal injury independent of the assumption how much refluxed acid is required to cause these symptoms and signs.

Aims & Methods: Patients referred for suspected LPR were screened and those with positive reflux finding score (RFS > 7), as determined by flexible laryngoscopy and/or positive reflux symptom index (RSI > 13), and at least one acidic LPR episode during 24 h pH/impedance study were enrolled. We recruited patients that were at least 30 days without PPI treatment. Appropriate distance between pH sensors was chosen based on manometrically determined LES and UES. We determined the number of LPR events during the recording. By definition each LPR event was preceded by reflux detection in the distal esophagus. For each event we determined the maximum drop of pH on the pH levels <6, <5.5, <5.0, <4.5 and <4.0 to perform the analysis independent of the assumption how acidic the pH of LPR is required to cause symptoms and signs of laryngeal injury. For each of these pH levels we determined pharyngeal acid exposure time calculated as cumulative time of pharyngeal reflux below that pH level during 24 h. We determined the correlations between the parameters describing acid exposure and RSI/RFS using Pearson correlation coefficient (r value).

Results: 27 patients (20M/7F) completed the study. RSI was 24 ± 2 and RFS was 9 ± 1. Pharyngeal refluxed acid exposure time below pH 6.0, 5.5, 5.0, 4.5 and 4.0 was 279 ± 49 s, 63 ± 18 s, 32 ± 12 s, 16 ± 6 s, 6 ± 3 s, respectively. There was no correlation between pharyngeal acid exposure time and RSI for pH 6.0, 5.5, 5.0, 4.5 and 4.0 (R = 0.03, −0.14, −0.15, −0.1, −0.08, respectively, P = NS in all cases). The number of LPR events that reached pH 6.0, 5.5, 5.0, 4.5 and 4.0 was 14[8–21], 4[2–7], 1[0–2], 1[0–1], 0[0–1]. There was also no correlation between the number of LPR events and RSI (R = 0.29, 0.03, −0.23, −0.27, −0.29). Analogous independent analysis revealed no correlation between LPR and RFS (signs of laryngeal injury) (P = NS in all cases).

Conclusion: Our data indicate that a simple direct relationship between the amount of acidic laryngopharyngeal reflux and symptoms and signs of laryngeal injury in LPR patients is improbable. This suggests that pathogenetic aspects of LPR other than those that are detectable on 24 hour dual pH metry might be of importance.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP140 ESOPHAGEAL MEAN NOCTURNAL BASELINE IMPEDANCE PREDICTS SYMPTOMATIC OUTCOME IN GERD EVEN WHEN ACID EXPOSURE TIME IS INCONCLUSIVE ON ESOPHAGEAL REFLUX MONITORING

A. Rengarajan 1 , E. Savarino 2 , A. Patel 3 , S. Roman 4 , R. Yadlapati 5 , J. Pandolfino 5 , C.P. Gyawali 1

1 Washington University in St. Louis, St Louis/United States of America/MO

2 Department Of Surgery, Oncology And Gastroenterology, University of Padua, Padua/Italy

3 Duke University, Durham/United States of America/NC

4 Digestive Physiology, Hôpital Edouard Herriot, Lyon/France

5 Northwestern University, Chicago/United States of America/IL

Contact E-mail Address: rengara@wustl.edu

Introduction: Abnormal esophageal acid burden measured using acid exposure time (AET) from 24-hour pH-impedance monitoring predicts favorable symptom outcome from both medical and surgical anti-reflux therapy. Alternate reflux evidence is deemed necessary when AET is borderline and inconclusive. Esophageal baseline mucosal impedance extracted from pH-impedance data during night-time hours (MNBI) represents a new paradigm that is co-linear with AET. The value of MNBI when AET is inconclusive has not been previously evaluated.

Aims & Methods: Our aim was to determine the value of MNBI in predicting symptom outcome from medical and surgical anti-reflux therapy when AET is borderline and inconclusive, in this ongoing multicenter collaboration. Esophageal function studies from patients with persisting reflux symptoms were reviewed from two centers (one each in Europe and US) for this preliminary report. For inclusion, patients with typical or atypical reflux symptoms were required to have completed ambulatory pH-impedance monitoring (Sandhill Scientific, Boulder, CO) off antisecretory therapy. AET data were extracted from ambulatory pH-impedance studies. Total AET was abnormal when >6%, and physiologic when <4%; AET 4–6% was considered borderline and inconclusive. Baseline impedance was calculated at the 5 cm impedance channel (to correspond to AET) at three stable 10-min time periods (1, 2, and 3 AM) during the ambulatory pH-impedance study, and averaged to yield MNBI, abnormal if <2292 ohms. Symptom response was assessed using change in global symptom scores from symptom questionnaires over follow-up; a 50% reduction in global symptoms constituted a response to anti-reflux therapy, both medical management and anti-reflux surgery. Data were analyzed to assess concordance between AET and MNBI, and to assess symptom response in relationship to physiologic, borderline and abnormal AET in the context of abnormal MNBI.

Results: A total of 371 patients (54.5 ± 0.7 yr, 60.0% female) had adequate pH-impedance studies performed off antisecretory therapy, and symptom data available for inclusion in this study. Of these, 107 (28.8%) had abnormal AET, and 234 (63.1%) had abnormal MNBI. Of 107 patients with abnormal AET, low MNBI was concordant with AET in 106 (99.1%), and discordant (abnormal AET, normal MNBI) in only 1 patient. Similarly, concordance between AET 4–6% and low MNBI was noted in 62 of 68 patients (91.2%), and discordance (AET 4–6%, normal MNBI) in only 8.8% (p = 0.011 compared to AET > 6%). In contrast, of 196 patients with physiologic AET, concordant normal MNBI was noted in only 130 (66.3%), and with the remainder 33.7% discordant with physiologic AET but low MNBI (p < 0.0001 for each comparison with AET > 6 and AET4–6%). Of 330 patients with symptom data available from medical therapy, 142 (43.0%) had at least 50% symptom improvement over 38.7 ± 0.8 months of follow up. Symptom response following antireflux surgery was available in 63 patients, and 48 (76.2%) responded (p < 0.0001 compared to medical therapy). Response to both medical therapy and surgery were better when AET > 6% (medical therapy: 74.2% response, surgery 78.3% response) and MNBI < 2292 (medical therapy: 60.1% response, surgery: 82% response). In contrast, response to therapy was worse when AET < 4% (medical therapy: 21.1% response, surgery: 69.6% response), and MNBI > 2292 (medical therapy: 17.4% response, surgery: 53.8% response). Response to medical therapy with AET 4–6% resembled that seen when AET > 6% when MNBI was low (Table, p = 0.44), significantly different from patients with AET < 4, regardless of whether MNBI was normal or low (p < 0.0001 for each comparison).

Conclusion: There is high concordance between both abnormal AET and borderline AET, and low MNBI. When low, MNBI identifies patients with abnormal as well as borderline AET (but not physiologic AET) who respond to medical and surgical anti-reflux therapy. MNBI therefore complements AET in defining esophageal reflux burden, and in predicting symptom response to anti-reflux therapy.

Disclosure of Interest: E. Savarino: Consulting fee from: Medtronic, Sofar, Malesci, Takeda, Abbvie, MSD

S. Roman: consulting fees: Medtronic research support: Sandhill, Crospon

J. Pandolfino: Medtronic, Sandhill, Torax- Consultants/Speaker Astra Zeneca, Takeda- speaker Ironwood, Impleo- consultant

C.P. Gyawali: Medtronic (research support, speakers' bureau); Torax (consulting); Ironwood (consulting); Allergan (speakers' bureau); Quintiles (consulting)

All other authors have declared no conflicts of interest.

References

Frazzoni M, Savarino E, de Bortoli N, et al. Clin Gastroenterol Hepatol . 2016;14:40–6.

Patel A, Wang D, Sainani N, e al. Aliment Pharmacol Ther 2016;44:890–8.

OP141 HIGH-RESOLUTION MANOMETRY IS SUPERIOR TO ENDOSCOPY AND RADIOLOGY IN ASSESSING AND GRADING SLIDING HIATAL HERNIA. A PROSPECTIVE COMPARISON WITH SURGICAL IN VIVO

S. Tolone 1 , E. Savarino 2 , G. Zaninotto 3 , N. De Bortoli 4 , I. Martinucci 4 , M. Furnari 5 , M. Frazzoni 6 , L. Frazzoni 7 , V. Savarino 8 , L. Docimo 1

1 Surgery, University of Campania "Luigi Vanvitelli", Naples, Naples/Italy

2 Department Of Surgery, Oncology And Gastroenterology, University of Padua, Padua/Italy

3 Surgery, Imperial College - Surgery, Imperial College; London/GB, London/United Kingdom

4 Division Of Gastroenterology, Department Of Internal Medicine, University of Pisa, Pisa/Italy

5 Di.m.i., Gastroenterology Unit, DiMI, Gastroenterology Unit, University of Genoa, Genoa/Italy

6 Digestive Pathophysiology Unit, Baggiovara Hospital, Modena/Italy

7 Department Of Medical And Surgical Sciences, S. Orsola-Malpighi Hospital, Bologna/Italy

8 Dept Internal Medecine, Universita di Genova, Genova/Italy

Contact E-mail Address: salvatore.tolone@unicampania.it

Introduction: Sliding hiatal hernia (HH) has been associated with abnormal esophageal acid exposure, prolonged esophageal clearance, increased reflux episodes and it is correlated with the severity of gastroesophageal reflux disease. The diagnosis of HH is made with a barium-swallow esophagogram (BSE), and it can be also described at upper endoscopy (UE). However, these methods are limited by the subjective and indirect evaluation of lower esophageal sphincter (LES) and crural diaphragm (CD). High resolution manometry (HRM) allows to clearly identify CD and LES. However, its diagnostic accuracy has been poorly investigated.

Aims & Methods: Aim of the study was to determine the diagnostic value of HRM in the detection of HH, compared to BSE and UE, using as reference the surgical in vivo measurement. We prospectively enrolled patients undergoing open foregut surgery between 2009 and 2014. All subjects underwent BSE, UE, HRM and in vivo evaluation of esophagogastric junction (EGJ). At BSE EGJ was classified as Type I (normal EGJ without evidence of the B ring or gastric folds), Type II ≤2 cm and Type III ≥2 cm, when the B ring or gastric folds were displaced above the proximal border of CD. At UE the distance from proximal border of CD impression and to the top of the proximal gastric folds was recorded. UE Type I indicated a normal EJG; Type II and Type III documented a HH ≥1 cm and ≤2 cm and ≥2 cm between the CD impression and the EGJ, respectively. At HRM, the distance between the maximal LES and CD pressure peaks was measured. EGJ was classified as Type I, no separation; Type II ≥1 and ≤2 cm separation; Type III >2 cm. In vivo HH measurement was performed during elective open surgery; a complete isolation of the EGJ and CD was obtained. A large endoscopic clip was applied to mark the EGJ. The distance in cm between the clip and the proximal border of the CD was recorded with a ruler. In vivo EGJ was classified as Type I, EGJ placed below or overlapping the CD, Type II EGJ above CD >1 cm but <2 cm, and Type III EGJ above CD >2 cm.

Results: We enrolled 100 patients. During surgery, 53% had a HH. In details, 47% were classified as Type I EGJ, 35% as Type II and 18% as Type III. Mean LES-CD separation in HH patients was 2.13 ± 1.14 cm. Referenced to the in vivo evaluation, HRM showed a superior diagnostic sensitivity and specificity (94.3% and 91.5%, respectively) than BSE and UE, in individuating HH presence, with 92.6% PVPT and 93.5% PVNT. Kappa value for HRM and in vivo evaluation was 0.85. HRM showed optimal diagnostic sensitivity and specificity in detecting Type I, II and III EGJ (Table 1).

Conclusion: HRM can accurately diagnose the presence of HH, with high sensitivity and specificity. In particular, HRM can better classify HH than endoscopy and radiology, reaching an optimal agreement with surgical in vivo assessment.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP142 THE EFFECT OF BILE REFLUX ON BASELINE IMPEDANCE VALUE AND CHEMICAL CLEARANCE IN PATIENTS WITH NERD

I. Martinucci 1 , N. De Bortoli 1 , M. Frazzoni 2 , S. Tolone 3 , L. Frazzoni 4 , E. Marabotto 5 , L. Macchia 6 , R. Tutuian 7 , S. Santi 8 , V. Savarino 9 , S. Marchi 1 , E. Savarino 10

1 Gastroenterology Unit, University of Pisa, Pisa/Italy

2 Digestive Pathophysiology Unit, Baggiovara Hospital, Modena/Italy

3 Surgery, Second University of Naples, Naples/Italy

4 Department Of Medical And Surgical Sciences, S. Orsola-Malpighi Hospital, Bologna/Italy

5 University of Genoa, Genoa, Italy, Genoa/Italy

6 Internal Medicine, Lugano/Switzerland

7 Klinik Für Gastroenterologie, Tiefenauspital - Inselgruppe, Bern/Switzerland

8 Esophageal Surgery Unit, Pisa/Italy

9 Dept Internal Medecine, Universita di Genova, Genova/Italy

10 Department Of Surgery, Oncology And Gastroenterology, University of Padua, Padua/Italy

Contact E-mail Address: martinucci.irene@gmail.com

Introduction: Nocturnal baseline impedance values (MNBI) and post-reflux swallowed induced peristaltic wave (PSPW) index were recently recognized as up-and-coming reliable makers of GERD. Anyway, no data are available regarding the effect of bile reflux (BR) on MNBI and PSPW index.

Aims & Methods: The aim of this study was to compare MNBI and PSPW in patients with NERD with or without presence of BR. We enrolled consecutive patients with heartburn (twice/week in the last six months). All patients underwent evaluation of their medical history together with endoscopy, esophageal manometry, impedance and pH monitoring (MII-pH) and BR monitoring (Bilitec) to investigate gastroesophageal reflux disease (GERD). All tests were performed previous a 20-day wash-out from proton pump inhibitors. Patients with major esophageal motor disorders were excluded. Impedance-pH tracings were blindly and manually reviewed, and we measured distal AET, PSPW and BI values. The PSPW index was calculated by dividing the number of refluxes followed within 30 seconds by swallow-induced peristaltic waves with the number of total refluxes. BI levels were assessed at 3 cm above the lower esophageal sphincter, during the overnight rest, for at least 30 minutes after excluding swallows and reflux induced changes. Patients were classified as NERD when abnormal AET or number of refluxes was detected. Further, patients were divided as BR+ (when absorbance Bilitec >0.14) and BR- (when absorbance Bilitec <0.14).

Results: We evaluated 22 patients (15 males/7 females, mean age 52 ± 9.8 yrs) with NERD. MII-pH showed a median AET 6.2 (IQR 2.1), median reflux number 63 (IQR 16) and median BR 3.2 (IQR 8.6). BR were normal in 10 patients (0.01; IQR 0–0.04) and abnormal in 12 (7.8 IQR 6.9) (p < 0.05). AET and number of reflux events did not differ between the two groups (p = ns). PSPW and MNBI were lower in patients with abnormal bile reflux (p < 0.001). All details are reported in Table 1. A strong linear correlation between BR and MNBI was observed (Pearson test; r = −0.771; p < 0.001).

Conclusion: Bile refluxes strongly affected MNBI in patients with NERD. Further, they are associated to an abnormal PSPW index reflecting the relevance of this parameter in identifying patients with abnormal chemical clearance and therefore at more risk to develop GERD symptoms.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP143 REDUCTION OF DAY TIME ACID GASTRO OESOPHAGEAL REFLUX BY TREATING INCREASED SUPRAGASTRIC BELCHING

E. Glasinovic 1 , E. Wynter 1 , J. Arguero 1 , P. Hajek 2 , D. Sifrim 3

1 Wingate Institute For Neurogastroenterology, Barts and the London School of Medicine, Queen Mary University, London/United Kingdom

2 Wolfson Institute Of Preventive Medicine, Barts and the London School of Medicine, Queen Mary University, London/United Kingdom

3 Wingate Institute, Queen Mary University London Wingate Institute Centre for Digestive Diseases, London/United Kingdom

Contact E-mail Address: eglasinovic@gmail.com

Introduction: Supragastric belching (SGB) is considered a behavioural disorder. SGB can manifest as a large number of belch episodes during daytime, or can be associated with reflux symptoms or rumination. Supragastric belches can be immediately followed by acid reflux and in some GERD patients, SGB-associated reflux can contribute to up to 1/3 of the total acid exposure (AET) (Koukias, 2015). Current treatments for SGB are cognitive behavioural therapy (CBT) and Baclofen. We hypothesized that reducing SGB might improve QOL and reduce acid GER.

Aims & Methods: The aim of our study was to assess the effectiveness of CBT in patients with pathological SGB and/or increased SGB-related acid reflux Methods: Patients were recruited from the upper GI Physiology Unit after performance of MII-pHmetry (Sandill Sci, USA). Visual analysis of tracing was performed to identify SGB and patients with more than 13 SGB/day were invited to participate. Patients attended a total of 5 CBT sessions. The CBT protocol was adapted from Katzka et al (2013) and consisted of teaching 1. diaphragmatic breathing, 2. mouth opening/tongue position and 3. recognition of a warning signal/feeling pre-belching. Patients exercised these manoeuvres daily and tried to apply them to prevent belching. Before and after CBT, subjective evaluation included a 4-item visual analog scale (VAS) regarding severity of belching. Objective evaluation included MII-pHmetry at baseline and after CBT therapy. Parameters were number of SGB, the acid exposure time (AET), and proportion of AET associated to SGB

Results: 45 patients were recruited since March 2016. So far , 34 patients completed the protocol (median age: 45, range 20–72, 16 females) of which 28 had a second MII pH study. Subjective evaluation : VAS scores decreased after CBT in 30/31 patients [before: 260 (220–320) mm vs. after: 140(80–200) mm, p < 0.0001]. 15/31 patients had VAS score improvement >50%. Objective evaluation: Number of SGB decreased significantly after CBT in 25/28 patients [before: 89 (45–230) vs. after 42 (19–138), p < 0.0001]. 15/28 patients had reduction of SGB by more than 50%. Fifteen patients had increased AET pre-treatment, [AET: 9.3 (SEM 0.84). In these patients SGB contributed to 31% of the AET. Overall, AET after CBT was: 6.2 (SEM 0.95), p = 0.0056). In 8/15 patients with baseline increased AET, we observed after CBT a reduction of number of reflux episodes driven by SGB and AET (by 40%).

Conclusion: Cognitive behavioural therapy ameliorates supragastric belching. It reduces the number of belches and improves social and daily activities in 50% of patients. Careful analysis of MII-pHmetry allows identification of a subgroup of GERD patients with acid reflux predominantly driven by SGB. In these patients, CBT can reduce day-time esophageal acid exposure.

Disclosure of Interest: D. Sifrim: research grant Sandhill Sci (Denver USA)

All other authors have declared no conflicts of interest.

OP144 POST-REFLUX SWALLOW-INDUCED PERISTALTIC WAVE INDEX AND MEAN NOCTURNAL BASELINE IMPEDANCE PREDICT HEARTBURN RESPONSE TO PROTON PUMP INHIBITORS BETTER THAN ACID EXPOSURE TIME IN GERD

L. Frazzoni 1 , M. Della Coletta 2 , M. Frazzoni 3 , N. De Bortoli 4 , S. Tolone 5 , M. Furnari 6 , I. Martinucci 7 , S. Marchi 8 , R. Conigliaro 9 , L. Fuccio 10 , V. Savarino 11 , E. Savarino 12

1 Department Of Medical And Surgical Sciences, S. Orsola-Malpighi Hospital, Bologna/Italy

2 Division Of Gastroenterology, Department Of Surgery, Oncology And Gastroenterology, University of Padua, Padua/Italy

3 Digestive Pathophysiology Unit, Baggiovara Hospital, Modena/Italy

4 Division Of Gastroenterology, Department Of Internal Medicine, University of Pisa, Pisa/Italy

5 Surgery, Second University of Naples, Naples/Italy

6 Di.m.i., Gastroenterology Unit, DiMI, Gastroenterology Unit, University of Genoa., Genoa/Italy

7 Gastroenterology Unit, University of Pisa, Pisa/Italy

8 Dipartimento Di Medicina Interna - Università Degli Studi Di Pisa, Clinica Medica I/II Complesso S. Chiara, Pisa/Italy

9 Aou Modena, Gastroenterology and Digestive Endoscopy Unit, Modena/Italy

10 Deprtment Of Medical And Surgical Sciences, S. Orsola-Malpighi University Hospital, Bologna/Italy

11 Dept Internal Medecine, Universita di Genova, Genova/Italy

12 Department Of Surgery, Oncology And Gastroenterology, University of Padua, Padua/Italy

Contact E-mail Address: marcodellacoletta@gmail.com

Introduction: Traditionally, acid exposure time (AET) has been regarded as the most useful parameter to predict heartburn improvement with proton pump inhibitor (PPI) therapy. However, recent studies showed high rates of heartburn response to PPIs also in patients with normal AET. Two novel impedance parameters, namely the post-reflux swallow-induced peristaltic wave (PSPW) index and mean nocturnal baseline impedance (MNBI) were found useful in identifying GERD patients and distinguishing between reflux hypersensitivity and functional heartburn (FH). Therefore, they could prove useful in predicting PPI-induced heartburn relief.

Aims & Methods: We aimed to investigate demographic, endoscopic and impedance-pH features able to predict PPI response in patients with heartburn. Off-therapy impedance-pH tracings from 425 patients, 317 with definitely PPI-responsive heartburn (i.e. heartburn repeatedly abolished by 4-week PPI-therapy and repeatedly recurring after PPI withdrawal) and 108 with PPI-refractory (i.e. <50% of symptom relief after 8-week high-dosage PPI therapy), were blindly and manually re-analyzed. Baseline demographic and endoscopic characteristics, conventional impedance-pH variables including acid exposure time (AET) and number of reflux episodes, PSPW index and MNBI were assessed by means of multivariate logistic regression to identify independent predictors of PPI responsiveness. Models based on independent predictors were then developed and compared for the ability to predict symptom improvement by calculating the area under the curve (AUC) at receiver-operating-characteristic analysis. MNBI values were calculated at 3 cm above the LES, during the overnight rest, for at least 30 minutes after excluding swallows and reflux-induced changes. The PSPW index was calculated by dividing the number of refluxes followed within 30 seconds by swallow-induced peristaltic waves with the number of total refluxes.

Results: AET, MNBI and PSPW index were the only factors associated with PPI responsiveness: abnormal values were found in 60%, 76% and 92% of PPI-responsive cases (P < 0.017 for all pairwise comparisons). As shown in the Table, comparing AUCs, PSPW index (AUC 0.794, P = 0.002) and MNBI (AUC 0.741, P = 0.003), both separately and combined (AUC 0.810, P < 0.001), predicted PPI responsiveness better than AET (AUC 0.687). Table. Baseline characteristics associated with PPI responsiveness (multivariate logistic regression analysis)

Conclusion: AET, PSPW index and MNBI are independent predictors of heartburn responsiveness to PPIs. However, PSPW index and MNBI can link PPI-responsive heartburn to reflux better than AET and should become part of the standard analysis of impedance-pH tracings.

Disclosure of Interest: V. Savarino: Consulting fee from Malesci, Reckitt, AlfaWasserman, Abbvie

E. Savarino: Consulting fee from Medtronic, Sofar, Takeda, Abbvie, MSD

All other authors have declared no conflicts of interest.

TUESDAY, OCTOBER 31, 201708:30-10:00

TSTM FREE PAPER: CLINICAL IMPLICATIONS OF HOST MICROBIOTA INTERACTIONS - ROOM E4____________________

OP145 ANALYSIS OF 1792 GUT METAGENOMES REVEALS MICROBIAL TREATMENT TARGETS FOR INFLAMMATORY BOWEL DISEASE AND IRRITABLE BOWEL SYNDROME

A. Vich Vila 1 , F. Imhann 1 , V. Collij 1 , T. Gurry 2 , A. Kurilshikov 3 , S. Jankipersadsing 3 , Z. Mujagic 4 , M. Bonder 3 , X. Jiang 2 , L. Franke 3 , G. Dijkstra 5 , E.A.M. Festen 5 , J. Fu 3 , R. Xavier 2 , E. Alm 2 , C. Wijmenga 3 , D.M. Jonkers 6 , A. Zhernakova 3 , R.K. Weersma 1

1 Department Of Gastroenterology And Hepatology, University Medical Centre Groningen, Groningen/Netherlands

2 The Center For Microbiome Informatics And Therapeutics, Massachusetts Institute of Technology, Cambridge/United States of America

3 Department Of Genetics, University Medical Centre Groningen, Groningen/Netherlands

4 Division Of Gastroenterology-hepatology, Department Of Internal Medicine, Maastricht University Medical Center+, Maastricht/Netherlands

5 UMC Groningen Gastroenterology and Hepatology, Groningen/Netherlands

6 Department Of Internal Medicine, Division Of Gastroenterology-hepatology, Maastricht University Medical Center - Department of Internal Medicine, Division of Gastroenterology, Maastricht/Netherlands

Contact E-mail Address: a.vich.vila@umcg.nl

Introduction: Irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD) are two of the most common gastrointestinal disorders. The gut microbiome - the collection of microorganisms in the gut - presumably plays a large role in both diseases. Therefore, the microbiome holds great promise both as a diagnostic tool and as a target for treatment. However, thus far, functional studies have focused on single organisms whereas low resolution microbial profiles based on marker genes (16S rRNA) have not been able to sufficiently understand the complex microbial changes in both diseases.

Aims & Methods: In this study, we aim to bridge the gap between functional studies and 16S, by identifying complete species-, strain-level and functional gut microbiome profiles, using high-resolution shotgun metagenomic sequencing. We performed a large case-control study comprising stool samples of 1792 individuals: 355 IBD patients (comprising patients with Crohn's disease (CD) and ulcerative colitis (UC)), 421 IBS patients and 1025 population controls. Fecal DNA was isolated and sequenced using the Illumina HiSeq generating ∼3.0 Gb of data per sample. In addition, a large number of phenotypes was collected for all participants, including lifestyle information and disease characteristics. Taxonomy was determined for bacteria, viruses and micro-eukaryotes. In addition, bacterial strain diversity, bacterial growth rates, gene families', virulence factors and antibiotic resistence protein abundances were inferred from the sequencing data.

Results: Extensive multi-layer gut microbiome profiles were uncovered for both IBD and IBS (See Table 1). Interestingly, our results show a substantial overlap in microbial species alterations in patients with IBD and IBS compared to controls (83 taxa, FDR <0.1). The overlap included the decreased Faecalibacterium prauznitzii abundance in both IBD and IBS. In CD, not only the abundance, but also the strain diversity and the bacterial growth rate of Escherichia coli was increased. Interestingly, gut microbial characteristics were able to distinguish between IBD and IBS (AUC = 0.90), performing better than fecal calprotectin (AUC = 0.79). Bacterial virulence factors involved in mucosal damage (Mu toxin) and in iron uptake (enterobactins and yersinibactins) were increased in patients with IBD. In addition, antibiotic resistances proteins, especially efflux pumps, were increased in both diseases. Large alterations in the microbial metabolic functions indicated that in CD an L-arginine deficiency, which is involved in wound healing, and vitamin B2 depletion, which acts as an anti-oxidant, could be targets for intervention.

Conclusion: Using high-resolution microbial sequencing data of patients with IBD and patients with IBS, we identified microbial characteristics that can distuingish between these gastrointestinal diseases. Moreover, our comprehensive analysis identified several targets for microbial therapeutic trials.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP146 IDENTIFICATION OF A MICROBIOTA BENEFICIAL AGAINST COLITIS AND COLITIS-ASSOCIATED CANCER

E. Viennois , A. Pujada, A. T. Gewirtz, B. Chassaing, D. Merlin

Institute For Biomedical Sciences, Georgia State University, Atlanta/United States of America/GA

Contact E-mail Address: bchassaing@gsu.edu

Introduction: PepT1 is an apical transporter expressed on intestinal epithelial cell surfaces and is responsible for the uptake of a broad range of di/tri-peptides. Colonic PepT1 is over-expressed in patients with inflammatory bowel disease (IBD) and colorectal cancer. Increasing evidence shows that disruption of the symbiosis between the host and the gut microbiota may lead to pathologies such as IBD.

Aims & Methods: We aimed here to investigate the role played by the intestinal microbiota and its interaction with the host mucosa in mediating the protection against inflammation observed in PepT1-KO animals. Microbiota composition and localization were analyzed in PepT1-KO and WT mice. In order to investigate functional roles played by the microbiota, and in order to prevent any genotype-driven phenotypes, microbiota from PepT1-KO and matched WT animals were transferred to WT germ-free recipient mice, which were subsequently subjected to either DSS (acute colitis model) or AOM/DSS (colitis-associated cancer model) treatment.

Results: An altered microbiota composition was observed in PepT1-KO mice compared to WT animals, characterized by a modified abundance in several species and a decreased firmicutes/bacteroidetes ratio. Moreover, we observed an increased microbiota/epithelial mucosa distance in PepT1-KO mice compared to WT animals. Colitis or CAC were induced by DSS or AOM/DSS treatment, respectively, in former germfree mice that received microbiota from PepT1-KO and matched WT animals. We observed that PepT1-KO microbiota was sufficient to protect recipient animals from colitis and CAC compared to WT microbiota, as evidenced by morphological and molecular parameters (spleen weight, colon weight, colon length, MPO, fecal LCN-2, tumor count and tumor size). We also observed that mice receiving PepT1-KO microbiota exhibited reduced microbiota-associated pro-inflammatory potential (as shown by lower levels of bioactive lipopolysaccharide and flagellin) and a greater mucus production.

Conclusion: This study demonstrates that the microbiota from PepT1-KO is sufficient to protect against colitis and CAC. The ongoing analysis of WT and PepT1-KO microbiota metagenomes is supporting the hypothesis that some bacterial products in PepT1-KO lead to the protective phenotype observed in those animals, and we are currently deciphering the underlying mechanisms. Identifying microbiota members and/or mediators that drive such protection might suggest a therapeutic approach to treat IBD and CAC.

Disclosure of Interest: All authors have declared no conflicts of interest.

References

1. Merlin, D. et al. Colonic epithelial hPepT1 expression occurs in inflammatory bowel disease: transport of bacterial peptides influences expression of MHC class 1 molecules. Gastroenterology 120, 1666–1679, doi:S0016508501910054 [pii] (2001).

2. Dalmasso, G. et al. The PepT1-NOD2 signaling pathway aggravates induced colitis in mice. Gastroenterology 141, 1334–1345, doi:S0016-5085(11)00935-8 [pii] 10.1053/j.gastro.2011.06.080 (2011).

3. Ayyadurai, S., Charania, M. A., Xiao, B., Viennois, E. & Merlin, D. PepT1 expressed in immune cells has an important role in promoting the immune response during experimentally induced colitis. Laboratory investigation; a journal of technical methods and pathology 93, 888–899, doi:10.1038/labinvest.2013.77 (2013).

4. Viennois, E. et al. Micheliolide, a new sesquiterpene lactone that inhibits intestinal inflammation and colitis-associated cancer. Laboratory investigation; a journal of technical methods and pathology 94, 950–965, doi:10.1038/labinvest.2014.89 (2014).

OP147 PROTECTIVE ROLE OF ESCHERICHIA COLI NISSLE 1917 ON INTESTINAL PERMEABILITY IN IRRITABLE BOWEL SYNDROME: AN IN VITRO STUDY

D. Fuschi 1 , M.R. Barbaro 1 , P. Dino 2 , M. Carapelle 2 , E. Capelli 1 , C. Cremon 2 , V. Stanghellini 3 , G. Barbara 1

1 Department Of Medical And Surgical Sciences, University of Bologna, Bologna/Italy

2 University of Bologna, Bologna/Italy

3 Department Of Digestive System, University of Bologna Policlinico S. Orsola-Malpighi Internal Med. & Gastroenterology - Department of, Bologna/Italy

Contact E-mail Address: d.fuschi91@outlook.it

Introduction: Several gastrointestinal diseases, such as inflammatory bowel diseases and Irritable Bowel Syndrome (IBS), are characterized by epithelial barrier alterations which likely play a key role in the pathogenesis. In the absence of pharmacological interventions to restore intestinal permeability in IBS, an interesting perspective is represented by probiotics, live microorganisms widely used in clinical practice. Escherichia coli Nissle 1917 (EcN) is a probiotic already approved for the maintenance of remission of ulcerative colitis, although the underlying molecular mechanism remains to be clarified.

Aims & Methods: The aim of this study was to characterize the potential effect of EcN in reversing the increase of intestinal permeability caused by known stimuli and to evaluate the potential efficacy of EcN in IBS. We used an in vitro model of intestinal permeability based on CaCo-2 cells. Two concentrations of EcN (108 and 106) were applied to CaCo-2 to assess their effect on paracellular permeability. We also investigated the ability of EcN in the prevention of increased epithelial monolayer permeability induced by SLIGRL (a protease-activated receptor-2 activating peptide), tumor necrosis factor (TNF)-a and interferon (IFN)-g. Inflammatory mediators spontaneously released (SUP) by biopsies of patients with IBS and healthy controls (HC) were collected by the incubation of biopsies in a buffer for 25’ at 37°C in oxygenation followed by a centrifugation and supernatant collection. Paracellular permeability was evaluated using sulfonic-acid-conjugated to fluorescein (FITC). qPCR was used to assess mRNA expression of tight junction proteins, zonula occludens-1 (ZO-1) and occludin.

Results: EcN induced a dose-dependent reinforcement of CaCo-2 monolayer of 52% (108, P < 0.05) and 32% (106) compared to untreated CaCo-2 (CTR). TNF-a and IFN-g induced an increase in CaCo-2 permeability compared to CTR (4- and 1-fold respectively) reverted by EcN. SLIGRL 50uM and 200uM induced a significant increase in CaCo-2 permeability compared to CTR (P < 0.05); the co-incubation of SLIGRL and EcN induced a recovery of epithelial integrity of 77% and 63% for 108 and 106 respectively, compared to SLIGRL alone. EcN induced a significant increase in ZO-1 and occludin gene expression compared to CTR (P < 0.05). SUP of patients with IBS induced a significant increase of paracellular permeability compared to HC SUP (P < 0.05). The co-incubation of EcN with IBS SUP showed a recovery of permeability rate compared to mediators alone (P < 0.05). In particular, the incubation of EcN 108 with SUP of patients with IBS-D led to a significant recovery of barrier integrity (P < 0.05).

Conclusion: EcN is able to act on different tight junction proteins by reinforcing the integrity of the intestinal epithelial barrier. EcN reverts the increase of epithelial monolayer permeability induced by inflammatory stimuli and mediators spontaneously released by IBS biopsies. Further study should look at EcN potential application in IBS.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP148 IS THE MICROBIOME IMPLICATED IN THE DEVELOPMENT OF GENUINE IRRITABLE BOWEL SYNDROME-TYPE SYMPTOMS IN INFLAMMATORY BOWEL DISEASE?

D.J. Gracie 1 , O. Shutkever 2 , C. Young 2 , H. Wood 2 , M. Taylor 2 , P. J. Hamlin 3 , A.C. Ford 3 , P. Quirke 2

1 St. James's University Hospital, Leeds Gastroenterology Institute, Leeds/United Kingdom

2 Licap, University of Leeds, Leeds/United Kingdom

3 Leeds Gastroenterology Institute, St. James's University Hospital, Leeds/United Kingdom

Contact E-mail Address: djgracie1982@doctors.org.uk

Introduction: Irritable bowel syndrome (IBS)-type symptoms affect 35% of patients with clinically quiescent inflammatory bowel disease (IBD). (1) The presence of these symptoms is associated with anxiety, depression, somatisation and reduced quality of life, (2) but their effect on disease outcomes remains uncertain. Alterations in the intestinal microbiome are implicated in pathogenesis of IBS and IBD, yet whether intestinal dysbiosis is also associated with the development of genuine IBS-type symptoms in quiescent IBD remains uncertain.

Aims & Methods: We aimed to assess the microbiome in 270 consecutive IBD patients who, using a combination of clinical disease activity indices, the Rome III criteria for IBS and faecal calprotectin (FC) (using a cut-off of 250ug/g to define active mucosal inflammation), were divided into four groups as follows: True IBS, quiescent disease, occult inflammation, active disease. Baseline demographic, disease-related and psychological variables were compared between those with true IBS-type symptoms and the other three groups individually using a chi-squared test for categorical variables and an independent samples t-test for continuous variables. Due to multiple comparisons, a P value of <0.01 was considered statistically significant. Microbial DNA was extracted and analysed with next-generation sequencing of the V4 region of the 16S rRNA gene, on an Illumina MiSeq. Sequence reads were clustered into operational taxonomic units, which were then assigned genus-level taxonomy. The relative abundance of different taxa, as well as alpha (within-sample) and beta (between-sample) diversity was analysed using the Quantitative Insights Into Microbial Ecology (QIIME) package.

Results: Baseline demographic, disease related and psychological data are described in Table 1.

Conclusion: The lack of marked alterations in the microbiome observed across the four subgroups of patients included in our analyses suggests that the microbiome is not implicated in the development of IBS-type symptoms in patients with IBD. In addition, no microbiome changes were observed in the subgroups of IBD patients where anxiety or depression was most commonly observed, despite evidence suggesting a link between the gastrointestinal microbiome and psychological health. (3) Despite these negative findings, the presence of microbiome alterations in CD patients highlights the potential for manipulation of the microbiome as a target for therapeutic trials of novel Crohn's-related pharmacotherapies in the future. It is possible that the overall lack of microbiome differences observed may have been secondary to several potential medication and lifestyle related confounding variables that are unaccounted for. These include diet, the effect of smoking, particularly in CD, and the effect of regular medications. Future studies should investigate the relationship between the intestinal microbiome, its associated metabolome and the presence of IBS-type symptoms in IBD, rather than the microbiome in isolation.

Disclosure of Interest: All authors have declared no conflicts of interest.

References

1. Halpin S and Ford AC. Am J Gastroenterol . 2012;107(10):1474–82.

2. Gracie DJ et al. Clin Gastroenterol Hepatol . 2017;15(3):376–384.

3. Fung TC et al. Nat Neurosci . 2017;20(2):145–155.

OP149 THE COMPLEMENT SYSTEM AS A REGULATOR OF THE HOST-MICROBIOTA RELATIONSHIP IN IBD

S. J. Reider 1 , W. Posch 2 , A. Pfister 1 , R. Koch 1 , D. Orth-Höller 2 , R. Würzner 2 , D. Wilflingseder 2 , H. Tilg 1 , A.R. Moschen 1

1 Department Of Internal Medicine I, Medical University Innsbruck, Innsbruck/Austria

2 Division Of Hygiene And Medical Microbiology, Medical University Innsbruck, Innsbruck/Austria

Contact E-mail Address: simon.reider@i-med.ac.at

Introduction: The complement system is the major humoral component of innate immunity. Despite its key role in sensing microbial surfaces, its impact on the equilibrium at the interface of gut immune system and microbiota in health and inflammation remains elusive. Recently, Complement protein C4 was implied in the pathogenesis of Crohn’s disease by a genome wide association study.

Aims & Methods: Thus, we performed a study to delineate the impact of the complement system on (i) the relationship of host and microbiota and (ii) the properties of the mucosal immune response in health and inflammation: The extent of complement opsonization of the microbiota was quantified by flow cytometry (FC): Bacteria were isolated from stool of IBD patients, stained for immunoglobulin A (IgA) and C3b/c and classified as double negative, double positive or single positive. The share of events in each of these populations was correlated with the level of inflammation, clinical disease activity, and therapeutic strategies employed. The 4 populations were sorted via fluorescence-assisted cell sorting (FACS) and metagenomic analysis of these bacterial fractions was performed. Expression of complement proteins in the intestine was analyzed by quantitative polymerase chain reaction (qPCR) of mRNA isolates from colonic and ileal biopsies. The target set involved soluble complement proteins as well as receptors and regulatory molecules. Expression was compared between IBD patients and controls undergoing routine colonoscopy. A cell culture-based model was established to investigate complement opsonization in the intracellular handling of pathogens: HeLa cells were infected with GFP-tagged Salmonella typhimurium (opsonized and non-opsonized) and intracellular growth was quantified over time by culture, confocal laser scanning microscopy and flow cytometry.

Results: Complement proteins were markedly overexpressed in ileal and colonic biopsies in active disease. However, this was not true for all targets and the observed change differed between genes. Mucosal expressions were different from the luminal environment: While most complement components were detectable in biopsies at the mRNA level, only certain complement proteins could be identified in stool. Importantly, this included C3, but not the terminal complement complex. The extent of C3b coating of bacterial surfaces correlated significantly with the level of inflammation signified by fecal calprotectin (p = 0.003). The proportion of complement opsonized bacteria ranged from 0 % to 4 % and did not correlate with intestinal inflammation. This was also different from IgA opsonization which correlated positively with the grade of inflammation. Employing FACS and 16S-based metagenomics, we were able to identify specific microbial species within the respective sorting groups (IgA/C3c double-positive, double-negative, and single-positive fractions) which showed some association with inflammation and specific disease. The cell culture experiments showed a significant difference in intracellular Salmonella loads after 6 and 24 hours (p = 0.019), which was independent of bacterial uptake by the cells or non-specific binding.

Conclusion: The complement system represents a relevant player in human IBD. We show that the complement system has some specificity for commensal bacteria distinct from IgA both in the steady state and during intestinal inflammation. Moreover, we show that complement opsonization optimizes the clearance of intracellular bacteria by epithelial cells.

Disclosure of Interest: All authors have declared no conflicts of interest.

References

Cleynen I, Konings P, Robberecht C, Laukens D, Amininejad L, Theatre E, et al. Genome-Wide Copy Number Variation Scan Identifies Complement Component C4 as Novel Susceptibility Gene for Crohn's Disease. Inflamm Bowel Dis . 2016; 22(3):505–15.

Jain U, Otley AR, van Limbergen J, Stadnyk AW. The complement system in inflammatory bowel disease. Inflamm Bowel Dis . 2014; 20(9):1628–37.

Palm NW, Zoete MRd, Cullen TW, Barry NA, Stefanowski J, Hao L, et al. Immunoglobulin A coating identifies colitogenic bacteria in inflammatory bowel disease. Cell . 2014; 158(5):1000–10.

OP150 METABONOMIC AND MICROBIOTA PROFILE OF CROHN'S PATIENTS IS A PREDICTOR OF PRIMARY NON-RESPONSE TO ANTI-TNF THERAPY

N. Ding 1 , M. Sarafian 2 , A. Perdones-Montero 2 , R. Misra 3 , P. Hendy 4 , L. Penez 3 , E. Holmes 5 , A. Hart 6

1 Medicine, University of Melbourne, Melbourne/Australia/VIC

2 Centre For Computational And Systems Medicine, Imperial College, London/United Kingdom

3 Gastroenterology, St. Marks Hospital, London/United Kingdom

4 IBD Unit, St. Mark's Hospital, Harrow/United Kingdom

5 Division Of Computational And Systems Medicine, Department Of Surgery And Cancer, Imperial College London, London/United Kingdom

6 Gastroenterology, St Mark’s Hospital and Academic Institue, London/United Kingdom

Contact E-mail Address: dingnik@gmail.com

Introduction: Biological therapy with anti-TNF blockade forms the backbone for treatment in moderate to severe Crohn’s disease (CD). Metabonomic approaches to profiling Crohn’s disease has led to numerous discoveries in disease pathogenesis and is an important in elucidating pathways responsible for interactions between human microbiota and host.

Aims & Methods: The aim of our longitudinal study was to identify predictive biomarkers of response to anti-TNF therapy using metabonomic and microbiome profiling. Moderate to severe CD patients with luminal disease commencing anti-TNF therapy had 3-monthly visits for 12 months with collection of biofluids (urine, faeces and serum) and disease assessment performed at each visit. Assessment of response was with biochemistry and faecal calprotectin or mucosal healing. A response index combining biochemistry (50% decrease in FC or CRP) and mucosal healing within 14 weeks was used to define therapeutic response in the presence of adequate drug level. We collected 179 urine, 210 serum and 168 faecal samples from 68 anti-TNF naive CD patients (luminal phenotype undergoing anti-TNF therapy without surgical resections) and 20 healthy controls. Liquid-Chromotography Mass Spectroscopy using Waters® instruments with lipid, bile acid (BA) and polar molecule (HILIC) profiling of metabolites and multivariate analysis compared to response index on SIMCA software was undertaken. 16SrRNA extraction using Powerlyzerkit®, sequencing with MiseQ illumina® and processing using Mothur was performed.

Results: There were 18 non-responders and 9 responders to anti-TNF therapy according to our strict criteria for response. Multiple biomarkers were identified across assays to be significant for predicting anti-TNF response to therapy across all visits (Table 1). The strongest models were from serum bile acid (R2X0.29, Q2Y0.41, p = 4.97 × 10 −7 ) and urinary HILIC (R2X0.14, Q2Y0.30, p = 1.28 × 10 −4 ). Serum BA profiling analysis identified 2 conjugated and 1 unconjugated BAs, while urinary HILIC profiling identified cysteine as biomarkers creating a model allowing prediction of anti-TNF response, with levels being significantly different between non-responders and responders. On 16SrRNA, comparison between HC and CD demonstrated that there were 21 OTU (operational taxonomic units) which were different including eschericia, streptococcus and bacteroides. Faecalibacterium was lower in the CD cohort while bacteroides was increased prior to anti-TNF therapy. Lactobacillis is higher in responders while clostridiales were lower in abundance for non-responders after bonferroni correction. Lactobacilles is known to synthesise cysteine from serine and for expansion in gut microbiota. Faecalibacterium and ruminococcus increased over time in responders to anti-TNF therapy. However, the overall quantities of species did not alter significantly over time nor with therapy.

Conclusion: The metabonomic approach is an important tool in demonstrating the chemical profile of alterations in human microbiota resulting from inflammatory bowel disease and therefore the interaction that occurs between the microbiome and host. This prospective, longitudinal cohort study of microbiome and metabonomic analysis demonstrates that there are predictive biomarkers involved with bile acid and inflammatory pathways. The microbiome of patients with Crohn’s disease does not alter significantly despite anti-TNF therapy response which allows for prediction of therapeutic outcome.

Disclosure of Interest: All authors have declared no conflicts of interest.

TUESDAY, OCTOBER 31, 201708:30–10:00

THE MICROBIOME AND IBD - ROOM 7.1____________________

OP152 PANETH CELLS DYSFUNCTION AND DEATH IS DIRECTLY LINKED TO IFN-LAMBDA SIGNALING

C. Günther 1 , B. Buchen 2 , H. Neumann 3 , S. Wirtz 1 , M. F. Neurath 4 , C. Becker 1

1 Medical Department, Universtity Hospital Erlangen, Erlangen/Germany

2 University Hospital Erlangen, Erlangen/Germany

3 Universitätsmedizin Johannes Gutenberg University Mainz, Mainz/Germany

4 Department Of Medicine, University Hospital of Erlangen, Erlangen/Germany

Contact E-mail Address: c.guenther@uk-erlangen.de

Introduction: The abundance of trillions of beneficial commensal microorganisms that reside in the gastrointestinal tract together with cells of the gut-associated immune system requires an effective barrier in order to preserve tissue homeostasis. There is overwhelming evidence corroborating the notion that the pathogenesis of Crohn's disease, an idiopathic inflammatory bowel disease, is characterized by an exaggerated immune reaction presumably directed against commensal enteric bacteria in a genetically susceptible host. While lymphocyte-derived type II IFN (IFN-gamma) has been implicated in the pathogenesis of Crohn´s disease, the impact of IFN-lambda (type III IFN) on small intestinal inflammation remains unknown.

Aims & Methods: The central aim of this project was the question if and by which pathways type III IFNs (in particular IL28, a member of this IFN family) contribute to intestinal inflammation in mice and men. In the long run, we aim to decipher novel functions of type III IFNs on mucosal cells that could be targeted for future therapeutic intervention.

Results: Here we discovered that IL28 (belonging to the type III IFN family) is strongly upregulated in the terminal ileum of human Crohn´s disease (CD) patients and in murine models of ileitis. Remarkably, IL28 immunostaining was particularly enhanced in intestinal epithelial cells in areas of severe inflammation accompanied by a reduced number of Paneth cells. These data strongly implicate that IL28 expression is linked to disease activity in CD. In line with our hypothesis, we identified that IL28 promotes massive epithelial cell death and loss of immune homeostasis in mice with an epithelial cell specific deletion of a central apoptosis mediator caspase-8 (Casp8ΔIEC). While these mice are genetically sensitized to epithelial cell death, we further uncovered that IL28 overexpression in wildtype animals resulted in a nearly complete depletion of Paneth cells. These data demonstrate that IL28 signaling affects Paneth cell homeostasis and thus antimicrobial defense. Notably, this effect was independent of type I and type II IFN signaling and directly mediated by STAT1 activation in intestinal epithelial cells. Moreover, we provide compelling evidence that Paneth cell death was dependent on MLKL, a master regulator of regulated necrosis and caspase-8 as a central regulator of cell death. Using the small intestinal organoid model we further uncovered that IL28 signaling affects the expression of tight-junction molecules suggesting an impact of this cytokine on intestinal barrier function.

Conclusion: In summary, our results strongly implicate a pathophysiological role for IFN-l during small intestinal inflammation by controlling Paneth cell homeostasis and barrier function and hence the rational for the investigation of this pathway in other inflammatory or infectious bowel diseases.

Disclosure of Interest: All authors have declared no conflicts of interest.

References

Günther C, Martini E, Wittkopf N, Amann K, Weigmann B, Neumann H, Waldner MJ, Hedrick SM, Tenzer S, Neurath MF, Becker C. Caspase-8 regulates TNF-alpha-induced epithelial necroptosis and terminal ileitis. Nature 2011, 477:335–339.

Günther C, Buchen B, He G, Hornef M, Torow N, Neumann H, Wittkopf N, Martini E, Basic M, Bleich A, Watson AJ, Neurath MF, Becker C. Caspase-8 controls the gut response to microbial challenges by TNFalpha -dependent and -independent pathways. Gut 2015, 64(4):601–610.

Wittkopf N*, Günther C*, Martini E, He G, Amann K, He YW, Schuchmann M, Neurath MF, Becker C. Cellular FLICE-Like Inhibitory Protein Secures Intestinal Epithelial Cell Survival and Immune Homeostasis by Regulating Caspase-8. Gastroenterology 2013, 145:1369–1379.

*shared first authorship Günther C , Gui-Wei H, Kremer AE, Murphy JM, Petrie EJ, Amann K, Vandenabeele P, Linkermann A, Probemba C, Schleicher U, Dewitz C, Krautwald S, Neurath MF, Becker C*, Wirtz S*. The pseudokinase MLKL mediates programmed hepatocellular necrosis independent of RIPK3 during hepatitis. J Clin Invest 2016, 126(11):4346–4360.

*shared senior authorship

OP153 THE STIMULATION OF MACROPHAGES WITH MICROBIAL-DERIVED COMPOUNDS SUPPORTS INCREASED IL-19 EXPRESSION IN PATIENTS WITH INFLAMMATORY BOWEL DISEASE AND COLITIS MODELS

A. Steinert 1 , I. Linas 2 , P. Hruz 1 , M. Ibrahim 3 , K. Radulovic 1 , A. Schlitzer 3 , L. Terracciano 4 , A. Macpherson 2 , J.H. Niess 1

1 Department Of Gastroenterology And Hepatology, Department Of Biomedicine, University of Basel, Basel/Switzerland

2 Maurice Müller Laboratories (dkf), Universitätsklinik Für Viszerale Chirurgie Und Medizi, University of Bern, Bern/Switzerland

3 Department Of Genomics And Immunoregulation, University of Bonn, Bonn/Germany

4 Institute Of Pathology, University of Basel, Basel/Switzerland

Contact E-mail Address: janhendrik.niess@usb.ch

Introduction: Interleukin (IL)-19, a member of the IL-10 cytokine family, that signals through the IL-20 receptor type I (IL-20Rα: IL-20Rβ) is a cytokine with rather unknown function. Although the expression of the type I IL-20 receptor in the colon is low compared to the IL-22 receptor (1, 2), some studies have suggested a role of IL-19 for IBD (3).

Aims & Methods: To investigate the significance of IL-19 for the development of colitis biopsies of patients with Crohn’s disease (CD) and ulcerative colitis (UC) were received from the Swiss IBD cohort study (SIBD project 2015–05). The importance of IL-19 for colitis was further studied with a newly generated Il19-tdTomato knockin mouse line.

Results: The expression of IL-19 is increased in biopsies from UC patients but not CD patients with active disease as compared to quiescent disease, whereas the expression of the type I IL-20 receptor is not significantly changed in IBD patients with active disease. In mice, Dextran Sodium Sulfate (DSS) colitis induced the expression of IL-19 and IL-20Rα in the colonic lamina propria but not epithelial cells in contrast to the IL-22 receptor, whose expression is restricted to epithelial cells. As consequence, the development of DSS colitis is attenuated in IL-19-deficient animals. Because germ-free animals succumb within a few days after exposure to DSS, we applied DSS to animals with a simplified oligo-mouse microbiota with 12 bacterial species (Oligo-MM 12 ) to test whether the pressure of a complex microbial flora is required for IL-19 expression. Although Oligo-MM 12 animals developed a severe DSS colitis, the expression of IL-19 was not induced in Oligo-MM 12 mice after exposure to DSS. Furthermore, direct activation of macrophages by CD40 ligation caused colitis, but did not induce IL-19 expression indicating that a barrier breach allowing the access of bacterial-derived products as observed in the DSS model is required for the expression of IL-19 during colitis. The stimulation of macrophages with the Toll-like receptors (TLR) ligands and injection of Lipopolysacharide (LPS) into mice confirmed in vitro and in vivo that microbial-derived compounds induced IL-19 expression, which depends on Myd88, because TLR −2, −4 and −9 ligands but not the TLR3 ligand poly (I:C) induced the expression of IL-19. Colonic macrophages but not dendritic cells were identified as a source of IL-19 in Il19-tdTomato reporter animals, which was further confirmed in vitro since M-CSF but not GM-CSF or Flt3L-differentiated bone marrow cells expressed IL-19. Unsupervised analysis of the transcriptome of IL-19 positive versus negative macrophages revealed that 1711 transcripts were downregulated and 1254 transcripts were up-regulated in IL-19 positive macrophages. The genetic and protein interactions extracted from transcripts that were >4-fold downregulated in IL-19/tdTomato positive cells included collagens and interactomes involved in cell adhesion and migration, cell motility and cell-extracellular matrix interactions. We could not detect the expression of IL-20Rα by bone marrow-derived macrophages (BMDMs), and IL-19 treatment did not activate the STAT3 pathway and did not regulate Il6 and Tnfα expression, suggesting that BMDMs did not express a functional type I IL-20 receptor. Attenuated colitis in IL-19-deficient animals was associated with reduced numbers of monocytes and macrophages in the inflamed lamina propria that produced reduced amounts of IL-6.

Conclusion: Microbial-derived products that have entered the host after intestinal barrier breach induce IL-19 expression by macrophages supporting the development of colitis. Although we did not observe an effect of IL-19 on signaling of BMDMs, IL-19 may have direct effects on intestinal macrophages, as we observed IL-20Rα in the lamina propria of humans and mice, and reduced IL-6 production by colonic macrophages of IL-19 deficient mice with colitis. The deletion of individual members of the IL-20 cytokine family and individual receptor chains is needed to further dissect the importance of this cytokine family for IBD.

Disclosure of Interest: All authors have declared no conflicts of interest.

References

1. Zenewicz LA et al. Immunity . 2008; 29(6):947–57

2. Zheng Y et al. Nat Med . 2008; 14(3):282–9

3. Yamamoto-Furusho JK et al. Hum Immunol . 2011; 72(11):1029–32

OP154 CD1D MODULATES COLONIC INFLAMMATION IN NOD2 −/− MICE BY ALTERING THE COMPOSITION OF INTESTINAL MICROBIOTA

S. Hong , C. Lee, Y. Kim

Gastroenterolgy, Samsung Medical Center, Seoul/Korea, Republic of

Contact E-mail Address: gisnhong@gmail.com

Introduction: NOD2 mutations are associated with the development of inflammatory bowel diseases. However most animal studies have reported no impact of NOD2 deficiency on experimental colitis. NOD2 deficiency only is insufficient for development of IBD and an additional hit is needed. Like NOD2, the deficiency of CD1d, non-classical MHC class I molecule, showed no impact on experimental colitis. Therefore, we tried to evaluate the effect of CD1d modulation on experimental colitis in NOD2 −/− mice.

Aims & Methods: In NOD2 −/− mice, the effect of CD1d ligand, α-GalCer, was evaluated on DSS-induced colitis. To evaluate the effect of the depletion of CD1d in NOD2 −/− mice, NOD2 −/− CD1d −/− mice were established. The colonic inflammation of NOD2 −/− CD1d −/− mice was assessed after exposure to dextran sodium sulfate (DSS) relative comparing NOD2 −/− , CD1d −/− , and wild-type mice. Furthermore, the change in intestinal microbiota and alteration in the function of Paneth cells degranulation in NOD2 −/− CD1d −/− mice was assessed.

Results: CD1d ligand, α-GalCer, alleviates body weight loss and histologic index in NOD2 −/− mice compared to those of littermate cohousing wild-type mice during DSS-induced colitis ( p <0.001 and p =0.029, respectively). NOD2 −/− CD1d −/− mice exhibit aggravated body weight loss and histologic index with DSS-induced colitis in NOD2 −/− mice compared to those of littermate cohousing NOD2 −/− , CD1d −/− , and wild-type mice during DSS-induced colitis ( p <0.001 and p= 0.019, respectively). The intestinal microbial composition of NOD2 −/− CD1d −/− mice was different (decreased relative abundance of Bacteroidetes and increased relative abundance of Firmicutes ). Paneth cell degranulation was decreased in NOD2 −/− CD1d −/− mice compared to those of littermate cohousing NOD2 −/− , CD1d −/− , and wild-type mice after pilocarpine administration ( p < 0.001).

Conclusion: The CD1d in NOD2 −/− mice modulates colonic inflammation by altering the composition of the intestinal microbiota, which may be caused by Paneth cell dysfunction.

Disclosure of Interest: All authors have declared no conflicts of interest.

References

1. DeGruttola AK, Low D, Mizoguchi A, et al. Current Understanding of Dysbiosis in Disease in Human and Animal Models. Inflamm Bowel Dis 2016; 22:1137–50.

2. Zhang Q, Pan Y, Yan R, et al. Commensal bacteria direct selective cargo sorting to promote symbiosis. Nat Immunol 2015; 16:918–26.

3. Hu C, Sun L, Hu Y, et al. Functional characterization of the NF-kappaB binding site in the human NOD2 promoter. Cell Mol Immunol 2010; 7:288–95.

4. Thachil E, Hugot JP, Arbeille B, et al. Abnormal activation of autophagy-induced crinophagy in Paneth cells from patients with Crohn's disease. Gastroenterology 2012; 142:1097–1099.e4.

5. Philpott DJ, Sorbara MT, Robertson SJ, et al. NOD proteins: regulators of inflammation in health and disease. Nat Rev Immunol 2014; 14:9–23.

OP155 ADAPTATION OF ADHERENT-INVASIVE E. COLI TO GUT ENVIRONMENT: IMPACT ON FLAGELLA EXPRESSION AND BACTERIAL VIRULENCE

G. Sevrin 1 , S. Massier 1 , B. Chassaing 2 , A. Agus 1 , J. Denizot 1 , J. Delmas 1 , E. Billard 1 , N. Barnich 1

1 M2iSH, UMR INSERM U1071/Université Clermont Auvergne, Clermont Ferrand/France

2 Institute For Biomedical Sciences, Georgia State University, Atlanta/United States of America

Contact E-mail Address: gwladys.sevrin@uca.fr

Introduction: Adherent-Invasive Escherichia coli strains (AIEC) isolated from ileal lesions of Crohn’s disease patients are flagellated bacteria able to invade intestinal epithelial cells and to survive within macrophages. Flagellin (FliC), major bacterial flagellum protein, is recognized by innate immune receptors leading to pro-inflammatory cytokines release, but is also required for motility.

Aims & Methods: In this study, we aim at deciphering the modulation of flagellin expression by environmental gut conditions in AIEC bacteria compared to commensal E. coli in order to better understand mechanisms of AIEC mucosa colonization and in vivo persistence. The flagellin promoter was cloned into pRS550 β-galactosidase reporter plasmid to assess fliC transcription level. AIEC LF82 and commensal E. coli HS strains, transformed with the construct, were cultured in presence of bile acids or were incubated with mucin-hyperproducing cells (HT29-MTX). Germ-free and transgenic mouse model expressing human CEACAM6 (CEABAC10) were used in this study. Bacterial persistence in the colonic mucosa of mice, treated or not with dextran sodium sulfate (DSS) used to disrupt mucus layer, was measured after infection by AIEC wild-type (WT) LF82, LF82-Δ fliC and LF82-Δ flgM mutants, as well as E. coli HS.

Results: In the presence of bile acids, we observed an increase of fliC transcription level in AIEC LF82 and commensal HS E. coli . In contrast, the presence of mucins from HT29-MTX cells only promoted activation of fliC transcription for AIEC bacteria, but not for commensal strain. This indicates that flagella expression for AIEC bacteria is enhanced by gut conditions, conferring a selective advantage to cross the mucus layer and reach epithelial surface. Use of germ-free mice monocolonized with AIEC LF82, LF82-Δ fliC or commensal HS E. coli confirmed that only AIEC LF82 is able to reach intestinal epithelial cells surface by a mechanism dependent on flagella expression. Moreover, at 4 days post-infection, AIEC-Δ fliC significantly better colonized colonic tissue of CEABAC10 mice treated with DSS than WT strain. However, when the mucus layer was not altered by DSS treatment, the higher persistence of AIEC-Δ fliC was no longer observed, highlighting the importance of flagella to cross intact mucus layer. Nevertheless, overexpression of flagellin in the contact of epithelial cells can be detrimental for AIEC virulence by inducing acute inflammation enhancing bacterial clearance. Indeed, we observed that LF82-Δ flgM oversecreting flagellin, compared to WT AIEC LF82, triggers a higher inflammation in vivo and in vitro , leading to a lower ability in vivo to colonize and to persiste in colonic mucosa.

Conclusion: AIEC bacteria have developed specific virulence gene regulation to improve adaptability and flexibility within the gut environment compared to commensal E. coli . In particular, flagella expression should be finely regulated for optimal virulence of AIEC pathobionts to efficiently colonize gut ecosystem. A better understanding of the pathogenicity mechanisms of AIEC strains will help to develop specific inhibitors interfering with bacteria/cell interaction.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP156 IL-10-INDEPENDENT PROTECTIVE ACTIVITIES OF HUMAN-DERIVED CLOSTRIDIUM STRAINS IN EXPERIMENTAL COLITIS

A. Oka 1 , Y. Mishima 2 , G. Bongers 3 , A. Baltus 3 , J. Herzog 1 , B. Liu 1 , S. Fukuda 4 , K. Atarashi 5 , K. Honda 6 , D. Marshall 3 , M. Hasse 3 , L. San 3 , R. B. Sartor 1

1 Cgibd, University of North Carolina at Chapel Hill, Chapel Hill/United States of America/NC

2 Internal Medicine II, Shimane University Faculty of Medicine, Izumo/Japan

3 Janssen Research & Development, Spring House/United States of America

4 Institute for Advanced Biosciences, Keio University, Tsuruoka/Japan

5 RIKEN Center for Integrative Medical Sciences, Yokohama/Japan

6 Department Of Microbiology And Immunology, Keio University School of Medicine, Shinanomachi/Japan

Contact E-mail Address: akihiko_oka@med.unc.edu

Introduction: Previous studies show that murine- and human-derived Clostridium strains, which are decreased in active human inflammatory bowel diseases (IBD), induce colonic TGFb and IL-10-producing Foxp3 + regulatory T cells (Tregs) and attenuate experimental colitis in murine models (Atarashi K, …, Honda K, Science 2011 and Nature 2013). However, additional protective effects of these commensal intestinal bacterial species independent of IL-10 are unknown.

Aims & Methods: To investigate IL-10-independent effects of the Clostridium strains, we treated Il10 −/− mice, which develop T cell-mediated chronic colitis, with 17 human Clostridium strains obtained from Dr. Honda and analyzed the degree of colitis and microbiota, metabolomic and immunological profiles. To establish a “humanized” colitis model, we colonized germ-free (GF) Il10 −/− mice with either a mixture of three aggressive human bacteria species ( Escherichia coli LF82, Enterococcus faecalis and Ruminococcus gnavus , EER) or feces from a normal human. We treated these EER- and human feces-induced colitis models with the mixture of human-derived 17 Clostridia before or 2 weeks after bacterial colonization. The severity of colitis was examined by blinded histological scores, as well as expression of IFNγ, IL-12p40 and IL-17 in colonic tissues. Flow cytometry analysis of Foxp3 and several cell surface markers was performed using lamina propria cells, mesenteric lymph node cells and splenocytes. The 16S ribosomal RNA (rRNA- by Illumina MiSeq and selective qPCR) and metabolomic profiles in fecal or cecal contents were analyzed.

Results: The EER- and human feces-colonized exGF Il10 −/− mice developed progressive colitis with increased Th1/Th17 responses, but the 17 Clostridia alone did not induce colitis. Clostridia treatment significantly attenuated histological scores and inflammatory cytokines (IFNγ, IL-12p40 and IL-17) (Table) and induced Foxp3 + cells in the colon lamina propria. Analysis of fecal 16S rRNA sequencing in human feces-colonized mice demonstrated significant reduction of luminal Fusobacterium species and E. coli in the Clostridia-treated preventive and delayed treatment groups compared to the untreated group, confirmed by qPCR. Metabolomic analysis showed that Clostridia treatment significantly reduced histamine and histidine decarboxylase, a key enzyme converting histidine to histamine, in colon tissues and fecal histamine levels compared to non-treated groups (Table).

Conclusion: Our findings suggest novel IL-10-independent protective mechanisms for a panel of human Clostridium strains that include correcting dysbiosis, reducing levels of Fusobacterium species and E. coli , and normalizing histamine metabolism. In addition, these results provide insights into the pathogenesis of IBD and provide a foundation and target for therapeutic use of carefully selected resident protective bacterial cocktails in IBD patients.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP157 FAECAL MICROBIOTA IN PAEDIATRIC INFLAMMATORY BOWEL DISEASE BEFORE AND AFTER THERAPY

C. Olbjørn 1 , M. C. Småstuen 2 , E. Thiis-Evensen 3 , B. Nakstad 4 , C. Casén 5 , M.H. Vatn 6 , G. Perminow 7

1 Institute Of Clinical Medicine, University of Oslo, Campus Ahus, Oslo/Norway

2 Faculty Of Health Sciences, Oslo and Akershus University College of Applied Sciences, Oslo/Norway

3 Department Of Gastroenterology, Rikshospitalet, Oslo University Hospital, Oslo/Norway

4 Pediatric And Adolescent Medicine, Akershus University Hospital, Lørenskog/Norway

5 Dept. Of Genetics, Genetic Analysis AS, Oslo/Norway

6 Epigen, Faculty Divison Ahus, Institute Of Clinical Medicine, University of Oslo, Oslo/Norway

7 Department Of Pediatrics, Ullevål, Oslo University Hospital, Oslo/Norway

Contact E-mail Address: chrisolb@gmail.com

Introduction: Imbalances in the faecal microbiota with a reduction in biodiversity; dysbiosis, have been reported in inflammatory bowel disease (IBD).

Aims & Methods: Our aim was to study and compare the faecal microbiota in paediatric patients with newly diagnosed untreated IBD with the microbiota of healthy children and paediatric patients with gastrointestinal symptoms but no IBD. We also wanted to study microbiota changes in IBD patients one year after initiation of treatment. Faecal samples were collected from 235 children below 18 years of age. IBD was diagnosed in 110 patients, 80 had Crohn’s disease (CD), 27 had ulcerative colitis (UC) and 3 had IBD unclassified. Fifty patients had gastrointestinal symptoms but no IBD; non-IBD symptomatic patients, and 75 were healthy children. Of the IBD patients, 31 (9 with UC and 22 with CD) had repeated faecal analysis one year after therapy, 16 (52%) had been treated with infliximab. The microbiota was analysed at baseline and follow-up using a 16s rRNA DNA based test with the GA-map technology, measuring probe signal intensity (PSI) of 54 DNA probes targeting 300 bacteria on different taxonomic levels.

Results: At baseline the majority of bacterial PSIs were reduced in IBD and non-IBD patients (both p < 0.001) compared to healthy controls. IBD patients had significantly reduced abundance of various Firmicutes p < 0.01 ( Eubacterium rectale, Eubacterium biforme ), Bacteroidetes p = 0.02 ( Parabacteroidetes) , and of Bifidobacterium p = 0.02, compared to non-IBD patients. In the 31 IBD patients with repeated faecal samples the microbiota was more dysbiotic after therapy, regardless of IBD type and whether the IBD patient had received infliximab or not, with less abundance of the Clostridia species Dorea spp., Lachnospiraceae and Eubacterium hallii (p < 0.001). Compared to healthy and non-IBD patients the microbiota composition after treatment had significantly (p < 0.001) less abundance of Akkermansia muciniphila, Bacteroides spp., Prevotella spp. and Veillonella spp. besides higher abundance of Streptococcus sanguinis, Atopobium rimae and pro-inflammatory Proteobacteria (Shigella spp., Escherichia spp.)

Conclusion: The faecal microbiota composition is significantly different in paediatric IBD and non-IBD symptomatic patients compared to healthy children and may be of value in diagnosing IBD. A severe dysbiotic microbiota profile seem to persist and even worsen after treatment in paediatric IBD patients regardless of treatment with infliximab or not.

Disclosure of Interest: All authors have declared no conflicts of interest.

Reference

1. Casén C et al. Deviations in human gut microbiota: a novel diagnostic test for determining dysbiosis in patients with IBS or IBD. Aliment Pharmacol Ther . 2015 Jul;42(1):71–83.

TUESDAY, OCTOBER 31, 201708:30-10:00

SYMPTOM PATTERNS IN FUNCTIONAL GI DISORDERS - ROOM E1____________________

OP158 ABDOMINAL DISTENTION SYMPTOMS WITHOUT FUNCTIONAL DYSPEPSIA OR IRRITABLE BOWEL SYNDROME ARE PERSISTENT: 10 YEAR FOLLOW-UP OF THE KALIXANDA STUDY

J. Ronkainen 1 , P. Aro 2 , L. Agréus 3 , S. Johansson 3 , M. M. Walker 4 , N.J. Talley 4

1 Center for Life Course Health Research, Primary Care Center, City of Tornio, University of Oulu, Tornio/Finland

2 Arokero OY, Tornio/Finland

3 Department Of Neurobiology, Care Sciences And Society (nsv), Division Of Family Medicine, Karolinska Institutet, Huddinge/Sweden

4 Faculty Of Health And Medicine And Priority Research Center For Digestive Health And Neurogastroenterology, The University of Newcastle Australia, Callaghan/Australia/NSW

Contact E-mail Address: jukka.ronkainen@fimnet.fi

Introduction: Functional dyspepsia (FD) and irritable bowel syndrome (IBS) are common conditions in the population. Symptomatic abdominal distention (AD) coexists with FD and IBS but may also exist as a separate symptom complex. The innate immune response, post gastrointestinal infection for example, may induce abnormal intestino-somatic reflex pathways such that with small amounts of gas production by bacteria after meals, the diaphragm fails to relax and distention arises.

Aims & Methods: Our aim was to identify risk factors for separate AD symptom complex and to examine whether they differ from risk factors for FD and IBS. In addition, we examined whether pure AD without FD or IBS persists in a prospective population based follow-up study. Study participants (n = 3000) were randomly selected from the national Swedish population register and surveyed in 1998 by a validated abdominal symptom questionnaire (ASQ) and hospital anxiety and depression scale (HADS). 1000 individuals were randomly selected to complete an esophagogastroduodenoscopy in 1999–2001. All eligible from the endoscoped cohort (n = 887) were invited to a follow-up in 2010 with the ASQ and HADS. Data were analyzed by chi square test and Fishers exact test.

Results: In total 703 out of 887 subjects (79.3%) completed the questionnaires. FD was reported by 108 subjects (15.4%) at baseline and by 91 (12.9%) at follow-up; overlap in 43 between baseline and follow-up; in total 155 subjects with FD. IBS was reported by 200 subjects (28.5) at baseline and by 185 subjects (26.3%) at follow-up (overlap in 97); in total 288 subjects. In total 315 (33.4%) subjects reported AD at baseline (n = 232) or at follow-up (n = 234). There were 72 cases with pure AD at baseline and 85 subjects with pure AD at follow-up, AD symptom complex persisting in 20 subjects, p < 0.001. FD was associated with female gender (72/107 vs. 293/596, p = 0.001) anxiety (7/102 vs. 14/569, p = 0.019), use of NSAIDs or ASA (12/107 vs. 34/596, p = 0.034) and use of PPIs (17/107 vs. 19/596, p < 0.001) at baseline. IBS was associated with female gender (120/200 vs. 245/503, p = 0.007), PPIs (18/200 vs. 18/503, p = 0.003), alcohol intake (16/200 vs. 70/503, p = 0.031) and obesity (41/197 vs. 70/500, p = 0.027) at baseline. Pure AD at baseline was associated with female gender (48/72 vs. 317/631, p = 0.008), PPIs (8/72 vs. 28/631, p = 0.015) and smoking (16/72 vs. 85/631, p = 0.045). Pure AD at follow-up was associated with smoking (16/83 vs. 54/593, p = 0.004, missing data in 27 subjects) and age at baseline(18/85 vs. 209/618, p = 0.019). Persistent AD was associated with PPIs at baseline (4/20 vs. 32/683, p = 0.016) and female gender (15/20 vs. 350/683, p = 0.036).

Conclusion: Although FD, IBS and AD coexist, one third of those with AD present without FD or IBS. Furthermore, it is persistent and there was no association with immune activating disorders such as Helicobacter pylori infection, asthma or allergy, suggesting that the AD symptom complex is a functional disorder and the pathogenesis is as yet unexplained.

Disclosure of Interest: All authors have declared no conflicts of interest.

References

Tack, J., et al., Functional gastroduodenal disorders. Gastroenterology , 130, 1466–79 (2006).

Aro, P., Ronkainen, J., Storskrubb, T. , et al. Valid symptom reporting at upper endoscopy in a random sample of the Swedish adult general population: the Kalixanda study. Scand J Gastroenterol 39, 1280–1288 (2004)

Aro, P., Talley, N.J., Johansson, S.E., Agreus, L. & Ronkainen, J. Anxiety is Linked to New-onset Dyspepsia in the Swedish Population - A 10 year follow-up Study. Gastroenterology 148, 928–37 (2015).

Talley, N.J., Walker, M.M:, Aro, P. , et al. Non-ulcer dyspepsia and duodenal eosinophilia: an adult endoscopic population-based case-control study. Clin Gastroenterol Hepatol 5, 1175–1183 (2007).

Walker, M.M., Aggarwal, K.R., Shim, L.S. , et al. Duodenal eosinophilia and early satiety in functional dyspepsia: confirmation of a positive association in an Australian cohort. J Gastroenterol Hepatol 29, 474–479 (2014).

Walker, M.M. and N.J. Talley, The Role of Duodenal Inflammation in Functional Dyspepsia. J Clin Gastroenterol , 51, 12–18 (2017).

OP159 THE PREVALENCE OF ROME IV FUNCTIONAL DYSPEPSIA AND ITS IMPACT ON HEALTH IMPAIRMENT; RESULTS FROM A THREE-COUNTRY GENERAL POPULATION STUDY

I. Aziz 1 , O.S. Palsson 2 , H. Törnblom 1 , A. Sperber 3 , W.E. Whitehead 2 , M. Simrén 4

1 Department Of Internal Medicine And Clinical Nutrition, Sahlgrenska Academy, University of Gothenburg, Gothenburg/Sweden

2 Dept. Of Medicine, University of North Carolina, Chapel Hill, NC/United States of America

3 Ben-Gurion University Of The Negev, Faculty of Health Sciences, Beer-Sheva/Israel

4 Dept Of Internal Medicine, Sahlgrenska University Hospital - Dept of Internal Medicine, Sahlgrenska University Hospital; Gothe, Gothenburg/Sweden

Contact E-mail Address: imy_aziz9@yahoo.co.uk

Introduction: The population prevalence of Rome IV functional dyspepsia and its effect on health impairment is unknown. We used data from a population-based study to address this, and compared somatisation, quality of life, healthcare utilisation, and presence of overlapping irritable syndrome and functional heartburn in individuals fulfilling criteria for Rome IV functional dyspepsia against non-dyspeptic controls.

Aims & Methods: An internet-based health survey was completed by 6300 general population adults from three English-speaking countries (2100 each from United States, Canada, and United Kingdom). Quota-based sampling was used to ensure equal sex, age, and education distribution across the countries. The survey included questions on demographics, healthcare visits, medication use, criteria for the Rome IV functional dyspepsia as well as for irritable bowel syndrome and functional heartburn, the patient health questionnaire-12 somatisation measure, and the Short Form-8 quality of life questionnaire.

Results: Data was available for analysis from 5931 subjects (49.2% female; mean age 47.4 years, range 18–92). Overall, 551 (9.3%) of the population fulfilled criteria for Rome IV functional dyspepsia. This comprised 339 (61.5%) with postprandial distress syndrome-PDS, 97 (17.6%) with epigastric pain syndrome-EPS, and 115 (20.9%) with overlapping PDS/EPS. Subjects with functional dyspepsia had significantly greater health impairment than non-dyspeptic controls, with on average 73% seeking healthcare more than once yearly and 77% taking GI-relevant medication (i.e. GI-specific, psychotropics, analgesia, or complementary medicine). Notably, those with overlapping Rome IV EPS and PDS had higher frequency of co-existing irritable bowel syndrome and functional heartburn, worse somatisation, and poorer mental and physical quality of life scores, compared to EPS- or PDS-alone (see table). Somatisation and quality of life scores were similar between EPS- and PDS- alone.

Conclusion: Almost 10% of the population fulfil criteria for Rome IV functional dyspepsia. Subjects with Rome IV functional dyspepsia, in particular those with overlapping PDS and EPS, have considerable health impairment. This is despite frequent healthcare visits and use of GI-relevant medication. Study support: The Rome Foundation

Disclosure of Interest: All authors have declared no conflicts of interest.

OP160 ROME III VERSUS ROME IV CRITERIA FOR IRRITABLE BOWEL SYNDROME: A COMPARISON OF CLINICAL CHARACTERISTICS IN A LARGE COHORT STUDY

L. Vork , Z.Z. R.M. Weerts, Z. Mujagic, J. Kruimel, M. Hesselink, D. Keszthelyi, D.M. Jonkers, A. A. M. Masclee

Division Of Gastroenterology-hepatology, Department Of Internal Medicine, Maastricht University Medical Center+, Maastricht/Netherlands

Contact E-mail Address: l.vork@maastrichtuniversity.nl

Introduction: The recently revised Rome criteria (IV) for irritable bowel syndrome (IBS) include two major adjustments compared to Rome III criteria: abdominal pain is now the key requirement after the removal of abdominal discomfort and the required symptom frequency has been increased to on average at least once a week. Therefore, it is expected that Rome IV only apply to a subset of Rome III IBS subjects with more severe and more frequent abdominal pain. The aim of this study was to determine the percentage of Rome III IBS subjects that fulfils Rome IV criteria and to evaluate differences in terms of characteristics between Rome IV-positive and -negative subjects, in a well-defined Rome III IBS population.

Aims & Methods: The aim of this study was to determine the percentage of Rome III IBS subjects that fulfils Rome IV criteria and to evaluate differences in terms of characteristics between Rome IV-positive and -negative subjects, in a well-defined Rome III IBS population. This study was part of a large cohort study, of which 404 subjects diagnosed with IBS according to the Rome III criteria, were included for the current analysis. Subjects completed an end-of-day symptom diary during 14 days assessing abdominal pain severity, amongst other gastrointestinal (GI) symptoms, on a 5-point Likert scale. Additionally, they completed the gastrointestinal symptom rating scale (GSRS), hospital anxiety and depression scale (HADS) and rand 36-item short-form health survey (SF-36). Diary-based surrogate Rome IV criteria were defined as the occurrence of abdominal pain at least one day each week with a severity of ≥2 (mild; definition A) or ≥3 (considerable; definition B). A subgroup of the participants underwent a rectal barostat procedure to assess visceral pain perception and was classified as normo- or hypersensitive according to previously defined cut-offs (Ludidi et al., Neurogastroenterol Motil , 2012).

Results: Using the surrogate Rome IV criteria, 353 (87.4%, definition A) and 249 (61.6%, definition B) of the Rome III subjects were defined as Rome IV-positive. Regardless of the definition used, Rome-IV positive patients were more often female, younger and recruited from secondary/tertiary care compared to Rome IV-negative subjects. They also presented with higher abdominal pain scores and GI symptom severity on both end-of-day diary ( i.e. abdominal discomfort, abdominal bloating, flatulence, constipation and diarrhoea) and GSRS ( i.e. indigestion-, regurgitation-, constipation- and diarrhoea syndrome) and were more often hypersensitive as assessed by rectal barostat. Furthermore, Rome IV-positive subjects scored higher for both depression and anxiety and presented with lower quality of life compared to Rome IV-negative subjects.

Conclusion: This study underlines an expected decrease in IBS prevalence when using surrogate Rome IV compared to Rome III criteria. The Rome IV IBS population likely represents a subgroup of Rome III IBS patients with more severe gastrointestinal symptomatology, psychological comorbidities and lower quality of life. This implies that results from Rome III IBS studies may not be directly extrapolated to those from Rome IV IBS populations.

Disclosure of Interest: All authors have declared no conflicts of interest.

Reference

Ludidi S, Conchillo JM, Keszthelyi D, Van Avesaat M, Kruimel JW, Jonkers DM, et al. Rectal hypersensitivity as hallmark for irritable bowel syndrome: defining the optimal cutoff. Neurogastroenterology and motility: the official journal of the European Gastrointestinal Motility Society . 2012;24(8):729–33, e345–6.

OP161 FACTOR ANALYSIS DEFINES DISTINCT UPPER AND LOWER SYMPTOM GROUPINGS COMPATIBLE WITH ROME IV IN A POPULATION-BASED STUDY

E. Clevers 1 , W.E. Whitehead 2 , O.S. Palsson 2 , H. Törnblom 3 , L. Van Oudenhove 4 , J. Tack 1 , M. Simrén 3

1 KU Leuven, Leuven/Belgium

2 Dept. Of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC/United States of America

3 Department Of Internal Medicine And Clinical Nutrition, Sahlgrenska Academy, University of Gothenburg, Gothenburg/Sweden

4 Translational Research Center For Gastrointestinal Disorders (targid), Katholieke Universiteit Leuven, Leuven/Belgium

Contact E-mail Address: egbert.clevers@kuleuven.be

Introduction: Previous studies have defined irritable bowel syndrome (IBS), as well as distinct upper and lower gastrointestinal (GI) symptom groupings, by factor analysis. However, most previous studies have not used population-based samples, and none have used the most recent validated diagnostic questionnaire to define functional GI disorders. The Rome IV criteria define these disorders based on specific symptom combinations. We investigated how these symptom combinations group together in a factor analysis.

Aims & Methods: The Rome IV questionnaire was completed online in English by a population-based sample of 5931 respondents from the United Kingdom, United States, and Canada (49% female, age range 18 to 92 years). We performed an exploratory factor analysis on a selection of questions from the validated Rome IV diagnostic questionnaire, including all symptoms used to define functional GI disorders. The number of factors was decided based on eigenvalues (>1.0), and varimax rotation was used to simplify the structures. Factor loadings greater than 0.40 were deemed relevant.

Results: Four factors were identified, which we characterised as upper GI symptoms (1), IBS (2), constipation (3), and diarrhoea (4). The upper GI symptoms factor contained a large number of items, including both oesophageal and gastroduodenal symptoms, and had no further breakdown. The IBS factor was defined by the key components in the Rome IV diagnostic criteria for IBS; abdominal pain associated with defecation and abnormal bowel habits (r > 0.75). Faecal incontinence was part of the diarrhoea factor, albeit with a small loading (r = 0.41). The fourth factor included all six symptoms in the diagnostic criteria for functional constipation. Not fitted were pain "anywhere in the abdomen" (complex structure), bloating/abdominal distension (unique), and anorectal pain (unique). Rotated factor loadings are listed in table 1.

Conclusion: Distinct upper and lower GI symptom groupings exist in the general population, and can be identified using the English Rome IV questionnaire in a large sample from three English-speaking countries.

Disclosure of Interest: W.E. Whitehead: William Whitehead received research grants from Ironwood Pharmaceuticals, Takeda Pharmaceuticals, and Salix Pharmaceuticals and the Rome Foundation, and is a consultant to Ono Pharma USA.

O.S. Palsson: Olafur Palsson received research grants from Ironwood Pharmaceuticals, Takeda Pharmaceuticals, and Salix Pharmaceuticals and the Rome Foundation.

H. Törnblom: Hans Törnblom has served as Consultant/Advisory Board member for Almirall and Allergan as a speaker for Tillotts, Takeda, Shire and Almirall.

L. Van Oudenhove: Lukas Van Oudenhove has received grant support from Abide Therapeutics and Nestlé and has given scientific advice to Grünenthal.

J. Tack: Jan Tack has given Scientific advice to Abide Therapeutics, AlfaWassermann, Allergan, Christian Hansen, Danone, Genfit, Ironwood, Janssen, Kiowa Kirin, Menarini, Mylan, Novartis, Nutricia, Ono Pharma, Rhythm, Shionogi, Shire, SK Life Sciences, Takeda, …

M. Simrén: Magnus Simrén has received unrestricted research grants from Danone and Ferring Pharmaceuticals, and served as a Consultant/Advisory Board member for AstraZeneca, Danone, Nestlé, Menarini, Almirall, Allergan, Albireo, Glycom and Shire, and as a spe …

All other authors have declared no conflicts of interest.

OP162 DO THE NEW ROME IV DIAGNOSTIC CRITERIA FOR OPIOID-INDUCED CONSTIPATION IDENTIFY PATIENTS WITH A GREATER BIOPSYCHOSOCIAL BURDEN?

A.V. Emmanuel 1 , V. Banerji 2 , G. Hall 2 , A. Lass 3 , V. Andresen 4

1 Neuro-gastroenterology, National Hospital for Neurology and Neurosurgery, London/United Kingdom

2 InsightDojo, London/United Kingdom

3 Medical, Shionogi Limited, London/United Kingdom

4 Gastroenterology, Israelitic Hospital, Hamburg/Germany

Contact E-mail Address: a.emmanuel@ucl.ac.uk

Introduction: For the first time, Rome IV diagnostic guidance for functional gastrointestinal disorders includes criteria for opioid-induced constipation (OIC). We investigated whether long-term opioid users with Rome IV-positive OIC differed in biopsychosocial disease burden versus those with constipation not satisfying these criteria.

Aims & Methods: A quantitative, questionnaire-based, online survey was conducted in France, Germany, Italy, Spain and the UK among respondents aged ≥40 years with largely non-cancer-related chronic pain, treated long-term with strong opioids ( e.g. buprenorphine, fentanyl) and experiencing constipation (N = 2016). The survey assessed symptoms, past medical history, opioid use, treatment and healthcare-seeking behaviour, impact of disease, and effects on quality of life.

Results: Overall, 1158 (57%) respondents had worsening constipation after starting strong opioid use, of whom, 951 (82%) met Rome IV OIC diagnostic criteria. Significantly more respondents who satisfied Rome IV criteria vs non-Rome IV respondents reported physical effects of OIC, with main symptoms being ‘straining to pass stools’, ‘abdominal bloating’ and ‘sensation of blockage/bowel obstruction’ (Table). A significantly greater proportion of Rome IV respondents felt emotional and psychological symptoms caused by OIC than did non-Rome IV respondents, with feelings of frustration, dependence and anxiety/worry being key (Table). While all respondents reported an impact of OIC on daily life/relationships, this was significantly greater in the Rome IV group: ‘excessive time spent in bathroom’, ‘difficulty following normal routine’ and ‘difficulty being intimate with others’. Overall, significantly more Rome IV than non-Rome IV respondents experienced quite a lot/a great deal of bother from their OIC symptoms (42% vs 31%; p < 0.0001).

Conclusion: Comparing respondents meeting Rome IV OIC criteria with those who did not, they appeared to experience greater symptom and biopsychosocial burden. This study suggests that Rome IV criteria can identify more severe OIC patients, but may underdiagnose OIC patients who do not demonstrate the full scale of symptoms.

Disclosure of Interest: A. Lass: Contractor to Shionogi Ltd.

All other authors have declared no conflicts of interest.

OP163 USERS OF WEAK OPIOIDS HAVE A SMALLER SPECTRUM OF CONSTIPATION SYMPTOMS, BUT A SIMILAR DEGREE OF BOTHER FROM CONSTIPATION, AS USERS OF POTENT OPIOIDS

V. Andresen 1 , A. Lass 2 , V. Banerji 3 , G. Hall 3 , A.V. Emmanuel 4

1 Gastroenterology, Israelitic Hospital, hamburg/Germany

2 Medical, Shionogi Limited, London/United Kingdom

3 InsightDojo, London/United Kingdom

4 Neuro-gastroenterology, National Hospital for Neurology and Neurosurgery, London/United Kingdom

Contact E-mail Address: v.andresen@ik-h.de

Introduction: Constipation is a common side effect of opioid use, and can affect up to 81% of patients, despite concomitant use of laxatives. 1 However, it is not clear whether there is any difference in biopsychosocial disease burden of constipation in patients using strong or weak opioids.

Aims & Methods: To assess the impact of strong ( e.g. buprenorphine, fentanyl) or weak ( e.g. codeine, dihydrocodeine) opioids in patients with chronic pain who have constipation. This was a quantitative, questionnaire-based, online survey of respondents aged ≥40 years with largely non-cancer-related chronic pain, treated long-term with strong opioids (N = 1210) or using weak opioids (n = 605) in Germany, Spain and UK. Past medical history, treatment, symptoms, disease burden, and effects on quality of life were assessed.

Results: A comparable degree of bother from constipation symptoms was felt by both weak- and strong-opioid users, with 38% and 40% of respondents, respectively, stating that constipation bothered them quite a lot/a great deal (between-group comparison, p = 0.40). This pattern was reflected in the main psychological symptoms experienced due to constipation (frustration, dependence, anxiety; Table). Both groups were similar in incidence of more common physical symptoms (straining to pass stools, abdominal bloating, sensation of bowel blockage/obstruction; Table). However, weak-opioid users experienced significantly fewer less-common physical symptoms of constipation vs strong-opioid users, including stomach cramps, rectal burning and haemorrhoids (all p < 0.02; Table). Moreover, the impact on quality of life/social symptoms was felt significantly less by weak- vs strong-opioid users (Table).

Conclusion: Both weak- and strong-opioid users experience considerable biopsychosocial burden caused by constipation. Weak-opioid users appear to be subjectively as bothered by their constipation as strong-opioid users, despite experiencing less severe physical symptoms and a less drastic impact on quality of life. This may reflect the latter group having more serious underlying pain conditions and/or requiring other concomitant therapies that cause debilitating side effects of greater concern than constipation, compared with the former group.

Disclosure of Interest: A. Lass: contractor to Shionogi Ltd.

All other authors have declared no conflicts of interest.

Reference

1. Poulsen JL et al. Ther Adv Gastroenterol 2015; 8: 360–72.

TUESDAY, OCTOBER 31, 201708:30-10:00

ACUTE AND CHRONIC PANCREATITIS: RISK FACTORS AND PREVENTION - ROOM E2____________________

OP164 ENDOSCOPIC ULTRASOUND-BASED MULTIMODAL EVALUATION OF THE PANCREAS FOR THE DIAGNOSIS OF EARLY CHRONIC PANCREATITIS

J. Iglesias-Garcia 1 , J. Lariño Noia 1 , A. Álvarez-Castro 1 , L. Nieto 2 , S. Lojo 3 , S. Leal 2 , J. E. Dominguez-Muñoz 1

1 Gastroenterology, University Hospital of Santiago de Compostela, Santiago de Compostela/Spain

2 Health Research Institute of Santiago (IDIS), Santiago de Compostela/Spain

3 Clinical Chemistry, University of Santiago de Compostela, Santiago de Compostela/Spain

Contact E-mail Address: julio.iglesias.garcia@sergas.es

Introduction: Early diagnosis of chronic pancreatitis (CP) is hindered by the limited accuracy of diagnostic methods. Endoscopic ultrasound (EUS) and the endoscopic pancreatic function test (ePFT) are the most sensitive morphological and functional method respectively in this setting. EUS-elastography allows for evaluating the degree of pancreatic fibrosis in CP, and the dynamic evaluation of the main pancreatic duct (MPD) after e.v. secretin provides with additional dynamic information. We developed a multimodal EUS-based approach for pancreatic evaluation by integrating these four methods.

Aims & Methods: Aim of our study was to evaluate the concordance among the different data obtained during EUS-based multimodal test in patients with suspected early CP. Methods: A prospective, cross-sectional, observational study was designed. Patients with clinically suspected CP and 3–4 EUS criteria for the disease at EUS were included after informed consent. For the multimodal test, EUS was performed under deep sedation with the Pentax EG-3270UK linear scope, attached to the HI-VISION Ascendus. Quantitative elastography was performed in the head, body and tail of the pancreas and the mean strain ratio (SR) was considered as the final result (normal SR < 2.25). After that, secretin (0.2 μg/kg) was given intravenously and duodenal fluid was collected at 15, 30 and 45 minutes thereafter for bicarbonate quantification (normal peak > 80 mEq/L). Diameter of the MPD was measured by EUS at 5, 10, 25 and 40 min after secretin stimulation. A maximal dilatation of the MPD of at least 50% from basal was considered as normal. A descriptive analysis was performed.

Results: 44 patients were included (mean age mean age 39.9 years, range 18–66, 22 male). The EUS-based multimodal procedure was feasible in 43 cases (30 with 3 EUS criteria and 13 with 4 EUS criteria of CP respectively). Elastography (SR) was abnormally high in all patients (3.55 ± 1.01). Peak bicarbonate concentration was decreased in 34 patients (76.7%) (66.0 ± 27.7 mEq/L). Dynamic dilatation of the MPD was reduced in 32 patients (74.4%). 27 patients (62.8%) had all three parameters abnormal (CP very likely). 12 patients (27.9%) had two parameters abnormal (elastography and bicarbonate in 7, and elastography and MPD distensibility in 5) (CP likely), and three patients (7%) had only abnormal elastography (CP less likely). There were 2 complications related to the procedure: Mild acute pancreatitis and pulmonary aspiration related to deep sedation.

Conclusion: The multimodal EUS-based pancreatic evaluation provides dynamic morphological and functional information of the pancreas supporting the diagnosis of early CP.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP165 THE IMPACT OF BARIATRIC SURGERY ON ACUTE PANCREATITIS MORTALITY AND OTHER OUTCOMES: A NATIONWIDE ANALYSIS

P.T. Kroener 1 , M. S. Abougergi 2 , V. Popov 3 , C. C. Thompson 4

1 Mt. Sinai St. Luke's/West, New York/United States of America

2 Catalyst Medical Consulting, Simpsonville/United States of America/SC

3 New York University School of Medicine, New York/United States of America

4 Division Of Gastroenterology, Hepatology, And Endoscopy, Brigham and Women's Hospital, Boston/United States of America

Contact E-mail Address: thomaskroner@gmail.com

Introduction: Rapid weight loss after bariatric surgery (BS) has been associated with the formation of gallstones, and subsequent acute cholecystitis and pancreatitis (AP). However, the complex post-surgical anatomy limits the possibility of performing an ERCP as part of AP treatment. Therefore, the aim of this study was to assess the impact of bariatric surgery on mortality, morbidity and resource utilization among patients with AP using a national database.

Aims & Methods: This was a case-control study using the National Inpatient Sample 2013, the largest publically available inpatient database in the United States. All patients with an ICD-9 CM code for a principal diagnosis of AP were included. There were no exclusion criteria. Patients with a past history of BS were identified using the appropriate ICD-9CM codes. The primary outcome was all cause mortality. The secondary outcomes were: 1-Morbidity: Intensive care unit (ICU) admission, shock and multi-organ failure. 2- Resource utilization: use of ERCP, cholecystectomy, total parenteral nutrition (TPN), length of hospital stay (LOS), total hospitalization charges and costs. Multivariate regression analyses were used to adjust for the following confounders: Age, sex, race, income in patients’ zip code, Charlson Comorbidity Index, hospital region, location, size and teaching status.

Results: A total of 274,775 patients with AP were included in the study, of which 4240 (1.7%) had undergone bariatric surgery. The mean patient age was 51 years and 48% were female. After adjusting for confounders, patients with and without history of bariatric surgery had similar adjusted odds of mortality (adjusted Odds Ratio (aOR): 1.37, 95% CI: 0.51–3.65, p = 0.52). Looking at morbidity, patients with and without a history of bariatric surgery had similar adjusted odds of shock (aOR: 0.71, 95% CI: 0.23 – 2.24, p = 0.57), multiple organ failure (aOR: 0.61, 95% CI: 0.08–4.37, p = 0.62), and ICU admission (aOR: 0.34, 95% CI: 0.11 – 1.06, p = 0.62). As far as resource utilization, patients with bariatric surgery had lower adjusted odds of ERCP (aOR: 0.55, 95% CI: 0.38 – 0.79, p < 0.01), but both patient groups had similar adjusted odds of cholecystectomy (aOR: 1.21, 95% CI: 0.98 – 1.49, p = 0.07) and TPN use (aOR: 1.21, 95% CI: 0.77 – 1.90, p = 0.41). Interestingly, although patients with bariatric surgery had shorter adjusted length of stay (adjusted mean difference: −0.48 days, 95% CI: −0.74 - −0.23, p < 0.01) and total hospitalization costs (adjusted mean difference: -$755, 95% CI: -$1295 to -$215, p < 0.01), both patient groups had similar total hospitalization charges (adjusted mean difference: -$1949, 95% CI: -$4366 – $467, p = 0.11)

Conclusion: Bariatric surgery has no impact on inpatient all-cause mortality among patients who develop acute pancreatitis, despite its association gallstone acute pancreatitis and limited ERCP performance. In addition, bariatric surgery does not affect morbidity in this patient population as measured by rate of shock, multiple organ failure and ICU admission. However, a history of bariatric surgery is associated with decreased rates of ERCP, shorter length of stay and lower hospitalization costs.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP166 THE OBESITY PARADOX IN ACUTE PANCREATITIS: AN INDIVIDUAL PATIENT DATA META-ANALYSIS

X. Smeets 1 , I. Knoester 1 , K. Grooteman 1 , V. K. Singh 2 , G.I. Papachristou 3 , A. Duarte Rojo 4 , G. Robles-Diaz 5 , M.G. h. Besselink 6 , H. Van Santvoort 7 , W. Kievit 8 , H. Van Goor 9 , M.J. Bruno 10 , J.P. h. Drenth 11 , E. Van Geenen 1

1 Gastroenterology & Hepatology, Radboudumc, Nijmegen/Netherlands

2 Gastroenterology And Hepatology, Johns Hopkins Hospital, Baltimore/United States of America

3 Gastroenterology And Hepatology, University of Pittsburgh, School of Medicine, Pittsburgh/United States of America

4 Division Of Gastroenterology And Hepatology, University Of Arkansas For Medical Sciences, Little Rock/United States of America

5 Department Of Experimental Medicine, Universidad Nacional Autónoma de México, México City/Mexico

6 Department Of Surgery, Academic Medical Center, Amsterdam/Netherlands

7 Department Of Surgery, St. Antonius Hospital, Nieuwegein/Netherlands

8 Radboud University Medical Center, Nijmegen/Netherlands

9 Department Of Surgery, Radboudumc, Nijmegen/Netherlands

10 Gastroenterology & Hepatology, Erasmus University Medical Center, Rotterdam/Netherlands

11 Gastroenterology And Hepatology, Radboud University Nijmegen Medical Centre - Gastroenterology and Hepatology, Radboud University Nij, Nijmegen/Netherlands

Contact E-mail Address: xaviersmeets@gmail.com

Introduction: There is emerging evidence that obesity in critically ill patients is protective. In this so called “obesity paradox” mortality is highest in cachectic patients, it decreases in normal and obese patients and finally rises again in the morbidly obese. So far, studies in acute pancreatitis have reported conflicting outcomes. Outcomes may also differ per disease severity of acute pancreatitis. Therefore, we performed the current study with the aim of investigating the presence of an obesity paradox in patients with acute pancreatitis by means of an individual patient data meta-analysis (IPDMA) of prospective studies.

Aims & Methods: A systematic review of the literature was performed to identify prospective cohort studies in the PubMed, EMBASE, Web of Science and Cochrane databases using the following search terms: obese, pancreatitis and prognosis. Authors of the studies retrieved in the systematic review were contacted to provide data for an IPDMA. Missing data were handled by multiple imputation. The primary outcome is the relative risk (RR) of mortality for each World Health Organization class of obesity: underweight (body mass index < 18.5), normal weight (18.5–24.9), overweight (25.0–29.9), obesity class I (30.0–34.9), class II (35.0–39.9) and class III (>40). Normal weight was taken as a reference. The primary analysis was multivariable logistic regression for patients with PSAP, secondary analyses were for the entire cohort and for patients admitted to the intensive care unit. The following co-variates were included to adjust for confounding: study, age, sex, comorbidity and aetiology. Results are presented as RR with 95% confidence intervals (CI).

Results: The search yielded 1163 studies. After critical review, 4 studies with 1139 patients were included. Mean age was 52 years (SD 18), 546 (52%) patients were female, mean BMI was 26.5 (SD 6.8), 294 (26%) patients were obese. The most prevalent aetiologies were biliary (n = 439; 39%) and alcohol (n = 195; 17%). 551 (48%) patients had predicted SAP, 299 (26%) had necrosis, 247 (22%) had organ failure, 255 (22%) were admitted to the ICU and 64 (6%) died. The table below depicts the primary results for patients with PSAP.

Conclusion: No evidence was found for the presence of an obesity paradox in acute pancreatitis.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP167 STATIN CONSUMPTION IS ASSOCIATED TO A LOWER RISK OF POST-ENDOSCOPIC RETROGRADE CHOLANGIOPANCREATOGRAPHY PANCREATITIS

E. De-Madaria 1 , K. Cárdenas-Jaén 1 , A. B. Fernández-Laso 2 , J. Millastre-Bocos 3 , A. Torralba-Gallego 4 , S. Martín-Arriero 2 , E. Alfaro-Almajano 3 , G. García-Rayado 3 , E. Martínez-Moneo 4

1 Gastroenterology, Hospital General Universitario de Alicante - Gastroenterology, Hospital General Universitario de Ali, San Juan de Alicante/Spain

2 Hospital Universitario Araba, Álava/Spain

3 Hospital Clínico Universitario Lozano Blesa, Zaragoza/Spain

4 Hospital Universitario de Cruces, Bilbao/Spain

Contact E-mail Address: madaria@hotmail.com

Introduction: The most frequent complication of endoscopic retrograde cholangiopancreatography (ERCP) is post-ERCP acute pancreatitis (PEP), which is associated to increased morbidity, mortality and costs. Statin consumption seems to lower the incidence of acute pancreatitis due to other etiologies, according to previous studies 1–3 . The relationship between statin use and the incidence of PEP has not been studied before.

Aims & Methods: We aimed to investigate the relationship between the use of statins and the incidence of PEP. Methods: multicenter (4 Spanish tertiary-care public hospitals) retrospective cohort study. Adult patients undergoing an ERCP between January 2015 and January 2016 were included in the study. We excluded patients with chronic pancreatitis, with ongoing acute pancreatitis and those who developed other complications after ERCP. Patients were classified into 2 groups: under statin treatment (group S) and controls (group C). A multivariate analysis was performed (binary logistic regression) including possible confounding variables: center, female gender, previous pancreatitis, suspected sphincter of Oddi dysfunction, difficult cannulation (>10 minutes), pancreatic guidewire passages >1, pancreatic injection, pancreatic stenting, presence of malignant biliary stenosis and presence of choledocholitiasis.

Results: Six hundred and ninety-four patients were included, median age 76 (63–83) years, 324 (47%) females, 209 (30%) in group S. Thirty-two (5%) patients developed PEP, 4 (2%) in group S and 28 (6%) in group C. Univariate analysis yielded an Odds Ratio (OR) for developing PEP for group S of 0.3 (0.1–0.9), p = 0.034; multivariate analysis showed an adjusted OR of 0.3 (0.1–0.8), p = 0.017. The number of patients to treat to prevent an episode of PEP was 28 (95% confidence interval 16 to 112). Statins reduced the incidence of mild PEP (0.5% vs 5%, ten times lower) but moderate-to-severe PEP remained similar (both groups 1%). Only 1 patient died (overall: 0.1%, within patients with PEP: 4%), who was in group C.

Conclusion: We conclude that in our sample of patients, statin consumption was independently associated to a 70% risk reduction of PEP.

Disclosure of Interest: All authors have declared no conflicts of interest.

References

1. Wu BU, Pandol SJ, Liu IL. Simvastatin is associated with reduced risk of acute pancreatitis: findings from a regional integrated healthcare system. Gut . 2015;64(1):133–8.

2. Thisted H, Jacobsen J, Munk EM, Norgaard B, Friis S, McLaughlin JK, et al. Statins and the risk of acute pancreatitis: a population-based case-control study. Aliment Pharmacol Ther . 2006;23(1):185–90.

3. Preiss D, Tikkanen MJ, Welsh P, Ford I, Lovato LC, Elam MB, et al. Lipid-modifying therapies and risk of pancreatitis: a meta-analysis. JAMA . 2012;308(8):804–11.

OP168 THE RISK FOR POST-ERCP PANCREATITIS AFTER INADVERTENT PANCREATIC DUCT CANNULATION CAN BE PREVENTED BY TEMPORARY PANCREATIC STENTING. A MULTICENTRE, PROSPECTIVE, RANDOMIZED TRIAL

V. Phillip 1 , A. Pukitis 2 , A. Epstein 3 , A. Hapfelmeier 4 , D. Haf 1 , M. Schwab 1 , J. Rosendahl 5 , A. Hofmeister 5 , I.E. Demir 6 , A. Weber 1 , H. Algül 1

1 Klinik Und Poliklinik Für Innere Medizin Ii, Technische Universität München, München/Germany

2 University Hospital, Pauls Stradins Clininic University Hopital Gastroenterology Center, Riga/Latvia

3 Northern State Medical University, Arkhangelsk/Russian Federation

4 Institut Für Medizinische Statistik Und Epidemiologie, Technische Universität München, München/Germany

5 Department Für Innere Medizin, Neurologie Und Dermatologie, Universitätsklinikum Leipzig, Leipzig/Germany

6 Klinik Und Poliklinik Für Chirurgie, Technische Universität München, München/Germany

Contact E-mail Address: veit.phillip@tum.de

Introduction: Acute pancreatitis (AP) is the most frequent complication of endoscopic retrograde cholangiopancreatography (ERCP) and the most frequent cause of iatrogenic AP. The rate of post-ERCP-Pancreatitis (PEP) is about 3.5% of all ERCPs, in high-risk patients up to 25% [1, 2]. Due to the lack of specific therapy of AP, prevention of PEP has to be a crucial goal. The most promising prophylactic approaches are non-steroidal anti-inflammatory drugs (NSAID) and pancreatic stents [3]. Although several studies showed a decreased risk of PEP for NSAID and pancreatic stents, the results of these studies are inconsistent [4]. All these studies included only high-risk patients and do not represent the cross-section of ERCPs typically performed [5]. Further, definition of high risk is inconsistent [6]. One of the described risk factors is inadvertent cannulation of the pancreatic duct [3, 5].

Aims & Methods: Aim of the study was to evaluate the effect regarding the rate of PEP of a prophylactic pancreatic stent in an unselected patient population with inadvertent cannulation of the pancreatic duct. Multicentre, prospective, randomized study. Patients undergoing first time ERCP were eligible. In case of inadvertent cannulation of the pancreatic duct patients were randomized for pancreatic stent or no prophylactic measurement.

Results: 169 patients were randomized (87 stent, 82 no stent). PEP occurred in 33/169 patients (19.5 %). Rate of PEP was statistically significantly lower in the stent group (12.6 %) compared to the no stent group (26.8 %; odds ratio 0.395; 95 %-confidence interval: 0.178–0.878; p = 0.020).

Conclusion: Rate of PEP after inadvertent cannulation of the pancreatic duct during first time ERCP can be significantly reduced by a temporary prophylactic pancreatic stent.

Disclosure of Interest: All authors have declared no conflicts of interest.

References

1. Andriulli A, Loperfido S, Napolitano G, Niro G, Valvano MR, Spirito F, et al. Incidence rates of post-ERCP complications: a systematic survey of prospective studies. Am J Gastroenterol . 2007;102(8):1781–8.

2. Fogel EL, Eversman D, Jamidar P, Sherman S, Lehman GA. Sphincter of Oddi dysfunction: pancreaticobiliary sphincterotomy with pancreatic stent placement has a lower rate of pancreatitis than biliary sphincterotomy alone. Endoscopy . 2002;34(4):280–5.

3. Dumonceau JM, Andriulli A, Elmunzer BJ, Mariani A, Meister T, Deviere J, et al. Prophylaxis of post-ERCP pancreatitis: European Society of Gastrointestinal Endoscopy (ESGE) Guideline - updated June 2014. Endoscopy . 2014;46(9):799–815.

4. Levenick JM, Gordon SR, Fadden LL, Levy LC, Rockacy MJ, Hyder SM, et al. Rectal Indomethacin Does Not Prevent Post-ERCP Pancreatitis in Consecutive Patients. Gastroenterology . 2016;150(4):911–7.

5. Freeman ML, Kozarek RA. Take 2 Indomethacin (Suppositories) and Call Me in the Morning? The Role of Nonsteroidal Anti-inflammatory Drugs in Protection Against Post-Endoscopic Retrograde Cholangiopancreatography Pancreatitis. Gastroenterology . 2016;150(4):805–8.

6. Mazaki T, Mado K, Masuda H, Shiono M. Prophylactic pancreatic stent placement and post-ERCP pancreatitis: an updated meta-analysis. J Gastroenterol . 2014;49(2):343–55.

OP169 EXOCRINE PANCREATIC INSUFFICIENCY AFTER ACUTE PANCREATITIS: SYSTEMIC REVIEW AND META-ANALYSIS

D. De La Iglesia-García 1 , W. Huang 2 , I. Baston Rey 3 , J. Lariño Noia 1 , J. Iglesias-Garcia 1 , P. Szatmary 2 , Q. M. Nunes 2 , R. Mukherjee 2 , J. E. Dominguez-Muñoz 3 , R. Sutton 2

1 Health Research Institute of Santiago (IDIS), Santiago de Compostela/Spain

2 NIHR Liverpool Pancreas Biomedical Research Unit, Royal Liverpool University Hospital, Liverpool/United Kingdom

3 Gastroenterology, University Hospital of Santiago, Santiago de Compostela/Spain

Contact E-mail Address: info@fienad.org

Introduction: Acute pancreatitis (AP) is an inflammatory process of the pancreas that can lead to pancreatic exocrine insufficiency (PEI). Previous studies have estimated the risk of PEI after AP; however, up to date, no study has evaluated the incidence of PEI after AP. Therefore, we undertake a systematic review and meta-analysis to determine the incidence of PEI after AP.

Aims & Methods: A systematic search was performed in major databases (Web of Science, Medline (Pubmed) and Embase) from 2000 to 2017. Only prospective studies in adult patients that evaluated the risk of PEI after AP were included. Diagnostic criteria and risk factors for PEI were also identified. The primary outcome was the incidence of PEI after AP. Incidence of PEI after necrotizing AP, incidence of PEI in those patients undergoing pancreatic necrosectomy and the risk of PEI after mild and severe AP was also evaluated. Data are shown as percentage and Odds Ratio (OR), with 95% confidence interval (CI).

Results: A total of 27 prospective clinical studies, involving 14, 407 patients (9, 674 male, median age 53 years) were included, only three of which used the Revised Atlanta Classification (original Atlanta in 24 studies). The diagnosis of PEI was made by the faecal elastase-1 test in 21 studies and symptoms of malabsorption in 6 studies. The pooled frequency of PEI after AP was 30% (95% CI 20, 3% to 40, 5%). The frequency of PEI in severe, in necrotizing AP and in those undergoing pancreatic necrosectomy was 32, 3% (95% CI 23% to 42, 4%), 46, 2% (95% CI 31, 3% to 61, 5%), 58, 5% (95% CI 39, 4% to 76, 8%), respectively. Risk of PEI after severe AP was significantly higher than after mild AP (OR 2, 1 (95% CI 1, 16 to 3, 83).

Conclusion: The methods used for the diagnosis of PEI in the included studies have limitations Up to one in three patients with AP can develop PEI. The risk is higher after necrotizing AP or in those patients undergoing pancreatic necrosectomy. Patients with severe AP have twice the risk of PEI than patients with mild AP.

Disclosure of Interest: All authors have declared no conflicts of interest.

TUESDAY, OCTOBER 31, 201708:30-10:00

PROGRESS IN ENDOSCOPIC DIAGNOSIS - ROOM E3____________________

OP170 TERMINOLOGY AND DESCRIPTION OF VASCULAR LESIONS IN SMALL BOWEL CAPSULE ENDOSCOPY: AN INTERNATIONAL DELPHI CONSENSUS STATEMENT

R. Leenhardt 1 , C. Li 1 , A. Koulaouzidis 2 , F. Cavallaro 3 , F. Cholet 4 , R. Eliakim 5 , I. Fernández-Urién 6 , U. Kopylov 7 , M. Mcalindon 8 , A. Németh 9 , J. N. Plevris 2 , G. Rahmi 10 , E. Rondonotti 11 , J.C. Saurin 12 , G.E. Tontini 13 , E. Toth 9 , D. E. Yung 2 , P. Marteau 1 , X. Dray 1

1 Gastroenterology & Digestive Endoscopy Unit, Saint-Antoine Hospital, Paris/France

2 The Royal Infirmary of Edinburgh, Edinburgh/United Kingdom

3 IRCCS Gastroenterology & Digestive Endoscopy Unit, Policlinico San Donato, Milan/Italy

4 Gastroenterology, CHU La Cavale Blanche, Brest/France

5 Dept. Of Gastroenterology, Sheba Medical Center, Ramat Gan/Israel

6 Gastroenterology, Complejo Hospitalario de Navarra, Pamplona/Spain

7 Gastroenterology, Chaim Sheba Medical Center, Ramat Gan/Israel

8 Dept. Of Gastroenterology, Royal Hallamshire Hospital, Sheffield/United Kingdom

9 Skåne University Hospital, Malmo/Sweden

10 Gastroenterology And Digestive Endoscopy, Georges-Pompidou European Hospital, Paris/France

11 Ospedale Valduce, Como/Italy

12 Hepatogastroenterology, Hopital Edouard Herriot, Lyon/France

13 Gastroenterology And Digestive Endoscopy Unit, IRCCS Policlinico San Domato, San Donato Milanese/Italy

Contact E-mail Address: romainleni@gmail.com

Introduction: The terminology and description of small bowel (SB) vascular lesions in capsule endoscopy (CE) are scarce in the medical literature. They are mostly based on the reader's background and opinion, and therefore remain mainly subjective, with a potential negative impact on clinical care, teaching and research regarding SB-CE. Our aim was to define and to describe the most frequent vascular lesions in SB-CE.

Aims & Methods: A panel of 18 European expert SB-CE readers, teachers and researchers was built aside the UEGW 2016 meeting. Three of these experts animated an internet-based, three-round Delphi consensus, but did not participate to any vote. They built questionnaires that included various still frames of vascular lesions from third-generation SB-CE videos. The remaining 15 experts were asked to rate different proposals for diagnostic, terminology, and description of various SB vascular lesions. Rare or protuding SB vascular lesions (Kaposi's sarcoma, Dieulafoy ulceratio simplex, varices, vascular tumors) were not considered for the study. A 6-point Likert rating scale (varying from strongly disagree to strongly agree) was used for all proposal in the 3 successive questionnaires. A consensus was considered to be reached when at least 80% voting members scored the statement within the "(dis)agree" or "strongly (dis)agree".

Results: Consensual terms and descriptions of angiodysplasia, erythematous patch, red dot or red spot, and phlebectasia were reached (table 1). No consensus was reached for definition or description of more subtle or small vascular mucosal abnormalities.mucosal layer (surrounded with intestinal villi). Table 1: Results

Conclusion: An international group has reached a consensus on the terminology and the description of the most frequent and relevant SB vascular lesions in CE. These terms and descriptions will be useful for daily practice but also for teaching and for medical research.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP171 A PROSPECTIVE MULTICENTER SINGLE-BLIND RANDOMIZED CONTROLLED TRIAL COMPARING FNA AND FNB IN THE DIAGNOSIS OF SOLID MASSESA PROSPECTIVE MULTICENTER SINGLE-BLIND RANDOMIZED CONTROLLED TRIAL COMPARING FNA AND FNB IN THE DIAGNOSIS OF SOLID MASSES

Q. Chen 1 , B. Cheng 1 , G. Wang 2 , T. Jiang 3 , L. Dou 2 , J. Wang 1 , Y. Li 1 , Y. Zhang 2 , B. Sun 4 , H. Shan 5 , Z. Deng 3 , G. Xu 5 , X. Yang 4

1 Gastroenterology And Hepatology Department, Tongji Hospital affiliated to Tongji Medical College, HUST, Wuhan/China

2 Cancer Institute and Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing/China

3 The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou/China

4 Fudan University Shanghai Cancer Center, Fudan University, Shanghai/China

5 Sun Yat-sen University Cancer Center, Guang Zhou/China

Contact E-mail Address: chenqian201579@yahoo.com

Introduction: Endoscopic ultrasound (EUS) guided fine needle biopsy (FNB) with side fenestration on the needle was developed aiming to obtain both cytological aspirates and histological core samples. To reveal the diagnostic yield of FNB sampling solid mass compared to standard fine needle aspiration (FNA), we conducted a large-scale multicenter study in patients with pancreatic and non-pancreatic masses. We also aimed to establish optimal techniques in EUS tissue acquisition.

Aims & Methods: This was a prospective multicenter single-blind randomized controlled trial. Between December 2014 and January 2016, 408 patients were enrolled from five tertiary-care academic medical centers and randomized at a 1:1 ratio to receive either 22G FNA or 22G FNB. Two tissue acquisition (TA) techniques (1 st and 2 nd passes using slow pull vs. 3 rd and 4 th passes using suction methods) were performed on all EUS needles. The primary outcome was the diagnostic yield comparing FNA and FNB on all solid lesions, pancreatic and non-pancreatic masses, respectively. Secondary endpoints were the quality of the histologic specimen (quantity of cell, tissue integrity, and blood contamination).

Results: Among all lesions, FNB group (n = 190) compared to FNA group (n = 187) gained superior histological diagnostic yield (91.44% vs. 80%; p = 0.0015), and higher cytological diagnostic yield (85.56% vs. 78.95%; p = 0.093). For pancreatic mass, FNB group (n = 123) achieved better histological diagnostic yield compared to FNA group (n = 126) (92.68% vs. 81.75%; p = 0.0099), and also higher cytological diagnostic yield (88.62% vs. 79.37%; p = 0.00468), respectively. For non-pancreatic mass, there was no difference between FNB and FNA on diagnostic accuracy. Furthermore for pancreatic mass, when slow pull technique was applied in the first and second passes, FNB was superior to FNA on specimen quality and diagnostic yield.

Conclusion: FNB needle achieved superior overall diagnostic yield compared to FNA needle among all studied solid lesions. For pancreatic masses, the 22G FNB needle also gained superior histological diagnostic accuracy and higher cytological diagnostic yield compared to 22G FNA. We further suggest choosing FNB over FNA on pancreatic lesion for TA when slow pull technique was applied in the first two passes.

Disclosure of Interest: All authors have declared no conflicts of interest.

Reference

Wang J, Wu X, Yin P, et al. Comparing endoscopic ultrasound (EUS)-guided fine needle aspiration (FNA) versus fine needle biopsy (FNB) in the diagnosis of solid lesions: study protocol for a randomized controlled trial. Trials 2016;17:198-016–1316-2.

OP172 RANDOMIZED TRIAL COMPARING THE 22 GAUGE FRANSEEN BIOPSY AND 22 GAUGE ASPIRATION NEEDLES FOR EUS-GUIDED SAMPLING OF SOLID PANCREATIC MASS LESIONS

J.Y. Bang , S. Hebert-Magee, U. Navaneethan, M. Hasan, R. Hawes, S. Varadarajulu

Center For Interventional Endoscopy, Florida Hospital, Orlando/United States of America/FL

Contact E-mail Address: jybang213@gmail.com

Introduction: Given the poor outcomes of traditional chemotherapy, there is increased focus on molecular profiling so that pancreatic cancer treatment can be personalized. Pancreatic tissue with architecture containing both tumor cells and desmoplastic stroma is pivotal for molecular analysis. Although EUS-guided fine needle aspiration (EUS-FNA) is diagnostically accurate, the cytological aspirate is suboptimal for DNA sequencing. Therefore, clinical trials evaluating personalized treatment in pancreatic cancer prefer tissue procurement via percutaneous or surgical biopsies over EUS-FNA. Recently, a three-plane symmetric needle with Franseen geometry has been developed for EUS-guided fine needle biopsy (FNB). The large crown-tip with three cutting edges and long insertion length were postulated to facilitate histological tissue procurement.

Aims & Methods: We aimed to compare tissue acquisition between the 22G Franseen biopsy and 22G FNA needles in patients undergoing EUS-guided sampling of pancreatic masses. Patients with solid pancreatic masses were randomized to undergo EUS-guided sampling using the 22G Franseen and 22G FNA needles. Two dedicated passes were first performed using both needles in individual patients for cell block. Subsequent passes were then performed for rapid onsite evaluation (ROSE) using both needles alternately until a diagnosis was rendered. The main outcome measure was to compare total tissue volume and presence of desmoplastic stroma in pancreatic cancer. The secondary outcome measure was to compare rates of diagnostic cell block between the cohorts. A specialized software (Nikon DS-Fi2) was used for histological assessment in order to measure tissue volume and isolate malignant cells from desmoplastic stroma. Sample size based on 50% difference in the presence of desmoplastic stroma at 80% power was estimated at 34 patients.

Results: Of the 46 patients randomized to undergo EUS-guided sampling, the final diagnosis was pancreatic cancer in 36, neuroendocrine tumor in 2, sarcoma in 1 and benign disease in 7. The median total tissue volume, 6.1 mm 2 (IQR 2.2–9.9) vs. 0.28mm 2 (IQR 0.045–0.93) (p < 0.001) and presence of desmoplastic stroma in tumor, 84.6 vs. 33.3% (p < 0.001) were significantly higher in the FNB cohort. Also, the diagnostic yield at cell block was significantly higher for the FNB cohort, 97.8 vs. 82.6% (p = 0.03). There was no difference in diagnostic adequacy at ROSE between the FNB and FNA cohorts, 100 vs. 95.7% (p = 0.50).

Conclusion: The Franseen biopsy needle yields significantly more tissue with superior histology than the FNA needle. This development is likely to advance the role of EUS in facilitating molecular-based anti-cancer therapy.

Disclosure of Interest: R. Hawes: Consultant for Olympus America inc. and Boston Scientific Corporation

S. Varadarajulu: Consultant for Olympus America Inc. and Boston Scientific Corporation

All other authors have declared no conflicts of interest.

OP173 CAN ARTIFICIAL INTELLIGENCE FOR ENDOCYTOSCOPY PROVIDES FULLY AUTOMATED DIAGNOSIS OF HISTOLOGICAL HEALING IN ULCERATIVE COLITIS?

Y. Maeda 1 , S. Kudo 1 , Y. Mori 2 , M. Misawa 1 , K. Wakamura 1 , S. Sasanuma 1 , N. Ogata 1 , Y. Ogawa 2 , K. Takeda 1 , K. Ichimasa 1 , T. Hayashi 1 , T. Kudo 1 , F. Ishida 1 , K. Ohtsuka 3

1 Digestive Disease Center, Showa University Northern Yokohama Hospital, kanagawa yokohamashi/Japan

2 Northen Yokohama Hospital, Showa University Northern Yokohama Hospital, Yokohama/Japan

3 Tokyo Medical And Dental University, Tokyo/Japan

Contact E-mail Address: yasuharumaeda610@hotmail.com

Introduction: Recent studies suggest that histological remission is a treatment goal in ulcerative colitis (UC). However there is a discrepancy between histological remission and conventional endoscopic mucosal healing. We have already reported two useful aspects of EC that is the next-generation ultra-magnifying endoscopy allowing visualization of microvessels; one is that findings of EC showed good correlation to histological activity in UC [1]. The other one is the potential of computer-aided diagnosis (CAD) systems in diagnosis of EC images of colorectal lesions [2].

Aims & Methods: The aim of this study is to develop a new CAD system for the histological remission in UC, with use of EC combined with NBI mode. Histological assessment was based on Geboes index. Geboes index ≦3.0 and absence of basal plasmacytosis was considered as histological remission, while Geboes index >3.0 or presence of basal plasmacytosis was as active. The algorithm of this CAD system was programmed based on texture analysis, which can quantify the pattern of endoscopic image and vessel features. Support vector machine was used as a classifier for two-category diagnostic output (histological remission or active status). A total of 1935 EC images (histological remission, 1042; active status, 893) were used for machine learning process. The overall accuracy to distinguish histological remission from active status was assessed by using leave-one-out cross validation. In this validation, randomly selected one EC image was evaluated by using the developed CAD system which was trained by using the remaining 1934 images.

Results: According to the leave-one-out cross validation which was repeatedly calculated for 1935 times, the average accuracy of the developed CAD system for identification of histological remission was 81.7%. The accuracy with high confidence (probability ≧90%) was 98.9%. The high confidence rate was 32.4%.

Conclusion: The diagnostic ability of artificial intelligence in classification of EC image for assessment of histological activeness of UC was substantially good, although it was tentative model. Higher accuracy could be expected with much more numbers of images for machine learning.

Disclosure of Interest: All authors have declared no conflicts of interest.

References

1. Maeda Y, et al. Endocytoscopic narrow-band imaging efficiency for evaluation of inflammatory activity in ulcerative colitis. World J Gastroenterol . 2015 Feb 21;21(7):2108–15.

2. Misawa M, et al. Characterization of Colorectal Lesions Using a Computer-Aided Diagnostic System for Narrow-Band Imaging Endocytoscopy. Gastroenterology . 2016 Jun; 150(7):1531–1532.

OP174 A PILOT INTERNATIONAL MULTICENTER RANDOMIZED CONTROLLED TRIAL OF CHROMOENDOSCOPY VERSUS AUTOFLUORESCENCE IMAGING FOR NEOPLASIA DETECTION IN PATIENTS WITH LONGSTANDING ULCERATIVE COLITIS (FIND-UC)

J. L. a. Vleugels 1 , J.E. East 2 , M.D. Rutter 3 , L.K. Wanders 1 , K. Ragunath 4 , C.J. Rees 5 , C.Y. Ponsioen 1 , S. Samuel 4 , F. Butt 5 , T. Kuiper 1 , S. Van Eeden 6 , E. Dekker 1

1 Gastroenterology And Hepatology, Academic Medical Center, Amsterdam/Netherlands

2 Department Of Gastroenterology, Gastroenterology Unit John Radcliffe Hospital - Department of Gastroenterology, Gastroenterology Uni, Oxford/United Kingdom

3 Gastroenterology, University Hospital North Tees NHS Dept. of Gastroenterology, Stockton-on-Tees/United Kingdom

4 Endoscopy & Gastroenterologist Wolfson Digestive Diseases Centre, Queens Medical Centre Campus Nottingham University Hospitals, Nottingham/United Kingdom

5 South Tyneside NHS Trust, South Tyneside General Hospital South Tyneside NHS Trust Dept. of Gastroenterology, South Tyneside/United Kingdom

6 Department Of Pathology, Academic Medical Center, Amsterdam, Netherlands, Amsterdam/Netherlands

Contact E-mail Address: j.l.vleugels@amc.uva.nl

Introduction: Patients with longstanding ulcerative colitis (UC) are at increased risk for developing colorectal cancer and regular surveillance is advised. Previous studies demonstrated that both surveillance with chromoendoscopy (CE) and autofluorescence imaging (AFI) increased dysplasia detection rates in patients with longstanding UC when compared to standard white light endoscopy. Chromoendoscopy is currently recommended in national guidelines, but is poorly adopted in clinical practice because it is time-consuming. AFI is a push-button technique in which endogenous autofluorescence is used to highlight neoplastic tissue. The aim of this pilot study was to determine whether AFI should be further studied as an alternative method for dysplasia surveillance in patients with longstanding UC.

Aims & Methods: In this prospective, non-inferiority pilot randomized trial with fixed design, patients undergoing colonoscopy surveillance for longstanding UC (Montreal E2 > 15 years or Montreal E3 > 8 years) in 5 centers in the Netherlands and the UK were randomized for inspection with either CE or AFI (1:1). Patients with active colitis (MAYO ≥ 1 in at least 1 segment) or Boston Bowel Preparation Scale <6 were excluded. Randomization was stratified for presence of previous dysplasia and/or primary sclerosing cholangitis (PSC). Targeted biopsies of visible lesions and random biopsies of each segment were collected. The main outcome was the relative dysplasia detection rate calculated by the quotient of CE over AFI. This relative detection rate was determined for the proportion of UC patients in which at least one dysplastic lesion was detected and for the mean number of dysplastic lesions per patient. A relative detection rate below 1.50 for both outcomes would support performing a subsequent large non-inferiority trial. For this study, 210 UC patients were needed to achieve a relative detection rate of 1.50 with an 80% confidence interval between 1.00 and 2.25. Dysplasia was diagnosed by an expert gastrointestinal pathologist in consensus with a second expert pathologist.

Results: Between August 2013 and March 2017, 210 UC patients were randomized to undergo surveillance with CE (N = 105) or AFI (N = 105). The mean age of patients at colonoscopy was 56.1 (SD 12.7) years, 58.1% were male and the median time since previous surveillance colonoscopy was 3 years (IQR 1–4) (Table 1). During CE, dysplasia was detected in 20 (19.0%) patients, while 14 patients (13.3%) were diagnosed with dysplasia during AFI. The relative dysplasia detection rate of CE versus AFI for the proportion of UC patients with at least one dysplastic lesion was 1.43 (95% CI; 0.76–2.68). The mean number of detected dysplastic lesions per patient was 0.37 for CE compared to 0.13 for AFI (relative dysplasia detection rate 2.79, 95% CI; 1.61–4.82)). During CE, the proportion of patients in whom targeted biopsies were taken (65.7% vs. 47.6%, p < 0.01) was larger and total extubation times were longer (25.1 min vs. 18.0 min, p < 0.01).

Conclusion: In this pilot randomized study with fixed design comparing CE with AFI for dysplasia surveillance in patients with longstanding UC, AFI was non-inferior to CE on a dysplasia per patient basis, but was inferior on the basis of mean number of dysplastic lesions detected. These results argue against a future large prospective randomized trial comparing these methods for dysplasia surveillance in patients with longstanding UC (NTR4062).

Disclosure of Interest: J.L.A. Vleugels: Vleugels' research department is receiving research support from Olympus and Fujifilm.

J.E. East: East has received research support and speaker’s fee from Olympus; research support and consultancy fees from Cosmo Technologies; is a member of the clinical advisory board of Lumendi.

M.D. Rutter: Rutter’s department is receiving research support from Olympus, Allergan, Pentax and Norgine.

K. Ragunath: Ragunath has received educational grants from Olympus, Cook and Covidien; speaker honorarium from Olympus; consultancy fees from Olympus and Boston Scientific; research support from COOK, Covidien, Astra Zeneca and Pentax.

C.J. Rees: Rees’s department receives research funding from Olympus Medical, ARC Medical, Aquilant Endoscopy, Almirall, and Cook (from 2010 to present).

C.Y. Ponsioen: Ponsioen’s department is receiving research support from Olympus and Fujifilm.

S. Samuel: Samuel has received speaker fees from Abbvie, MSD and Pharmacosmos; consultancy fees from Pfizer and Falk and educational grant from Abbvie, MSD and Ferring.

F. Butt: Butt’s department receives research funding from Olympus Medical, ARC Medical, Aquilant Endoscopy, Almirall, and Cook (from 2010 to present).

E. Dekker: Dekker has equipment on loan from Olympus Europe and Fujifilm, has received a research grant from Olympus Europe and Fujifilm, and consulted for Tillotts Pharma (one time).

All other authors have declared no conflicts of interest.

OP175 MULTICENTRE EUROPEAN EVALUATION OF A NOVEL TECHNOLOGY (BLUE LIGHT IMAGING) IN THE OPTICAL DIAGNOSIS OF SMALL COLORECTAL POLYPS

S. Subramaniam 1 , K. Kandiah 1 , P. Aepli 2 , G. Wurm Johansson 3 , E.J. Schoon 4 , M. Stefanovic 5 , P. Bhandari 1

1 Gastroenterology, Queen Alexandra Hospital, Portsmouth/United Kingdom

2 Gastroenterology And Hepatology, Luzerner Kantonsspital, Lucerne/Switzerland

3 Clinical Sciences, Skane University Hospital, Malmo/Sweden

4 Dept. Of Gastroenterology, Catharina Hospital Gastroenterology and Hepatology, Eindhoven/Netherlands

5 Gastroenterology And Hepatology, Diagnostic Center Bled, Ljubljana/Slovenia

Contact E-mail Address: shar811@googlemail.com

Introduction: The advent of image-enhanced endosopic modalities have paved the way for better optical diagnosis of colorectal polyps. Fujifilm recently introduced a new technology – Blue Light Imaging (BLI) that utilises powerful light emitting diode (LED) technology and short wavelength absorption of haemoglobin with no post processor digital reconstruction to enhance mucosal surface and vessel patterns. This is a novel concept.

Aims & Methods: The aim of this study was to investigate the diagnostic ability of BLI in the optical diagnosis of diminutive colorectal polyps. Images from a library of 32 polyps (size 1–9 mm, combination of 19 adenomas and 13 non adenomas) was used. 64 images with equal proportions of high definition white light (HDWL) and BLI were shown to a panel of 6 expert endoscopists with experience in using image enhanced endoscopy. The endoscopists were blinded to the proportion of adenomas in the images viewed. They independently classified each of the 64 images as adenoma or hyperplastic using the established Narrow band imaging International Colorectal Endoscopic (NICE) classification 1 as no standard BLI classification exists. A level of confidence was assigned to each prediction. The sensitivity, specificity, negative (NPV) and positive predictive values (PPV) for adenoma detection on HDWL and BLI were calculated alongside the confidence levels.

Results: A total of 384 observations were made with an adenoma prevalence of 59.4%. The table below shows the sensitivity, specificity, NPV and PPV for adenoma detection on HDWL and BLI. Both sensitivity and NPV improved significantly when BLI was used.

The utility of individual NICE descriptors (colour, surface and vessel pattern) when applied to BLI was also analysed. In this case, vessel pattern showed the highest sensitivity [84.2 (76.2–90.4)%] and NPV [78.12 (70.77–84.05)%]. The diagnostic accuracy using BLI was significantly higher (109/119, 91.6%) for high confidence predictions compared to 75.6% (59/78) for predictions made with low confidence (p = 0.002).

Conclusion: We have demonstrated the feasibility of using novel BLI technology in the optical diagnosis of small colorectal polyps. BLI improves the accuracy and sensitivity of endoscopic diagnosis with accuracy rates reaching 92% when high confidence predictions were made. These gains can be maximised by developing a dedicated BLI specific classification system and training module to enable its validation and subsequent application in clinical practice.

Disclosure of Interest: P. Bhandari: Educational grants received from Fujifilm, Olympus and Pentax

All other authors have declared no conflicts of interest.

Reference

1. Hewett DG, Kaltenbach T, Sano Y et al. Validation of a Simple Classification System for Endoscopic Diagnosis of Small Colorectal Polyps Using Narrow-Band Imaging. Gastroenterology 2012;144:599–607

TUESDAY, OCTOBER 31, 201708:30-10:00

NEW INSIGHTS IN MICROBIOTA: GUT AND LIVER ASPECTS - ROOM B5____________________

OP176 GUT MICROBIOTA INVOLVES IN NON-ALCOHOLIC FATTY LIVER DISEASE VIA AFFECTING INTRA-HEPATIC CD4+ T LYMPHOCYTE

L. Su , Z. Wu, J. Tan, J. Xu, Y. Song, Y. L. Liu

Deparment Of Gastroenterology, Peking University People`s Hospital, Bejing/China

Contact E-mail Address: drsulin@163.com

Introduction: Gut microbiota plays an important role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). CD4+ T lymphocytes have also emerged as an important player in NAFLD since the function of their immune was realized. But the effects of gut bacteria on intra-hepatic T lymphocytes are not very clear.

Aims & Methods: To investigate the impact of gut microbiota on hepatic CD4+ T lymphocyte in the pathogenesis of non-alcoholic fatty liver disease. High fat diet (HFD) was used to induce NAFLD. After 8 weeks of HFD feeding, mice were given PBS, Antibiotics (neomycin and polymixin B) or Lactobacillus by gavage once a day for 4 weeks and sacrificed. Primary hepatocytes isolated from 12 weeks of normal diet feeding mice were co-cultured with CD4+ T lymphocytes or its cultured supernatants, of which CD4+ T lymphocytes were isolated from mesenteric lymph nodes of mice fed 12 weeks of HFD or normal diet.

Results: Compared with the PBS group, lymphocytic infiltration in livers of antibiotics group and lactobacillus group are less, as well as lower ALT and AST. Consistent with this, the mRNA expression of liver MCP-1, IL-6 and TNF-a in antibiotics group and IL-6 and TNF-a in lactobacillus group were significantly lower than PBS group, respectively. In the meantime, administration of antibiotics or lactobacillus induced the increase of CD4+IL4+ Th2 (anti-inflammatory character) and decrease of CD4+IL-17+ Th17 and CD4+IFN-y+Th1 (pro-inflammatory character) in the liver and mesenteric lymph nodes. Primary hepatocytes cultured with CD4+ T lymphocytes derived from mice fed with HFD normal diet resulted in higher ALT and AST in cultured supernatants compared with control. ALT was increased when hepatocytes were cultured with cultured supernatants of CD4+ T cells derived from HFD mice.

Conclusion: The impact of CD4+ T lymphocytes to hepatocytes involves in the pathogenesis of NAFLD. Either antibiotics or lactobacillus administration induced the scales of CD4+ T lymphocytes tilting to Th2 versus Th1/17, which might be partly accounts for the improvement of hepatic inflammation.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP177 METHYL DONOR MOLECULES SUPPLEMENTATION IMPAIRS E. COLI COLONISATION BACTERIA BY MODULATING IGA PATHWAY

E. Gimier , A. Agus, N. Barnich, J. Denizot

Université Clermont Auvergne, Inserm U1071, INRA USC2018, M2iSH, Clermont-Ferrand/France

Contact E-mail Address: elodie.gimier@uca.fr

Introduction: Crohn's disease (CD) patients frequently present deficiencies in methyl-donor molecules (folate, B12 vitamin …) and are colonized by Adherent-invasive E. coli which are clearly involved in triggering and maintaining ileal CD. AIEC bacteria adhere to the enterocytes through high-affinity interaction between their variant FimH adhesin and abnormally expressed CEACAM6 protein on host cells. Decreasing CEACAM6 expression in CD intestinal cells is one strategy that could prevent AIEC bacteria colonization of the intestinal mucosa and subsequent inflammation. This work aims at studying the effect of a methyl-donor enriched diet (HMD: High Methyl Diet) on AIEC colonization, on DNA methylation, and on genes expression with a specific focus on CEACAM6.

Aims & Methods: CEABAC10 female mice were fed a HMD (supplemented in folate, biotin, B12 vitamin, zinc and methionine) for 2 weeks before pregnancy. After weaning, the colonic epithelial cells from offspring were purified using EDTA. We analyzed different physiological parameters such as the lipocalin-2 level in stools and intestinal permeability. E. coli population was quantified using a cultural and qPCR approaches. DNA methylation of CEACAM6 promoter was measured using bisulfite-sequencing and qPCR was used to quantify CEACAM6 mRNA in colonic epithelial cells. RNA-seq was used to highlight transcriptomic changes in colonic cells and ELISA was used to quantify IgA concentration in stools.

Results: Mice fed a HMD did not present any sign of spontaneous inflammation or altered intestinal permeability when compared to mice fed a conventional diet. Microbiota analysis revealed a 1000-fold decrease in E. coli population in mice fed HMD compared to mice receiving a conventional diet. As expected, bisulfite sequencing showed a hyper-methylation of the CEACAM6 promoter, associated with a significant decrease in CEACAM6 expression as measured by qPCR, following HMD treatment. RNA-seq data confirmed the decrease in CEACAM6 expression and highlighted 309 up-regulated genes following HMD. Among them, 88 were involved in adaptive immunity and 15 took part into the IgA synthesis pathway. Further analysis revealed an increase in E. coli -specific IgA concentration in intestinal lumen of mice treated with HMD compared to control diet group.

Conclusion: This work shows that the addition of a few vitamins and oligo-elements to the diet could interfere with the DNA-methylation metabolism leading to changes in genes expression such as a decrease in CEACAM6 and to activation of genes involved in IgA synthesis. The excessive specific E. coli -IgA quantity secreted into the lumen during HMD could explain the decrease in E. coli colonization. A diet-based strategy could help decreasing E. coli colonization in CD patients by modulating DNA methylation and favoring IgA production.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP178 COMMD10 NEGATIVELY REGULATES LY6C HI MONOCYTE-DRIVEN INFLAMMATION AND PROMOTES BACTERIAL CLEARANCE BY KUPFFER CELLS DURING SEPSIS

N. Gluck 1 , S. Ben-Shlomo 1 , O. Mouhadeb 1 , C. Varol 1

1 Gastroenterology, Tel-Aviv Sourasky Medical Center, Tel-Aviv/Israel

Contact E-mail Address: nathang@tlvmc.gov.il

Introduction: COMMD proteins regulate inflammation and intracellular vesicular trafficking. Yet, the immunoregulatory functions of COMMD10 in Ly6C hi monocyte and tissue-resident macrophages are unknown.

Aims & Methods: COMMD10-deficiency in mice was targeted to total myeloid cells (LysM ΔCommd10 ) or to resident macrophages (Cx3cr1 ΔCommd10 ).

Results: COMMD10-deficient BM-derived macrophages (BMDM ΔCommd10 ) exhibited hyper-activation of NF-kB and augmented production of its governed inflammatory mediators in response to LPS. In LPS-induced sepsis, LysM ΔCommd10 mice developed more severe disease resulting in elevated levels of serum inflammatory cytokines concomitantly with hyper-activation of NF-kB and NLRP3 inflammasome in affected organs. They also exhibited a breached intestinal barrier manifested by reduced expression of colonic tight junction genes and higher bacterial load in the liver and other viscera. The elevated septic response and impairment in intestinal barrier were abolished by the inducible ablation of Ly6C hi monocytes. The increased bacterial dissemination in LysM ΔCommd10 mice during LPS-induced sepsis may also be the outcome of impaired bacterial clearance by tissue-resident macrophages. Therefore, we next subjected Cx3cr1 ΔCommd10 mice to systemic S.aureus infection. Cx3cr1 ΔCommd10 mice showed higher bacterial burden in the blood and liver, resulting in ultimate Kupffer cell depletion, implicating COMMD10 as a pivotal player in Kupffer cell-governed bacterial handling. Moreover, BMDM ΔCommd10 exhibited defective killing of staphylococci that was NFkB-independent. Notably, lysosome formation was decreased in infected BMDM ΔCommd10 , suggesting a defect in lysosomal-dependent bacterial killing pathway. Intriguingly, elimination of S. Typhimurium was improved, suggesting target-specific regulation of macrophages by COMMD10.

Conclusion: Collectively, our results highlight COMMD10 as a pivotal regulator of monocyte-driven inflammation and macrophage handling of bacteria.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP179 IMPROVED HEMODYNAMIC AND LIVER FUNCTION MARKERS IN BILE-DUCT-LIGATED RATS AFTER ADMINISTRATION OF B. PSEUDOCATENULATUM CECT7765

I. Gomez-Hurtado 1 , P. Zapater 2 , K. Portune 3 , J.M. Gonzalez-Navajas 2 , Y. Sanz 3 , R. Frances 2

1 CIBERehd-Hospital General Universitario de Alicante, Alicante/Spain

2 (isabial-fundación Fisabio), Instituto de Investigación Sanitaria y Biomédica de Alicante, Alicante/Spain

3 Microbial Ecology, Nutrition & Health Research Group, nstitute of Agrochemistry and Food Technology, National Research Council (IATA-CSIC), Valencia/Spain

Contact E-mail Address: gomezhurtado_isa@gva.es

Introduction: Cirrhosis is an advanced liver disease resulting from a chronic liver injury, characterized by generalized progressive vasodilatation, related to portal hypertension, mainly due to increased intrahepatic resistance (1). A dysbiosis in gut microbiota has been described to play an important role in the progression of the complications of cirrhosis (2). B. Pseudocatenulatum CECT7765 has previously shown to help in improving gut barrier integrity and reducing bacterial antigen translocation in experimental cirrhosis (3), and the capacity of inducing the transition of cirrhotic patients' macrophagues towards an anti-inflammatory phenotype (4).

Aims & Methods: The aim was to evaluate whether changes in gut microbiota induced by a bifidobacterial strain have an effect on the vascular function in experimental cirrhosis. Bile-duct ligation was performed in rats. A subgroup of animals received B. pseudocatenulatum CECT7765 (10 9 cfu/daily ig.) for one week prior to laparotomy. Hemodynamic parameters were evaluated by Doppler analysis and biochemical markers were evaluated in all animals. Ileal microbiota composition was also identified. Statistical analyses were performed using the R software.

Results: Sham-operated, BDL and BDL treated with bifidobacteria rats (n = 10/each) were included. B. Pseudocatenulatum CECT7765 significantly decreased the total OTUs in the BDL model (p = 0.02) and compared with sham-operated rats (p = 0.02). B. pseudocatenulatum CECT7765 modified the intestinal content mainly in the firmicutes and the bacteroides phyla, increasin the abundance of clostridium XI whila decreasing alistipes and prevotella genus. Microbial diversity was significantly increased in BDL rats compared with sham-operated rats. However, the administration of the bifidobacterial strain was associated with a reduction in all diversity scores, although differences were only statisticaly significant when comparing Shannon (p = 0.002) and Simpson (p = 0.002) scores with sham-operated rats. Median Simpson scores in the three groups of animals were 0.02, 0.04 and 0.03 respectively (p = 0.007). The Non-Metric Multidimensional Scaling Distance analysis clustered BDL rats treated with the bifidobacterial strain separately from the rest of groups. BDL surgery in rats was also clustered separately from sham-operated rats. The portal vein area, portal flow, and congestion index were significantly reduced in BDL rats treated with B. Pseudocatenulatum CECT7765. Total bilirubin and alkaline phosphatase levels were also significantly improved in these animals (Table 1). Quantitiative changes in the Clostridiales and Bacteroidales classes were independently associated with variations in portal vein area and portal flow, while changes in the Proteobacteria phylum were independently associated with congestion. Although variations in all biochemical markers significantly correlated with total OTUs mainly in the firmicutes, only changes in the Clostridiales were independently associated with variations in alkaline phosphatase in the ANCOVA analysis.

Conclusion: Hemodynamic alterations and liver disfunction induced by bile-duct ligation in cirrhotic rats is partially restored after administration of B. Pseudocatenulatum CECT7765. Results provide a proof-of-concept to design further studies on the effects of the bifidobacterial strain in patients with cirrhosis.

Disclosure of Interest: All authors have declared no conflicts of interest.

References

1. Bosch J, et al. Gastroenterol Clin North Am 1992; 21:1–14

2. Bauer TM et al. Am J Gastroenterol 2001; 96: 2962–2967

3. Juanola O. et al. Liver Int 2016; 36: 1811–1820

4. Moratalla A. et al. J Hepatol 2016; 65:135–145

OP180 THE ROLE OF B LYMPHOCYTES WITHIN MESENTERIC ADIPOSE TISSUE IN NON-ALCOHOLIC FATTY LIVER DISEASE

Z. Wu 1 , F. Zhang 1 , J. Tan 1 , J. Xu 1 , Y. Song 1 , Y. L. Liu 1

1 Department Of Gastroenterology, Peking University People's Hospital, Beijing/China

Contact E-mail Address: 18811799308@163.com

Introduction: Visceral adipose tissue inflammation is involved in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). As one part of visceral adipose tissue, mesenteric adipose tissue (MAT) can directly affect liver via portal vein. There are amounts of researches focusing on the role of innate immune cells in adipose tissue inflammation and hepatic inflammation, while the role of adaptive immune cells, especially B lymphocytes, is relatively neglected.

Aims & Methods: Mice fed with high fat diet (HFD) or normal diet (ND) were sacrificed in time gradients (4w, 8w, 12w). CD19+ B cells, CD3+ T cells and F4/80+ macrophages in liver and MAT were analyzed by flow cytometry. Liver homogenate, primary hepatocytes and B lymphocytes within MAT were acquired or isolated from mice fed with 12 weeks of HFD or ND. Transwell assay was carried out to explore the chemotaxis of liver homogenate to B lymphocytes isolated from ND mice. The effects of B lymphocytes on primary hepatocytes of ND mice were studied using co-culture assay.

Results: Compared with ND mice, CD45 + CD19+ B lymphocytes in liver and MAT increased at 4th week and lasted to 12th week in HFD mice, infiltrated earlier than CD45 + CD3+ T lymphocytes or CD45 + F4/80+ macrophages (increased at 12th week). B lymphocytes that migrated through the membrane were obviously higher when cultured with liver homogenate from HFD mice than that from ND mice (P < 0.01). Coculturing primary hepatocytes with B lymphocytes either derived from ND mice or HFD mice resulted in higher mRNA expression of MCP-1 (P < 0.01) and TNF-a(P < 0.05), and B lymphocytes derived from HFD mice induced higher mRNA expression of MCP-1(P < 0.01), lower IL-10(P < 0.01) in hepatocytes than B lymphocytes derived from ND mice

Conclusion: During the development of NAFLD, B lymphocytes infiltrates earlier than T lymphocytes and macrophages in liver and MAT. Besides, liver homogenate of HFD mice promotes the chemotaxis of B lymphocytes within MAT, which induces the hepatocellular inflammation. All these results suggest increased B lymphocytes within MAT may involved in the pathogenesis of NAFLD via migrating to liver and promoting hepatic inflammation.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP181 METABOLOMICS: IN THE SEARCH FOR NEW BIOMARKERS OF DECOMPENSATION AND INFECTION IN PATIENTS WITH CIRRHOSIS

P. Fischer 1 , C. Moraru 2 , A. Bugariu 1 , C. Grigoras 1 , O. Farcau 1 , H. Stefanescu 1 , M. Tantau 1 , C. Socaciu 2 , B.D. Procopet 1

1 3rd Medical Clinic, University of Medicine and Pharmacy “Iuliu Hatieganu”, Cluj-Napoca/Romania

2 Research and Development Centre BIODIATECH for Applied Biotehnology in Diagnostic and Molecular Therapy, Cluj-Napoca/Romania

Contact E-mail Address: fischerpetra23@yahoo.com

Introduction: Decompensated cirrhosis is an evolutionary stage in the natural history of cirrhosis, with important consequences on prognosis. The causes for transitioning in decompensated stage, explained physiopathologically by the occurrence of clinically significant portal hypertension, are only partially known. Frequently, the transition to decompensation is precipitated by bacterial infections but the diagnosis is rather difficult in this particular group of patients. Previous metabolomic analysis studies have shown a core metabolic phenotype represented by decreased serum lysophosphatidylcholines and increased serum bile acids that occurs relatively early in liver diseases regardless of etiology, and remains stable in their evolution, including liver cirrhosis and hepato/cholangiocarcinoma [1].

Aims & Methods: The aim of the study was to assess the differences between the metabolic profile of patients with compensated and decompensated cirrhosis and to identify potential new biomarkers for infections in the decompensated patients. Between December 2015 and September 2016, 92 patients with liver cirrhosis were included (55 with ascites decompensation and 37 with HCV compensated liver disease prior to direct acting antiviral treatment). Among the decompensated patients (MELD score 20 ± 7), 36 (65%) were infected at presentation (44% urinary tract infections, 25% spontaneous bacterial peritonitis and 25% cellullitis). Fasting venous blood was collected and serum was stored at −80 degrees after centrifugation at 5000 rpm for 10 minutes. After a specific purification protocol non-targeted metabolomic analysis was performed using Thermo Scientific UHPLC UltiMate 3000 system, equipped with a Dionex quaternary pump delivery system and a Bruker Daltonics MaXis Impact MS detection equipment (version 2012). Biostatistical analysis The chromatograms obtained were processed using Compass Data Analysis 4.2 software (Bruker, Germania) and about 3000–4000 molecular masses were identified. Those data were further processed using Profile Analysis (Bruker, Daltonics): time alignment, normalization by sum of bucket values in analysis, 80% bucket filter, internal recalibration, etc. The matrix obtained was further processed by MetaboAnalysis, to analyze samples through univariate and multivariate statistical analysis.

Results: Univariate and multivariate statistical analysis by MetaboAnalysis highlighted a different metabolic phenotype for the two groups. Thirteen potential biomarkers were identified for decompensated disease. From these biomarkers two, with m/z = 830.542 (phosphatidylcoline 20:4), and with m/z = 558/293 (lysophosphatydilcholine 18:2), had significant lower serum concentration in decompensated stage. Four metabolites (creatine; triglyceride 20:5/20:4; acid 18-hidroxyarachidonic; epoxy-8, 11, 14-eicosatrienoic acid) reached the threshold (fold changes analysis) as possible candidates for infection biomarkers. However, in univariate analysis by principal component analysis none of the markers reached statistical significance difference between infected and non-infected groups.

Conclusion: There is a different metabolic profile for patients with decompensated cirrhosis, expressed primarily through phosphatidylcholine metabolism disorders. Metabolomic analysis is a promising method to find new markers of infections in decompensated patiens but targeted metabolomical studies are required.

Disclosure of Interest: All authors have declared no conflicts of interest.

Reference

1. Idle J, Beyoglu D, The metabolomic window into hepatobiliary disease J Hepatol . 2013 Oct; 59(4): 842–858.

TUESDAY, OCTOBER 31, 201710:30-12:00

PERIANAL FISTULISING CROHN'S DISEASE: FROM PATHOPHYSIOLOGY TO MANAGEMENT - ROOM C1____________________

OP182 ANTI-TNF THERAPY FOR RECTOVAGINAL FISTULAS COMPLICATING CROHN'S DISEASE: A GETAID STUDY

G. Le Baut 1 , P. Seksik 2 , G. Bouguen 3 , A. Amiot 4 , D. Laharie 5 , R. Altwegg 6 , F. Mathurin 7 , C. Trang 8 , L. Vuitton 9 , M. Simon 10 , C. Gilletta De Saint Joseph 11 , L. Caillo 12 , E. Del Tedesco 13 , L. Plastaras 14 , A. Aubourg 15 , L. Peyrin-Biroulet 16 , S. Viennot 17

1 Normandie, Caen, Caen/France

2 Gastroenterology & Nutrition Department, Paris/France

3 CHU Rennes, Rennes/France

4 Dept. Of Gastroenterology, Henri Mondor Hospital, APHP Dept. of Gastroenterology, Creteil/France

5 Gastroenterology, CHU de Bordeaux, Pessac/France

6 Hopital Saint Eloi Hepatologie Gastro enterologie, Montpellier/France

7 CHU Amiens, Amiens/France

8 Hepato-gastroenterology Unit, hospital, Nantes/France

9 Dept. Of Gastroenterology, Besançon university hospital gastroenterology, Courbevoie/France

10 Institut Mutualiste Montsouris, Paris/France

11 Hopital Rangueil, Toulouse/France

12 Gastro Enterology, hospital, Nîmes/France

13 CHU Saint-Etienne, Saint-Etienne/France

14 Hopital Colmar, Colmar/France

15 CHRU Tours, Tours/France

16 Gastroenterology Unit, Inserm U954, Nancy University and Hospital, Nancy/France

17 Caen Hospital, Caen/France

Contact E-mail Address: lebaut.guillaume@gmail.com

Introduction: Anti-TNF therapy is effective for fistulizing Crohn’s disease (CD). Rectovaginal fistulas can represent a devastating condition in CD patients and a challenge for gastroenterologists and surgeons. Given the small size of available studies, it is difficult to draw definite conclusions regarding the efficacy of anti-TNF therapy in treating rectovaginal fistulas complicating CD. We thus evaluated the efficacy of anti-TNFs for the treatment of rectovaginal fistulas in a large cohort of CD patients.

Aims & Methods: This GETAID multicenter retrospective study included all adult patients from 16 French tertiary centers who were treated with anti-TNF therapy for rectovaginal fistula complicating CD. Only patients who received anti-TNF induction treatment (adalimumab, infliximab or certolizumab) and at least one maintenance injection/infusion were analyzed. Clinical response was evaluated at 1 year and at date of latest news. The main endpoint was complete clinical fistula closure at 1 year. We also looked at predictors of anti-TNF therapeutic response.

Results: One hundred and six patients received at least one anti-TNF injection/infusion. Nine patients stopped anti-TNF therapy during induction due to lack of efficacy and/or intolerance. Ninety-seven patients who started anti-TNF maintenance therapy were included in the analysis. Median follow-up was 76 months. Four types of fistulas were reported: 34 recto-vaginal fistulas (35 %), 7 entero-vaginal fistulas (7%), 36 ano-vaginal fistulas (37%), and 20 ano-vulvar fistulas (21%). Rectal involvement was present in 48% of patients. Only 25% of the patients were active smokers. Ten percent of patients were previously exposed to anti-TNF therapy. Seventy-two patients were treated with infliximab (74%), 23 with adalimumab (24%), 2 with certolizumab (2%); 55 % of patients received combination therapy. Of the 97 patients receiving maintenance therapy, the rate complete clinical response, as defined by complete fistula closure, was 38% at one year and 43 % at last news. A partial response was observed in 25% of patients and a lack of response in 37% of the patients. At least one surgery for fistula was performed in 39% of 97 patients. In univariate analysis, no factors were associated with a clinical response at one year. Among patients with a clinical response at 6 months, 91% maintained a clinical response at one year, whereas only 25% had a response at one year in case of lack of response at 6 months.

Conclusion: In this large cohort of CD patients, anti-TNF therapy induced a clinical response at one year in 63% of patients and 38% had a complete fistula closure following induction therapy. Anti-TNF therapy seems to be a good option for the treatment of rectovaginal fistulas complicating CD in clinical practice in both the short- and long-term.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP183 HIGHER INFLIXIMAB AND ADALIMUMAB SERUM LEVELS CORRELATE WITH PERIANAL FISTULA CLOSURE IN CROHN’S DISEASE PATIENTS

A. Strik 1 , M. Lowenberg 2 , C.Y. Ponsioen 1 , C.J. Buskens 3 , W.A. Bemelman 4 , G. R. D'Haens 1

1 Gastroenterology, Academic Medical Centre, Amsterdam/Netherlands

2 Academic Medical Center Amsterdam, Academisch Medisch Centrum, Amstelveen/Netherlands

3 Colorectal Surgery, Academic Medical Center, Amsterdam/Netherlands

4 Department Of Surgery, Academisch Medisch Centrum Dept. of Surgery, Amsterdam/Netherlands

Contact E-mail Address: a.s.strik@amc.uva.nl

Introduction: Anti-tumour necrosis factor (anti-TNF) agents are effective to treat perianal Crohn’s disease (CD). It has been suggested that CD patients with perianal fistulas need higher serum concentrations of infliximab compared to patients with pure luminal disease in order to attain remission.

Aims & Methods: For this analysis, we identified all CD patients with perianal fistula(s) receiving active treatment with infliximab or adalimumab at our centre. Serum drug concentrations of infliximab and adalimumab in CD patients with perianal fistula were collected. Anti-TNF antibody concentrations in patients with closed fistula, defined by the absence of active draining fistula at physical examination and/or confirmed by magnetic resonance imaging were compared to drug levels in patients with persistently draining perianal fistulas. Only patients receiving anti-TNF maintenance treatment were included and if the time interval between physical examination/imaging and serum drug level measurement did not exceed four weeks. Patients who underwent surgical interventions (i.e. ligation of intersphincteric fistula tract surgery or fecal diversion procedure) between physical examination/imaging and measurement of anti-TNF serum levels were excluded, as well as patients with internal fistulas.

Results: We identified 66 CD patients (out of a total cohort of 352) that received active treatment with infliximab or adalimumab and had perianal fistula(s). Forty seven out of 66 were treated with infliximab and 19/66 with adalimumab. The median serum concentrations of infliximab at trough ([interquartile range]) were significantly higher in patients with closed fistula(s) (n = 32) compared to patients with actively draining fistula (n = 15): (6.0 µg/ml [5.4–6.9] versus 2.3 µg/ml [1.1–4.0], respectively (p < 0.001)). The same outcome was seen in 19 patients treated with adalimumab (13 with closed fistula and 6 with active fistula) with a median serum concentration of 7.4 µg/ml [6.5–10.8] versus 4.8 µg/ml [1.7–6.2] respectively; p = 0.003. ROC analysis of anti-TNF serum measurements showed a high accuracy for both infliximab and adalimumab with an AUC of respectively 0.92 (95% CI: 0.82–1.00) and 0.89 (95% CI: 0.71–1.00). An infliximab serum trough concentration ≥5 µg/ml yielded the optimal results in terms of combined sensitivity of 86.67% (95% CI: 59.5–98.3) and specificity of 84.38 % (95% CI: 67.2–94.7). An adalimumab serum concentration ≥5.9 µg/ml was associated with fistula closure with a sensitivity of 83.3% (95% CI: 35.9–99.6) and specificity of 92.3% (95% CI: 64.0–99.81). There were no differences seen in infliximab and adalimumab dose and intervals between patients with active draining fistula and closed fistula.

Conclusion: An association was found between the level of anti-TNF serum concentrations and fistula closure in CD patients. Pursuing higher serum anti-TNF serum levels in CD patients with perianal fistula might improve fistula closure rates.

Disclosure of Interest: A. Strik: has received lecture fees from Merck Sharp & Dohme, Takeda, Tillots, AbbVie, Johnson and Johnson, Biogen and Mundipharma.

M. Lowenberg: has received speaking fees from Abbvie, Covidien, Dr. Falk, Ferring Pharmaceuticals, Merck Sharp & Dohme, Receptos, Takesa, Tillotts and Tramedico. He has received research grants from AbbVie, Merck Sharp & Dohme, Achmea healthcare and ZonMW.

C.Y. Ponsioen: has received grant support from Takeda, Dr. Falk Pharma, lecture fees from Abbvie, Takeda, Ferring, Dr. Falk Pharma and consultancy fees from AbbVie and Takeda.

G.R. D'Haens: received speaker fees from Abbvie, Ferring, Johnson and Johnson, Merck Sharp & Dohme, Mundipharma, Norgine, Pfizer, Shire, Millenium/Takeda, Tillotts and Vifor.

All other authors have declared no conflicts of interest.

TUESDAY, OCTOBER 31, 201710:30-12:00

LONGTERM MANAGEMENT IN IBD WITH BIOLOGICS - ROOM A3____________________

OP184 EFFICACY OF VEDOLIZUMAB ON EXTRAINTESTINAL MANIFESTATION IN PATIENTS WITH INFLAMMATORY BOWEL DISEASES: A POST-HOC ANALYSIS OF THE OBSERV-IBD COHORT OF THE GETAID

S. Tadbiri 1 , M. Serrero 2 , L. Peyrin-Biroulet 3 , J. Filippi 4 , B. Pariente 5 , X. Roblin 6 , A. Buisson 7 , C. Stefanescu 8 , C. Trang 9 , R. Altwegg 10 , P. Marteau 11 , T. Vaysse 12 , A. Bourrier 13 , S. Nancey 14 , D. Laharie 15 , M. Allez 16 , G. Savoye 17 , J. Moreau 18 , C. Gagniere 1 , L. Vuitton 19 , Y. Bouhnik 20 , A. Amiot 1

1 Dept. Of Gastroenterology, Henri Mondor Hospital, APHP Dept. of Gastroenterology, Creteil/France

2 Gastroenterology, APHM, Marseille Cedex/France

3 Department Of Gastroenterology, Nancy University Hospital Inserm U954 Dept. of Hepato-Gastroenterology, Vandoeuvre les Nancy/France

4 Dept. De Gastroenterologie, Hopital de l'Achet Dept. de Gastroenterlogie Dept. de Nutrition Oncologie, Nice Cedex/France

5 Gastroenterology Unit, Hôpital Huriez, Lille University Hospital, Lille/France

6 University of St. Etienne Dept. de Gastroenterologie, Saint Etienne/France

7 Dept. Of Gastroenterology, CHU Estaing Clermont-Ferrand, Clermont-ferrand/France

8 Service De Gastroenterologie Et Assistance Nutritive, Beaujon Hospital, Clichy, Clichy/France

9 Hepato-gastroenterology Unit, hospital, Nantes/France

10 Hopital Saint Eloi Hepatologie Gastro enterologie, Montpellier cedex/France

11 Gastroenterology & Digestive Endoscopy Unit, Saint-Antoine Hospital, Paris/France

12 Bicetre Hospital, Kremlin-Bicetre/France

13 Gastroenterology, Saint Antoine Hospital, Paris/France

14 Dept. De Gastroenterologie, Hospices Civils de Lyon, Pierre Benite/France

15 CHU de Bordeaux Hopital Haut-Leveque Dept. de Gastroenterologie, Pessac cedex/France

16 Gastroenterology, Hopital Saint-Louis APHP, Université Denis Diderot Paris 7 Paris/France

17 Gastroenterology Unit, Epimad Registry, Hôpital Charles Nicolle, Rouen University Hospital, Rouen/France

18 Gastroenterology And Nutrition, Centre Hospitalier Universitaire de Toulouse, Hopital Rangueil, Toulouse/France

19 Dept. Of Gastroenterology, Besançon university hospital gastroenterology, Courbevoie/France

20 Dept. Of Gastroenterology, CHU Beaujon Dept. of IBD and Nutrition, Clichy/France

Contact E-mail Address: sara.tadbiri@gmail.com

Introduction: Up to 50% of patients with inflammatory bowel disease (IBD) experience at least one extraintestinal manifestation (EIM), arthropathies being the most common one. EIM can also occur upon treatment with anti-TNF agents. Such paradoxical inflammation typically involving the skin is usually considered as a drug class effect and is reversible upon drug cessation. Vedolizumab (VDZ) is a humanized monoclonal antibody that specifically antagonizes α4β7 integrin and not TNF in a gut-specific manner. Whether or not VDZ is effective on EIM needs to be assessed.

Aims & Methods: Between June and December 2014, 173 patients with Crohn’s disease (CD) and 121 with ulcerative colitis (UC) were included in the OBSERV-IBD cohort study. Patients were followed up until week 54. Vedolizumab was administered intravenously, 300 mg every 8 weeks through week 54 and every 4 weeks in case of lack of efficacy. EIM was assessed at each visit at weeks 0, 6, 14, 22, 30 and 54. Efficacy of vedolizumab on EIM was estimated by using a 3-step scale: (1) complete remission meaning absence or almost absence of all clinical symptoms without increasing the steroid dose or introducing any other IBD-specific treatment (2) partial response meaning improvement of symptoms or reduction of the steroid dose without worsening of symptoms (3) no response, meaning no improvement or worsening of symptoms.

Results: Among the 294 patients with IBD, 50 (17.2%) presented with EIM at baseline including 46 (15.6%) with arthropathies and 5 (1.7%) with skin manifestations. At week 14, complete remission was observed in 24 (52.2%) patients with arthropathies and in 4 (80%) patients with skin manifestation. At week 54, 21 (45.7%) and 3 (60%) were still in complete remission for athropathies and skin manifestations, respectively. During the follow-up period, 32 (15.8%) patients without any EIM at baseline, presented with arthropathies. The probabilities of developing arthropathies during VDZ therapy was 5.2%, 10% 13.9% and 17.5% at weeks 14, 22, 30 and 54, respectively. In multivariate analysis, predictors of arthropathies occurrence were prior ankylosing spondylitis (OR = 3.70, IC95%[1.49–9.10], p = 0.005) and Crohn’s disease (OR = 2.50, IC95%[1.04–5.88], p = 0.04). During the follow-up period, 14 (4.8%) patients presented with paradoxical skin manifestation of whom 8 (57.1%) had previously experienced paradoxical skin manifestation associated with anti-TNF therapy. Among the 173 patients with Crohn’s disease, 35 (20.2%) presented with active perianal disease at baseline including 30 (17.3%) with perianal fistula and 5 (2.9%) with perianal fissure. At week 14, complete remission of perianal Crohn’s disease was observed in 15 (42.9%) of patients whereas partial remission was observed in 2 (5.7%) patients. At week 54, 12 (34.3%) patients were still in complete remission whereas 12 discontinued VDZ therapy and 13 had no response. Additionally, three patients presented with perianal disease during the follow-up period despite VDZ therapy.

Conclusion: VDZ therapy was effective for achieving complete resolution of EIM in patients with IBD in approximately half of the cases. VDZ was also effective for perianal CD in one third of the patients. Paradoxical skin manifestation may occur upon VDZ therapy suggesting as a class effect not restricted to anti-TNF agents.

Disclosure of Interest: L. Peyrin-Biroulet: Merck, Abbvie, Janssen, Genentech, Ferring, Norgine, Tillots, Vifor, Shire, Therakos, Pharmacosmos, Pilège, BMS, UCB-Pharma, Hospira, Celltrion, Takeda, Biogaran, Boerhinger-Ingelheim, Lilly, Pfizer, HAC-Pharma and Mitsubishi.

J. Filippi: Jerome Filippi has received consulting fees from Abbvie, Astellas Pharma, Covidien, Ferring, Jansen Cilag, MSD, Pfizer, and Takeda.

B. Pariente: Benjamin Pariente has received consulting fees from Abbvie, MSD and Pfizer. This author has also received speaking fees from Abbvie, MSD, Ferring, and Takeda.

X. Roblin: Xavier Roblin reported a relationship with Abbvie, MSD, Janssen Cilag, and Takeda.

A. Buisson: Anthony Buisson has received lecture fees from Abbvie, MSD, Ferring, Takeda, Hospira and Vifor Pharma. This author has also received a consulting fee from Abbvie.

C. Trang: Caroline Trang-Poisson has received lecture fees from MSD, Abbvie, Vifor Pharma and Norgine. This author has also received travel accommodations from Biogaran, Takeda, Hospira, MSD and Mayoly Spindler.

S. Nancey: Stephane Nancey has received consulting fees from Merck, Abbvie, Takeda, Ferring, Norgine, Vifor Pharma, Novartis, Janssen Cilag, Hospira, Takeda and HAC-Pharma.

D. Laharie: David Laharie has received consulting and lecture fees from AbbVie, Ferring, Janssen Cilag, MSD, Pfizer, and Takeda.

M. Allez: Matthieu Allez has received honoraria from Novo Nordisk, MSD, Abbvie, Ferring, Genentech, Janssen, Pfizer, GSK, Hospira, UCB, Novartis, Takeda, Mayolo-Spindler.

G. Savoye: Guillaume Savoye has received lecture fees from Vifor Pharma, Takeda, Pfizer, HAC Pharma, Abbvie, MSD, and Ferring France. This author has also received travel accommodations from Ferring, Abbvie, and MSD France as well as a research grant from Ferring.

L. Vuitton: Lucine Vuitton has received lecture fees from Abbvie, MSD, Takeda, Norgine, and Ferring. This author has also received consulting fees from Abbvie and Takeda.

Y. Bouhnik: BMS, Shire, Sanofi, Norgine Pharma, MSD, Abbvie, Astra Zeneca, Roche, Takeda Millenium and Janssen Cilag. This author also declares shareholding in Inception IBD, San Diego, CA, USA.

A. Amiot: AA has received consulting fees from AbbVie, Takeda, Gilead and Biocodex as well as lecture fees and travel accommodations from AbbVie, Biocodex, Ferring, Takeda and MSD and advisory board fee from Gilead, Takeda and Abbvie.

All other authors have declared no conflicts of interest.

OP185 HISTOLOGICAL FEATURES OF JOINT AND COLONIC INFLAMMATION IN INFLAMMATORY BOWEL DISEASE PATIENTS TREATED WITH ANTI-TNFA

S. Alivernini 1 , D. Pugliese 2 , B. Tolusso 1 , L. Petricca 1 , L. Bui 3 , L. Guidi 2 , G.L. Rapaccini 2 , F. Federico 3 , G. Ferraccioli 1 , A. Armuzzi 2 , E. Gremese 1

1 Institute of Rheumatology, Fondazione Policlinico Universitario A. Gemelli - Catholic University of the Sacred Heart, Rome, Italy, Rome/Italy

2 IBD Unit, Fondazione Policlinico Universitario A. Gemelli - Catholic University of the Sacred Heart, Rome, Italy, Rome/Italy

3 Institute of Pathology, Fondazione Policlinico Universitario A. Gemelli - Catholic University of the Sacred Heart, Rome, Italy, Rome/Italy

Contact E-mail Address: danipug@libero.it

Introduction: New onset of joint inflammation in patients under anti-TNFa for inflammatory bowel disease (IBD) has been previously described. However, histological characterization of synovial and bowel compartments has not been reported so far. Aim of the study was to evaluate the histological characteristics of paired synovial (ST) and colonic tissues in IBD patients under TNFa blockers.

Aims & Methods: Consecutive IBD patients without history of co-existing joint involvement who developed peripheral arthritis under TNFa blockers, were prospectively enrolled. Each patient underwent rheumatological evaluation and ultrasound (US) assessment (using Gray scale for synovial hyperthrophy and Power Doppler Signal) of the affected joints. Each patient underwent US guided ST biopsy of the knee, following a standardized procedure 1 and colonoscopy with mucosal biopsies. Each ST and colonic paired sample was stained through immunohistochemistry (IHC) for CD68, CD21, CD20, CD3 and CD117 2 . H&E staining was performed for Paneth cells identification. Clinical and immunological parameters [Anti-citrullinated peptides antibodies (ACPA), IgM-Rheumatoid Factor (RF) and IgA-RF respectively] were collected for each patient.

Results: 10 patients with IBD [46.0 ± 9.7 years old, 13.2 ± 9.9 years of disease duration, 2.5 ± 1.6 years of TNF-a blockers exposure, 6 with Crohn’s Disease and 4 with Ulcerative Colitis respectively] were studied. All patients were negative for ACPA, IgM-RF or IgA-RF and 4 patients were under Methorexate therapy. 5(50.0%) patients showed endoscopic and histologically proven inflammation of colonic mucosa. Moreover, IHC revealed that 6 (60.0%) patients had diffuse and 4 (40.0%) had follicular synovitis, respectively. In particular, there was a direct correlation between CD68 + , CD21 + , CD3 + , CD20 + and CD117 + cells distribution in paired ST and gut tissues in the whole cohort (p < 0.05). No significant differences in terms of disease duration (p = 0.48), TNF-a blockers exposure time (p = 0.29), ESR (p = 0.26) and CRP (p = 0.91) values were found comparing patients with follicular and diffuse synovitis respectively.

Conclusion: Our findings suggest that patients with IBD may develop histologically proven synovitis during TNF-a treatment, showing similar histological features in terms of CD68 + , CD21 + , CD20 + , CD3 + and CD117 + cells between synovial and colonic compartments. Molecular mechanisms triggered by TNF-a blockers leading to joint inflammation have to be clarified.

Disclosure of Interest: D. Pugliese: Lecture fees from AbbVie and Takeda.

L. Guidi: Lecture fees by AbbVie, MSD, Mundipharma, Takeda, Zambon

A. Armuzzi: Lecture fee(s) from: Abbvie, Astra-Zeneca, Chiesi, Ferring, MSD, Otsuka, Takeda, Zambon; Consultancy for: Abbvie, Hospira, Lilly, MSD, Mundipharma, Sofar, Takeda; Grant for research from MSD.

All other authors have declared no conflicts of interest.

References

1. van de Sande MJT et al. Ann Rheum Dis 2011.

2. Alivernini S. et al. Nat Communications 2016.

OP186 LONG-TERM EFFICACY AND SAFETY OF USTEKINUMAB IN REFRACTORY CROHN’S DISEASE PATIENTS: A MULTICENTER RETROSPECTIVE EXPERIENCE

P. Wils 1 , Y. Bouhnik 2 , P. Michetti 3 , B. Flourie 4 , H. Brixi 5 , A. Bourrier 6 , M. Allez 7 , B. Duclos 8 , J. Grimaud 9 , A. Buisson 10 , A. Amiot 11 , M. Fumery 12 , X. Roblin 13 , L. Peyrin-Biroulet 14 , J. Filippi 15 , G. Bouguen 16 , V. Abitbol 17 , B. Coffin 18 , M. Simon 19 , D. Laharie 20 , B. Pariente 1

1 Gastroenterology Unit, Hôpital Huriez, Lille University Hospital, Lille/France

2 Dept. Of Gastroenterology, CHU Beaujon Dept. of IBD and Nutrition, Clichy/France

3 Division Of Gastroenterology, La Source-Beaulieu Crohn´s and Colitis Center Dept. of Gastroenterology - Division of Gastroenterolo, Lausanne/Switzerland

4 Gastroenterology, Lyon-Sud University Hospital, Pierre Benite/France

5 Hépato-gastroenterologiee, Hôpital Robert Debré, Reims Cedex/France

6 Gastroenterology, Saint Antoine Hospital, Paris/France

7 Gastroenterology, Hopital Saint-Louis APHP, Université Denis Diderot Paris 7 Paris/France

8 Hôpitaux Universitaires de Strasbourg, Courbevoie Cedex/France

9 Gastroenterology, Marseille Hospital, Marseille/France

10 Dept. Of Gastroenterology, CHU Estaing Clermont-Ferrand, Clermont-ferrand/France

11 Dept. Of Gastroenterology, Henri Mondor Hospital, APHP Dept. of Gastroenterology, Creteil/France

12 Gastroenterology, Amiens University Hospital, Amiens/France

13 University of St. Etienne Dept. de Gastroenterologie, Saint Etienne/France

14 Department Of Gastroenterology, Nancy University Hospital Inserm U954 Dept. of Hepato-Gastroenterology, Vandoeuvre les Nancy/France

15 Dept. De Gastroenterologie, Hopital de lAchet Dept. de Gastroenterlogie Dept. de Nutrition Oncologie, Nice Cedex/France

16 Gastroenterology, CHU Rennes, Rennes/France

17 Hopital Cochin Gastroentérologie, Paris Cedex/France

18 Gastroenterology, Hopital Louis Mourier Dept. de Gastroentérologie, Colombes Cedex/France

19 Gastroenterology, Institut Mutualiste Montsouris, Paris/France

20 Gastroenterology, CHU de Bordeaux Hopital Haut-Leveque Dept. de Gastroenterologie, Pessac cedex/France

Contact E-mail Address: pauline.wils@chru-lille.fr

Introduction: Ustekinumab, a monoclonal antibody targeting the p40 subunit of interleukin-12 and interleukin-23, has been shown to be effective in Crohn's disease (CD) patients in phase III trials. However, long-term outcome of ustekinumab in CD has never been evaluated. The aim of the present study was to evaluate the long-term efficacy and safety of ustekinumab and to identify predictive factors of ustekinumab failure-free survival in a cohort of anti-TNF refractory CD patients.

Aims & Methods: We performed a retrospective study in 20 tertiary centers from the GETAID, including all patients who received subcutaneous (SC) ustekinumab for an active CD from March 2011 to December 2014 and were followed until November 2016. The primary outcome was ustekinumab failure-free; failure was defined as withdrawal of ustekinumab due to loss of response, intolerance or need of surgery. Predictive factors of ustekinumab failure-free survival at 24 months, and safety data were also evaluated.

Results: Until December 2014, 122 CD patients received SC ustekinumab induction. Eighty-eight patients responded to ustekinumab during the first year and were followed until November 2016. Among these patients (64 females, median age: 32.5 years), median disease duration at baseline was 11.8 years (IQR: 7.7–17.1); all patients have failed to at least one anti-TNF agent. At time of ustekinumab introduction, 13 (14.8%) patients received immunosuppressant (IS) and 13 (14.8%) steroids. Median time on ustekinumab was 26.6 (13.4–34.4) months. Ustekinumab failure-free survival was observed in 78.4% at 12 months, 65.8% at 24 months and 54.7% at 36 months. Ustekinumab discontinuation was observed for loss of response in 30.6% (27 patients), for intolerance in 5.6% (5 patients), for remission in 5.6% (5 patients), and for pregnancy in one patient. Sixteen (18.2%) patients underwent intestinal resection during the follow-up. In univariate analysis, concomitant IS at time of ustekinumab introduction and female sex were associated with ustekinumab failure-free survival at 24 months, but not significantly (p = 0.07;IC95%(1.2–24.8) and p = 0.05;IC95%(0.11–1.05), respectively). In multivariate analysis, no predictive factor of ustekinumab failure-free survival was identified. An adverse event occurred in 20 patients (22.7%). One anal adenocarcinoma was reported during follow-up.

Conclusion: We here report the first real-life experience of long-term outcome of ustekinumab treatment in CD refractory patients, with a median follow-up of more than 2 years. More than 50% of patients maintained ustekinumab during the follow-up without loss of response, intolerance or surgery, with a good safety profile. No predictive factor of ustekinumab failure-free survival was identified in multivariate analysis.

Disclosure of Interest: P. Wils: Janssen

All other authors have declared no conflicts of interest.

OP187 USEFULNESS OF COMBINATION THERAPY WITH ADALIMUMAB AND IMMUNOMODULATORS IN PATIENTS WITH CROHN’S DISEASE: A LARGE, MULTI-CENTRE COHORT STUDY

H. Tanaka 1 , N. Kamata 2 , A. Yamada 3 , T. Fujii 4 , K. Endo 5 , T. Yoshino 6 , S. Bamba 7 , T. Sugaya 8 , T. Kawaguchi 9 , M. Ishii 10 , S. Shinzaki 11 , Y. Toya 12 , Y. Yanai 13 , Y. Yokoyama 14 , J. Umeno 15 , T. Okada 16 , T. Kobayashi 17 , M. Nojima 18 , T. Hibi 17

1 IBD Center, Sapporo Kosei General Hospital, Sapporo/Japan

2 Department Of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka/Japan

3 Department Of Internal Medicine, Toho University Sakura Medical Center, Sakura/Japan

4 Department Of Gastroenterology And Hepatology, Tokyo Medical and Dental University, Tokyo/Japan

5 Division Of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai/Japan

6 Department Of Gastroenterology And Hepatology, Graduate School of Medicine, Kyoto University, Kyoto/Japan

7 Division Of Gastroenterology, Shiga University of Medical Science, Shiga/Japan

8 Department Of Gastroenterology, Dokkyo Medical University, Mibu/Japan

9 Department Of Internal Medicine, Division Of Ibd, Tokyo Yamate Medical Center, Tokyo/Japan

10 Department Of Internal Medicine, Division Of Gastroenterology, Kawasaki Medical School, Kurashiki/Japan

11 Department Of Gastroenterology And Hepatology, Osaka University Graduate School of Medicine, Suita/Japan

12 Division Of Gastroenterology, School of Medicine, Iwate Medical University, Morioka/Japan

13 Department Of Gastroenterology, Oita Red Cross Hospital, Oita/Japan

14 Division Of Internal Medicine, Department Of Inflammatory Bowel Disease, Hyogo College of Medicine, Nishinomiya/Japan

15 Department Of Medicine And Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka/Japan

16 Second Department Of Internal Medicine, Osaka Medical College, Takatsuki/Japan

17 Center For Advanced IBD Research And Treatment, Kitasato University Kitasato Institute Hospital, Tokyo/Japan

18 Center For Translational Research, The Institute Of Medical Science, The University of Tokyo, Tokyo/Japan

Contact E-mail Address: hirokit@mtc.biglobe.ne.jp

Introduction: The benefits of combination therapy with adalimumab and immunomodulators for patients with Crohn’s disease (CD) is still open to debate.

Aims & Methods: The aim of this study was to investigate the usefulness of combination therapy with adalimumab and immunomodulators based on the long-term retention rate of those who participated in the Adalimumab Japanese Multi-centre Cohort Study of Crohn’s Disease (ADJUST). The ADJUST study is a retrospective multi-centre cohort study conducted at 41 institutions in Japan. Data were retrospectively collected from all patients with CD who had received at least one induction dose of 160 mg of adalimumab between October 2010 and December 2013. Patients with active CD who received adalimumab for induction of remission were included, while those with inactive CD who started on adalimumab for prevention of postoperative recurrence or for unknown reasons were excluded. The cumulative rates of retention following the first administration of adalimumab were estimated by the Kaplan–Meier method. Prognostic factors related to the cumulative retention rates of adalimumab were evaluated by multivariate Cox regression analysis. We also compared the cumulative rates of retention between the groups with/without immunomodulators stratified by potential confounding factors.

Results: A total of 970 patients (median age, 33.6 years; female, 31%) were included in the study. The median duration of CD was 7.5 years. Forty-three percent of the patients had undergone at least 1 intestinal resection. The median C-reactive protein (CRP) and albumin levels of the patients were 0.90 mg/dL and 3.7 g/dL, respectively. Concomitant treatment with immunomodulators and prednisolone was administered to 37% and 16% of the patients, respectively. Forty-nine percent of the patients had been previously treated with infliximab. The 1-, 2-, 3- and 4-year cumulative retention rates of adalimumab were 78%, 69%, 62% and 58%, respectively. In the multivariate Cox regression analysis, female sex, perianal disease, lower albumin levels, concomitant treatment with prednisolone and previous infliximab use were identified as independent predictors for discontinuation of adalimumab, whereas concomitant treatment with immunomodulators was a prognostic factor for higher retention rate of adalimumab. According to the stratified analyses, combination therapy with adalimumab and immunomodulators significantly improved the cumulative retention rates in patients with CRP levels of ≥4.00 mg/dL and those receiving concomitant treatment with prednisolone, especially patients previously treated with infliximab.

Conclusion: Our data suggested that combination therapy of adalimumab and immunomodulators significantly increased the retention of adalimumab, especially in infliximab-treated CD patients with higher CRP levels and those who received concomitant treatment with prednisolone at initiation of adalimumab treatment.

Disclosure of Interest: H. Tanaka: H. Tanaka has received lecture fees from Mitsubishi Tanabe Pharma, AbbVie, EA Pharma and Eisai.

A. Yamada: A. Yamada has received lecture fees from AbbVie and EA Pharma.

T. Fujii: T. Fujii has received a research grant from Eisai.

S. Shinzaki: S. Shinzaki has received lecture fees from Mitsubishi Tanabe Pharma, AbbVie, EA Pharma and Eisai.

T. Kobayashi: T. Kobayashi has received research grant and lecture fee from EA Pharma; lecture fee from AbbVie.

T. Hibi: T. Hibi has received research grants and lecture fees from AbbVie and EA Pharma.

All other authors have declared no conflicts of interest.

OP188 SPACING OF INFLIXIMAB THERAPY IN PATIENTS WITH INFLAMMATORY BOWEL DISEASES IN CLINICAL REMISSION: PRELIMINARY RESULTS OF A RETROSPECTIVE MULTICENTRE FRENCH NATIONAL COHORT

G. Dufour 1 , B. Pariente 2 , R. Altwegg 1 , L. Caillo 3 , J. Valats 1 , M. Bismuth 1 , J. Bourgaux 3 , L. Peyrin-Biroulet 4 , P. Desreumaux 5 , P. Pouderoux 3 , P. Blanc 1 , G. Pineton De Chambrun 1

1 Gastroenterology, Montpellier University Hospital, Montpellier/France

2 Gastroenterology Unit, Hôpital Huriez, Lille University Hospital, Lille/France

3 Gastroenterology, Nimes University Hospital, Nîmes/France

4 Department Of Gastroenterology, Nancy University Hospital Inserm U954 Dept. of Hepato-Gastroenterology, Vandoeuvre les Nancy/France

5 Gastroenterology department, CHRU Lille, Université Lille 2 Lille/France

Contact E-mail Address: g-dufour@chu-montpellier.fr

Introduction: Infliximab (IFX) is efficient to maintain clinical remission in patients with inflammatory bowel diseases (IBD) refractory to conventional therapies. To date, there is no clear guideline regarding the withdrawal of anti-TNF agents and the majority of IBD patients are treated with IFX for long term. An alternative to withdrawal of IFX may be the spacing of IFX infusion interval. This strategy was only evaluated in a large prospective controlled trial in rheumatoid arthritis patients with interesting results (Fautrel B, Ann Rheum Dis , 2016).

Aims & Methods: The primary aim of this study was to evaluate the effect of a spacing of IFX infusion interval on the maintenance of clinical remission in IBD patients. Secondary aims of this study were to evaluate the occurrence of allergic reactions to IFX after spacing and the efficacy of IFX intensification after clinical relapse. This was a retrospective multicenter French national cohort including all IBD patients treated with infliximab who were in clinical remission according to the referring physician and had a spacing of their infusion interval over 9 weeks for at least two consecutive infusions. Clinical relapse after spacing according to referring physician and leading to IFX intensification was considered as primary endpoint. The clinical efficacy of IFX intensification after spacing and occurrence of drug reactions were also monitored.

Results: Eighty-nine patients were included in the study (61 patients with Crohn’s disease [CD] and 28 with an ulcerative colitis [UC]). Median delay between IFX introduction and spacing was 35.6 months (IQR: 17.6–64). Thirty-five (39%) patients were already treated with an immunosuppressive drug (thiopurine or methotrexate) at the time of IFX spacing. Maximum infusion interval spacing was of 13 weeks and 41 patients (46%) had infusion interval spacing ≥12 weeks. Cumulative probability of clinical relapse-free survival after spacing was 82.7% ± 4.1 and 72.6% ± 4.9 at one and two years, respectively. All IBD patients with a clinical relapse after spacing had an intensification of IFX therapy (n = 27) with a clinical response in 89% of patients. Only one patient had to withdrawal IFX therapy after clinical relapse due to IFX allergic reaction occurring three years after spacing. Regarding clinical relapse, the median delay between IFX introduction and spacing of infusion interval was significantly shorter in IBD patients with clinical relapse compared to patients without clinical relapse (22.9 months [IQR: 13.3–42] vs. 41.3 months [IQR: 22.5–67.1], respectively, p = 0.027). For CD patients, in univariate analysis, a delay >4 years between IFX introduction and spacing was significantly associated to the maintenance of clinical remission after spacing (RR = 0.26; CI 95%: 0.07–0.89, p = 0.032). For UC patients, radiologic inflammatory activity before spacing was associated to clinical relapse after spacing (RR = 13.9; CI 95%: 1.24–157.1, p = 0.033). In multivariate analysis, a delay >4 years between IFX introduction and spacing (RR 0.36, CI 95%: 0.19–0.68, p = 0.002), concomitant treatment with an immunosuppressant (RR = 0.31; CI 95%: 0.11–0.85, p = 0.022) and penetrating phenotype (RR = 0.57; CI 95%: 0.34–0.97, p = 0.039) were significantly associated to the maintenance of clinical remission after spacing in CD patients.

Conclusion: After spacing of IFX infusions over 9 weeks more than 70% of IBD patients remained in clinical remission over two years. Only one patient stopped IFX for allergic reaction after clinical relapse and IFX intensification. A short delay between IFX introduction and spacing seems to be a good predictive factor of clinical relapse after spacing, at least in CD. The collection and analysis of data from a larger national cohort is ongoing.

Disclosure of Interest: L. Peyrin-Biroulet: Merck, Abbvie, Janssen, Ferring, Norgine, Tillots, Vifor, Therakos, Pharmacosmos, Pilège, BMS, UCB-pharma, Hospira, Takeda, Biogaran, Pfizer, HAC-Pharma

G. Pineton de Chambrun: Lecture fees: Abbvie, Takeda, MSD, Ferring Consulting fees: Takeda, Tillots Pharma

All other authors have declared no conflicts of interest.

OP189 HIGHER RATE OF CORTICORESISTANCE AND CORTICODEPENDENCE IN ELDERLY-ONSET UC PATIENTS DIAGNOSED <70 YEARS COMPARED TO ≥70 YEARS OF AGE: A POPULATION-BASED STUDY

D. Duricova 1 , H. Sarter 1 , M. Fumery 2 , A. Leroyer 1 , C. Charpentier 3 , B. Pariente 4 , L. Armengol-Debeir 5 , L. Peyrin-Biroulet 6 , C. Gower-Rousseau 1 , G. Savoye 5

1 Public Health, Epidemiology And Economic Health, Registre Epimad, Maison Régionale De La Recherche Clinique, Lille University and Hospital, Lille/France

2 Gastroenterology Unit, Epimad Registry, CHU Amiens Sud, Avenue Laennec-Salouel, Amiens University Hospital, Amiens/France

3 Gastroenterology Unit, Epimad Registry, Hôpital Charles Nicolle, Rouen University Hospital, Rouen/France

4 Gastroenterology Unit, Hôpital Huriez, Lille University Hospital, Lille/France

5 Gastroenterology Unit, Epimad Registry, Hôpital Charles Nicolle, Rouen University Hospital, Rouen/France

6 Gastroenterology Unit, Inserm U954, Nancy University and Hospital, Nancy/France

Contact E-mail Address: Benjamin.PARIENTE@chru-lille.fr

Introduction: Recent French population-based study reported that elderly-onset patients with Crohn's disease diagnosed over age of 70 years have different disease course regarding localization, disease progression and exposure to medication than patients aged 60–69 years (1).

Aims & Methods: The aims of this study was to assess whether the disease phenotype and long-term outcome also differs in elderly-onset (ulcerative colitis) UC diagnosed before and after the age of 70 years. Elderly-onset UC patients (≥60 years at diagnosis) from a French prospective population-based Registry (EPIMAD) were included. Demographic and clinical data at diagnosis and at maximal follow-up were collected using predefined questionnaire.

Results: 468 elderly-onset UC patients were included (median follow-up 6.2 years) of whom 277 (59%) were <70 years and 191 (41%) ≥70 years at diagnosis. Male gender was more frequent in patients <70 years than in older individuals (54% vs. 65%; p = 0.01) while patients ≥70 years had higher rate of left-sided colitis than younger ones (63% vs. 49%; p = 0.02). The 1 and 5-year cumulative probabilities of medication exposure were similar between the two age groups (5-aminosalicylic acid: 60% vs. 70% and 77% vs. 77%, p = 0.75; corticosteroids: 19% vs. 23% and 30% vs. 34%, p = 0.54; immunosuppressants: 3% vs. 2% and 10% vs. 9%, p = 0.78). However, patients <70 years compared to older individuals experienced significantly more corticoresistance (12% vs. 3%, p = 0.03) and tended to be more corticodependent (24% vs. 16%, p = 0.08). Only 4 patients received anti-TNFa therapy, 3 of them diagnosed <70 years. The rate of surgery was not influenced by age at diagnosis (1 and 5 year risk: 6% vs. 4% and 10% vs. 6%, p = 0.39).

Conclusion: Elderly-onset UC is heterogeneous group of patients with respect to disease phenotype and prognosis. Patients ≥70 years at diagnosis had higher frequency of left-sided colitis than younger ones. Importantly, patients diagnosed <70 years had more severe disease course in terms of higher rate of corticoresistance and corticodependence than those ≥70years.

Disclosure of Interest: All authors have declared no conflicts of interest.

Reference

1. Fumery et al., Natural history of Crohn´s disease in elderly patients diagnosed over the age of 70 years: a population-based study. Inflamm Bowel Dis 2016; 22: 1698–1707.

TUESDAY, OCTOBER 31, 201710:30-12:00

EVIDENCE-BASED MANAGEMENT OF BARRETT'S AND OESOPHAGEAL ADENOCARCINOMA - ROOM B2____________________

OP190 INCIDENCE OF MALIGNANT PROGRESSION IN PERSISTENT NONDYSPLASTIC BARRETT'S ESOPHAGUS - A DUTCH NATIONWIDE COHORT STUDY

Y. Peters 1 , J. Honing 1 , W. Kievit 2 , C. Kestens 3 , W. Pestman 4 , I.D. Nagtegaal 5 , P.D. Siersema 6

1 Gastroenterology And Hepatology, Radboud UMC, Nijmegen/Netherlands

2 Radboud Institute For Health Science, Radboud University Medical Center, Nijmegen/Netherlands

3 University Medical Center Utrecht Gastroenterology, Utrecht/Netherlands

4 Department For Health Evidence, Radboud University Medical Center, Nijmegen/Netherlands

5 Radboud University Nijmegen Medical Center, Radboud University Nijmegen Medical Center Dept. of Pathology, Nijmegen/Netherlands

6 Gastroenterology & Hepatology, University Merdical Center Gastroenterology & Hepatology - Gastroenterology & Hepatology, University, Nijmegen/Netherlands

Contact E-mail Address: y.peters@radboudumc.nl

Introduction: The risk of esophageal adenocarcinoma (EAC) in patients with non-dysplastic Barrett’s esophagus (NDBE) may have been overestimated in some studies. Lower progression rates could lead to changes in the current surveillance strategy, thereby reducing its associated risks and costs.

Aims & Methods: The aim of this study was to evaluate whether persistence of NDBE during consecutive surveillance endoscopies identifies patients at a very low risk for malignant progression. In this population-based retrospective study, patients with a first diagnosis of NDBE between 2003 and 2012 were selected using the Dutch nationwide registry of histopathology (PALGA). Patients were followed until the development of EAC or high-grade dysplasia (HGD), or until the last endoscopy contact with biopsy sampling (through May 2016). Incidence rates and rate ratios for EAC and HGD/EAC combined were calculated to evaluate whether persistence of NDBE during consecutive endoscopies and progression-free time reduce the risk of malignant progression.

Results: In this study, 12,729 patients with NDBE were included, with a total follow-up of 64,563 (median 4.4 (IQR 3.0 – 6.8)) years. Malignant progression was seen in 437 patients (3.4%) after a median follow-up of 5.1 years (IQR 3.2 – 7.3). This resulted in an overall progression rate to EAC of 0.47 (95% CI: 0.42 – 0.53) per 100 person-years and a progression rate to HGD/EAC combined of 0.68 (95% CI: 0.62 – 0.74) per 100 person-years. At first follow-up endoscopy after a median of 2.3 years (IQR 1.8 – 3.2), 11,782 patients (93%) were found to have persistent NDBE, whereas 727 (5.7%) and 220 (1.7%) patients showed progression to low-grade dysplasia and HGD/EAC, respectively. In patients with two consecutive endoscopies showing NDBE after a median of 2.8 years (IQR 1.8 – 4.0), the malignant progression rate was 0.52 (95% CI: 0.40 – 0.67) per 100 person-years (RR 0.61 (95% CI: 0.45 – 0.81)) versus 0.86 in patients after one endoscopy. Patients with five consecutive non-progressive endoscopies had a 60% rate reduction (RR 0.40 (95% CI: 0.13 – 0.97)) for development of EAC (progression rate: 0.34 (95% CI: 0.11- 0.41) per 100 person-years). The incidence of EAC decreased with 30% (adjusted HR 0.71, 95%: CI: 0.67 – 0.75 for each year of FU without progression (progression-free time).

Conclusion: Persistent NDBE at two consecutive surveillance endoscopies reduces the risk of malignant progression towards HGD/EAC by approximately twofold. As progression risk reduces even further after more consecutive negative follow-up endoscopies, this study contributes to the growing evidence that surveillance intervals in subgroups of patients with persistent BE might be lengthened and/or that surveillance may be discontinued at an earlier endpoint than currently recommended.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP191 MULTICENTER FEASIBILITY STUDY OF COMBINED INJECTION AND ARGON PLASMA COAGULATION (HYBRID-APC) IN THE ABLATION THERAPY OF NEOPLASTIC BARRETT ESOPHAGUS

T. Rösch 1 , H. Manner 2 , A. May 3 , M. Knabe 3 , G. Schachschal 1 , H. Ehlken 1 , H. Neuhaus 4 , T. Beyna 4 , J.J. G. h.m. Bergman 5 , B.L. a.m. Weusten 6 , O. Pech 7 , S. Faiss 8 , M. Anders 9 , C. Ell 3

1 Department Of Interdisciplinary Endoscopy, University Medical Center Hamburg-Eppendorf, Hamburg/Germany

2 Dept. Of Internal Medicine II, HSK Wiesbaden, Wiesbaden/Germany

3 Medical Clinic II, Sana Klinikum Offenbach, Offenbach/Germany

4 Dpt. Of Internal Medicine, Evangelisches Krankenhaus Düsseldorf, Düsseldorf/Germany

5 Gastroenterology & Hepatology, Academic Medical Centre - Gastroenterology & Hepatology, Academic Medical Centre; Amsterdam/NL, Amsterdam/Netherlands

6 Departement Of Gastroenterology And Hepatology, St Antonius Hospital, Nieuwegein/Netherlands

7 Klinik Für Gastroenterologie Und, Krankenhaus Barmherzige Brüder Klinik für Gastroenterologie und Interventionelle Endoskopie - Klinik, Regensburg/Germany

8 Dept. Of Gastroenterology And Interventional Endoscopy, Asklepios Hospital Barmbek, Hamburg/Germany

9 Dept. Of Gastroenterology And Interdisciplinary Endoscopy, Vivantes Hospital Wenckebach, Berlin/Germany

Contact E-mail Address: t.roesch@uke.de

Introduction: Neoplastic Barrett esophagus (BE) is currently treated by a combined endoscopic resection and ablation therapy of the entire BE. For the ablation part, argon plasma coagulation (APC) had recently been introduced in a combination with prior submucosal injection (Hybrid-APC, H-APC) and reached results in a range comparable to radiofrequency ablation (RFA) in a small pilot study.

Aims & Methods: Multicenter study in 9 European centers on patients with biopsy proven neoplastic BE. Therapy consisted of combination of endoresection (EMR/ESD) plus maximum of 5 H-APC sessions for visible lesions and/or cancer diagnosis, or of exclusive ablation for neoplastic BE (LGIN/HGIN) without visible lesions at the discretion of the endoscopists. Immediate therapeutic success was defined as one follow-up endoscopy showing normal endoscopic neo-Z-line with negative biopsies.

Results: 106 of 164 included patients (92 male, 14 female, mean age 63, 8 years) completed therapy and had 3-month follow-up. Final diagnoses were mucosal cancer (n = 66), high-grade (HGIN, n = 17), low-grade dysplasia (LGIN n = 21) and normal BE (n = 1). Therapy consisted of combined resection and ablation (n = 94) or exclusive ablation (n = 12) with a mean number of H-APC sessions of 2.5 (range 1–5). Short-term treatment outcome: Endoscopic treatment success (normal Z line) was seen in 80 cases, but in 4 cases histopathology showed intestinal metaplasia (minor residual BE disease) or (n = 1) residual cancer. 20 further cases had unclear endoscopy (minor residual BE possible) but negative biopsies. Failure was seen in 6 cases, 4 of whom had minor residual BE and 2 had macroscopic and histologic diagnosis of complete ablation failure. Based on histopathologic proof, short-term eradication rates were 91, 5% (97/106). Treatment for minor residual BE is currently ongoing in some patients of the entire cohort (n = 164): Immediate complications: bleeding n = 2, post-procedure fever n = 9 and 1 perforation treated conservatively by clipping. Strictures requiring dilatation: n = 5.

Conclusion: H-APC appears to be feasible and safe and has a short-term efficacy of 92% in this interim analysis; final results of this large prospective study have to be awaited. The comparative value of H-APC to alternative methods such as RFA is then to be assessed in a prospective randomized trial.

Disclosure of Interest: T. Rösch: Erbe Co. supported the study with study Nurse Support. T. Rösch has a cooperation contract for Research Support covering this and other projects

H. Manner: Erbe Co. supported the performance of this study

A. May: Erbe Co. supported the performance of this study

M. Knabe: Erbe Co. supported the performance of this study

G. Schachschal: Erbe Co. supported the performance of this study

H. Ehlken: Erbe Co. supported the performance of this study

H. Neuhaus: Erbe Co. supported the performance of this study

T. Beyna: Erbe Co. supported the performance of this study

J.J.G.H.M. Bergman: Erbe Co. supported the performance of this study

B.L.A.M. Weusten: Erbe Co. supported the performance of this study

O. Pech: Erbe Co. supported the performance of this study

S. Faiss: Erbe Comp. supported the Performance of the study

M. Anders: Erbe Comp. supported the performance of this study

C. Ell: Erbe Comp. supported the performance of this study

OP192 SAFETY OF THE SIX-SHOOTER MULTIBAND MUCOSECTOMY DEVICE FOR ENDOSCOPIC RESECTION IN BARRETT’S ESOPHAGUS IN 4327 RESECTIONS: A RETROSPECTIVE INTERNATIONAL MULTICENTER STUDY

K. Belghazi 1 , M. A. Everson 2 , R. Haidry 2 , P. Kandel 3 , L.K. Mejia 3 , M.J. Bourke 4 , F. Bahin 4 , B.L. a.m. Weusten 5 , G.G. Ginsberg 6 , G. Ma 6 , A.D. Koch 7 , R.V. Milano 1 , S. Seewald 8 , K. Ragunath 9 , R. Bisschops 10 , J.J. G. h.m. Bergman 1 , R. E. Pouw 1

1 Gastroenterology, Academic Medical Center, Amsterdam/Netherlands

2 Gastroenterology, University College Hospital, London/United Kingdom

3 Gastroenterology, Mayo Clinic Florida, Jacksonville/United States of America

4 Gastroenterology And Hepatology, Westmead Hospital, University of Sydney, Sydney/Australia

5 Gastroenterology, St Antonius Hospital, Nieuwegein/Netherlands

6 Gastroenterology, University of Pennsylvania, Philadelphia, PA/United States of America

7 Erasmus MC - University Medical Center Rotterdam, Rotterdam/Netherlands

8 Gastroenterology, GastroZentrum Hirslanden, Klinik Hirslanden, Zurich/Switzerland

9 Gastroenterology, Queens Medical Centre campus Nottingham University Hospitals, Nottingham/United Kingdom

10 Gastroenterology, UZ Gasthuisberg, Leuven/Belgium

Contact E-mail Address: k.belghazi@amc.uva.nl

Introduction: Endoscopic resection (ER) is an important treatment modality for patients with Barrett’s esophagus (BE) containing high-grade dysplasia (HGD) or early cancer. The most widely used device for ER is the six-shooter multi-band mucosectomy (MBM) device. This six-shooter consists of a modified variceal band ligator and requires no submucosal lifting or prelooping of a snare in the cap. A randomized study demonstrated that MBM with the six-shooter was equally effective and safe as ER with the classic cap-technique, but significantly faster and cheaper. However, large studies enabling accurate assessment of the associated complication risk are lacking.

Aims & Methods: The aim of this investigator-initiated non-sponsored study was to assess safety of ER with MBM using the six-shooter in BE in a large patient cohort. We retrospectively analyzed all patients treated with MBM using the six-shooter for ER in BE in 9 international tertiary referral centers for Barrett’s neoplasia. Primary outcome: perforation rate. Secondary outcomes: significant bleeding rate (defined as bleeding requiring an intervention), stricture rate, macroscopically radical resection rate (defined as complete resection of the target area, including all delineation markings).

Results: Between 2001 and 2017 a total of 1510 MBM procedures with the six-shooter were performed in 1100 patients (921 men, median 68 yrs, median BE C2M4) for the following indications: focal lesion suspicious for neoplasia (n = 961), diffuse HGD (n = 190), part of radical ER protocol (n = 213), escape treatment after endoscopic ablation (n = 29). A median of 3 (IQR 2–4) resections were performed per procedure, with a total of 4327 resections in this study. The median diameter of the ER specimens was maximum of 13 mm (IQR 10–16) and a minimum of 9 mm (IQR 6–12). Worst pathology was cancer in 511, HGD in 499, low-grade dysplasia in 209, and no-dysplasia in 267 procedures. In 9/1510 (0.6%, 95% CI 0.32% – 1.1%) MBM procedures a perforation occurred, treated with clips (n = 6), a stent (n = 2) or conservative treatment (n = 1). No surgery was required. Significant bleeding was seen in 7.1% (95% CI 5.9% – 8.5%) of MBM procedures and 8.3% (95% CI 6.8% – 10%) of the patients developed a stricture, requiring a median of 2 dilatations. Macroscopically radical resection of the target lesion was achieved in 92%.

Conclusion: This is the largest study on MBM using the six-shooter for ER in BE. This study therefore provides the most accurate assessment of the risk of serious complications associated with this procedure. Our results show that MBM using the six-shooter is a safe and effective procedure with a low rate of perforation of 0.6% (95% CI 0.32% – 1.1%), all of which could be managed endoscopically.

Disclosure of Interest: B.L.A.M. Weusten: Financial support for research: Covidien/Medtronic, C2Therapeutic.

A.D. Koch: Lecturing fees: Boston Scientific, COOK, ERBE, Olympus

S. Seewald: Consulting for Olympus and Boston Scientific.

K. Ragunath: Research support: Olympus, Pentax, Cook. Educational grants: Olympus, Cook, Boston Scientific, Medtronics, Erbe. Consultancy: Olympus, Boston Scientific.

J.J.G.H.M. Bergman: Research support: Olympus, Fujifilm, Erbe, Ninepoint Medical, C2 therapeutics, Cernostics, Interpace, Lumen-R, Medtronic, Boston Scientific. Speakers fee: Medtronic, Boston Scientific, Olympus, Fujifilm, WATTS-3D.

All other authors have declared no conflicts of interest.

OP193 ENDOSCOPIC SUBMUCOSAL DISSECTION FOR BARRETT’S EARLY NEOPLASIA: A SYSTEMATIC REVIEW AND META-ANALYSIS

D. Yang 1 , F. Zou 1 , S. Xiong 2 , J. J. Forde 3 , P.V. Draganov 1

1 Gastroenterology, University of Florida, Gainesville/United States of America/FL

2 Biostatistics, University of Florida, Gainesville/United States of America/FL

3 Medicine, University of Florida, Gainesville/United States of America/FL

Contact E-mail Address: dennis.yang@medicine.ufl.edu

Introduction: Endoscopic submucosal dissection (ESD) is an endoscopic technique that permits en-bloc resection of lesions, irrespective of size. Recent studies suggest that ESD is superior to endoscopic mucosal resection (EMR) in terms of en-bloc resection, curative resection rates, and local recurrence for tumors of the gastrointestinal tract, including esophageal adenocarcinoma (EAC). The role of ESD for the management of dysplastic Barrett’s esophagus (BE) and early EAC has not been fully evaluated.

Aims & Methods: We aimed to evaluate the safety and efficacy of ESD for visible dysplastic BE and EAC lesions. Methods: Systematic review and meta-analysis of studies published up to March 2017 that reported on clinical outcomes of ESD on BE early neoplasia. Three online databases (Medline, Ovid, Embase) were searched. Pooled means and proportions were computed. The Cochran’s Q test and I 2 were used to test for heterogeneity. If yes, then a fixed meta-analysis approach (FE Model) was applied; otherwise, random meta-analysis (RE Model) was used. For the main outcomes, evaluation for potential sources of heterogeneity were evaluated via meta-regression analysis.

Results: A total of 11 studies involving 501 patients (83% male; mean age 64.4) were included. The mean visible lesion size was 27 mm (95% confidence interval [CI] 20.9–33.1). Mean total procedure time was 107.5 minutes (95% CI 86.4–128.5). The pooled estimate for en-bloc resection was 92.9% (95% CI: 90.3 to 95.2%). The pooled R0 (negative lateral and deep margins for dysplastic BE and EAC) and curative resection rates were 74.5% (95% CI: 66.3 to 81.9%) and 64.9% (95% CI: 55.7 to 73.6%) respectively. There was significant heterogeneity found in both R0 (Cochran Q test P < 0.001, I 2 = 70.5) and curative (Cochran Q test P < 0.001, I 2 = 72.3) resection rates. However, there was no statistically significant association between R0 or curative resection rates and study location (Asia vs. Europe/United States), length of BE, lesion characteristics, procedural time or length of follow-up. The pooled estimate for adverse events such as perforation and bleeding were 1.5% (95% CI 0.4–3.0%) and 1.7% (95% CI 0.6–3.4%) respectively. The incidence of esophageal stricture formation was 11.6% (95% CI: 0.9–29.6%). All of these were managed successfully with endoscopic dilation. In aggregate, the estimated recurrence rate for dysplastic BE and EAC following curative resection was 0.17% (95% CI 0–0.3%) at a mean follow-up 22.9 months (95% CI: 17.5 to 28.3).

Conclusion: ESD is a safe endoscopic treatment option for BE early neoplasia associated with high-en bloc resection and R0 (complete) resection rates. The recurrence rate of dysplastic BE and EAC is low in patients with curative resection after ESD. Overall, ESD can be considered for the evaluation and management of visible neoplastic BE; especially for large lesions not amenable for en-bloc resection with standard EMR techniques.

Disclosure of Interest: All authors have declared no conflicts of interest.

References

Nehaus H, Terheggen G, Rutz EM. Endoscopy 2012; 44: 1105–1113.

Hoteya S, Matsui A, Lizuka T, et al. Digestion 2013; 87: 29–33.

Nagami Y, Machida H, Shiba M, et al. Endosc Int Open 2014; 02:E15-E20.

Kagemoto K, Oka S, Tanaka S, et al. Gastrointest Endosc 2014; 80:239–245.

Probst A, Aust D, Markl B, et al. Endoscopy 2015; 47: 113–121.

Chevaux JB, Piessevaux H, Jouret-Mourin A, et al. Endoscopy 2015; 47: 103–112.

Hobel S, Dautel P, Baumbach R, et al. Surg Endosc 2015; 29:1591–1597.

Barret M, Cao DT, Beuvon F, et al. United European Gastroenterol J 2016; 4:207–215.

Terheggen G, Horn EM, Vieth M, et al. Gut 2016; 0:1–11.

Yang D, Coman RM, Kahaleh M, et al. Gastrointest Endosc 2016 [Epub ahead of print].

Subramaniam S, Chedgy F, Wheaton GL, et al. Gastrointest Endosc 2017; [Epub ahead of print].

OP194 NEUTROPHIL LYMPHOCYTE RATIO AS PREDICTIVE MARKER OF SURVIVAL IN ESOPHAGEAL CANCER: SYSTEMATIC REVIEW AND META-ANALYSIS

G. Pirozzolo 1 , S.S. Gisbertz 2 , C. Castoro 1 , M.I. Van Berge Henegouwen 2 , M. Scarpa 1

1 Esophageal And Digestive Tract Surgical Unit, Regional Centre For Esophageal Disease, Veneto Institute of Oncology (IOV-IRCCS), Padova/Italy

2 Surgical Department, Academic Medical Centre, Amsterdam/Netherlands

Contact E-mail Address: giovanni.pirozzolo@gmail.com

Introduction: Several studies showed that a high preoperative Neutrophil-Lymphocyte Ratio (NLR) is a predictor of worse survival in many solid tumors, including esophageal cancer. Neutrophils are a consistent part of the peritumoral inflammatory cell infiltrate, called tumor-associated neutrophils (TANs). This infiltrate seems to be a direct result of cancer cells activity, suggesting that TANs are related to tumor growth. The aim of this systematic review and meta-analysis is to collect all the data about this marker in order to quantify its strength in esophageal cancer prognostication.

Aims & Methods: The meta-analysis was performed using the Preferred reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. We used inclusion criteria adapted from the REporting recommendations for tumor MARKer prognostic studies criteria. We conducted a comprehensive search of all prospective or observational studies reporting NLR prognostic data in esophageal cancer patients. The primary outcome measure was Overall Survival (OS) while Disease Free Survival (DFS) and Progression Free Survival (PFS) were secondary outcome measures. All included studies had a directly or indirectly available HR. We analyzed data using fixed effect model or random effect model depending on heterogeneity.

Results: We included in the quantitative synthesis 17 studies published between 2011 and 2017, comprising 5672 patients. The NLR cut-off value ranged from 2 to 5. Our analysis about OS of all included studies showed that a high preoperative NLR is an effective predictor of a worse survival (HR 1.72, p < 0.00001). Similar results were obtained about DFS (HR 1.94, p < 0.00001) and PFS (HR 1.66, p < 0.00001). We conducted sub-analysis both for cut-off ranges subgroups and treatment modality subgroups obtaining the same prognostic relevance.

Conclusion: Retrospective design of included study is the major bias. There is heterogeneity about treatment modalities, patients characteristics, duration of follow-up and cut-off threshold. Moreover, NLR has been proposed in several studies as a prognostic marker for non-oncological diseases, mostly heart disease. However, our meta-analysis confirmed that preoperative high NLR is associated with a worse outcome in esophageal cancer. Some issues about its clinical use are still unclear; first of all the most effective cut-off in survival prognostication, and its role in predicting postoperative complications.

Disclosure of Interest: All authors have declared no conflicts of interest.

References

Arigami T, (2015) Medicine (Baltimore)

Balkwill F and Mantovani A (2001), Lancet

Bui JD and Schreiber RD (2007), Curr Opin Immunol

Chua W, (2011) Br J Cancer

Cook EJ, (2007) Int J Surg

Cunningham D (2010) N Engl J Med

Duan H, (2015) World J Gastroenterol

Dutta S, (2011) World J Surg

Feng JF, (2014) World J Surg Oncol

Gregory AD and Houghton AM (2011) Cancer Res

Grenader T, (2016) Ann Oncol

Han LH, (2015) Asian Pac J Cancer Prev

Hirahara N, (2015) Eur J Surg Oncol

Ji WH, (2016) Dis Esophagus

Jung J, (2016) Tumour Biol

Liberati A, (2009) BMJ

Mantovani A, (2008) Nature

Miyata H, (2011) Exp Ther Med

Nakamura K, (2017) Int J Clin Oncol

Parmar MK, (1998) Stat Med

Shao Y, (2015) Sci Rep

Sharaiha RZ, (2011) Ann Surg Oncol

Templeton AJ, (2014) J Natl Cancer Inst

Xie X, (2016) Dis Esophagus

Yoo EJ, (2014) Dig Liver Dis

Yuan D, (2014) J Surg Oncol

Zhou XL, (2017) Sci Rep

OP195 THE OPTIMAL TIME INTERVAL BETWEEN NEOADJUVANT CHEMORADIOTHERAPY AND ESOPHAGECTOMY: A NATIONWIDE STUDY

L. R. Van Der Werf 1 , J. Dikken 2 , E. Van Der Willik 3 , M.I. Van Berge Henegouwen 4 , V. E.p.p. Lemmens 5 , G. A.p. Nieuwenhuijzen 6 , B.P.l. Wijnhoven 7 On Behalf Of The Dutch Upper Gi Cancer Audit Group 8

1 Oncological Surgery, Erasmus Medical Center, Rotterdam/Netherlands

2 Surgery, LUMC, Leiden/Netherlands

3 Methodology, Dutch Institute of Clinical Auditing, Leiden/Netherlands

4 Surgical Department, Academic Medical Centre, Amsterdam/Netherlands

5 Epidemiology, Erasmus Medical Centre, Rotterdam/Netherlands

6 Oncological Surgery, Catharina ziekenhuis, Eindhoven/Netherlands

7 Surgery, Erasmus MC Rotterdam Dept. of Surgery, Rotterdam/Netherlands

8 Dutch Institute for Clinical Auditing, Leiden/Netherlands

Contact E-mail Address: L.vanderwerf@dica.nl

Introduction: The most optimal timing of oesophagectomy after neoadjuvant chemoradiotherapy (nCRT) is unknown. Theoretically, an extended interval between nCRT and surgery might increase the chance of the best pathological respons: pathological complete respons (pCR) because of a prolonged effect of the nCRT and this might possibly improve disease-free and overall survival. Conversely, it is thought that an extended interval might lead to residual tumor outgrowth, a more difficult surgical resection, with a higher complication rate, and possibly a worse survival. The aim of this study was to assess the time interval between nCT and surgery in the Netherlands and to correlate this with pathological response of the tumor and surgical morbidity and mortality.

Aims & Methods: Patients with esophageal cancer treated with nCRT and surgery between 2011 and 2016 were selected from a national database of the Dutch Upper gastrointestinal Cancer Audit.(1) Differences in patient and treatment characteristics, tumor stage and morbidity/mortality after surgery were compared across six subgroups discriminated by the length between end of nCRT and surgery. To evaluate the association between the interval and pathological complete respons (pCR), intraoperative, postoperative complications and mortality, multivariable logistic regression analysis was used.

Results: In total 3102 patients were included. The median [interquartile range] time interval between the end of nCT and surgery was 8 [7–10] weeks. The interval between end of nCRT and surgery was divided into six (A-F) groups: 0–5 weeks (A; n = 157), 6–7 weeks (B; n = 878), 8–9 weeks (C; n = 972), 10–12 weeks (D; n = 720), 13–14 weeks (E; n = 195) and 15 or more weeks (F; n = 180). In intervals E and F, there were significantly more patients with ASA III+ and with proximal to mid-esophageal tumors. The pCR rate in group A to F was 31%, 28%, 26%, 31%, 40%, and 37%, respectively. In multivariable analysis, a longer interval (groups D-F for adenocarcinoma and groups E and F for squamous cell carcinoma) was associated with a higher probability of a pCR. These groups had the same probability for intraoperative and severe postoperative complications. The extended interval groups were associated with higher total postoperative complications (E and F) and mortality (D and F).

Conclusion: An extended interval (≥10 weeks for adenocarcinoma and ≥12 weeks for squamous cell carcinoma) between nCRT and esophagectomy is associated with a higher probability of a pCR and does not lead to a higher occurrence of intraoperative and severe complications. We suggest that the higher total postoperative complications and mortality is due to selection bias.

Disclosure of Interest: All authors have declared no conflicts of interest.

Reference

Busweiler LA, Wijnhoven BP, van Berge Henegouwen MI, et al. Early outcomes from the Dutch Upper Gastrointestinal Cancer Audit. Br J Surg . 2016;103(13):1855–1863.

TUESDAY, OCTOBER 31, 201710:30-12:00

H. PYLORI: TREATMENT AND ANTIBIOTIC RESISTANCE - ROOM 7.1____________________

OP196 HELICOBACTER PYLORI ERADICATION AND THE RISK OF GASTRIC CANCER: A POPULATION-BASED COHORT STUDY

E. Doorakkers 1 , J. Lagergren 2 , L. Engstrand 3 , N. Brusselaers 4

1 Department Of Molecular Medicine And Surgery, Upper Gastrointestinal Surgery, Karolinska Institutet, Stockholm/Sweden

2 Department Of Molecular Medicine And Surgery, Karolinska Institutet, Stockholm/Sweden

3 Dept. Of Of Microbiology, Tumor & Cell Biology, Karolinska Institutet, Stockholm/Sweden

4 Centre For Translational Microbiome Research, Department Of Microbiology, Tumor And Cell Biology, Karolinska Institutet, Stockholm/Sweden

Contact E-mail Address: eva.doorakkers@ki.se

Introduction: Helicobacter pylori is a stomach bacterium associated with an increased risk for gastric cancer. We aimed to assess if the risk of gastric cancer remains increased after H. pylori eradication.

Aims & Methods: This was a population-based, nationwide cohort study in Sweden conducted between 1 July 2005 and 31 December 2012. Data on H. pylori eradication were retrieved from the Swedish Prescribed Drug Registry and eradication consisted of triple therapy with a proton pump inhibitor and 2 antibiotics (clarithromycin and amoxicillin or metronidazole). The cancer incidence in the cohort was compared to that of the corresponding background population using standardized incidence ratios (SIRs) with 95% confidence intervals (CIs).

Results: In total, 92, 852 individuals (46.3% men) received eradication therapy during the study period. The total follow-up time after eradication was 331, 694 person-years (mean 3.6 years). Of the eradicated participants, 76 (0.08%) developed gastric cancer, corresponding with an incidence of 22.9/100, 000 person years. The SIR of gastric cancer after eradication was increased (SIR 1.46, 95% CI 1.15–1.83). The SIR for men was 1.30 (95% CI 0.94–1.77) and for women the SIR was 1.70 (95% CI 1.18–2.36). The SIRs were higher in the age groups <40 years (SIR 3.18, 95% CI 0.04–17.69), 40–49 years (SIR 3.78, 95% CI 1.38–8.22), 50–59 years (SIR 2.36, 95% CI 1.22–4.11), and not consistently increased in the age groups 60–69 years (SIR 0.97, 95% CI 0.50–1.69) and ≥70 years (SIR 1.38, 95% CI 1.00–1.84).

Conclusion: The overall risk for gastric cancer after eradication for H. pylori remained increased compared to the general population.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP197 PAN-EUROPEAN REGISTRY ON H. PYLORI MANAGEMENT (HP-EUREG): FIRST-LINE TREATMENTS AND INTERIM ANALYSIS OF 20,000 PATIENTS

A.G. Mcnicholl 1 , O.P. Nyssen 1 , D. S. Bordin 2 , B. Tepeš 3 , M.Á. Perez Aisa 4 , B. Vaira 5 , M. Caldas Álvarez 6 , L. Bujanda Fernández De Piérola 7 , M. Castro Fernández 8 , F. Lerang 9 , M. Leja 10 , L. Rodrigo 11 , T. Rokkas 12 , L. Kupcinskas 13 , J. Perez-Lasala 14 , L. Virginijus Jonaitis 15 , O. Shvets 16 , A. Gasbarrini 17 , H. Şimşek 18 , A. Axon 19 , G.M. Buzás 20 , J.C.L. Machado 21 , Y. Niv 22 , J. Molina Infante 23 , L. Boyanova 24 , A. Goldis 25 , V. Lamy 26 , M. Katicic 27 , K. Przytulski 28 , C. Beglinger 29 , M. Venerito 30 , P. Bytzer 31 , L. Capelle 32 , T. Milosavljevic 33 , L. Veijola 34 , L. Vologzhanina 35 , G. Fadeenko 36 , I. Ariño 37 , G. Fiorini 5 , M. Caldas 1 , M. Ramas 1 , M. Garcia Donday 1 , F. Megraud 38 , C. O'Morain 39 , J. P. Gisbert 1

1 Gastroenterology, H La Princesa, IIS-IP and Ciberehd, Madrid/Spain

2 Department Of Pancreatic, Biliary And Upper Gi Diseases, Moscow Clinical Scientific Center, Moscow/Russian Federation

3 Gastroenterology, AM DC Rogaska, Rogaska Slatina/Slovenia

4 Digestive, Agencia Sanitaria Costa del Sol, Marbella/Spain

5 Gastroenterology, S. Orsola Malpighi Hospital, Bologna/Italy

6 Gastroenterology, H La Princesa, Madrid/Spain

7 Gastroenterology, Hospital Donostia/Instituto Biodonostia, CIBERehd. Universidad del País Vasco (UPV/EHU), San Sebastian/Spain

8 Digestive Unit, Hospital de Valme, Sevilla/Spain

9 Medical, Central Hospital of Ostfold, Frdedrikstad/Norway

10 Gastroenterology, Institute of Clinical and Preventive Medicine & Faculty of Medicine, University of Latvia, Riga/Latvia

11 Gastroenterology, Hospital Universitario Central de Asturias, Oviedo/Spain

12 Gastroenterology, Henry Dunant Hospital, Athens/Greece

13 Lithuanian University of Health Sciences Inst. for Digestive Research, Kaunas/Lithuania

14 Digestive, HM Sanchinarro, Madrid/Spain

15 Gastroenterology, Lithuanian University of Health Sciences, Kaunas/Lithuania

16 Internal Medicine, Internal Diseases Department No. 1 National Medical University named after O.O. Bogomolets, Kyiv/Ukraine

17 Gastronterology, Fondazione Policlinico Universitario A. Gemelli, Rome/Italy

18 Internal Medicine/gastroenterology, Hacettepe University Faculty of Medicine, Ankara/Turkey

19 Gastroenterology, University of Leeds, Leeds/United Kingdom

20 Gastroenterology, Ferencváros Policlinic, Budapest/Hungary

21 Gastroenterology, Instituto de Investigação e Inovação em Saúde, Universidade do Porto, and Ipatimup - Institute of Molecular Pathology and Immunology of the University of Porto, Porto/Portugal

22 Gastroenterology, Rabin Medical Center, Tel Aviv University, Petach Tikva/Israel

23 Gastroenterology, Hospital San Pedro de Alcantara and CIBERehd, Caceres/Spain

24 Medical Microbiology, Medical University of Sofia, Sophia/Bulgaria

25 Gastroenterology, Timisoara Hospital, Timisoara/Romania

26 Gastroenterology, Hepatology & Nutrition, CHU Charleroi, Charleroi/Belgium

27 Gastroenterology, University Hospital Merkur Polyclinic Nola, Zagreb/Croatia

28 Gastroenterology, Medical Centre for Postgraduate Education, Warszawa/Poland

29 Gastroenterology, Hospital de Basel, Basel/Switzerland

30 Gastroenterology Hepatology And Infectious Diseases, Otto-von-Guericke University Hospital, Magdeburg/Germany

31 Medicine, Zealand University Hospital, Copenhagen University, Copenhagen/Denmark

32 Gastroenterology And Hepatology, Erasmus MC University, Rotterdam/Netherlands

33 Medical, Zealand University Hospital, Copenhagen University, Belgrade/Serbia

34 Internal Medicine, Herttoniemi Hospital, Helsinki/Finland

35 Gastroenterology, Gastrocentr, Perm, Perm/Russian Federation

36 Gastroenterology, Digestive Ukrainian Academy of Medical Sciences, Kyiv/Ukraine

37 Gastroenterology, Hospital ClÍnico Universitario Lozano Blesa, Zaragoza/Spain

38 Gastroenterology, Laboratoire de Bactériologie, Hôpital Pellegrin, Bordeaux/France

39 Clinical Medicine, Trinity College Dublin, Dublin/Ireland

Contact E-mail Address: adrian.mcn@gmail.com

Introduction: Due to the diversity of strains, resistances and geographical particularities, the best approach for Helicobacter pylori management remains unclear.

Aims & Methods: We aimed to assess the management of H. pylori infection by gastroenterologists in Europe and to evaluate the efficacy of first-line treatments. A systematic prospective registry of the clinical practice of European gastroenterologists regarding H. pylori infection and treatment (30 countries and 250 recruiting investigators). A local coordinator was selected from each country with more than 10 H. pylori references on PubMed. Each coordinator selected a representative group of recruiting investigators from its country. An electronic clinical research file was created on AEG-REDCap to systematically register all adult patients infected with H. pylori . Variables included: Patients’ demographics, previous eradication attempts, prescribed eradication treatment, adverse events, and outcomes (cure rates, compliance, follow up, etc.).

Results: Up to now, 20,175 patients (60% women) have finished follow up. Mean age was 49 years. Of all patients, 4.2% had drug allergies (81% to penicillin), 56% of had dyspepsia, 18% had gastroduodenal ulcer. Two-thirds (66%) were diagnosed using endoscopy-based methods. The treatments were: first-line in 78% of the patients, second-line in 16%, third-line in 4.4%, fourth-line in 1.2%, and fifth-line in 0.4%. Within the first-line prescriptions, 56% of first-line prescriptions were triple regimens (PPI + 2 antibiotics), 21% non-bismuth quadruple concomitant, 9% sequential, and 7% bismuth quadruple. Overall, first-line modified intention-to-treat (mITT) eradication rate was 78%. First-line efficacy per antibiotic combination is shown in the table.

Conclusion: H. pylori management by gastroenterologists in Europe is extremely diverse and the overall eradication rate is suboptimal, mainly due to the frequent use of triple therapies where they are ineffective (most European regions). In order to achieve ≥90% eradication, physicians are encouraged to use quadruple therapies.

Disclosure of Interest: A.G. McNicholl: Dr. McNicholl has received retribution from Allergan for formative actions.

D.S. Bordin: Dr. Bordin has served as lecturer for Astellas, AstraZeneca, KRKA and Abbott.

Perez Aisa: Dr. Perez-Aísa has received retribution from Allergan and Mylan for formative actions.

B. Vaira: has received retribution from Allergan for formative actions.

M. Castro Fernández: Dr. Castro-Fernandez has received retribution from Allergan for formative actions.

J. Molina Infante: Dr. Molina-Infante has served as a consultant for Casen Recordati and has received retribution from Allergan for formative actions.

P. Bytzer: has served as speaker, consultant and advisory member for or has received research funding from Almirall, Allergan and Reckitt Benckiser.

J.P. Gisbert: Dr. Gisbert has served as speaker, consultant and advisory member for or has received research funding from Almirall, Nycomed, AstraZeneca, Casen Recordati, and Allergan.

All other authors have declared no conflicts of interest.

Reference

On behalf of the European Helicobacter and Microbiota and the Hp-EuReg investigators

OP198 HELICOBACTER PYLORI ERADICATION THERAPY WITH VONOPRAZAN WAS MORE EFFECTIVE COMPARED TO PROTON PUMP INHIBITORS, AND THE EFFECT WAS NOT DISTURBED IN THE PATIENTS WITH LIFE STYLE-RELATED DISEASES

H. Endo 1 , Y. Takara 1 , T. Matsunaga 1 , H. Hidaka 1 , S. Shirai 2 , R. Shimoda 2 , R. Iwakiri 3 , K. Fujimoto 3

1 Department Of Internal Medicine, Saiseikai Kratsu Hospital, Karatsu/Japan

2 Internal Medicine And Gastrointestinal Endoscopy, Saga Medical School, Saga/Japan

3 Internal Medicine, Saga Medical School, Saga/Japan

Contact E-mail Address: hiro714@vc1.people-i.ne.jp

Introduction: Vonoprazan (VPZ) combined with two anti-biotics therapy has been applied for Helicobacter pylori (HP) eradication in Japan, and there is still little information of the detailed eradication results. The aim of the present study was to retrospectively compare the HP eradication outcomes between proton pump inhibitors (PPI) and VPZ with 1,774 subjects of our hospital in 2012–2016. In addition, we evaluated whether the eradication effect with VPZ was affected by lifestyle-related diseases including obesity, hypertension (HT) and diabetes mellitus (DM).

Aims & Methods: In total, 1774 subjects (primary eradication: 1485, secondary: 289) received HP eradication therapy in our hospital in 2012 – 2016. The eradication judgment was performed by 13 C-urea breath test (UBT), and the eradication rate (%, per-protocol analysis) was calculated. Eradication therapy was performed with PPI (lansoprazole (LPZ) 30 mg or rabeprazole (RPZ) 10 mg or esomeprazole (EPZ) 20 mg) or VPZ 20 mg + clarithromycin (CAM) 200 mg + amoxicillin (AMPC) 750 mg twice/day for 7 days as primary eradication. Failure of the primary eradication was follows by the secondary eradication with PPI or VPZ 20 mg + metronidazole (MNZ) 250 mg + AMPC 750 mg twice/day for 7 days.

Results: The primary eradication rates were VPZ 90.5% (371/410), LPZ 73.7% (246/334), RPZ 75.9% (366/482), and EPZ 83.0% (215/259). The eradication rate of VPZ was significantly high compared to that of all the other three PPI 77.0% (828/1076) (P < 0.001) and each PPI. The secondary eradication rate was VPZ 93.1% (54/58), LPZ 87.7% (50/57), RPZ 90.5% (67/74), EPZ 91.0% (91/100). Secondary eradication rate tended to be high in VPZ (93.1%) but not significant compared to that in all the other PPI (90.0%) (208/231) (P = 0.47). Next, we analyzed the influence of the lifestyle-related diseases on eradication. The primary HP eradication rate did not depend on the body weight: obese subjects (BMI > 25, n = 262: VPZ 97.0% vs PPI 72.4%) and no obese subjects (n = 771: VPZ 90.5% vs PPI 77.7%). As indicated, VPZ worked better in the obese subjects compared to the non-obese subjects (BMI > 25: 97.0% vs BMI < 25: 90.5%: P = 0.089), suggesting the effect of VPZ was not influenced by the body weight. Regarding HT, primary eradication rate was better in VPZ compared to PPI (VPZ 87.3%, PPI 76.8%). The primary eradication rate of the 118 patients with DM (VPZ 89.3%, PPI 68.9%) was not different from 1368 non-DM subjects (VPZ 90.6%, PPI 77.7%). There was not the serious adverse event with VPZ and PPI during the investigation period.

Conclusion: HP eradication therapy using VPZ was effective compared to that of PPI, and life-style related diseases including obesity, hypertension, DM, had no influence on the HP eradication with VPZ.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP199 OPTIMIZED 14-DAY SEQUENTIAL VERSUS 10-DAY BISMUTH QUADRUPLE THERAPY CONTAINING HIGH DOSE ESOMEPRAZOLE IN THE FIRST-LINE TREATMENT OF HELICOBACTER PYLORI –A MULTICENTER RANDOMIZED TRIAL

J. Liou 1 , Y. Fang 2 , C. Chen 1 , M. Bair 3 , J. Lin 4 , M. Wu 1

1 Dept. Of Internal Medicine, National Taiwan University Hospital Dept. of Internal Medicine Taiwan Helicobacter Consortium, Taipei/Taiwan

2 National Taiwan University Hospital, Yun-Lin Branch, Yun-Lin/Taiwan

3 Mackay Memorial Hospital, Taitung Branch, Taitung/Taiwan

4 College Of Medicine, Fu-Jen Catholic University, New Taipei City/Taiwan

Contact E-mail Address: dtmed046@pchome.com.tw

Introduction: Our previous trial and meta-analysis showed that 14-day sequential therapy was superior to 14-day triple therapy in the first line treatment of H. pylori infection. However, whether the optimized 14-day sequential therapy is superior to 10-day bismuth quadruple therapy has not been reported. We aimed to compare the efficacy and safety of 14-day sequential therapy and 10-day bismuth quadruple therapy containing high dose esomeprazole in the first-line treatment of H. pylori .

Aims & Methods: For this multicenter, open-label, randomized trial, we recruited adult patients (≥20 years of age) with H. pylori infection naïve to treatment from 9 centers in Taiwan. Eligible patients were randomized to receive either sequential therapy (esomeprazole 40 mg and amoxicillin 1 g for the first 7 days, followed by esomeprazole 40 mg, clarithromycin 500 mg, and metronidazole 500 mg for another 7 days; with all drugs given twice daily) for 14 days or bismuth quadruple therapy (bismuth tripotassium dicitrate 300 mg four times a day, esomeprazole 40 mg twice daily, tetracycline 500 mg four times a day, and metronidazole 500 mg three times a day) for 10 days. Our primary outcome was the eradication rate in the first-line therapy by intention-to-treat (ITT) analysis. The minimum inhibitory concentrations were determined by agar dilution test.

Results: A total of 620 patients have been recruited. The prevalence of clarithromycin resistance was about 14.3% in the study population. The eradication rates of the optimized 14-day sequential therapy and 10-day bismuth quadruple therapy were 95.0% (245/258) and 94.7% (249/263) in the ITT analysis (p = 0.884), respectively and were 96.1% (245/255) and 95.8% (249/260) in the PP analysis (p = 0.859). The frequencies of any adverse effects were 37.3% (109/292) and 72.8% (219/301) in patients treated with 14-day sequential therapy and 10-day bismuth quadruple therapy, respectively (p < 0.001). The eradication rates of 14-day sequential therapy for clarithromycin resistant and susceptible strains were 75% (12/16) and 100% (114/114), respectively (p < 0.001), whereas that of 10-day bismuth quadruple therapy was not affected by clarithromycin resistance.

Conclusion: Both bismuth quadruple therapy and 14-day sequential therapy containing high dose esomeprazole are highly effective in regions with low to intermediate clarithromycin resistance rate. Sequential therapy is better tolerated but is less effective in the presence of clarithromycin resistance.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP200 THE ABUNDANCE OF ANTIBIOTIC RESISTANCE GENES IN HUMAN GUTS AFTER H. PYLORI ERADICATION THERAPY

S. Y. Malanin 1 , D. D. Safina 1 , D. R. Khusnutdinova 1 , I. Y. Vasilyev 1 , T.V. Grigoryeva 1 , M. N. Siniagina 1 , M.I. Markelova 1 , E. A. Boulygina 1 , S.R. Abdulkhakov 2 , R. A. Abdulkhakov 3 , V. M. Chernov 1

1 Kazan Federal University, Kazan/Russian Federation

2 Department Of Normal Human Anathomy, Kazan State Medical University, Kazan/Russian Federation

3 Kazan State Medical University, Kazan/Russian Federation

Contact E-mail Address: tatabio@inbox.ru

Introduction: It is well known that one of the adverse effects of antibiotic therapy is the enrichment of antibiotic-resistant strains of bacteria. Resistance may be due to the presence of the resistance genes that can be acquired through mutations or horizontal transfer and spread not only among pathogenic bacteria, but also among the members of the normal microflora. Thus the intestinal microflora may serve as a potential reservoir of resistance genes and contribute to the spread of antibiotic resistance genes. H. pylori eradication therapy consisting of treatment by several antimicrobial drugs is a good model for studying the effect of antibiotics on the abundance of antibiotic resistance genes in the gut.

Aims & Methods: The aim of the study was to explore the gut resistome before and after antibiotic therapy by shotgun metagenomic sequencing. Seventy stool samples were used for analysis: 35 samples from H. pylori -positive patients before eradication therapy, 35 - from the same patients after the completion of eradication therapy consisted of treatment by amoxicillin (1000 mg), clarithromycin (500 mg), proton pump inhibitor in a standard dose, bismuth subsalicylate (240 mg) bid for 14 days, lactulose was added as a prebiotic. Total DNA was isolated from the stool samples using beat beating method and sequenced on Solid 5500xl-W platform. Reads were aligned to the Comprehensive Antibiotic Database (CARD, version 1.1.7) using bowtie 1.2.0. Significant changes of antibiotic resistance genes abundances in the microbiomes of patients before and after eradication were assessed using Wilcoxon signed-rank test (p-value <0.05 was considered significant).

Results: Eradication therapy of H. pylori infection leads to increasing of abundance of different antibiotic resistance genes. Significant changes of abundance were shown for genes conferring resistance to 12 from 27 groups of antibiotics (CARD). The largest significant fold changes were found for beta-lactams (for some patients quantity of TEM beta-lactamases increased up to 125-fold), for macrolides (mrx and mphA genes up to 288 and 360-fold increase, respectively), for aminoglycoside (aph, aadA, increase up to 297, 352-fold), fluoroquinolones (oqxB up to 133-fold increase). Moreover significant expansion of genes coding several multidrug efflux pumps was also detected. Notably, a large number of antibiotic resistance genes were found to appear in the microbiome after therapy. Most of these genes confer resistance to beta-lactams (TEM beta-lactamases and shv genes), aminoglycoside (aac, aad), vancomycin (vanXYC), fluoroquinolones (qnr genes). Thus eradication therapy leads to the accumulation of genes promoting the resistance to antibiotics, that were not part of the treatment.

Conclusion: The antibiotic therapy of H.pylori infection favours the accumulation of the wide range of antibiotic resistance genes, implying higher risks for resistance acquisition by pathogenic bacteria. Further research should be aimed to studying mechanisms of gene spreading, as well as determining the duration of these changes in intestinal resistome.

Disclosure of Interest: All authors have declared no conflicts of interest.

Reference

This work was financially supported by the Ministry of Education and Science of Russian Federation (agreement #14.575.21.0076, ID RFMEFI575I4X0076).

OP201 PAN-EUROPEAN REGISTRY ON H. PYLORI MANAGEMENT (HP-EUREG): BACTERIAL RESISTANCE OF 2241 H. PYLORI ISOLATES

A.G. Mcnicholl 1 , O.P. Nyssen 1 , D. S. Bordin 2 , B. Tepeš 3 , M.Á. Perez Aisa 4 , B. Vaira 5 , M. Caldas Álvarez 6 , L. Bujanda Fernández De Piérola 7 , M. Castro Fernández 8 , F. Lerang 9 , M. Leja 10 , L. Rodrigo 11 , T. Rokkas 12 , L. Kupcinskas 13 , J. Perez-Lasala 14 , L. Jonaitis 15 , O. Shvets 16 , A. Gasbarrini 17 , H. Şimşek 18 , A. Axon 19 , G.M. Buzás 20 , J.C.L. Machado 21 , Y. Niv 22 , L. Boyanova 23 , A. Goldis 24 , V. Lamy 25 , M. Katicic 26 , K. Przytulski 27 , C. Beglinger 28 , M. Venerito 29 , P. Bytzer 30 , L. Capelle 31 , T. Milosavljevic 32 , L. Veijola 33 , J. Molina Infante 34 , L. Vologzhanina 35 , G. Fadeenko 36 , I. Ariño 37 , G. Fiorini 5 , M. Ramas 1 , M. Garcia Donday 1 , F. Megraud 38 , C. O'Morain 39 , J. P. Gisbert 1

1 Gastroenterology, H La Princesa, IIS-IP and Ciberehd, Madrid/Spain

2 Department Of Pancreatic, Biliary And Upper Gi Diseases, Moscow Clinical Scientific Center, Moscow/Russian Federation

3 Gastroenterology, AM DC Rogaska, Rogaska Slatina/Slovenia

4 Digestive, Agencia Sanitaria Costa del Sol, Marbella/Spain

5 Gastroenterology, S. Orsola Malpighi Hospital, Bologna/Italy

6 Gastroenterology, H La Princesa, Madrid/Spain

7 Gastroenterology, Hospital Donostia/Instituto Biodonostia, CIBERehd. Universidad del País Vasco (UPV/EHU), San Sebastian/Spain

8 Digestive Unit, Hospital de Valme, Sevilla/Spain

9 Medical, Central Hospital of Ostfold, Frdedrikstad/Norway

10 Institute For Clinical And Preventive Medicine, University of Latvia, Riga/Latvia

11 Gastroenterology, Hospital Universitario Central de Asturias, Oviedo/Spain

12 Gastroenterology, Henry Dunant Hospital, Athens/Greece

13 Lithuanian University of Health Sciences Inst. for Digestive Research, Kaunas/Lithuania

14 Digestive, HM Sanchinarro, Madrid/Spain

15 Gastroenterology, Lithuanian University of Health Sciences, Kaunas/Lithuania

16 Internal Medicine, Internal Diseases Department No. 1 National Medical University named after O.O. Bogomolets, Kyiv/Ukraine

17 Gastronterology, Fondazione Policlinico Universitario A. Gemelli, Rome/Italy

18 Internal Medicine/gastroenterology, Hacettepe University Faculty of Medicine, Ankara/Turkey

19 Gastroenterology, University of Leeds, Leeds/United Kingdom

20 Gastroenterology, Ferencváros Policlinic, Budapest/Hungary

21 Gastroenterology, Instituto de Investigação e Inovação em Saúde, Universidade do Porto, and Ipatimup - Institute of Molecular Pathology and Immunology of the University of Porto, Porto/Portugal

22 Gastroenterology, Rabin Medical Center, Tel Aviv University, Petach Tikva/Israel

23 Medical Microbiology, Medical University of Sofia, Sophia/Bulgaria

24 Gastroenterology, Timisoara Hospital, Timisoara/Romania

25 Gastroenterology, Hepatology & Nutrition, CHU Charleroi, Charleroi/Belgium

26 Gastroenterology, University Hospital Merkur Polyclinic Nola, Zagreb/Croatia

27 Gastroenterology, Medical Centre for Postgraduate Education, Warszawa/Poland

28 Gastroenterology, Hospital de Basel, Basel/Switzerland

29 Gastroenterology Hepatology And Infectious Diseases, Otto-von-Guericke University Hospital, Magdeburg/Germany

30 Medicine, Zealand University Hospital, Copenhagen University, Copenhagen/Denmark

31 Gastroenterology And Hepatology, Erasmus MC University, Rotterdam/Netherlands

32 Medical, Zealand University Hospital, Copenhagen University, Belgrade/Serbia

33 Internal Medicine, Herttoniemi Hospital, Helsinki/Finland

34 Gastroenterology, Hospital San Pedro de Alcantara and CIBERehd, Caceres/Spain

35 Gastroenterology, Gastrocentr, Perm, Perm/Russian Federation

36 Gastroenterology, Digestive Ukrainian Academy of Medical Sciences, Kyiv/Ukraine

37 Gastroenterology, Hospital ClÍnico Universitario Lozano Blesa, Zaragoza/Spain

38 Gastroenterology, Laboratoire de Bactériologie, Hôpital Pellegrin, Bordeaux/France

39 Clinical Medicine, Trinity College Dublin, Dublin/Ireland

Contact E-mail Address: adrian.mcn@gmail.com

Introduction: Antibacterial resistance is the major cause of failed eradication attempts in the management of H. pylori infection.

Aims & Methods: We aimed to evaluate the resistance rates encountered by European gastroenterologists in their routine clinical practice A Local Coordinator was selected from each country with more than 10 H. pylori references in PubMed. Each Coordinator selected a representative group of recruiting investigators from his/her country. An e-CRF was created on AEG-REDCap to systematically register all adult patients infected with H. pylori . Variables included: H. pylori diagnostic test used, use of culture and susceptibility testing methods, or molecular tests for the evaluation of antibiotic resistance.

Results: So far 20, 175 patients have finished follow-up. Culture was performed in 12% of cases: 2241 isolates of which 1878 are first-line. Table shows antibiotic resistance (% and 95% CI) per antibiotic and line of treatment.

Conclusion: The mean rate of H. pylori clarithromycin resistance in European naïve patients has surpassed the threshold established by consensus conferences (15%) in which empirical use of standard triple therapy should be discarded. Dual resistance to clarithromycin and metronidazole is close to reach the 15% prevalence in which non-bismuth quadruple therapies efficacy is significantly challenged. There is a strong acquisition of antibiotic resistance after failed treatments.

Disclosure of Interest: A.G. McNicholl: Dr. McNicholl has received retribution from Allergan for formative actions.

D.S. Bordin: Dr. Bordin has served as lecturer for Astellas, AstraZeneca, KRKA and Abbott. The rest of authors declare no conflict of interest.

Perez Aisa: Dr. Perez-Aísa has received retribution from Allergan and Mylan for formative actions.

M. Castro Fernández: Dr. Castro-Fernandez has received retribution from Allergan for formative actions.

P. Bytzer: Dr. Bytzer has served as speaker, consultant and advisory member for or has received research funding from Almirall, Allergan and Reckitt Benckiser.

J. Molina Infante: Dr. Molina-Infante has served as a consultant for Casen Recordati and has received retribution from Allergan for formative actions.

J.P. Gisbert: Dr. Gisbert has served as speaker, consultant and advisory member for or has received research funding from Almirall, Nycomed, AstraZeneca, Casen Recordati, and Allergan.

All other authors have declared no conflicts of interest.

TUESDAY, OCTOBER 31, 201710:30-12:00

DIVERTICULAR DISEASE: FROM BENCH TO BEDSIDE - ROOM E2____________________

OP202 CALCITONIN GENE-RELATED PEPTIDE INNERVATING ENTERIC PLEXUSES IS DOWNREGULATED IN DIVERTICULAR DISEASE: IMPLICATIONS FOR PATHOGENESIS

J.I. Lukosiene 1 , A. G. Pauza 2 , K. Rysevaite-Kyguoliene 2 , J. Kupcinskas 3 , Z. Saladzinskas 4 , A. Tamelis 4 , N. Pauziene 2

1 Department Of Gastroenterology, Lithuanian University of Health Sciences, Kaunas/Lithuania

2 Institute Of Anatomy, Lithuanian University of Health Sciences, Kaunas/Lithuania

3 Lithuanian University Of Helath Sciences, Kaunas, Kaunas/Lithuania

4 Department Of Surgery, Lithuanian University of Health Sciences, Kaunas/Lithuania

Contact E-mail Address: jaune.lukosiene@gmail.com

Introduction: Diverticular disease (DD) of the colon is a frequent gastrointestinal disorder and an important cause of hospital admissions in Western and industrialized nations [1]. Several aetiological cofactors have been implicated in the pathogenesis of the disease, that involve both structural remodelling and functional alterations [1]. It is hypothesized that abnormal colonic motility, likely resulting from changes to enteric nervous system [2], and increased intraluminal pressure are both important predisposing factors in the development of colonic diverticula. CGRP (calcitonin gene related peptide) is a potent smooth muscle relaxant involved in a variety of physiological processes throughout the digestive system. Within the alimentary tract, CGRP is capable to induce peristaltic reflexes [3], relax smooth muscle cells [4], induce phasic contractile activity [5] and excite myenteric neurons [6].

Aims & Methods: The aim of the study was to investigate CGRP signalling pathway in symptomatic (SDD) and asymptomatic diverticular disease (ADD) patients. Full-thickness sigmoid specimens were obtained from patients undergoing surgery for non-obstructing colorectal carcinoma, that served as control (n = 10, age: 50–75 years) and as ADD (n = 10, age: 57–76 years) if colonic diverticula were present and patient had no previous anamnesis of DD associated symptoms. Tissue specimens for SDD (n = 10, age: 39–80 years) were obtained from patients who underwent sigmoid resection or left hemicolectomy after recurrent attacks of diverticulitis. Full-thickness colon sections were processed for CGRP and its receptors CRLR (calcitonin receptor-like receptor) and RAMP1 (receptor activity-modifying protein 1) immunohistochemistry and analysed by means of quantitative fluorescence microscopy. Protein expression was determined by measuring densitometric fluorescence within the ganglia of myenteric (MP), outer (oSP) and inner (iSP) submucosal plexuses.

Results: We found that in SDD patients CGRP expression is decreased by 40 % within all divisions of enteric nervous system (MP – p < 0.001, oSP – p < 0.01, iSP – p < 0.001), with ADD patients having the intermediate values. CGRP receptor – CRLR – was found to be upregulated in an opposite manner in DD patients, with SDD being 25 % greater than control patients (MP – p < 0.01, oSP – p < 0.01, iSP – n.s.). Second protein necessary for CGRP signalling – RAMP1 – expression was found to be unaltered.

Conclusion: We can conclude that CGRP signalling pathway is subjected to alteration in DD. Gradual decrease of CGRP may be suspected since ADD had the intermediate values for both CGRP and CRLR. Knowing that CGRP is involved both in smooth muscle contractility and intestinal motility it is reasonable to hypothesize that upregulation CRLR may have develop as a compensatory mechanism for declining levels of CGRP.

Disclosure of Interest: All authors have declared no conflicts of interest.

References

1. Reichert MC, Lammert F. The genetic epidemiology of diverticulosis and diverticular disease: Emerging evidence. United Eur Gastroenterol J 2015;3:409–18.

2. Wedel T, Büsing V, Heinrichs G, Nohroudi K, Bruch H-P, Roblick UJ, et al. Diverticular disease is associated with an enteric neuropathy as revealed by morphometric analysis. Neurogastroenterol Motil 2010;22:407–14.

3. Tursi A. Diverticulosis today: unfashionable and still under-researched. Therap Adv Gastroenterol 2016;9:213–28.

4. Von Rahden BHA, Germer CT. Pathogenesis of colonic diverticular disease. Langenbeck’s Arch Surg 2012;397:1025–33.

5. Sugihara K, Muto T, Morioka Y. Motility study in right sided diverticular disease of the colon. Gut 1983;24:1130–4.

6. Gallego D, Espin F, Mikulka J, Smirg O, Gil V, Faundez-Zanuy M, et al. In vitro motor patterns and electrophysiological changes in patients with colonic diverticular disease. Int J Colorectal Dis 2013;28:1413–22.

OP203 IMMUNE ACTIVATION AND NERVE SPROUTING IN THE COLONIC MUCOSA OF PATIENTS WITH DIVERTICULAR DISEASE

M.R. Barbaro 1 , C. Cremon 1 , D. Fuschi 1 , E. Scaioli 1 , G. Marasco 1 , M. Carapelle 2 , E. Benatti 1 , E. Capelli 1 , A. Colecchia 1 , D. Festi 1 , V. Stanghellini 1 , G. Barbara 1

1 Dept. Medical And Surgical Sciences, University of Bologna Dept. of Medical and Surgical Sciences, Bologna/Italy

2 University of Bologna, Bologna/Italy

Contact E-mail Address: maria.barbaro2@unibo.it

Introduction: Colonic diverticulosis is a common clinical condition in industrialized countries, with the highest rates in the United States and Europe. Symptomatic uncomplicated diverticular disease (SUDD) is a syndrome characterized by abdominal symptoms similar to irritable bowel syndrome (IBS) attributed to diverticula. A role for low-grade inflammation, sensory-motor dysfunction, and dysbiosis may be suggested in a clinical picture that mimics IBS. We hypothesized that mucosal immune activation, nerve fiber density and sprouting may play a role in symptom generation in patients with SUDD.

Aims & Methods: The aim of the present study was to characterize immune cells, nerve density and sprouting in patients with SUDD, diverticulosis and healthy controls (HC). 14 HC, 16 patients with diverticulosis and 10 with SUDD were enrolled in the study. In patients with diverticula, mucosal biopsies were obtained close to diverticula and at least 20 cm from the last observed diverticula (normal mucosa). In HC, biopsies were performed at sigmoid and at descending colon. Quantitative immunohistochemistry was used to assess the expression of tryptase (mast cell marker), CD3 (T cell marker), CD68 (macrophage marker), neuronal specific enolase (NSE) [nerve marker], and growth-associated protein 43 (GAP-43) [neuronal outgrowth marker]. IBS-like symptoms severity and frequency were graded using a 5 point Likert scale. Correlation analyses were performed between immune cell counts and nerve fiber ones.

Results: Mast cells were significantly increased in the peridiverticular mucosa of patients fulfilling the Roma III criteria for the diagnosis of IBS in comparison with HC (5.9 ± 0.7% vs 3.6 ± 0.5%; P < 0.05), but not in patients with SUDD as compared to diverticulosis or HC. No differences were detected in the T-cell counts among the three groups. Macrophages were significantly increased in patients with SUDD and diverticulosis as compared to HC, both in the peridiverticular (5.8 ± 0.4%, 6.9 ± 0.6%, 4.9 ± 0.4%, respectively; P < 0.05) and in normal mucosa (7.1 ± 0.7%, 6.6 ± 0.4%, 4.0 ± 0.3%, respectively; P < 0.001). The percentage of NSE + fibers over lamina propria area was significantly enhanced in patients with SUDD and diverticulosis in comparison with HC (5.1 ± 0.7%, 5.5 ± 0.8% vs 3.4 ± 0.4%, respectively; P < 0.05) in the peridiverticular region. Interestingly, GAP-43 immunoreactivity was significantly increased only in patients with SUDD as compared to HC (5 ± 0.6% vs 2.4 ± 0.7%, respectively; P < 0.05) in the peridiverticular region, while no differences were found in the normal mucosa. Significant correlations were found between GAP43+ fibers and immune cells in the peridiverticular region but not in the normal mucosa.

Conclusion: Patients with SUDD and diverticulosis are characterized by increased macrophage counts, while nerve fiber sprouting is increased only in patients with SUDD and is specific of the peridiverticular region. The significant correlation between immune cell counts and nerve sprouting suggests an interesting cross-talk potentially involved in symptom generation in SUDD.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP204 PROLONGED RECURRENT ABDOMINAL PAIN IS ASSOCIATED WITH ON-GOING UNDERLYING MUCOSAL INFLAMMATION IN PATIENTS WHO HAD AN EPISODE OF ACUTE COMPLICATED DIVERTICULITS

A. Lahat 1 , D. Necula 2 , M. Yavzori 2 , O. Picard 2 , R. Eliakim 2 , S. Ben-Horin 2

1 Gastroenterology, Chaim Sheba Medical Center, Ramat Gan/Israel

2 Chaim Sheba Medical Center, Ramat Gan/Israel

Contact E-mail Address: zokadi@gmail.com

Introduction: Recent data suggest continuous chronic inflammation in patients post complicated acute diverticulitis (AD).

Aims & Methods: We aimed to compare clinical parameters, inflammatory cytokine expression and immune-cell infiltrates between patients post complicated versus uncomplicated AD. Sixteen patients post AD were included, of them 8 had a complicated disease. Demographic data, disease characteristics and inflammatory markers were collected. Tissue samples from diverticular and healthy tissue were obtained during colonoscopy. Mucosal inflammation was assessed histologically and by measuring inflammatory cytokines messenger -RNA expression using reverse transcription polymerase chain reaction (RT- PCR).

Results: Clinically, continued non-specific abdominal symptoms were significantly more prevalent among patients post-complicated AD compared to patients after non-complicated AD (p = 0.0002). Patients after complicated AD also had significantly higher CRP levels (9.85 ± 7.5 vs 3 ± 2.1 mg/dl p = 0.027) and tendency for higher calprotectin levels (115.7 ± 85 vs 35 ± 8.7 mg/gr, p = 0.08). Table 1 shows differences in cytokine expression between healthy and diverticular tissue in both groups. Histologic scores for crypt distortion, lymphoid aggregates, lymphocytes infiltration and chronic inflammation were 1.37 ± 0.5, 1.37 ± 0.5, 16.53 ± 10.2, 2.125 ± 1.1, respectively in the complicated group compared to 0.42 ± 0.5, 0.42 ± 0.5, 6.01 ± 1.7, 0.57 ± 0.5, respectively in the uncomplicated group (p = 0.049, 0.004, 0.012, 0.004, respectively). Additionally, lymphocytes presence in the lamina propria differed significantly between the groups (average of 1.75 ± 0.4 for complicated versus 0.85 ± 0.3 for uncomplicated, p = 0.006).

Conclusion: In our current study we showed that following an attack of complicated AD, patients suffer from prolonged inflammatory process, manifesting clinically by recurrent abdominal pain and high inflammatory markers in the blood and stool, and structurally with high expression of inflammatory cytokines and inflammatory infiltrates in the affected tissue. In contrary, patients post uncomplicated AD did not suffer from continued inflammation. If corroborated by further research, our results can contribute to patient's risk stratification and guide therapeutic decisions.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP205 INCIDENCE OF COMPLICATED DIVERTICULAR DISEASE (ABSCESS AND PERFORATION): A POPULATION BASED COHORT STUDY FROM ENGLAND

H.E. Otete 1 , C.J. Crooks 2 , J. West 3 , D. J. Humes 4

1 Division Of Pharmacology, The University Of Nottingham, Nottingham/United Kingdom

2 Nottingham City Hospital, University of Nottingham, Nottingham/United Kingdom

3 Division Of Epidemiology And Public Health, Univesity of Nottingham, Nottingham/United Kingdom

4 NDDC NIHR BRC, University of Nottingham, Nottingham/United Kingdom

Contact E-mail Address: david.humes@nottingham.ac.uk

Introduction: Diverticular perforation and abscess are the two most significant complications of diverticular disease with a substantial associated morbidity and mortality. Prior population-based studies have suggested the incidence of perforated disease is increasing; however, these studies are no longer contemporary and were unable to describe the change in incidence by age over time [1–3].

Aims & Methods: This study aimed to provide contemporary population-based estimates of the incidence of complicated diverticular disease and assess variation by age, calendar time and sex. We used linked primary and secondary care data from 2000–2014 from the Clinical Practice Research Datalink and Hospital Episode Statistics to identify cases of complicated diverticular disease in England who were older than 18 years. Incidence rates were calculated and modelled using Poisson regression.

Results: We identified 3717 cases of complicated diverticular disease with an overall incidence of 9.23 per 100, 000 person years (pyrs) (interquartile range (IQR) 9.94–9.53 per 100, 000 pyrs). The incidence was higher in women 10.81 per 100, 000 pyrs than in men representing a 1.2 fold increase in risk (Incidence Rate Ratio (IRR) 1.21, 95% Confidence Interval (CI) 1.13–1.29). The incidence increased from 7.51 per 100, 000 pyrs (95% CI 6.38–8.79 per 100, 000 pyrs) in 2000 to 10.88 per 100, 000 pyrs in 2013 (95% CI, 9.65–12.23 per 100, 000 pyrs) representing a 1.4 fold increase (IRR 1.42, 95% Confidence Interval (CI) 1.17–1.72). Incidence increased with increasing age with the highest absolute rate in those over the age of 85 years (45.23 per 100, 000 pyrs) which represented a 5.5 fold increase in incidence compared to those aged 45–54 years (IRR 5.45, 95% CI 4.78–6.22). The increase in incidence of complicated diverticular disease from 2000 to 2013 predominantly occurred in those less than 65 years of age with rates in those over the age of 65 years remaining similar across the time period (Table 1). Table 1. Incidence of complicated diverticular disease by age group and calendar year.

Conclusion: The incidence of complicated diverticular disease has increased by 1.4 fold from 2000 to 2013 and this increase in incidence appears to be in those under the age of 65 years. This could be due to the increase in known risk factors for complicated diverticular disease such as obesity and physical inactivity or the increased use of prescription medications such as steroids or opiate analgesics which are associated with an increased risk of perforation. It is also possible part of this increase may be due to increased ascertainment of cases due to increased use of diagnostic imaging and endoscopy.

Disclosure of Interest: All authors have declared no conflicts of interest.

References

1. Humes DJ. A Population-Based Study of Perforated Diverticular Disease Incidence and Associated Mortality. Gastroenterology . 2009;136(4):1198–205.

2. Makela J. Prevalence of perforated sigmoid diverticulitis is increasing. Dis Colon Rectum . 2002;45(7):955–61.

3. Morris C. Incidence of perforated diverticulitis and risk factors for death in a UK population. Br J Surg . 2008;95:876–81.

OP206 COLONIC DIVERTICULA ARE NOT ASSOCIATED WITH MUCOSAL INFLAMMATION OR CHRONIC GASTROINTESTINAL SYMPTOMS

A. Peery , T. Keku, C. Addamo, A. Mccoy, C. Martin, J. Galanko, R. Sandler

Department Of Medicine, Division Of Gastroenterology And Hepatology, University of North Carolina at Chapel Hill, Chapel Hill/United States of America

Contact E-mail Address: anne_peery@med.unc.edu

Introduction: Colonic diverticula are prevalent in Western countries. 1, 2 While diverticula are classically complicated by acute diverticulitis, there is some thought that diverticula may be associated with low-grade mucosal inflammation. 3 This low-grade diverticular inflammation is believed to drive chronic gastrointestinal symptoms. 3 Chronic gastrointestinal symptoms from colonic diverticula (in the absence of overt inflammation) has been termed symptomatic uncomplicated diverticular disease. 3 Despite the literature associating colonic diverticulosis with low-grade mucosal inflammation and symptomatic uncomplicated diverticular disease, there is little evidence for these associations.

Aims & Methods: We aimed to determine whether colonic diverticula are associated with markers of colonic mucosal inflammation in a prospective study of patients undergoing a complete screening colonoscopy. We also assessed whether colonic diverticula are associated with chronic gastrointestinal symptoms and explored whether markers of mucosal inflammation were increased among participants with chronic gastrointestinal symptoms. We analyzed data from a prospective study of 619 patients who had a first-time screening colonoscopy. We included those with a satisfactory preparation for colonoscopy and complete exam to the cecum. We excluded those wtih a prior colonoscopy, colon resection, history of diverticulitis or overt diverticular inflammation. Colonic mucosal biopsies were taken and analyzed for cytokine gene expression of interleukin (IL)-6, IL-10 and tumor necrosis factor-α by quantitative reverse-transcriptase PCR and immune cells (CD4, CD8, CD57 and mast cell tryptase) by immunohistochemistry. Gastrointestinal symptoms were assessed by Rome III criteria. Proportional odds models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs).

Results: Our primary analysis included 619 participants; 255 (41%) had one or more colonic diverticula. Participants with diverticula were more likely to be older, male, and overweight or obese than those without diverticula. Compared to those without diverticula, there was no association between participants with diverticulosis and gene expression levels of tumor necrosis factor (TNF-α) (OR 0.85; 95% CI 0.63–1.16) and no association with CD4 (OR 1.18; 95% CI 0.87–1.60), CD8 (OR 0.97; 95% CI 0.71–1.32), or CD57 (OR 0.80; 95% CI 0.59–1.09) after adjusting for age, sex and body mass index. There was no association with mast cell tryptase (OR 1.02; 95% CI 0.75–1.39). There was a reduced likelihood of mucosal concentrations of IL-6 (OR 0.58; 95% CI 0.41–0.83) and IL-10 (OR 0.67; 95% CI 0.49–0.91). Our analysis of gastrointestinal symptoms included 448 participants; 12% met diagnostic criteria for Rome III irritable bowel syndrome and 14% reported chronic abdominal pain. Compared to those without diverticula, there was no association between diverticulosis and irritable bowel syndrome (OR 0.53; 95% CI 0.26–1.05) or chronic abdominal pain (OR 0.68; 95% CI 0.38–1.23). There was no evidence for chronic mucosal inflammation among symptomatic participants comparing those with and without diverticulosis.

Conclusion: In this large colonoscopy-based study, we found no evidence that colonic diverticulosis is associated with mucosal inflammation, chronic abdominal pain or the symptoms of irritable bowel syndrome. Among those with symptoms and diverticula, we found no mucosal inflammation. Our work challenges the theory that colonic diverticula are associated with mucosal inflammation or chronic gastrointestinal symptoms.

Disclosure of Interest: All authors have declared no conflicts of interest.

References

1. Everhart JE, Ruhl CE. Burden of digestive diseases in the United States part II: lower gastrointestinal diseases. Gastroenterology . 2009;136(3):741–54

2. Peery AF, Keku TO, Martin CF, et al. Distribution and Characteristics of Colonic Diverticula in a United States Screening Population. Clin Gastroenterol Hepatol . 2016;14(7):980–5 e1.

3. Strate LL, Modi R, Cohen E, et al. Diverticular disease as a chronic illness: evolving epidemiologic and clinical insights. The American journal of gastroenterology . 2012;107(10):1486–93.

OP207 UTILITY TO ENDOSCOPIC SUBMUCOSAL DISSECTION IN THE COLORECTAL TUMORS NEAR OR WITHIN DIVERTICULUM: CASE SERIES

V.A. Jimenez-Garcia 1 , M. Yamada 1 , H. Ikematsu 2 , S. Abe 1 , T. Sakamoto 1 , T. Nakajima 1 , T. Matsuda 1 , Y. Saito 1

1 Endoscopy Division, National Cancer Center Hospital, Tokyo, Tokyo/Japan

2 Endoscopy Division, National Cancer Center Hospital East, Chiba/Japan

Contact E-mail Address: drajimenezg@hotmail.com

Introduction: Surgery is standard treatment for colon tumors coexistence with diverticulum . However, it is currently controversial whether colon tumors near or within diverticulum can be treated by endoscopic submucosal dissection (ESD).

Aims & Methods: The aim of this retrospective case series was to clarify feasibility of ESD for superficial colorectal tumors near or within diverticulum. Consecutive patients with colorectal tumors near or within diverticulum removed by ESD in two referral centers were involved. Clinicopathological characteristics and clinical outcomes were analyzed.

Results: There were 11 patients including 6 cases of the near-type and 5 cases of within-type diverticulum. The tumor showed type 2 in NBI International Colorectal Endoscopic (NICE) Classification in 10 cases [1, 2]. Pit pattern diagnosis in Kudo’s classification was type IIIL for one case, type IV with serration features for one case, type IV without serration features in 2 cases and type VI in 7 cases [3]. In 4 of them the diverticulum could not be recognized in the tumor before the ESD. En-bloc R0 resection was achieved in 7 patients (64%). Median tumor size and procedure time were 23 mm (15–80) and 120 min (50–210), respectively. The ESD could not be continued in four cases due to the intra-diverticulum tumor extension and required strip biopsy, band ligation, polypectomy and/or argon plasma coagulation. Traction device using the “clip-and-line method” [4] was used in one case having two diverticulum within the tumor and had kept good traction during ESD. One pin-hole perforation was occurred at the diverticulum and was endoscopically managed by immediate closure by endoclips. Emergency surgery was not required in any cases. During median 12 month follow-up period, only two cases detected residual tumors. One case was successfully ablated and other case required additional surgery.

Conclusion: The present study demonstrated that ESD was effective and safe for the treatment of colorectal tumors near or within diverticulum. The use of traction device may be helpful to see the cutting site at the diverticulum and to achieve en-bloc R0 resection.

Disclosure of Interest: All authors have declared no conflicts of interest.

References

1. Tanaka S, Sano Y. Aim to unify the narrow band imaging (NBI) magnifying classification for colorectal tumors: current status in Japan from a summary of the consensus symposium in the 79th Annual Meeting of the Japan Gastroenterological Endoscopy Society. Dig Endosc . 2011;23 Suppl 1:131–9.

2. Hayashi N, Tanaka S, Hewett DG, Kaltenbach TR, Sano Y, Ponchon T, et al. Endoscopic prediction of deep submucosal invasive carcinoma: validation of the narrow-band imaging international colorectal endoscopic (NICE) classification. Gastrointest Endosc . 2013;78(4):625–32.

3. Kudo S, Tamura S, Nakajima T, Yamano H, Kusaka H, Watanabe H. Diagnosis of colorectal tumorous lesions by magnifying endoscopy. Gastrointest Endosc . 1996;44(1):8–14.

4. Oyama T. Counter traction makes endoscopic submucosal dissection easier. Clin Endosc . 2012;45(4):375–8.

TUESDAY, OCTOBER 31, 201710:30–12:00

MECHANISMS OF CARCINOGENESIS IN THE PANCREAS - ROOM E3____________________

OP208 ENHANCED EXPRESSION OF K-RAS PROTEIN IN PANCREAS PROMOTES DEVELOPMENT OF CIGARETTE SMOKE INDUCED CHRONIC PANCREATITIS IN MICE

J. Daniluk 1 , U. Daniluk 2 , J. Reszec 3 , A. Dabrowski 1

1 Department Of Gastroenterology And Internal Medicine, Medical University of Bialystok, Bialystok/Poland

2 Department Of Pediatrics, Gastroenterology And Allergology, Medical University of Bialystok, Bialystok/Poland

3 Department Of Medical Pathomorphology, Medical University of Bialystok, Bialystok/Poland

Contact E-mail Address: danilukj@poczta.onet.pl

Introduction: Epidemiological studies have demonstrated a strong association between smoking and the increased risk for developing chronic pancreatitis (CP) and pancreatic ductal adenocarcinoma (PDAC). The exact mechanism underlying the effects of cigarette smoke (CS) on pancreatic injury remains unknown. We have previously showed that increased Ras activity is a key element in development of pancreatic inflammation and its progression to PDAC. However, it is not clear if similar phenomenon is involved in CS-induced CP.

Aims & Methods: Therefore, the aim of our study was to determine if CS will promote development of CP in mice exposed to repeated episodes of acute pancreatitis (AP). Our secondary aim was to evaluate the involvement of K-Ras protein in this process. Mice were exposed to CS or a sham treatment (no smoke exposure) using a cigarette smoking inhalation system for 12 weeks. After two weeks of experiment, half of the animals from the CS and sham exposure groups were additionally subjected to a repeated caerulein treatment (7-hourly i.p. injections 50μg/kg/dose, once a week, for 10 consecutive weeks) to mimic recurrent episodes of AP. At the end of experiment the extension of pancreatic damage was determined by H&E and Trichrome staining. The expression of K-Ras protein was evaluated by immunohistochemistry (K-Ras-2B Antibody (C-19): sc-521).

Results: C57BL6/cmdb mice exposed to CS or caerulein injections alone did not develop any pancreatic damage determined by histopathology examination. However, concomitant treatment with both of these agents caused focal acinar atrophy, with slight intralobular and perivascular areas of fibrosis, resembling mild CP. Moreover, immunohistochemistry examinations revealed increased pancreatic expression of K-Ras only in mice treated both with CS and caerulein.

Conclusion: CS promotes development of CP in mice exposed to repeated episodes of AP. This process may be, at least partially, related to increased expression of K-Ras protein. Further studies are needed to determine the exact role of K-Ras and downstream signaling pathways in CS-induced CP.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP209 EXPRESSION OF TN ANTIGEN CAUSES CHRONIC PANCREATITIS IN A TRANSGENIC MOUSE MODEL

B. Mercanoglu , K. Karstens, C. Güngör, J.R. Izbicki, M. Bockhorn, G. Wolters-Eisfeld

Department Of General, Visceral And Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg/Germany

Contact E-mail Address: b.mercanoglu@uke.de

Introduction: Dysfunctionalities of Cosmc result in the expression of Tn antigen (Tn) and thereby in formation of truncated O-GalNAc glycans with pathophysiological implications. 1 Tn expression also arises in up to 90% of pancreatic ductal adenocarcinomas (PDAC) and is associated with poor prognosis. 2 This is of particular relevance, since PDAC is one of the most aggressive human tumors with a dismal overall prognosis. 3 Additionally, ppGalNAcT 2 (GalNT2) overexpression is observed in numerous tumor entities, further supporting the appearance of Tn. 4

Aims & Methods: The aim of this study was to mimicry the circumstances in PDAC and thus to investigate the effect of tumor-associated O-glycosylation on physiological functions of the pancreas in vivo. For this purpose, we generated a transgenic mouse model with a conditional Cosmc knockout and simultaneous GalNT2 overexpression mediated by the pancreas specific transcription factor 1a ( Ptf1a )-cre mouse strain. Immunohistochemical, molecular biological, biochemical and immunological investigations of wildtype and transgenic murine pankreata were performed. Furthermore, Tn-modified proteins were identified to explore their pathophysiological implications using the Tn antigen-binding plant lectin Vicia villosa agglutinin ( VVA ) for purification and subsequent mass spectrometric proteome analysis.

Results: Deletion of Cosmc with simultaneous overexpression of GalNT2 induces Tn expression in murine pancreas. Histopathological staining reveals a chronic pancreatitis phenotype with interlobulär fibrosis and focal necroses already at 4 weeks of age. Furthermore, flow cytometric and immunohistochemical analysis display immune cell infiltration. In the course, loss of parenchyma results in exocrine pancreatic insufficiency and malnutrition, compared to wildtype littermates.

Conclusion: Altogether, in our transgenic mouse model presented here, causality between Tn expression and the etiopathogenesis of chronic pancreatitis is shown, which highlights the pathophysiological relevance of truncated O-glycan formation. Moreover, it is conceivable that the inflammatory microenvironment, caused by Tn expression, influences on the tumor progression in PDAC.

Disclosure of Interest: All authors have declared no conflicts of interest.

References

1. Schietinger, A. et al. A mutant chaperone converts a wild-type protein into a tumor-specific antigen. Science 314 , 304–308, doi:10.1126/science.1129200 (2006).

2. Springer, G. F. T and Tn, general carcinoma autoantigens. Science 224 , 1198–1206 (1984).

3. Siegel, R. L. et al. Cancer statistics, 2016. CA Cancer J Clin 66 , 7–30, doi:10.3322/caac.21332 (2016).

4. Stowell, S. R., Ju, T. & Cummings, R. D. Protein glycosylation in cancer. Annu Rev Pathol 10 , 473–510, doi:10.1146/annurev-pathol-012414-040438 (2015).

OP210 LIPOXIN A4 INHIBITS PANCREATIC STELLATE CELL DIFFERENTIATION INTO PANCREATIC TUMOR STROMAL MYOFIBROBLASTS AND PANCREATIC TUMOR GROWTH IN VIVO

M. Heinrich , J. Schnittert, J. Prakash

Biomaterials Science And Technology/Targeted Therapeutics, University of Twente, Enschede/Netherlands

Contact E-mail Address: j.schnittert@utwente.nl

Introduction: The pancreatic tumor stroma has shown to strongly support tumor growth and metastasis. Human pancreatic stellate cells (hPSCs), as precursors of cancer-associated fibroblast like myofibroblasts (CAF), are a main component of the tumor stroma of pancreatic ductal adenocarcinoma (PDAC). Upon activation, human hPSCs differentiate into CAF and promote tumor growth, invasion and metastasis in PDAC [1]. LipoxinA4 (LXA4), a natural bioactive lipid, has shown to inhibit fibroblast activation [2]. This makes LXA4 a potential therapeutic to diminish the pro-tumorigenic effects of the pancreatic tumor stroma, by inhibiting hPSC activation into CAF.

Aims & Methods: The aim of the present study was to investigated whether LXA4 can inhibit the differentiation of human pancreatic stellate cells (hPSCs) into CAF and thereby inhibit hPSC-induced tumor growth in 3D co-culture heterospheroids in vitro and in a co-injection tumor model in vivo. TGF-β was used to activate hPSCs into CAF. The expression of the LXA4-specific surface receptor FRP2/ALX on hPSCs and hPSCs activated with TGF-β was investigated using qPCR. Actin staining, migration assay, QPCR and Western Blot analysis was used to analyze the inhibitory effect of LXA4 on hPSC activation. Western Blot and immunostaining were performed to analyze the ability of LXA4 to control Smad2/3 phosphorylation. LXA4 effect on paracrine signaling between hPSCs and Panc-1 endothelial tumor cell growth were investigated in conditioned medium experiments by monitoring cell growth and migration. 3D heterospheroids composed of hPSCs and Panc-1 as well as stroma rich hPSC/Panc-1 tumors in mice were used to investigate the effect of LXA4 on pancreatic tumor growth.

Results: The LXA4-specific surface receptor FPR2/ALX was found to be upregulated in TGFβ activated hPSCs. LXA4 treatment, significantly inhibited TGF-b induced activation markers (e.g. αSMA, collagen, PDGFRβ), migration and morphological changes in hPSCs. These inhibition of hPSC differentiation were caused by inhibition of Smad2/3 phosphorylation by LXA4. Conditioned medium obtained from TGF-b-activated hPSCs induced the migration and proliferation of Panc-1. These inductions could be inhibited by conditioned medium of LXA4-treated hPSCs. Additionally, LXA4 inhibited the activation of hPSCs with conditioned medium of Panc-1. These results demonstrated that LXA4 could inhibit pro-tumoral paracrine signaling between hPSC and Panc-1 cells. We investigated the effect of LXA4 on hPSC/Panc-1 heterospheroids, which we used as an in vitro tumor model. LXA4 significantly decreased the size & growth rate of the heterospheroids, supported by a decreased expression of ECM proteins and cell number. Furthermore an increased loss of E-Cadherin in control spheroids indicated that LXA4 is able to inhibit the endothelial-to-mesenchymal transition of Panc-1 cells within the spheroid. Finally, injection of LXA4 reduced the growth of subcutaneous tumors in mice.

Conclusion: LXA4 is capable to inhibit the hPSC differentiation into CAF and hPSC induced tumor promoting effects and the growth of stroma containing subcutaneous tumors in mice making it a potential therapeutic agent to modulate the tumor promoting effects of the pancreatic tumor stroma and ultimately treatment of pancreatic cancer.

Disclosure of Interest: All authors have declared no conflicts of interest.

References

1. Apte MV, Wilson JS, Lugea A, Pandol SJ. A starring role for stellate cells in the pancreatic cancer microenvironment. Gastroenterology 144(6), 1210–1219 (2013).

2. Roach KM, Feghali-Bostwick CA, Amrani Y, Bradding P. Lipoxin A4 Attenuates Constitutive and TGF-beta1-Dependent Profibrotic Activity in Human Lung Myofibroblasts. J Immunol 195(6), 2852–2860 (2015).

OP211 PROTEIN FACTORS PRESENTED IN SERUM OF PANCREATIC CANCER PATIENTS ENHANCES THE MOTILITY OF CANCER CELLS - A NOVEL VIEW OF PANCREATIC CANCER CELL METASTASIS

A. Poniewierska-Baran 1 , K. Dąbkowski 2 , T. Starzynska 2 , M.Z. Ratajczak 3

1 Department Of Physiology, Pomeranian Medical University in Szczecin, Szczecin/Poland

2 Department Of Gastroenterology, Pomeranian Medical University in Szczecin, Szczecin/Poland

3 Regenerative Medicine, Warsaw Medical University, Warsaw/Poland

Contact E-mail Address: agata.poniewierska@gmail.com

Introduction: Pancreatic cancer remains a serious clinical problem and a challenge for doctors and scientists. Despite the new possibilities in the diagnosis and treatment of cancer, 5-year survival rate applies to less than 5% of patients. Although many studies pathogenesis of pancreatic cancer, as well as other cancers remains unknown and needs further investigation. The process of metastasis is a cascade of events involving proteolysis, cell motility and migration, proliferation and neoangiogenesis. Cells released from the primary tumor must penetrate into the lymphatic vessels and/or blood vessels, which occurs by spreading. Circulating cells can then migrate through the walls of blood into surrounding tissues, where they settle, proliferate and form a new outbreak of disease. Understanding cellular processes responsible for the spread of cancer can be useful to improve the diagnosis and prognosis of the disease in patients diagnosed with pancreatic cancer.

Aims & Methods: The aim of study was to supplement the knowledge about the metastasis process of pancreatic cancer and to understand the role of protein factors presented in serum of pancreatic cancer patients that enhances the motility of cancer cells. The effect of pancreatic cancer patients serum were compared to the serum of control group and were added to pancreatic cancer cell line BxPC-3 (adenocarcinoma, ATCC® cell bank CRL-1687 ™). We evaluated cell migration, proliferation, adhesion response, activation of MAPK44/42 kinase and Akt kinase, and we measured the concentrations of pro-metastatic factors (including HGF, VEGF and SDF-1) in the blood of patients, by ELISA test.

Results: We report that 1) serum from patients group and control group, and factors such as SDF-1, HGF and VEGF can activate migration, adhesion and proliferation of pancreatic cancer cell line CRL1687; 2) we discovered higher metastatic potential of serum from patients with pancreatic cancer compared to control serum; 3) we report higher concentration of SDF-1, HGF/SF, VEGF in the serum of patients with pancreatic cancer. We report for the first time that diluted (1%) serum and plasma induces migration of malignant pancreatic cancer cell line much more strongly than any others knowns potent pro-metastatic factors. We found that this remarkable pro-migratory activity of diluted plasma is associated with a ∼50–100-kD protein that interacts with GαI protein-coupled receptors and activates p42/44 MAPK and AKT signaling in target cells. We report for the firs time that this pro-migratory factor, chaperoned by fibrinogen, is vitronectin and that this effect can be inhibited by fibrinogen.

Conclusion: The results prove a strong metastatic activity of blood serum and a significant role of HGF/SF, VEGF and SDF-1 factors in pancreatic cancer cell metastasis. Our results provide a novel mechanism for the metastasis of pancreatic cancer cells to lymphatics and body cavities, in which the concentration of fibrinogen is low, and thus suggests that free vitronectin stimulates migration of tumor cells.

Disclosure of Interest: All authors have declared no conflicts of interest.

References

1. Starzyńska T, Dąbkowski K, Błogowski W, Zuba-Surma E, Budkowska M, Sałata D, Dołęgowska B, Marlicz W, Lubikowski J, Ratajczak M.Z: An intensified systemic trafficking of bone marrow-derived stem/progenitor cells in patients with pancreatic cancer. J Cell Mol Med . 2013.

2. Sakamoto H, Kimura H, Sekijima M, Matsumoto K, Arao T, Chikugo T, Yamada Y, Kitano M, Ito A, Takeyama Y., Kudo M., Nishio K.: Plasma concentrations of angiogenesis-related molecules in patients with pancreatic cancer. Jpn J Clin Oncol . 2012.

3. Schneider G, Bryndza E, Poniewierska-Baran A, Serwin K, Suszynska M, Sellers Z. P, Merchant M. L, Kaliappan A, Ratajczak J, Kucia M, Garbett N.C, Ratajczak M. Z. Evidence that vitronectin is a potent migration-enhancing factor for cancer cells chaperoned by fibrinogen-a novel view of the metastasis of cancer cells to low-fibrinogen lymphatics and body cavities. Oncotarget , 2016.

4. Karayiannakis A.J, Bolanaki H, Syrigos K.N, Asimakopoulos B, Polychronidis A, Anagnostoulis S, Simopoulos C: Serum vascular endothelial growth factor levels in pancreatic cancer patients correlate with advanced and metastatic disease and poor prognosis. Cancer Lett . 2003.

OP212 ATM-DEFICIENCY GENERATES GENOMIC INSTABILITY IN PANCREATIC DUCTAL ADENOCARCINOMA AND SENSITIZES TOWARD THERAPEUTIC DNA-DAMAGE

L. Perkhofer 1 , A. Schmitt 2 , E. Hessmann 3 , D. A. Ruess 4 , M. Lesina 4 , A. Neese 3 , B. Sipos 5 , T. Seufferlein 1 , H.C. Reinhardt 2 , P. Frappart 1 , A. Kleger 1

1 Internal Medicine 1 Universitätsklinik Ulm, Ulm/Germany

2 Department of Internal Medicine, Division I, Cologne/Germany

3 University Medical Center Göttingen Gastroenterology and Gastrointestinal Oncology, Göttingen/Germany

4 II. Med. Klinik, TU Munich, Klinikum rechts der Isar, Munich/Germany

5 Department of Pathology and Neuropathology, Tübingen/Germany

Contact E-mail Address: alexander.kleger@uni-ulm.de

Introduction: Pancreatic ductal adenocarcinomas (PDAC) are characterized by an accumulation of oncogenic mutations. Recent genome sequencing studies identified recurrent protein-damaging ataxia telangiectasia-mutated (ATM) mutations in human PDAC. We previously showed in a mouse model of PDAC, and also in human cancer that loss of Atm accelerates pancreatic cancer formation and epithelial–mesenchymal transition. ATM, a serine/threonine kinase, is a master regulator of the DNA damage response (DDR), impacting on cell cycle checkpoint control and apoptosis. ATM thus has a barrier function to prevent outgrowth of genomically instable incipient tumor cells.

Aims & Methods: Genomic instability, chromosomal aberrations and aneuploidy are characteristic features of most human cancers. To study whether and how Atm-deficiency affects genome integrity, we used a conditional deletion of Atm in a mouse model of PDAC and performed in depth functional and molecular analyses.

Results: First, an independent cohort of resected human PDAC was analyzed via immunostaining with an antibody previously described in a trial setting for tailored therapies in ATM low expressing human metastatic gastric cancer. Interestingly, we frequently observed areas of clonal ATM loss along with a weak staining pattern leading to a correlation between ATM protein expression and survival in a cohort of 49 resected human PDAC. Next, we made use of our previously described ATM-deficient mouse model and subsequently isolated cell lines to characterise the DNA damage response upon ATM deletion. Interestingly, we found increased mitotic defects, recurrent genomic rearrangements and deregulated DNA integrity checkpoints in ATM-deficient murine PDAC reminiscent of human counterparts. Array CGH and SKY analysis show that ATM deficiency leads to chromosomal instability with recurrent and dramatic structural aberrations including chromotripsis. We hypothesized that altered genome integrity might allow synthetic lethality-based options for targeted therapeutic intervention. Indeed, DDR defects sensitize ATM-deficient PDAC toward additional genotoxic stress as shown for gamma-irradiation. In addition and in line with our hypothesis, we found synthetic lethality between Atm deletion and PARP-inhibition in PDAC tumor cells in vitro and in vivo upon orthotopic transplantation by a genotype-selective increase in apoptosis.

Conclusion: Thus, our data establish a novel route for the treatment of ATM -mutant PDAC patients.

Disclosure of Interest: All authors have declared no conflicts of interest.

Reference

Loss of ATM accelerates pancreatic cancer formation and Epithelial-Mesenchymal-Transition. Russell R, Perkhofer L, Liebau S, Lin Q, Lechel A, Feld FM, Zenke M, Illing A, Hartmann D, von Figura G, Weissinger SE, Rudolph KL, Möller P, Lennerz JK, Seufferlein T, Wagner M, Kleger A. Nature Communications , 2015 Jul 29;6:7677.

OP213 COMBINED INHIBITION OF HISTONE DEACETYLASES AND SIRTUIN 1 LEADS TO PARTIAL REDIFFERENTIATION OF DUCTAL NEOPLASIA TOWARDS A MORE ACINAR PHENOTYPE IN MOUSE PANCREATIC TUMOR ORGANOIDS

S. Zhang , X. Zou

Department Of Gastroenterology, Nanjing Drum Tower Hospital, Nanjing/China

Contact E-mail Address: 13770771661@163.com

Introduction: Recent studies in genetically engineered mouse models (GEMMs) suggest that ductal neoplasia predominantly initiates from acinar cells after transdifferentiation to a ductal phenotype. We hypothesized that it might be possible to redifferentiate pancreatic intraepithelial neoplasia (PanIN) and pancreatic ductal adenocarcinoma (PDAC) to a more acinar phenotype by blocking selected cell signaling pathways.

Aims & Methods: We treated Mist1 CreERT2/+ ;LSL-Kras G12D ; R26 mTmG (“KC iMist1 G”) mouse PanIN 3D organoids and Pdx1-Cre;Kras +/LSL−G12D ;Trp53 +/LSL−R172H (“KPC”) mouse PDAC 3D organoids with selected compounds in vitro, including histone deacetylase (HDAC) inhibitor SAHA, DNA methyltransferase inhibitor (5-Aza), and sirtuin 1 (SIRT1) inhibitor EX527. We analyzed the differentiation status of the organoids by detecting the expression of typical acinar and ductal markers using immunoblot, reverse transcription PCR, and immunofluorescence (IF) analyses.

Results: Although single use of SAHA, 5-Aza, and EX527 all failed to upregulate the mRNA expression of the acinar markers, combined use of SAHA and EX527 was able to increase the mRNA expression of the acinar markers Amylase, Elastase, and CPA1 in “KC iMist1 G” PanIN organoids by a factor of two- to four-fold, associated with a simultaneous decrease in ductal markers, including SOX9, HNF1B, and Muc5ac. We then performed a kinetic analysis in “KPC” PDAC organoids at day 3, day 6, and day 9. We found that combined use of SAHA and EX527 significantly upregulated the mRNA expression of the acinar markers including Amylase and CPA1 by a factor of more than 10-fold, and downregulated the mRNA expression of the ductal markers including SOX9 (p < 0.05), HNF1B (p < 0.05), and Muc5ac (p < 0.01) at day 9, indicating partial conversion to a more acinar phenotype. We then treated the same PDAC organoid with SAHA and EX527 for 9 days, and observed an obvious increase in the protein expression of the acinar marker Mist1. Besides, IF staining showed that combined use of SAHA and EX527 induced remarkable expression of the acinar marker Amylase in the same “KPC” PDAC organoid.

Conclusion: Blocking selected cell signaling pathways could lead to partial redifferentiation of murine Kras-mutant pancreatic ductal neoplasia to a more acinar phenotype, of which combined inhibition of HDACs and SIRT1 had the greatest efficacy. HDACs and SIRT1 might therefore be potential therapeutic targets for PDAC. The underlying mechanisms of the redifferentiating effect need to be further investigated.

Disclosure of Interest: All authors have declared no conflicts of interest.

TUESDAY, OCTOBER 31, 201710:30-12:00

MICROBIOLOGY AND IMMUNOLOGY OF THE SMALL INTESTINE - ROOM B5____________________

OP214 VERIFICATION OF IMMUNOGLOBULIN A REGULATION OF MICROFLORA AND PROTECTION OF INTESTINAL MUCOSA

N. Tsugawa 1 , T. Nagaishi 1 , T. Watabe 1 , N. Jose 1 , A. Hosoya 1 , Y. Kojima 1 , T. Adachi 2 , R.S. Blumberg 3 , M. Watanabe 1

1 Gastroenterology, Tokyo Medical and Dental University, Graduate School of Medical Science, Tokyo/Japan

2 Immunology, Tokyo Medical and Dental University, Medical Research Institute, Tokyo/Japan

3 Brigham and Womens Hospital, Boston/United States of America

Contact E-mail Address: ntsgast@tmd.ac.jp

Introduction: Immunoglobulin (Ig) A is believed to be involved in maintaining mucosal homeostasis in the gut. In fact, IgA deficiency has been associated with gastrointestinal diseases such as celiac disease and inflammatory bowel diseases. In addition, it has been reported that the lack of Ig class-switching in B cells due to deficiency of activation-induced cytidine deaminase (AID) in mice results in aberrant microflora composition in the gut. However, it is still unclear whether this is directly caused by the lack of secreted IgA since AID deficiency also results in the suppressed expression of other classes of Ig.

Aims & Methods: The aim of this study was to verify the importance of IgA secretion in the regulation of intestinal microflora. To this end, we have recently generated an animal model of IgA deficiency (IgA −/− ) by using the CRISPR/Cas9 system, and then analyzed their intestinal flora as well as histopathological changes of the gastrointestinal tissues.

Results: The guide RNAs specific for IgE and IgA cytoplasmic domains and Cas9 mRNA were injected into C57BL/6 zygotes. Sequencing of the regions between IgE and IgA tails from the offsprings revealed that one of these had a deletion of the entire IgA region and thus identified as IgA −/− . We confirmed that the expressions of other Ig classes except IgA were not altered in these animals. To assess the alterations of microflora in these mice, we first analyzed the intestinal mucosa. Scanning electron microscopy revealed significantly increased segmented filamentous bacteria on the intestinal epithelia in IgA −/− compared to that of littermate control. Next, microbial 16S rRNAs were isolated from the luminal contents of jejunum, ileum or colon, and then applied for metagenomic analysis. We observed significantly altered diversity in microflora especially in the ileum. Given these observation, we sought to assess the effects of altered intestinal flora on mucosal homeostasis in IgA −/− . Histopathologcal analysis revealed inflamed ileal mucosa and no significant changes in other tissues including stomach, duodenum, jejunum and colon. Flow cytometry showed increased CD4 + T cells in the ileal lamina propria associated with increased IFN-g and IL-17 and decreased IL-4 production in the IgA −/− . Given these data, we intercrossed IgA −/− with CD19 Cre and YC3.60 transgenic mice to observe Ca 2+ influx specifically in the B cells. We had originally expected suppressed B cell function due to decrease of Th2 cytokine production in the IgA −/− ileum. However, interestingly, intra-vital imaging revealed activated B cells in Peyer’s patches at the IgA −/− ileum.

Conclusion: Our current study is the first to provide evidence to verify that the lack of IgA induce altered microflora as previously observed in AID −/− mice. In addition, our observation also implied that such alteration may result in mucosal inflammation specifically in the ileum caused by disregulated homeostasis in the gut. Additional experiments are currently ongoing.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP215 MONOCYTE-DERIVED MACROPHAGES RESTORE GUT MOTILITY IN POSTOPERATIVE ILEUS BY LIMITING ENTERIC NEURONAL DAMAGE

M. Stakenborg 1 , G. Farro 1 , G. Goverse 1 , V. De Simone 1 , P. J. Gomez-Pinilla 1 , Z. Lisowski 2 , D. Laoui 3 , J. Van Ginderachter 3 , D. A. Hume 2 , G. E. Boeckxstaens 1 , G. Matteoli 1

1 Translational Research Center For Gastrointestinal Disorders, KU Leuven, Leuven/Belgium

2 The Roslin Institute And Royal School Of Veterinary Studies, University of Edinburgh, Edinburgh/United Kingdom

3 Lab Of Cellular And Molecular Immunology, Vrije Universiteit Brussel, Brussel/Belgium

Contact E-mail Address: gianluca.matteoli@kuleuven.be

Introduction: Patients undergoing open abdominal surgery often suffer from a transient episode of intestinal dysmotility referred to as postoperative ileus (POI). The current view is that ileus depends upon a local inflammatory response in the intestinal muscularis externa (ME) and current therapies mainly focus on reducing influx of leucocytes to the ME. However, recent studies have shown that recruitment of leukocytes, and in particular monocytes, is crucial to the timely resolution of inflammation and to prevent excessive tissue damage.

Aims & Methods: In the current study, we used a murine model of intestinal manipulation (IM)-induced POI to clarify whether monocytes mediate tissue damage and intestinal dysfunction or they are rather involved in the recovery of intestinal motility. IM was performed in mice with defective monocyte migration to tissues (C-C motif chemokine receptor 2, Ccr2 −/− mice) and wild-type (WT) mice to study the role of monocytes and monocyte-derived MΦs during the resolution of ME inflammation. The severity of POI was evaluated by assessing GI transit, neuronal damage (IHC) and ME inflammation via flow cytometric analysis of recruited immune cells.

Results: IM in Ccr2 −/− mice resulted at day 1 in the same GI transit delay as in WT mice (geometric center WT: 3.72 ± 0.29; Ccr2 −/− : 3.55 ± 0.22), proving that monocyte infiltration to the ME is not responsible for the development of intestinal stasis after abdominal surgery, as previously hypothesized. However, GI transit recovery after IM was significantly delayed in Ccr2 − / − mice compared to WT mice, associated with increased neutrophil-mediated immunopathology and impaired neuromuscular function (see table). To assess whether the lack of monocytes could induce neuronal alteration at the morphological level, we used confocal microscopy to dissect the sub-cellular localization of HuC/D in enteric neurons in the ME of WT and Ccr2 − / − mice 5 days after IM. Although our data showed that HuC/D + neurons are comparable in volume (WT: 671.1 ± 9.44; K Ccr2 −/− : 692.1 ± 9.77 µm 3 ), we detected significantly higher nuclear localization of HuC/D + in enteric neurons of Ccr2 − / − mice (% HuC/D nucleus/cell in WT: 51.32 ± 0.54%; Ccr2 −/− : 55.51 ± 0;54%), suggestive of neuronal dysfunction. Given that the MΦ growth factor colony-stimulating factor 1 (CSF1) promotes tissue repair via monocyte recruitment and maturation, we administered CSF1-Fc in WT and Ccr2 −/− mice during the recovery phase after IM. CSF1-Fc treatment resulted in reduced neutrophil infiltration and restored circulating monocytes and accumulation of MΦs in the ME of Ccr2 − / − mice 3 days after IM. Moreover, with regard to intestinal motility, CSF1-Fc-treated Ccr2 − / − mice recovered GI transit 3 days after IM.

Conclusion: Our study reveals a critical role for monocyte-derived MΦs in supporting neuromuscular function and restoring intestinal homeostasis after surgical trauma. From a therapeutic point of view, our data indicate that inappropriate targeting of monocytes may increase neutrophil-mediated immunopathology and prolong the clinical outcome of POI, while future therapies should be aimed at enhancing MΦ repair functions.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP216 VONOPRAZAN, A NOVEL ACTIVE POTASSIUM-COMPETITIVE ACID BLOCKER, AND RABEPRAZOLE INDUCE SMALL INTESTINAL DYSBIOSIS AND EXACERBATE THE NON-STEROIDAL ANTI-INFLAMMATORY DRUG-INDUCED SMALL INTESTINAL ENTEROPATHY

Y. Nadatani 1 , T. Watanabe 1 , N. Sugimura 1 , K. Otani 1 , K. Taira 1 , S. Hosomi 1 , Y. Nagami 1 , F. Tanaka 1 , N. Kamata 1 , H. Yamagami 1 , T. Tanigawa 1 , M. Shiba 1 , Y. Fujiwara 2

1 Dept. Of Gastroenterology, Osaka City University Graduate School of Medicine Dept. of Gastroenterology, Osaka/Japan

2 Dept. Of Gastroenterology, Osaka City University, Osaka/Japan

Contact E-mail Address: dada@med.osaka-cu.ac.jp

Introduction: Vonoprazan fumarate, a novel active potassium-competitive acid blocker, was launched in Japan before it entered the world market. Vonoprazan has a stronger inhibitory effect on gastric acid secretion than proton pump inhibitors (PPIs) such as rabeprazole and esomeprazole. Recent studies show that PPIs alter the composition of the intestinal microbiome, and the resulting dysbiosis exacerbates the non-steroidal anti-inflammatory drug (NSAID)-induced small intestinal enteropathy.

Aims & Methods: Aim of this study is to investigate the effect of vonoprazan on the microbiota in the small intestine and NSAID-induced small intestinal enteropathy in mice. C57BL/6J mice received intraperitoneal administration of vonoprazan, rabeprazole, or vehicle for 7 days, and were administered indomethacin by gavage to induce damage to the small intestine. Some mice administered either of the 2 drugs were killed without administration of indomethacin. We analyzed the microbiota in their small intestine by using operational taxonomic units (OTU) sequenced on MiSeq using the V1–V2 region of the 16S rRNA. The mice administered with the antibiotic cocktail in drinking water for 28 days were transplanted with contents from the small intestine of the mice treated with either vonoprazan or rabeprazole; thereafter the donor mice were administered with indomethacin.

Results: Administration of vonoprazan and rabeprazole altered the diversity and composition of the microbiota of the small intestine. Vonoprazan and rabeprazole significantly increased the OTU number by 1.39- and 1.87-fold, respectively. Analysis of similarities (ANOSIM) of the unweighted Unifrac distances showed significant differences between the vehicle- and vonoprazan- or rabeprazole-treated groups (p < 0.01). ANOSIM of weighted Unifrac distances showed significant differences between the vehicle- and rabeprazole-treated groups (p < 0.01). Lactobacillus johnsonii was the predominant microbial species in each group, and the population ratio of this species decreased by 53% and 45%, respectively after administration of vonoprazan and rabeprazole. Compared to the vehicle-treated group, the vonoprazan- and rabeprazole-treated groups showed 2.8-fold and 1.7-fold increases in indomethacin-induced damage to the small intestine, respectively. This high sensitivity to indomethacin-induced damage was caused by the intestinal microbiota obtained from the mice treated with vonoprazan or rabeprazole.

Conclusion: Vonoprazan and rabeprazole induced small intestinal dysbiosis, which exacerbated the NSAID-induced small intestinal enteropathy.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP217 COMPOSITION OF MUCOSA-ASSOCIATED MICROBIOME ALONG THE ENTIRE GASTROINTESTINAL TRACT IN HUMANS

F.E. r. Vuik 1 , G. M. Fuhler 1 , S. R. Konstantinov 1 , J. Dicksved 2 , L. Engstrand 3 , A. Van De Winkel 1 , M.C. w. Spaander 1 , E.J. Kuipers 1 , M. P. Peppelenbosch 1

1 Gastroenterology And Hepatology, Erasmus MC University Medical Center, Rotterdam/Netherlands

2 Animal Nutrition And Management, Swedish University of Agricultural Sciences, Uppsala/Sweden

3 Dept. Of Of Microbiology, Tumor & Cell Biology, Karolinska Institutet, Stockholm/Sweden

Contact E-mail Address: f.vuik@erasmusmc.nl

Introduction: The importance of the gastrointestinal (GI) microbiome in human health and disease is unambiguous. However, while the colonic microbiome is well studied due to easy accessibility of faecal material, the microbiome composition along the full GI-tract remains underexplored. Furthermore, luminal bacterial content is not a direct reflection of the microbiome at the mucosal interface, the latter being arguably more important due to its closer interaction with host cells.

Aims & Methods: We therefore aimed to analyse the mucosal microbiome along the entire gastrointestinal tract within the same individuals. Patients with unexplained complaints, such as weight loss, abdominal pain, diarrhea and iron deficiency anaemia were scheduled for anterograde and subsequent retrograde double-balloon enteroscopy (DBE). Mucosal samples were taken from 9 different sites: oesophagus, antrum, proximal duodenum, distal jejunum, proximal ileum, distal ileum, colon ascendens, colon descendens and rectum. The microbiome was analysed using Illumina Miseq sequencing of the 16S rRNA gene.

Results: Fourteen patients were included with a median age of 51 (IQR 42–60) years. No significant clinical abnormalities were seen at DBE, except for one patient with a cecum tumour and ulcerative lesions in the distal ileum. Microbiome profiles in this patient were characterised by a high abundance of enterobacteriaceae along the entire digestive tract, and were excluded for further analysis. Diversity of the microbiome at genus level increased from upper gastric locations to the lower intestine. Although differences in community structure were seen between individuals, the major difference was between the upper and lower GI-tract. In the upper digestive tract firmicutes (relative abundance of 37, 5%), proteobacteria (relative abundance of 39, 8%) and actinobacteria (relative abundance of 8, 3%) dominate, whereas bacteroides (relative abundance of 28, 0%) and firmicutes (relative abundance of 62, 2%) are the major phyla in the lower digestive tract.

Conclusion: To the best of our knowledge we are the first to describe the microbiome along the entire GI-tract within in the same individuals. Diversity of the microbiome increases in the lower digestive tract and a clear difference is seen between the upper and lower GI-tract microbiome composition.

Disclosure of Interest: All authors have declared no conflicts of interest.

References

Jandhyala SM, Talukdar R, Subramanyam C, Vuyyuru H, Sasikala M, Nageshwar Reddy D. Role of the normal gut microbiota. World J Gastroenterol . 2015;21(29):8787–803.

Watt E, Gemmell MR, Berry S, Glaire M, Farquharson F, Louis P, et al. Extending colonic mucosal microbiome analysis-assessment of colonic lavage as a proxy for endoscopic colonic biopsies. Microbiome . 2016;4(1):61.

Zoetendal EG, Raes J, van den Bogert B, Arumugam M, Booijink CC, Troost FJ, et al. The human small intestinal microbiota is driven by rapid uptake and conversion of simple carbohydrates. ISME J . 2012;6(7):1415–26.

OP218 HYPOXIA DISRUPTS INTESTINAL BARRIER VIA REGULATING NHE8-TIGHT JUNCTION IN SEVERE ACUTE PANCREATITIS RAT MODELS

X. Li 1 , C. Geng 1 , X. Lei 1 , C. Wang 1

1 Department Of Gastroenterology, West China Hospital of Sichuan University, Chengdu/China

Contact E-mail Address: lixiao5166@hotmail.com

Introduction: Intestine barrier dysfunction is attributed to various diseases, including inflammation, hypoxia, ischemia, intoxication, and considered as an important pathogenic factor for many diseases. In severe acute pancreatitis (SAP), it is well established that intestinal barrier dysfunction is a major element to promote SAP development and hypoxia plays a crucial role in infectious complications. Thus, deeply comprehending the mechanisms of intestine barrier dysfunction is indeed required for SAP treatment. Extensive evidences has indicated that intestine hypoxia triggered by SAP disrupting tight junction (TJ) is responsible for barrier dysfunction. Recently, the protective role of sodium/hydrogen exchanger 8 (NHE8) in intestine in various conditions has been well documented. We have previously demonstrated that inflammation reduced intestinal NHE8 expression. However, the role of NHE8 in SAP induced intestine barrier dysfunction has not been reported.

Aims & Methods: The aim of this study is to explore the intestinal expression of NHE8 in SAP rat model, and further explore the effects of hypoxia on NHE8 expression and potential mechanisms in Caco-2 cells hypoxia model. To induce SAP, SD rats were retrograde injected with 3% sodium taurocholate into the pancreatic duct, and ileum mucosal tissues were collected 24 hours later. For mechanism study, Caco-2 cells were incubated with 200μM cobalt chloride (Cocl 2 ) for 6 hours to induce acute hypoxia model. Hypoxia-inducible factor-1alpha (HIF-1α) specific inhibitor 2-Methoxyestradiol (2-MeOE2) was incubated with Caco-2 cells for 6 hours under hypoxia. To further investigate the relationship between NHE8 and TJ proteins, NHE8-shRNA plasmid (shNHE8) were constructed.

Results: In SAP group, NHE8 protein expression was significantly decreased compared with the control group (0.5 ± 0.04 vs. 1.2 ± 0.04, n = 12, P < 0.05). For Cocl 2 intervened Caco-2 cells, HIF-1α protein expression were significantly stimulated compared with the control (4.53 ± 0.25 vs. 1.21 ± 0.15, n = 3, P < 0.05), whereas NHE8 proteins expression were significantly reduced compared with the control (0.58 ± 0.06 vs. 1.02 ± 0.09, n = 3, P < 0.05). Additionally, Cocl 2 treatment significantly reduced Claudin-1 and ZO-1 proteins expression when compared with the control (1.05 ± 0.02 vs. 2.38 ± 0.15; 1.33 ± 0.06 vs. 1.53 ± 0.06, n = 3, P < 0.05). 2-MeOE2 treatment obviously blocked Cocl 2 induced HIF-1α protein expression (3.59 ± 0.29 vs. 4.53 ± 0.25, n = 3, P < 0.05). Furthermore, 2-MeOE2 treatment dramatically increased the expression of NHE8 (0.91 ± 0.07 vs. 0.58 ± 0.06, n = 3, P < 0.05), Claudin-1 (1.6 ± 0.16 vs. 1.05 ± 0.02, n = 3, P < 0.05) and ZO-1 (1.56 ± 0.08 vs. 1.33 ± 0.06, n = 3, P < 0.05) compared with Cocl 2 pretreated cells (P < 0.05). Interestingly, compared with the mock shRNA transfected cells, the expressions of Claudin-1 and ZO-1 proteins in the cells transferred with shNHE8 were significantly decreased (1.87 ± 0.15 vs. 2.38 ± 0.12; 1.06 ± 0.06 vs. 1.44 ± 0.06, n = 3, P < 0.05).

Conclusion: In SAP, the decrease of intestinal NHE8 expression is responsible for intestine barrier dysfunction. Moreover, intestinal hypoxia caused by SAP might alter intestinal function through HIF-1α-NHE8-TJs signal pathway.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP219 MODULATION OF THE ENDOCANNABINOID SYSTEM BY FATTY ACID AMIDE HYDROLASE, MONO- AND DIACYLGLYCEROL LIPASE INHIBITORS AS AN ATTRACTIVE TARGET FOR SECRETORY DIARRHEA THERAPY

A. Wasilewski 1 , A. Misicka 2 , M. Sacharczuk 3 , J. Fichna 1

1 Department Of Biochemistry, Medical University of Lodz, Łódź/Poland

2 Department Of Neuropeptides, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw/Poland

3 Laboratory Of Neurogenomics, Institute of Genetics and Animal Breeding, Polish Academy of Sciences, Magdalenka/Poland

Contact E-mail Address: jakub.fichna@umed.lodz.pl

Introduction: Secretory diarrhea remains a major global public health problem and is the second leading cause of death, particularly in children and the elderly. Thus, it is clear that there is an urgent need for developing effective anti-diarrheal strategies. Many disorders can disrupt intestinal fluid and electrolyte absorption, including Crohn’s disease, ulcerative colitis, and diarrhea-predominant irritable bowel syndrome. The aim of our study was to characterize the effect of inhibition of selected enzymes involved in the synthesis and degradation of endocannabinoids on electrolyte equilibrium in the mouse colonic tissue.

Aims & Methods: Male Swiss-Webster mice were used in this study. The effects of PF-3845, JZL-184 and RHC-80267 (inhibitors for fatty acid amide hydrolase (FAAH), mono- (MAGL) and diacylglycerol lipase (DAGL), respectively) on epithelial ion transport were characterized in isolated mouse colon stimulated by forskolin (FSK), veratridine (VER) and bethanechol (BET). Next, colonic tissue was co-incubated with selected inhibitors and cannabinoid receptor antagonists: AM 251 and AM 630 (CB 1 and CB 2 antagonists, respectively). To assess changes in the active ion transport in response to addition of tested drugs, the measurements of short-circuit current (Isc) in mouse colon and ileum in vitro were performed.

Results: We observed that basolateral addition of PF-3845 induced antisecretory effect in FSK-stimulated colonic tissue (p < 0.01), which was significantly reversed by AM 251 (p < 0.001) and AM 630 (p < 0.01). JZL-184 significantly reduced epithelial ion transport (p < 0.05) under FSK-stimulated conditions. Furthermore, co-incubation with AM 630 reversed this effect leading to an increase in ion transport when compared to JZL-184 alone (p < 0.05). After addition of JZL-184 and tissue stimulation by VER, we did not observe any significant effect on colonic Isc. However, application of AM 630 to colonic tissue treated subsequently with JZL-184 led to a pronounced increase in Isc compared with JZL-184 alone (p < 0.01). In turn, basolateral addition of PF-3845, JZL-184 or RHC-80267 was without any statistically significant effect on BET-evoked ion transport when compared to control.

Conclusion: For the first time, we report that the modulation of the endocannabinoid system may play a crucial role in providing a novel effective secretory diarrhea treatment, devoid of side effects on the central nervous system caused by direct administration of cannabinoid receptor agonists.

Disclosure of Interest: All authors have declared no conflicts of interest.

TUESDAY, OCTOBER 31, 201710:30-12:00

ABSTRACTS ON FIRE: PREDICTING AND OPTIMISING IBD OUTCOME - HOTSPOT____________________

OP220 ENRICHMENT OF CIRCULATING DOUBLE POSITIVE INTERLEUKIN-17 PRODUCING FOXP3+ CD4+ T CELL SUBSETS ARE ASSOCIATED WITH A HIGHER RISK OF FURTHER RELAPSE IN CROHN’S DISEASE IN REMISSION: AN OBSERVATIONAL, PROSPECTIVE MULTICENTER STUDY

G. Boschetti 1 , B. Flourie 1 , X. Roblin 2 , S. Paul 3 , J. Bienvenu 4 , G. Bommelaer 5 , A. Buisson 6 , E. Del Tedesco 2 , C. Josson 7 , S. Legastelois 7 , S. Nancey 1

1 Gastroenterology, Lyon-Sud University Hospital, Pierre Benite/France

2 Gastroenterology, CHU Saint-Etienne, Saint-Etienne/France

3 Laboratory Of Immunology And Immunomonitoring, CHU Saint-Etienne, Saint-Etienne/France

4 Laboratory Of Immunology, Lyon-Sud University Hospital, Pierre Benite/France

5 Chu Estaing, Clermont-Ferrand/France

6 Dept. Of Gastroenterology, CHU Estaing Clermont-Ferrand, Clermont-ferrand/France

7 Indicia, Lyon/France

Contact E-mail Address: gilles.boschetti@chu-lyon.fr

Introduction: The balance between Foxp3 + regulatory T-cells (Tregs) and effector T cells, including Th1 and Th17 CD4 + T cell subsets are critical for protecting the host from infection while maintaining gut homeostasis. All these T-cell subsets contribute to the pathogenesis of Crohn’s disease (CD). The dynamics of most of the peripheral effector and regulator T-cell subsets during the course of CD in remission and their relationships with the risk of relapse remain unknown. We aimed to systematically analyse the evolution of frequencies of circulating Th1, Th17 and Tregs with respect to disease remission - relapse in CD.

Aims & Methods: A cohort of 113 CD patients in clinical remission were regularly followed up on a 3-month basis. Blood samples were collected at each visit for routine monitoring inflammatory markers, including ultrasensitive CRP and for measurements of various serum cytokines, including IL-6, IL-8, IL-10, IL-13, IL-17A, IL-23, TNFa, IFNg, TGFb, by an ultrasensitive Erenna method. The frequencies of circulating single positive Th1, Th17 and Tregs CD4 + T cell subsets, as well as double positive CD4+ T cell subsets co-expressing IFNg-IL17, Foxp3-IFNg and Foxp3-IL-17 were analysed by multicolour flow cytometry.

Results: Among the whole cohort, 34 (30%) out of 113 patients relapsed within the follow-up period. The prevalence of circulating IFNg-secreting CD4 + T cells (Th1), IL-17-secreting CD4 + T cells (Th17) and Foxp3-expressing CD4+ T cells (Treg) as well as the concentrations of a wide broad of cytokines (IL-6, IL-8, 17A, TGFb, TNFa, IFNg, IL-13, IL-23) measured in the serum were not significantly different all over the time between patients who relapsed and those who stay in clinical remission. Various circulating double positive CD4 + T-cell subsets co-expressing Foxp3 and IL-17, Foxp3 and IFNg and triple positive Foxp3 + IL-17 + and IFNg + were detectable in CD patients in remission. The subset of CD4 + T cells co-expressing IL-17 and Foxp3 was found significantly enriched (≈2-fold increase) in the circulating compartment in the cohort of patients in remission who further experienced a clinical relapse 3 months later compared with that of CD patients who stayed in remission all over the follow-up period. In a multivariate analysis, elevated serum usCRP, low serum IL-10 and high number of double positive IL-17 and Foxp3 CD4 + T cells were 3 independent factors significantly associated with the risk of further clinical relapse in CD patients in remission.

Conclusion: Detectable circulating crossover immune CD4 + T-cell subsets co-expressing Foxp3, IL-17 and IFNg in CD patients in remission argues in favour of the recent concept of T cell plasticity. A significant enrichment of a unique CD4 + T-cell subset co-expressing Foxp3 and IL-17 that preceding the occurrence of a flare suggests the potential contribution of this double positive T-cell subset in the pathogenesis of CD.

Disclosure of Interest: C. Josson: Cendrine Josson is an employee of Indicia

S. Legastelois: Stéphane Legastelois is an employee of Indicia

All other authors have declared no conflicts of interest.

OP221 INFLIXIMAB TROUGH LEVELS ABOVE 7 MG/ML IN INFLAMMATORY BOWEL DISEASE TREATED WITH INFLIXIMAB: BETTER CONTROL OF INFLAMMATION WITHOUT INCREASED RISK OF INFECTION

D. Drobne 1 , T. Kurent 1 , S. Golob 1 , P. Svegl 1 , P. Rajar 1 , S. Terzic 2 , M. Kozelj 1 , G. Novak 1 , N. Smrekar 1 , S. Plut 1 , A. Smid 1 , N. Sever 1 , L. Strnisa 1 , J. Brecelj 1 , D. Urlep 1 , J. Osredkar 3 , M. Homan 1 , R. Orel 1 , B. Stabuc 1 , I. Ferkolj 1

1 Department Of Gastroenterology And Hepatology, University Medical Centre Ljubljana Slovenia, Ljubljana/Slovenia

2 Department Of Infectious Diseases, University Medical Centre Ljubljana Slovenia, Ljubljana/Slovenia

3 Clinical Institute Of Clinical Chemistry And Biochemistry, University Medical Centre Ljubljana Slovenia, Ljubljana/Slovenia

Contact E-mail Address: david.drobne@gmail.com

Introduction: Target infliximab trough level for optimal control of inflammation in inflammatory bowel disease (IBD) is not clear. A prospective trial suggested target infliximab trough level of 3 – 7 µg/ml [1], but data on additional therapeutic benefit of higher trough levels are conflicting. It is also not clear if higher infliximab trough levels increase the risk of infection.

Aims & Methods: Our aim was to explore whether infliximab trough levels above 7 µg/ml are more effective and still safe regarding the risk of infection compared to levels below this threshold. In this single-centre cohort study we included 183 IBD patients (109 Crohn's disease, 74 ulcerative colitis including IBD - unclassified) who received infliximab maintenance treatment between 2010 and 2015 at tertiary referral university IBD Centre (162 adults, 21 children) with available infliximab trough level data. Effectiveness and safety of high trough levels (≥7 µg/ml) was compared to trough levels below 7 µg/ml. Effectiveness was assessed by correlating fecal calprotectin (114 matched samples), CRP (379 matched samples) and endoscopy (69 colonoscopies) data to infliximab trough levels (426 samples, ELISA assay). Safety was assessed by comparing rates of infections in semesters (defined by 3-month periods) with high trough levels (≥7 µg/ml) compared to semesters with infliximab trough levels below this threshold. Data on trough levels were available in 473/1681 (28%) semesters. Continuous variables were described using the median and interquartile range (IQR) and analyzed with the Mann–Whitney U test. Chi-square test or Fisher’s exact test was used for categorical variables.

Results: Median fecal calprotectin and median C-reactive protein (CRP) were lower in patients with high infliximab trough levels (fecal calprotectin median 66 mg/kg [IQR: 30–257]; CRP median 3 mg/L [IQR: 3–3]) compared to infliximab trough levels below 7 µg/ml (fecal calprotectin median 155 mg/kg [IQR: 72–474]; CRP median 3 mg/L [IQR: 3–14.5]) (fecal calprotectin p < 0.001; CRP p < 0.001). Similarly, the proportion of patients with fecal calprotectin below 100 mg/kg and with normal CRP was higher in patients with high trough levels (Table 1). Superior effectiveness of high trough levels compared to trough levels below 7 µg/ml was maintained also after excluding samples with low trough levels (<3 µg/ml) from the analysis. Furthermore, in 14/17 (82%) patients who had available paired trough level samples and had increased fecal calprotectin/CRP at trough level between 3–7 µg/ml, fecal calprotectin/CRP decreased (to normal in 62%) when trough levels increased to >7 µg/ml after infliximab dose optimization. In Crohn’s disease, patients with mucosal healing had higher trough levels (4.62 [IQR: 2.21–7.31]) compared to patients with ulcers (2.29 [IQR: 0.3–4.45]) (p = 0.034). Eleven out of 14 (79%) patients with TL ≥ 7 µg/ml and available endoscopy data had mucosal healing. During the total follow-up time of 420 patient-years 160 infections which necessitated postponing infusion of infliximab (101 viral, 59 bacterial) occurred. None of the infections were fatal. No differences in rates of infections were observed in semesters with high trough levels (16 semesters out of 129 (12.4%)) compared to semesters with trough level <7 µg/ml (32 semesters out of 344 (9.3%)) (p = 0.32). In addition, there was no difference in median infliximab trough levels in semesters with infections (4.25 [1.04 to 8.34] µg/ml) compared to semesters without infections (4.09 [1.58 to 7.2]) (p = 0.867). Eighteen out of 48 (37.5%) of infections occurred in semesters on combination therapy (systemic steroids in 5 patients; systemic steroids and thipurines in 13 patients).

Conclusion: Infliximab trough levels above 7 µg/ml provide better control of inflammation in IBD without increasing the risk of infection compared to infliximab trough levels below 7 µg/ml. Our data suggest that patients who have active disease despite infliximab trough levels between 3–7 µg/ml should have their dose of infliximab optimized to achieve higher trough levels as this is clinically effective and safe.

Disclosure of Interest: D. Drobne: MSD, Abbvie, Takeda, Pfizer, Janssen, Krka: Lecture fees, consultant

All other authors have declared no conflicts of interest.

Reference

1. Vande Casteele et al. Gastroenterology 2015

OP222 AN UPDATED ANALYSIS OF IN VITRO CYTOKINE INHIBITION PROFILES OF A NUMBER OF JANUS KINASE INHIBITORS AT CLINICALLY MEANINGFUL CONCENTRATIONS

M. E. Dowty 1 , T. H. Lin 2 , L. Wang 1 , J. M. Jussif 1 , L. Li 1 , E. Moy 1 , J. Telliez 1

1 Pfizer Worldwide R&D, Cambridge/United States of America/MA

2 Pfizer Inflammation & Immunology Research Unit, Cambridge/United States of America/MA

Contact E-mail Address: Martin.Dowty@pfizer.com

Introduction: Tofacitinib is an oral, small molecule Janus kinase (JAK) inhibitor that is being investigated for ulcerative colitis (UC). A number of JAK inhibitors are being investigated for the treatment of inflammatory diseases such as UC and rheumatoid arthritis, including tofacitinib, baricitinib and filgotinib (GLPG0634). However, it is unclear how these drugs may differentiate from each other in clinic, based on their profiles of JAK-dependent cytokine inhibition.

Aims & Methods: We aimed to provide an integrated modelling approach – using knowledge of both in vitro whole cell JAK inhibition potencies and plasma pharmacokinetics – to better understand profiles of cytokine inhibition for clinical JAK inhibitors in the context of clinically meaningful doses. IC 50 values for interferon (IFN)α, IFNγ, interleukin (IL)-6, IL-15, IL-21, IL-10, IL-27, IL-12, IL-23 and erythropoietin (EPO) signalling of tofacitinib, baricitinib and filgotinib and its metabolite were measured in total lymphocytes, CD34+ cells (EPO) and CD3+ cells (IL-6) in human whole blood by a flow cytometry-based assay, quantifying the phosphorylation state of various signal transducer and activator of transcription proteins. Human daily average plasma concentrations (C av ) were used as reported for tofacitinib (5 mg BID; 68 nM), baricitinib (4 mg QD; 27 nM) and filgotinib (200 mg QD; 474 nM) and its metabolite (7438 nM) and converted to unbound values with measured plasma fraction unbound (f u ) values of 0.61, 0.59, 0.49 and 0.42, respectively. Whole blood IC 50 values were converted to unbound values with measured blood/plasma ratios of 1.2, 1.3, 1.2 and 1.1, respectively, and f u values. Percentage levels of cytokine inhibition (IC xx = 100*C av /(IC 50 + C av )) were then determined at clinically meaningful doses.

Results: Compared between JAK inhibitors, tofacitinib and baricitinib were overall more potent inhibitors than filgotinib and its metabolite (data not shown). Combining potency with clinical pharmacokinetics showed a similar profile of cytokine inhibition (Table), with some exceptions. A greater level of IL-6 inhibition was noted with filgotinib and its metabolite. However, this did not translate into greater levels of published C-reactive protein reductions compared with tofacitinib 1 and baricitinib. 2 Likewise, the minor difference noted in IL-15 inhibition between tofacitinib 1 and baricitinib 3 did not translate into a clinically meaningful difference in natural killer cell populations.

Conclusion: These analyses illustrate the importance of studying a broad range of JAK pairing potencies and clinical concentrations when comparing JAK inhibitor compounds. Calculated profiles of cytokine inhibition for a number of JAK inhibitors were generally similar when efficacious doses are considered, with only minor differences in percentage cytokine inhibition, suggesting limited differentiation of these JAK inhibitors based on JAK pharmacology. Ultimately, only robust clinical testing will determine whether there are clinical differences between JAK inhibitors.

Disclosure of Interest: M.E. Dowty: Employee and shareholder of Pfizer Inc

T.H. Lin: Employee and shareholder of Pfizer Inc

L. Wang: Employee and shareholder of Pfizer Inc

J.M. Jussif: Employee and shareholder of Pfizer Inc

L. Li: Employee and shareholder of Pfizer Inc

E. Moy: Employee and shareholder of Pfizer Inc

J. Telliez: Employee and shareholder of Pfizer Inc

References

1. Hodge JA et al. Clin Exp Rheumatol 2016;34:318–28

2. Fleischmann R et al. Arthritis Rheumatol 2015;67(S10):Abstract 1045

3. Emery P et al. Arthritis Rheumatol 2015;67(S10):Abstract 1047

OP223 IDENTIFICATION OF GENETIC SIGNATURES AND IMMUNE MECHANISMS THAT DEFINE THERAPEUTIC RESPONSE AND FAILURE TO ANTI-INTEGRIN THERAPY WITH VEDOLIZUMAB IN IBD PATIENTS

T. Rath 1 , U. Billmeier 1 , F. Ferrazzii 2 , M. Vieth 3 , A. Ekici 2 , M.F. Neurath 1 , R. Atreya 1

1 Department Of Medicine I, Division Of Gastroenterology, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen/Germany

2 Department Of Human Genetics, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen/Germany

3 Abt. Pathologie, Klinikum Bayreuth, Bayreuth/Germany

Contact E-mail Address: Timo.Rath@uk-erlangen.de

Introduction: In 2014 Vedolizumab (VDZ), a humanized monoclonal antibody targeting the α4β7 integrin, was approved for the treatment of Crohn’s disease (CD) and ulcerative colitis (UC). Despite proven clinical efficacy for inducing and maintaining remission, subgroups of patients have no clinical benefit from anti-adhesion therapy with VDZ.

Aims & Methods: Within this study, we aimed to identify genetic, cellular and immunological mechanisms that define and predict response and failure of VDZ therapy. For this purpose, intestinal RNA Sequencing was performed in UC and CD patients (remitters and non-remitters) before and at week 14 of VDZ therapy. α4β7 expression on peripheral and mucosal immune cells was assessed by flow cytometry and immunohistochemistry. Cellular modes of VDZ mediated action were analysed ex vivo and in VDZ treated IBD patients.

Results: Transcriptome analysis showed an impairment of signaling cascades associated with adhesion, diapedesis and migration of granulocytes and agranulocytes upon VDZ therapy. In non-remitters to VDZ therapy, a tissue-destructive and leucocyte-mediated inflammatory activity with activation of TNF dependent pathways was present, all of which were inhibited in remitters to VDZ. Clinical remission was associated with a significant reduction of α4β7 expression on Th2 and Th17 polarized mucosal CD4 + T cells at week 14 of VDZ therapy and with significantly higher numbers of α4β7 expressing mucosal cells prior to the initiation of VDZ therapy compared to non-remitters.

Conclusion: Intestinal α4β7 expression prior to VDZ therapy might represent a biomarker that predicts therapeutic response to subsequent VDZ treatment. Due to high activation of TNF signaling in VDZ non-remitters, anti-TNF treatment might represent a promising therapeutic strategy in VDZ refractory patients.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP224 EXPANSION OF IL-23 RECEPTOR BEARING TNFR2 + T CELLS DRIVES RESISTANCE TO ANTI-TNF THERAPY IN CROHN'S DISEASE

H. Schmitt 1 , U. Billmeier 1 , W. Dieterich 1 , T. Rath 1 , S. Hirschmann 1 , C. Neufert 1 , K. Hildner 1 , M. J. Waldner 1 , J. Mudter 2 , T. Münster 3 , M.F. Neurath 1 , R. Atreya 1

1 Medicine 1 University Erlangen-Nuremberg, Erlangen/Germany

2 Sana Kliniken Ostholstein, Eutin/Germany

3 Anesthesiology, University Erlangen-Nuremberg, Erlangen/Germany

Contact E-mail Address: Heike.Schmitt@uk-erlangen.de

Introduction: Anti-tumor necrosis factor (TNF) antibodies are successfully used for the treatment of Crohn’s disease. Nevertheless, approximately 40% of patients display failure to anti-TNF therapy. Here, we characterized molecular mechanisms that drive resistance to anti-TNF therapy. Although various studies have addressed potential mechanisms of action of anti-TNF antibodies in inflammatory bowel disease (IBD), the molecular pathways that drive anti-TNF resistance are still poorly understood. The mechanistic reasons responsible for anti-TNF refractory disease in Crohn’s disease are still unknown, but it has been shown that inhibition of IL-23 was particularly effective in patients with non-response to previous anti-TNF therapy.

Aims & Methods: Although the pro-inflammatory cytokine IL-23 has been linked to IBD pathogenesis, the context-dependent functions of IL-23 mediated signaling in anti-TNF refractory mucosal inflammation have not been resolved yet. The aim of the current study was therefore to characterize the functional role of IL-23 in this context. Lamina propria mononuclear cells and peripheral blood mononuclear cells were isolated from Crohn’s disease patients before and after anti-TNF therapy. Cytokine profiles and expression of cell surface markers and signaling proteins were assessed by immunohistology, qPCR, ELISA and FACS, respectively. Cell apoptosis was determined in cultured mononuclear cells and gut sections.

Results: Crohn’s disease patients responding to anti-TNF therapy displayed a significantly higher expression of TNF receptor 2 (TNFR2) but not IL23R on mucosal T cells than non-responders prior to the initiation of therapy. During anti-TNF therapy, there was a significant up-regulation of mucosal IL-23 p19, IL23R and IL-17A levels in anti-TNF non-responders as compared to responders. Apoptosis-resistant TNFR2 + IL23R + T cells were significantly expanded in anti-TNF non-responders compared to responders and exhibited increased expression of IFN-γ, T-bet, IL-17A and RORγt compared to TNFR2 + IL23R − cells, indicating a mixed Th1/Th17-like phenotype. Intestinal TNFR2 + IL23R + T cells were activated by IL-23 derived from CD14 + macrophages, whose presence was significantly elevated in non-responders prior to the start of anti-TNF therapy. Functional studies demonstrated that anti-TNF induced apoptosis in lamina propria T cells from Crohn’s disease patients is abrogated by IL-23. TNFR2 + IL23R + mucosal T cells express the activated anti-apoptotic protein pSTAT3 and produce marked amounts of both Th1 and Th17 cytokines. They accumulate in the mucosa of anti-TNF refractory Crohn's disease patients where they may perpetuate chronic intestinal inflammation through IL-23 stimulation.

Conclusion: Expansion of apoptosis-resistant TNFR2 + IL23R + T cells in the mucosa drives resistance to anti-TNF therapy in Crohn’s disease patients. These findings identify IL-23 as suitable molecular target in IBD patients refractory to anti-TNF therapy.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP225 SUPERIOR ENDOSCOPIC AND DEEP REMISSION OUTCOMES IN ADULTS WITH MODERATE TO SEVERE CROHN'S DISEASE MANAGED WITH TREAT-TO-TARGET APPROACH VERSUS CLINICAL SYMPTOMS: DATA FROM CALM

J. Colombel 1 , R. Panaccione 2 , P. Bossuyt 3 , M. Lukas 4 , F. Baert 5 , T. Vanásek 6 , A. Danalıoğlu 7 , G. Novacek 8 , A. Armuzzi 9 , X. Hebuterne 10 , S. Travis 11 , S. Danese 12 , W. Reinisch 8 , W.J. Sandborn 13 , P. Rutgeerts 14 , D. Hommes 15 , S. Schreiber 16 , E. Neimark 17 , B. Huang 17 , Q. Zhou 17 , J. Petersson 17 , K. Wallace 17 , A.M. Robinson 17 , R. Thakkar 17 , G. R. D'Haens 18

1 Icahn School of Medicine at Mount Sinai, New York/United States of America

2 University of Calgary, Calgary/Canada

3 Imelda General Hospital, Bonheiden/Belgium

4 Charles University, Prague/Czech Republic

5 Dept Of Gastroenterology, AZ Delta Roeselare-Menen, Menen/Belgium

6 Hepato-Gastroenterologie HK, s.r.o., Hradec Králové/Czech Republic

7 Gastroenterology, Bezmialem Vakif University, İstanbul/Turkey

8 Medical University of Vienna, Vienna/Austria

9 Presidio Columbus, Fondazione Policlinico Gemelli Università Cattolica, Rome/Italy

10 Service de Gastroentérologie et Nutrition Clinique, Nice/France

11 Oxford University Hospitals, Oxford/United Kingdom

12 Istituto Clinico Humanitas, Millan/Italy

13 University of California, San Diego/United States of America

14 University of Leuven, Leuven/Belgium

15 University of California, Los Angeles/United States of America

16 Uksh, University Hospital Schleswig-Holstein, Kiel/Germany

17 AbbVie Inc., North Chicago/United States of America

18 Academic Medical Center, Amsterdam/Netherlands

Contact E-mail Address: jean-frederic.colombel@mssm.edu

Aims & Methods: Adult pts naïve to immunosuppressive and biologic therapy included in CALM had: 1) baseline (BL) CDAI > 150 and ≤450 (for receiving prednisone >20 mg or equivalent) or ≥220 and ≤450 (for receiving no or ≤20 mg prednisone or equivalent); 2) active endoscopic CD, defined as total CD endoscopic index of severity (CDEIS) > 6 and sum of CDEIS subscores > 6 in ≥1 segment with ulcers; 3) CRP ≥ 5 mg/L and/or FC ≥ 250 μg/g. Pts were randomized 1:1 to T2T or CM groups, following up to an 8 week (wk) of 40 mg/day prednisone burst and taper. Pts were eligible for early randomization between BL (wk 0) and wk 8 if CDAI > 220 and were either on corticosteroids for 4 wks, or had intolerance/contraindication for prednisone therapy or per investigator assessment. Pts received the following treatment options (TO) 1–4 administered in a stepwise manner: TO1 = no treatment; TO2 = 160/80 mg adalimumab (ADA) wks 0/2, 40 mg every other wk; TO3 = ADA 40 mg wkly; TO4 = ADA 40 mg wkly + azathioprine [AZA] 2.5 mg/kg/day. Early randomized pts were assigned to TO2. Treatment at randomization and 3 following visits was based on failure to fulfil success criteria: CDAI < 150, CRP < 5 mg/L, FC < 250μg/g, and no prednisone for the T2T group and CDAI decrease ≥70 or 100 (at randomization or post-randomization, respectively) or CDAI < 200 and no prednisone for the CM group. The primary endpoint was CDEIS < 4 and absence of deep ulcers at wk 48. Secondary endpoints at wk 48 included deep remission (CDAI < 150, discontinuation of steroids ≥8 wks, absence of draining fistula, CDEIS < 4, and no deep ulcers), biologic remission (FC < 250μg/g, CRP < 5 mg/L, and CDEIS < 4), CDEIS < 4, and CDEIS < 4 in each segment, and CDEIS = 0. Missing data were imputed using non-responder imputation.

Introduction: The concept of “treat to target” (T2T) implies that close serial monitoring of patients (pts) with Crohn’s disease (CD) using biomarkers of inflammation, serum C-reactive protein (CRP) and fecal calprotectin (FC), assists in timely treatment escalation in order to improve outcome. CALM, a prospective, open-label, multicenter, active-controlled, Phase 3 study, assessed the benefit of T2T versus standard clinical management (CM) of CD.

Results: A total of 244 pts were randomized. At BL, the mean ± SD age was 31.6 ± 11.7 years, mean ± SD CD duration was 0.95 ± 1.98 years and 57.8% were female. BL characteristics between T2T and CM groups were similar. Results are shown in the Table. No new safety signals with ADA were observed. The overall rate of adverse events was similar between T2T and CM groups.

Table. Summary of primary and select secondary endpoints of CALM study

Conclusion: This is the first study showing that the treat-to-target approach leads to superior endoscopic and deep remission outcomes in CD compared with symptom-driven care.

Disclosure of Interest: J. Colombel: Consultant, advisory board member or speaker for AbbVie, Bristol-Myers Squibb, Ferring Pharmaceuticals, Genentech, Giuliani SPA, Given Imaging, Merck, Millennium Pharmaceuticals, Pfizer, Prometheus Laboratories, Sanofi, and others.

R. Panaccione: Consultant and/or lecture fees from AbbVie, Amgen, AstraZeneca, Axcan Pharma (now Aptalis), Biogen Idec, Bristol-Myers Squibb, Centocor, ChemoCentryx, Eisai Medical Research Inc, Elan Pharmaceuticals, Ferring, Genentech, GlaxoSmithKline, and others

P. Bossuyt: Received educational grants from AbbVie; speaker fees from AbbVie, Takeda, and Vifor Pharma; and advisory board fees from Hospira, Janssen, MSD, Mundipharma, Roche, Pfizer, and Dr Falk Benelux.

M. Lukas: Served as a consultant or speaker or advisory member for Abbvie, MSD, Takeda, Egis, Hospira, Celltrion, Janssen and Vifor

F. Baert: Received research grants from Abbvie, Chiesi, Ipsen, MSD, Roche, speakers and consultancy fees from Abbvie, Falk, Ferring, Janssen, Mundipharma, MSD, Pfizer, Takeda, Vifor.

T. Vanásek: Served as advisory member for Hospira, Pfizer and Takeda, has received lecture fees from Takeda.

G. Novacek: Served as a consultant/advisory board member/speaker for AbbVie, MSD, Takeda, Ferring, Vifor, Merck

A. Armuzzi: Consultant or advisory member for AbbVie, Biogen, Celltrion, Ferring, Hospira, Janssen, Lilly, MSD, Mundipharma, Pfizer, Samsung, Sofar and Takeda, has received lecture fees from AbbVie, AstraZeneca, Chiesi, and others, eceived research funding from MSD.

X. Hebuterne: Received funding from AbbVie, Fresenius Kabi, Janssen, and Takeda for activity as an advisory board member, and from AbbVie, Arard, Ferring, Fresenius Kabi, Mayoli-Spindler, MSD, Nestlé, Norgine, and others for educational activities.

S. Travis: Received advisor/lecturer fees from AbbVie, Amgen, Asahi, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Chemocentryx, Cosmo, Ferring, and others; research support from AbbVie, IOIBD, Lilly, UCB, Vifor and Norman Collisson Foundation

S. Danese: Served as speaker, consultant and/or advisory board member for AbbVie, Actelion, Alphawasserman, Astra Zeneca, Cellerix, Cosmo Pharmaceuticals, Ferring, Genentech, Grunenthal, Johnson&Johnson, Millennium, Merck & Co., and others.

W. Reinisch: Speaker: Abbott, Abbvie, Aesca, Aptalis, Astellas, others; consultant: Abbott, Abbvie, Aesca, Amgen, AM Pharma, Astellas, others; advisory board: Abbott, Abbvie, Aesca, Amgen, AM Pharma, others; research funding: Abbott, Abbvie, Aesca, Centocor, others.

W.J. Sandborn: Consultant: AbbVie, ActoGeniX NV, AGI Therapeutics, Alba Therapeutics Corporation, Albireo, and others; Speaker: AbbVie, Bristol-Myers Squibb, and Janssen; Research support: AbbVie, Bristol-Myers Squibb, Genentech, GlaxoSmithKline, Janssen, and others.

P. Rutgeerts: Consultancy fees from AbbVie, Bristol-Myers Squibb, Centocor, Merck, Takeda, and UCB Pharma; speaker fees and research support from AbbVie, Centocor, MSD, and UCB Pharma.

D. Hommes: Consulting fees, lecture fees and/or research support: AbbVie, AstraZeneca, Bristol-Myers Squibb, Cellerix, Centocor, Chemocentryx, Giuliani Pharma, IBM, Janssen, Johnson & Johnson, Leo Pharma, MSD, Otsuka, Novimmune, Tramedico, UCB Pharma and others.

S. Schreiber: Consultancy and lecture fees from AbbVie, Falk Pharma, Ferring, Genentech, GSK, MSD, Pfizer, Shire, Takeda.

E. Neimark: Abbvie employee; may own AbbVie stock and/or options

B. Huang: Abbvie employee; may own AbbVie stock and/or options

Q. Zhou: Abbvie employee; may own AbbVie stock and/or options

J. Petersson: Abbvie employee; may own AbbVie stock and/or options

K. Wallace: Abbvie employee; may own AbbVie stock and/or options,

A.M. Robinson: Abbvie employee; may own AbbVie stock and/or options.

R. Thakkar: Abbvie employee; may own AbbVie stock and/or options

G.R. D'Haens: Consulting and/or lecture fees: AbbVie, ActoGeniX, AIM Centocor, Ferring, GlaxoSmithKline, MSD, Pfizer and others; Research grants: AbbVie, Janssen, Given Imaging, MSD, and others; Speaking honoraria: AbbVie, Tillotts, Tramedico, Norgine, and others.

All other authors have declared no conflicts of interest.

OP226 EFFICACY AND SAFETY OF A BRIDGING STRATEGY WITH CALCINEURIN INHIBITORS TO VEDOLIZUMAB IN PATIENTS WITH SEVERE ULCERATIVE COLITIS

G. Pellet 1 , C. Stefanescu 2 , F. Carbonnel 3 , L. Peyrin-Biroulet 4 , X. Roblin 5 , C. Allimant 6 , M. Nachury 7 , S. Nancey 8 , J. Filippi 9 , R. Altwegg 10 , H. Brixi 11 , G. Fotsing Makougang 12 , S. Shili 1 , D. Laharie 1

1 CHU de Bordeaux Hopital Haut-Leveque Dept. de Gastroenterologie, Pessac cedex/France

2 Service De Gastroenterologie Et Assistance Nutritive, Beaujon Hospital, Clichy, Clichy/France

3 Dept. De Hepato-gastroenterologie, CHU Bicetre - Dept. de Hepato-Gastroenterologie, CHU Bicetre; Le Kremlin Bicetre/FR, Le Kremlin Bicetre/France

4 Department Of Gastroenterology, Nancy University Hospital Inserm U954 Dept. of Hepato-Gastroenterology, Vandoeuvre les Nancy/France

5 University of St. Etienne Dept. de Gastroenterologie, Saint Etienne/France

6 Dept. Of Gastroenterology, CHU Estaing Clermont-Ferrand, Clermont-ferrand/France

7 Gastroenterology department, CHRU Lille, Université Lille 2 Lille/France

8 Gastroenterologie, CH Lyon Sud Gastro secteur Jules Courmont, Pierre Benite Cedex/France

9 Dept. De Gastroenterologie, Hopital de lAchet Dept. de Gastroenterlogie Dept. de Nutrition Oncologie, Nice Cedex/France

10 Hopital Saint Eloi Hepatologie Gastro enterologie, Montpellier cedex/France

11 Hépato-gastroenterologiee, Hôpital Robert Debré, Reims Cedex/France

12 Service D'hépato-gastro-entérologie, CHU de Poitiers, Poitiers/France

Contact E-mail Address: david.laharie@chu-bordeaux.fr

Introduction: Vedolizumab showed efficacy as induction and maintenance therapy in patients with ulcerative colitis (UC). Patients with an acute severe UC (ASUC) were excluded from pivotal trials. The aim of this study was to assess efficacy and safety of the bridging strategy with a calcineurin inhibitor to vedolizumab in patients with steroid-refractory ASUC or non-severe UC.

Aims & Methods: A retrospective cohort study was conducted in 12 referential centers, including all consecutive patients who have been treated for an active steroid-refractory UC (ASUC or non-severe UC) by a calcineurin inhibitor (ciclosporin or tacrolimus) as induction therapy and vedolizumab as maintenance therapy. Inclusion was defined by the day of the first vedolizumab infusion. Outcomes were survival without colectomy and safety.

Results: Thirty-eight patients (22W, mean age 34 years) were recruited and received a calcineurin inhibitor - ciclosporin in 36 and tacrolimus in 2 - and vedolizumab with a median interval of 9.5 days, for treating a steroid-refractory ASUC in 31 or for a steroid-refractory non-severe UC in 4 cases. Regarding previous medications, 34 (89%) patients had failed to respond to conventional immunosuppressants (thiopurines and/or methotrexate) and they were contra-indicated in 4 (11%); 35 (92%) patients had failed to at least one anti-TNF agent, while these drugs were contra-indicated in 3 (8%). At inclusion, 29 (76%) patients had pancolitis, 23 (61%) had already presented an ASUC; median CRP was 12.9 mg/L; median Lichtiger score and Total Mayo Score were 9 and 10, respectively. The median duration of calcineurin inhibitor treatment was 2.7 months. After a median follow-up duration of 6.9 months, 12 (31.6%) patients underwent colectomy (5 ASUC, 7 refractory UC) after a median interval of 4.2 months. Rates of survival without colectomy at 1, 3 and 6 months were 89.5% [IC95%: 80.2–99.8], 86.8% [IC95%: 76.7–98.3], and 70.7% [IC95%: 56.7–88], respectively. During follow-up, 22 (58%) patients were optimized for vedolizumab and 5 (13%) stopped the drug due to lack of efficacy; among the 22 patients receiving steroids at inclusion, 13 (59%) were weaned. Concerning safety, 3 patients developed mild and transient renal failure, leading to ciclosporin withdrawal in one case, and one had Campylobacter jejuni colitis. No death was observed.

Conclusion: In steroid-refractory UC, a bridging strategy combining a calcineurin inhibitor with vedolizumab seems effective for avoiding emergent colectomy with an acceptable safety profile. About one-third of patients underwent colectomy. This therapeutic strategy might be considered in patients with ASUC and non-severe UC refractory to conventional therapies, including anti-TNF. The safety profile of this approach will require further investigation.

Disclosure of Interest: L. Peyrin-Biroulet: Takeda

X. Roblin: Takeda

S. Nancey: Takeda

D. Laharie: Takeda

All other authors have declared no conflicts of interest.

OP227 A TREAT-TO-TARGET APPROACH DECREASES THE RATE OF CD-RELATED ADVERSE OUTCOMES VERSUS A CLINICAL APPROACH IN PATIENTS WITH MODERATE TO SEVERELY ACTIVE CROHN'S DISEASE: DATA FROM CALM

J. Colombel 1 , R. Panaccione 2 , P. Bossuyt 3 , F. Baert 4 , T. Vanásek 5 , A. Danalıoğlu 6 , G. Novacek 7 , A. Armuzzi 8 , X. Hebuterne 9 , S. Travis 10 , S. Danese 11 , W. Reinisch 7 , W. J. Sandborn 12 , P. Rutgeerts 13 , D. Hommes 14 , S. Schreiber 15 , E. Neimark 16 , B. Huang 16 , Q. Zhou 16 , W. J. Lee 16 , J. Petersson 16 , K. Wallace 16 , A.M. Robinson 16 , R. B. Thakkar 16 , G. D'Haens 17

1 Icahn School of Medicine at Mount Sinai, New York/United States of America

2 University of Calgary, Calgary/Canada

3 Imelda General Hospital, Bonheiden/Belgium

4 AZ Delta, Roeselare/Belgium

5 Hepato-Gastroenterologie HK, s.r.o., Hradec Králové/Czech Republic

6 Gastroenterology, Bezmialem Vakif University School Of Medicine, İstanbul/Turkey

7 Medical University of Vienna, Vienna/Austria

8 Presidio Columbus, Fondazione Policlinico Gemelli Università Cattolica, Rome/Italy

9 Service de Gastroentérologie et Nutrition Clinique, Nice/France

10 Oxford University Hospitals, Oxford/United Kingdom

11 Istituto Clinico Humanitas, Millan/Italy

12 University of California San Diego, La Jolla/United States of America/CA

13 University of Leuven, Leuven/Belgium

14 University of California, Los Angeles/United States of America

15 University Hospital Schleswig-Holstein, Kiel/Germany

16 AbbVie Inc., North Chicago/United States of America

17 Academic Medical Center, Amsterdam/Netherlands

Contact E-mail Address: jean-frederic.colombel@mssm.edu

Introduction: The primary results of the Phase 3 CALM study demonstrated that a treat-to-target (T2T) approach using tight control of inflammation by the biomarkers (i.e., C-reactive protein [CRP] and fecal calprotectin [FC]), led to superior endoscopic and deep remission (combined clinical plus endoscopic remission) outcomes in moderate to severely active Crohn’s disease (CD) compared to standard clinical management (CM). This analysis assessed major adverse outcomes, such as hospitalizations, surgical procedures, including major surgeries, and serious disease-related complications in patients enrolled in CALM.

Aims & Methods: Immunosuppressive and biologic-naïve adult patients with CD treated with or without corticosteroids (CS), and with baseline (BL; week 0) CDAI>150–450 (for high-dose CS) or 200–450 (low-dose CS) or 220–450 (for no CS), active endoscopic CD (overall CD Endoscopic Index of Severity [CDEIS]>6 and sum of CDEIS subscores >6 in ≥1 segment with ulcers), and CRP ≥ 5 mg/L and/or FC ≥ 250 μg/g were treated with prednisone burst and taper for up to 8 weeks and then randomized to the T2Tor CM arms at week 9. Some patients with CDAI > 220 and CS for >4 weeks or intolerance/contraindication for CS or per investigator assessment were able to be randomized early. Patients received up to four treatment options (TO) administered in a stepwise manner based on pre-defined success criteria: TO1 = no treatment; TO2 = 160/80 mg adalimumab (HumiraÒ; ADA) weeks 0/2, 40 mg every other week; TO3 = ADA 40 mg weekly; TO4 = ADA 40 mg weekly + azathioprine 2.5 mg/kg/day. CD-related hospitalizations, CD-related surgical procedures (major CD-related surgeries [bowel resection, ostomy, by-pass, strictureplasty, and surgical drainage of abdominal/pelvic abscess] and non-major CD-related surgeries [debridment, abscess drainage, seton placement, fistulotomy, placement of a TPN access line]) after randomization and a composite endpoint of CD-related hospitalization or serious complication (presence of abscess, fistula or stricture, skin and ocular extra-intestinal manifestation, and serious adverse drug reaction) from randomization to up to week 48 or last dose date, whichever was later, were summarized as incidences or rates (events [E]/100 Patient Years [PY]). Differences between treatment groups in rates of CD-related hospitalizations and surgical procedures or in incidences of the composite endpoint were analyzed using a Chi-square test. Hazard ratio (95% CI) of the composite endpoint was determined using Cox proportional hazard model. Any hospitalization on or after randomization and up to 70 days after last dosing were summarized in all randomized patients.

Results: A total of 244 patients were randomized 1:1 to the T2T and CM arms. Mean age ± SD at BL was 31.6 ± 11.7 and 57.8% were female. The rate of CD-related hospitalizations after randomization was significantly lower in the T2T compared to CM arm: 14 events (13.2 E/100 PY) vs 29 events (28.0 E/100 PY), P = 0.021. The rates of CD-related surgical procedures between treatment arms were not significantly different: 7 events (6.6 E/100 PY) in T2T and 9 events (8.7 E/100 PY) in CM, P = 0.582. The proportion of patients with CD-related hospitalization or serious complication was numerically lower in T2T compared with CM: 18 patients (14.8%) vs 25 patients (20.5%), P = 0.240. T2T was associated with numerically lower risk of CD-related hospitalization or serious complication than CM: hazard ratio = 0.7, 95% CI 0.4–1.3, P = 0.249.

Conclusion: The T2T approach using tight control of inflammation by biomarkers lead to a reduction of major adverse outcomes indicative for a detrimental course of disease, including CD-related hospitalizations. A longer study would be needed to confirm these findings.

Disclosure of Interest: J. Colombel: Consult/ad board/speaker: AbbVie, Bristol-Myers Squibb, Ferring Pharmaceuticals, Genentech, Giuliani SPA, Given Imaging, Merck, Millennium Pharmaceuticals, Pfizer, Prometheus Laboratories, Sanofi, Schering-Plough, Takeda, Teva Pharmaceuticals, UCB Pharma

R. Panaccione: Consult/lecture:AbbVie, Amgen, AstraZeneca, Axcan, Biogen, Bristol-Myers, Centocor, ChemoCentryx, Eisai, Elan, Ferring, Genentech, GSK, Janssen, Merck, Takeda, Ocera, Otsuka, Pfizer, Shire, Prometheus, Schering-Plough, Synta, Teva, UCB, Warner Chilcott

P. Bossuyt: educational grants from AbbVie; speaker fees from AbbVie, Takeda, and Vifor Pharma; and advisory board fees from Hospira, Janssen, MSD, Mundipharma, Roche, Pfizer, and Dr Falk Benelux

F. Baert: Research/speaker/consultancy: Abbvie, Chiesi, Ipsen, MSD, Roche, speakers and consultancy fees from Abbvie, Falk, Ferring, Janssen, Mundipharma, MSD, Pfizer, Takeda, Vifor

T. Vanásek: advisory member for Hospira, Pfizer and Takeda, has received lecture fees from Takeda

G. Novacek: consultant/advisory board member/speaker for AbbVie, MSD, Takeda, Ferring, Vifor, Merck

A. Armuzzi: consultant/lecture/research/advisory member:AbbVie, AstraZeneca, Biogen, Celltrion, Chiesi, Ferring, Hospira, Janssen, Lilly, MSD, Mundipharma, Otsuka, Pfizer, Samsung, Sofar and Takeda, Zambon

X. Hebuterne: AbbVie, Fresenius Kabi, Janssen, and Takeda for advisory activity as a member of an advisory board, and from AbbVie, Arard, Ferring, Fresenius Kabi, Mayoli-Spindler, MSD, Nestlé, Norgine, Nutricia and Takeda for educational activities

S. Travis: advisor/lecture/research: AbbVie, Amgen, Asahi, Biogen, Boehringer Ingelheim, Bristol-Myers, Celgene, Chemocentryx, Cosmo, Ferring, Giuliani, GSK, IOIBD, Janssen, Lilly, MSD, Neovacs, NovoNordisk, Novartis, NPS, Pfizer, Proximagen, Receptos, Shire, etc

S. Danese: speaker/consultant/ad board: for AbbVie, Actelion, Alphawasserman, Astra Zeneca, Cellerix, Cosmo, Ferring, Genentech, Grunenthal, Johnson&Johnson, Millennium, Merck, NovoNordisk, Nycomed, Pfizer, Pharmacosmos, Schering-Plough, Salix, Takeda, UCB, Vifor

W. Reinisch: speaker/consult/research/ad board: Abbott, Abbvie, Aesca, Amgen, AM Pharma, Aptalis, Astellas, Astra Zeneca, Avaxia, Bioclinica, Biogen, Boehringer-Ingelheim, Bristol-Myers Squibb, Centocor, Celltrion, Cellerix, Chemocentryx, Celgene, Centocor, etc

W.J. Sandborn: consult/speaker/research: AbbVie, ActoGeniX NV, AGI, Alba, Albireo, Alfa Wasserman, Amgen, AM-Pharma BV, Anaphore, Astellas, Athersys, Atlantic Healthcare, Aptalis, BioBalance, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Celek, Cellerix SL, etc

P. Rutgeerts: P. Rutgeerts: consultancy fees from AbbVie, Bristol-Myers Squibb, Centocor, Merck, Takeda, and UCB Pharma; speaker fees and research support from AbbVie, Centocor, MSD, and UCB Pharma.

D. Hommes: received consulting fees, lecture fees and/or research support from AbbVie, AstraZeneca, Bristol-Myers Squibb, Cellerix, Centocor, Chemocentryx, ELAN, Falk, Ferring, Genentech, Giuliani Pharma, IBM, Janssen, Johnson & Johnson, Leo Pharma, MSD, etc

S. Schreiber: consultancy and lecture fees from AbbVie, Falk Pharma, Ferring, Genentech, GSK, MSD, Pfizer, Shire, Takeda.

E. Neimark: Abbvie employee; may own AbbVie stock and/or options

B. Huang: Abbvie employee; may own AbbVie stock and/or options

Q. Zhou: Abbvie employee; may own AbbVie stock and/or options

W.J. Lee: Abbvie employee; may own AbbVie stock and/or options

J. Petersson: Abbvie employee; may own AbbVie stock and/or options

K. Wallace: Abbvie employee; may own AbbVie stock and/or options

A.M. Robinson: Abbvie employee; may own AbbVie stock and/or options

R.B. Thakkar: Abbvie employee; may own AbbVie stock and/or options

G. D'Haens: Consulting/speaker/research: AbbVie, ActoGeniX, AIM, Boehringer Ingelheim, Centocor, Chemo Centryx, Cosmo Tech, Dr Falk Pharma, Elan, enGene, Ferring, Galapagos, Giuliani SpA, Given Imaging, GSK, Janssen, MSD, Neovacs, Novo Nordisk, Norgine, etc

All other authors have declared no conflicts of interest.

OP228 PROFILE TRIAL: PREDICTING OUTCOMES FOR CROHN’S DISEASE USING A MOLECULAR BIOMARKER

J. C. Lee 1 , D. Biasci 1 , N. M. Noor 1 , E. F. Mckinney 1 , T. Ahmad 2 , N. R. Lewis 3 , A. Hart 4 , P. A. Lyons 1 , M. Parkes 1 , K. G. Smith 1

1 Department Of Medicine, University of Cambridge School of Clinical Medicine, CBQQ/United Kingdom

2 Exeter IBD And Pharmacogenetics Research Group, University of Exeter, EXDW/United Kingdom

3 Department Of Gastroenterology, Nottingham University Hospitals NHS Trust, NGHA/United Kingdom

4 Gastroenterology, St Mark’s Hospital and Academic Institue, London/United Kingdom

Contact E-mail Address: nn281@cam.ac.uk

Introduction: The course of Crohn’s disease (CD) varies substantially between affected individuals, but reliable prognostic markers are not available in clinical practice. This hinders disease management because patients with aggressive disease will be undertreated by conventional “step-up” therapy, while those with indolent disease would be exposed to the risks of unnecessary immunosuppression of a “top-down” approach. Previously, we have described a transcriptional signature that is detectable within peripheral blood CD8 T cells at diagnosis and which correlates with subsequent disease course. To translate this work to the bedside and overcome the technical challenges of separating cell populations, we sought to develop a whole blood qPCR-based biomarker that can re-capitulate the CD8 subgroups without the need for cell separation. Here we describe the development and validation of this biomarker and the upcoming biomarker-stratified trial that will test whether it can deliver personalised medicine in CD.

Aims & Methods: From a training cohort of 69 newly diagnosed IBD patients, we simultaneously obtained a whole blood PAXgene RNA tube and peripheral blood CD8 T-cell sample. Gene expression in both samples was measured by microarray. After confirming that the CD8 transcriptional signature was detectable and correlated with prognosis, we used machine learning to identify a transcriptional classifier in whole blood gene expression data that would re-capitulate the CD8 transcriptional subgroups. Model selection was performed using Bayesian Information Criterion (BIC) and the genes identified were subsequently tested by qPCR and optimised to produce an 18 gene qPCR assay.

Results: Independent validation of this biomarker was established using a second, independent cohort of 85 newly diagnosed patients with CD from 4 sites around the United Kingdom. This validated the biomarker and confirmed that the subgroups it identified had significantly different disease courses (analogous to those observed with the CD8 T-cell subgroups). The hazard ratio for time to treatment escalation in this validation cohort was 3.52 (1.84–6.76, 95% confidence intervals, P = 0.0002). We now propose to conduct the first ever biomarker-stratified trial in any inflammatory disease to determine whether this biomarker can deliver personalised medicine in CD.

Conclusion: We have developed, optimised and validated a whole blood qPCR classifier that is able to predict disease course from diagnosis in IBD patients. This represents a major step towards personalised therapy in IBD, and we will soon investigate whether this could make personalised medicine a reality in CD.

Disclosure of Interest: All authors have declared no conflicts of interest.

TUESDAY, OCTOBER 31, 201714:00-15:30

HOW TO MANAGE EARLY GASTRIC CANCER? - ROOM F2____________________

OP229 LYMPHATIC INVASION MAY BE MOST RELEVANT TO NODAL METASTASES IN EARLY-STAGE GASTRIC CANCERS: A RETROSPECTIVE ANALYSIS IN 65 CASES

T. Akimoto 1 , O. Goto 1 , N. Ueki 2 , H. Kawakubo 3 , H. Noda 2 , G. Ikeda 2 , K. Higuchi 2 , Y. Mitsunaga 1 , H. Yamawaki 2 , Y. Kodaka 2 , A. Nakayama 1 , M. Kato 1 , A. Fujimoto 1 , Y. Ochiai 1 , T. Maehata 1 , K. Suda 3 , T. Uraoka 1 , T. Kawagoe 2 , S. Futagami 2 , I. Fujita 4 , M. Kaise 2 , Y. Kitagawa 3 , K. Iwakiri 2 , N. Yahagi 1

1 Division Of Research And Development For Minimally Invasive Treatment, Cancer Center, Keio University, School of Medicine, Tokyo/Japan

2 Department Of Gastroenterology, Nippon Medical School, Tokyo/Japan

3 Department Of Surgery, Keio University School of Medicine, Tokyo/Japan

4 Department Of Surgery, Nippon Medical School, Tokyo/Japan

Contact E-mail Address: t-akimoto@nms.ac.jp

Introduction: Endoscopic submucosal dissection (ESD) for early-stage gastric cancer (EGC)s is gaining an acceptance as one of curative treatment options. With regard to the possibility of lymph node metastasis (LNM) or residual cancer in the stomach after ESD, ESD specimens having non-curative pathological factors (positive lymphovascular invasion, undifferentiated cancer invading submucosal layer, undifferentiated mucosal cancer sized more than 2 cm, differentiated cancer sized more than 3 cm invading submucosal layer or having ulceration, and R1 resection), which were based on the Japanese gastric cancer treatment guidelines from Japanese Gastric Cancer Association (JGCA), are thought to require additional treatments after endoscopic resection. However, additional gastrectomy and lymph node dissection frequently reveal neither LNM nor residual cancer in the extracted stomach. Regarding the guidelines from JGCA, non-curative pathological factors of endoscopic resection were defined according to the LNM rates of past surgical cases for EGCs. On the other hands, the LNM rate detected according to endoscopically resected specimens, which is more detailedly assessed pathologically than operatively extracted specimens, has not been fully investigated.

Aims & Methods: To compare the potential risk of LNM and residual cancer between these pathological characteristics of specimen resected endoscopically, we retrospectively assessed the surgical cases following non-curative endoscopic resection. We identified 1137 patients who underwent ESD from August 2006 to December 2016. Of these, pathological diagnosis was non-curative resection in 142 lesions in 142 patients excluding the cases of only having positive horizontal margin without any other non-curative factors. Out of the patients, 66 patients received additional gastrectomy and lymph node dissection. Excluding 1 lesion, which could not be endoscopically resected with en bloc specimen, we investigated 65 lesions in 65 patients. The rates of LNM and residual cancer after surgery were analyzed with pathological factors of ESD specimens: tumor size, histological type (differentiated type/undifferentiated type), invasion depth (M/SM), ulceration (negative/positive), lymphatic invasion (negative/positive), vascular invasion (negative/positive), and curability (R0 resection/R1 resection).

Results: The mean age was 66.6 years old. The tumor locations were U/M/L/R: 16/16/31/2. The mean size of lesions was 31.3 ± 20.1 mm. R0 resection rate of ESD was 52.3% (34/65). The rate of nodal metastasis in dissected lymph nodes and the rate of residual cancer in extracted stomach were 16.9% (11/65) and 16.9% (11/65), respectively. Univariate analyses indicated the LNM rates of each pathological factor: differentiated type/undifferentiated type was 15.6% (7/45)/20.0% (4/20) (p = 0.4547); M/SM was 0% (0/14)/16.9% (11/51) (p = 0.0532); ulceration negative/positive was 11.9% (5/42)/26.1% (6/23) (p = 0.1337), lymphatic invasion negative/positive was 3.1% (1/32)/30.3% (10/33) (p = 0.0035); vascular invasion negative/positive was 16.3% (8/49)/18.8% (3/16) (p = 0.5451). The tumor sizes of LNM negative/positive were 30 ± 25 mm/38 ± 19 mm (p = 0.0871); the tumor sizes of residual cancer negative/positive were 29 ± 18 mm/41 ± 27 mm (p = 0.0467). Residual cancer rates of R0 resection/R1 resection and was 0% (0/34)/35.5% (11/31) (p < 0.0001). There was no difference between residual cancer rates of any other pathological factors. Multivariate analyses indicated that lymphatic invasion was an only significant independent factor of lymph node metastasis (p = 0.0445) and that the tumor size and R1 resection were significant independent factors of residual cancer (p = 0.0211 and p < 0.0001).

Conclusion: The probability of LNM and residual cancer may contribute more to lymphatic invasion and tumor size and R1 resection, respectively, compared to any other pathological factors of ESD specimens. Therefore, additional treatments after ESD should be positively considered in cases of having them. On the other hand, the data implied that further treatment could be avoided after ESD in some non-curative cases of R0 resection without lymphatic invasion.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP230 CLINICAL CHARACTERISTICS AND MANAGEMENT OF PATIENTS WITH GASTRIC PRECANCEROUS LESIONS IN FRANCE: A LARGE 15-YEAR SINGLE CENTER RETROSPECTIVE STUDY

M. Péron 1 , N. Chapelle 2 , A. Bourget 1 , J. Mosnier 3 , S. Bruley Des Varannes 4 , Y. Touchefeu 4 , E. Coron 2 , E. Cauchin 5 , T. Matysiak Budnik 2

1 Loire Atlantique, Institut des Maladies de l'Appareil Digestif, Hopital Hotel Dieu, Nantes, France, Nantes/France

2 Université de Nantes, Nantes/France

3 Loire Atlantique, Service d’anatomie et cytologie pathologiques, Hopital Hotel Dieu, Nantes/France

4 Institut Des Maladies De L'appareil Digestif, CHU de Nantes IMAD, Nantes/France

5 U1235, INSERM, Nantes/France

Contact E-mail Address: matthieu.peron13@gmail.com

Introduction: Early detection and adequate surveillance of gastric precancerous lesions (GPL) may prevent the development of gastric adenocarcinoma (GADK) and reduce GADK-related mortality. The epidemiological and clinical data on GPL lesions in France are missing.

Aims & Methods: Our aim was to analyse, in a large retrospective study, the frequency, clinical characteristics, evolution, and modalities of surveillance of GPL in France. All the patients having undergone endoscopy with gastric biopsies between 2000 and 2015 in one academic center, and in whom GPL [atrophic gastritis (AG), or intestinal metaplasia (IM), or dysplasia (D)] was diagnosed by histology, were identified in the hospital pathology database. The clinical, endoscopic, histological and follow-up data were collected from the electronic files and analysed using SAS software.

Results: During a 15-year period, out of 16,764 patients having undergone upper endoscopy with gastric biopsies, 485 patients (60% of men, median age 68 years, min 11 - max 97) with GPL, were identified (detection rate 2.9%). The most frequent indications for endoscopy were anaemia (38%), digestive bleeding (22%), abdominal pain (17%), surveillance (15%), alteration of general status (11%), and dyspepsia (6%). At initial endoscopy, 11 patients (2.2%) had AG, 362 (75%) IM, 80 (16%) low grade dysplasia (LGD), 10 (2%) high grade dysplasia (HGD), and 22 (4.5%) had GADK with concomitant GPL (IM or D). H. pylori infection was found by histology in 204 patients (42%). Endoscopic aspect was considered normal in 17.5% of patients with IM, in 6% of patients with LGD, and in 20% of patients with HGD. The median number of biopsies obtained during initial endoscopy was 4 (min 0 - max 30, Q1-Q3: 2–6). Patients with HGD, were significantly older than those with IM and LGD (median age 75 vs 68 years, p = 0.006). From 485 patients, 326 (67%) had at least one follow-up endoscopy (median: 1, min 0 - max 24, Q1-Q3: 0–3), after the median time period of 2.9 months (min 0 - max 124, Q1-Q3: 1–14) since the initial diagnosis of GPL. During a median follow-up of 40 months (min 0.3 - max 137 months), out of 362 patients with IM, 18 (5%) showed progression to LGD, 2 (0.6%) to HGD, and 5 (1.4%) to GADK. Among 485 patients, 8 developed GADK during follow-up (annual incidence rate 0.11%). Altogether, with the 22 patients in whom GADK was found already at the time of the diagnosis of GPL, 30 GADK were identified in the studied population (6.2%).

Conclusion: This study showed that in France: 1) Most of GPL were diagnosed in patients referred for endoscopy for anaemia or digestive bleeding, 2) Patients with HGD were older than those with LGD and IM, 3) The progression from IM to more severe lesions (LGD, HGD, GADK) was observed in 7% of patients during a median follow-up of 3.3 years, and the annual incidence of GADK in this population was 0.11%, 4) Modalities of surveillance of GPL were heterogeneous, 5) New endoscopic techniques may improve the endoscopic diagnosis of GPL in the future.

Disclosure of Interest: All authors have declared no conflicts of interest.

TUESDAY, OCTOBER 31, 201714:00-15:30

MALIGNANT COLORECTAL POLYP: WHAT TO DO? - ROOM A2____________________

OP231 WATER EXCHANGE SIGNIFICANTLY IMPROVED ADENOMA DETECTION RATE AND RELATED MEASURES AND COLON CLEANLINESS IN PROPOFOL-SEDATED PATIENTS

F. W. Leung 1 , M. Koo 2 , Y. Hsieh 2 , C. Tseng 2 , C. Hu 3 , L. Zhang 4 , T. Dong 4 , H. Jia 4 , Y. Pan 4

1 Medicine, Sepulveda Ambulatory Care Center, VAGLAHS; David Geffen School of Medicine at UCLA, North Hills/United States of America/CA

2 Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chiayi/Taiwan

3 Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien/Taiwan

4 Xijing Hospital of Digestive Diseases, Fourth Military Medical U, Xian/China

Contact E-mail Address: felixleung@socal.rr.com

Introduction: Increase in adenoma detection rate (ADR, proportion of patients with at least one adenoma) decreased risks of interval colorectal cancer and related deaths after usual air insufflation (AI) colonoscopy. In randomized controlled trials (RCTs) of unsedated and minimally sedated patients, compared with AI, water exchange (WE) significantly decreased insertion pain (primary outcome) and increased ADR (secondary outcome). We recently completed two RCTs each with ADR as the primary outcome comparing WE vs. AI in Chinese patients, some of whom were sedated with propofol.

Aims & Methods: We pooled the data of two RCTs ( NCT02135601 , 01894191) to assess the hypothesis that WE could significantly increase ADR and secondary outcomes of adenoma-related measures in propofol sedated patients. 510 patients were randomized to either AI (n = 258) or WE (n = 252).

Results: Demographic data were comparable. Despite a significantly shorter inspection time, ADR (38.9% vs. 26.7%), flat (32.3% vs. 19.4%), combined advanced & sessile serrated ADR (13.1% vs. 7.4%), adenoma/colonoscopy, and right colon ADR of WE were significantly higher than those of AI. WE showed significantly cleaner colons and longer insertion time. Comparable withdrawal time without polypectomy and adenoma/positive colonoscopy suggested equivalent withdrawal techniques were used (Table).

Conclusion: WE enhanced quality of colonoscopy in propofol-sedated patients by significantly improving ADR, adenoma-related measures and colon cleanliness, even when its pain-alleviating impact was not critical.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP232 COLONIC POST-POLYPECTOMY BLEEDING IN PATIENTS ON NEW ORAL ANTI-COAGULANT – A CASE CONTROL STUDY

L.Y.K. Lam , T.Y.T. Lam, J.Y.L. Ching, S.H. Wong, S.C. C. Ng, F.K.L. Chan

Medicine And Therapeutics, Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong/Hong Kong PRC

Contact E-mail Address: yanlam2@hotmail.com

Introduction: Anticoagulants are commonly used to treat patients with cardiovascular and cerebrovascular diseases. Recently developed new oral anticoagulants (NOAC) that are direct thrombin inhibitor and direct factor Xa inhibitor overcome some limitations of vitamin K antagonist, including drug drug interaction and regular dose adjustments on the basis of laboratory monitoring(1–3). The risk of post-polypectomy bleeding (PPB) in patients on anti-platelet therapy and vitamin K antagonist has been well studied(4, 5). However, data on the risk of post polypectomy bleeding in patients on NOAC are scanty.

Aims & Methods: This aim of this study aim was to determine the risk of colonic post-polypectomy bleeding in patients on NOAC. Data of consecutive inpatients with age between 18 – 89 in five-year period (from 2012 to 2016), who underwent colonic polypectomy with NOAC therapy (dabigatran, rivaroxaban and apixaban), were collected in 16 Hong Kong Public Hospitals by Clinical Data Analysis and Reporting System (CDARS). NOAC were stopped 1–2 days before colonoscopy and resumed after procedure according to the local hospital practice. The control cohort who underwent colonic polypectomy without anti-platelet, anti-coagulation and NOAC were collected from the same system, matched with centre of procedure, age and sex during the same study period with a ratio 1:3. Post polypectomy bleeding was defined as fresh PR bleed after procedure with at least 2 g/dL drop in haemoglobin, requiring blood transfusion, repeat endoscopy for haemostasis or surgical intervention within 30 days of index colonoscopy. The relative risk and characteristics of PPB were analysed.

Results: Among 272 patients on NOAC underwent colonoscopy, 106 patients underwent colonic polypectomy. 7/106 (6.6%) patients had PPB. Among 51980 patients with colonic polypectomy without anti-platelet, anticoagulants and NOAC, 318 controls were selected with centre, age and sex matched. In the control group, 6/318 (1.9%) patients had PPB. The relative risk of PPB in patients on NOAC was 3.5 (p = 0.022). The onset of PPB in patients on NOAC ranged from day 1 to day 25 (median day 4). 4 patients underwent repeat colonoscopy and 3 patients were treated with supportive transfusion. No patients required surgery for haemostasis.

Conclusion: The risk of colonic post-polypectomy bleeding in patients with NOAC is high and often delayed in presentation. Resuming NOAC 4 days after colonoscopy may reduce the bleeding risk by half. However, this strategy should be study in prospective trial to address the bleeding and thrombotic risk.

Disclosure of Interest: All authors have declared no conflicts of interest.

References

1. Connolly SJ et al. RE-LY Steering Committee and Investigators. Dabigatran vs. warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139–1151.

2. Patel MR et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883–891.

3. Granger CB et al. AR- ISTOTL Committees and Investigators. Apixaban vs. warfarin in patients with atrial fibrillation. N Engl J Med 2011;365:981–992.

4. AJ Hui, JJ Sung et al. Risk of colonoscopic polypectomy bleeding with anticoagulants and antiplatelet agents: analysis of 1657 cases. GIE 2004 Jan;59(1):44–8

5. Shalman D, Gerson LB. Systematic review with meta-analysis: the risk of gastrointestinal haemorrhage post-polypectomy in patients receiving anti-platelet, anti-coagulant and/or thienopyridine medications. APT 2015 Oct;42(8):949–56

TUESDAY, OCTOBER 31, 201714:00-15:30

IMPACTS OF BIOLOGICS IN IBD - ROOM B2____________________

OP233 MRI IMPROVEMENT AFTER ANTI-TNF THERAPY IS PREDICTIVE OF SUSTAINED CLINICAL REMISSION AND IS A POTENTIAL THERAPEUTIC TARGET IN CROHN’S DISEASE

A. Buisson 1 , L. Messadeg 2 , G. Bouguen 3 , F. Goutorbe 4 , J. Reimund 5 , M. Goutte 1 , C. Sautel 6 , A. Boucher 6 , I. Ticlete 6 , C. Duron 7 , J. Scanzi 1 , M. Reymond 1 , C. Allimant 1 , M. Dapoigny 1 , G. Bommelaer 1 , B. Pereira 8 , C. Hordonneau 2

1 Dept. Of Gastroenterology, CHU Estaing Clermont-Ferrand, Clermont-ferrand/France

2 Dept. Of Radiology, CHU Estaing Clermont-Ferrand, Clermont-ferrand/France

3 CHU Rennes, Rennes/France

4 CH Bayonne, Bayonne/France

5 Hépato-gastroentérologie Et Assistance Nutritive, Hôpitaux Universitaires De Strasbourg, Chu De Hautepierre, Strasbourg Cedex/France

6 CH Issoire, Issoire/France

7 Dept. Of Gastroenterology, CH Montluçon, Montluçon/France

8 Dept. Of Statistics, CHU Clermont-Ferrand, Clermont-ferrand/France

Contact E-mail Address: a_buisson@hotmail.fr

Introduction: MRI has been suggested as a potential alternative to endoscopy to evaluate therapeutic efficacy in ileocolonic Crohn’s disease (CD).

Aims & Methods: We aimed to determine if MRI endpoints at week 12 (W12) are able to predict corticosteroids-free deep remission (CFREM) and MRI remission at W52 in patients treated with anti-TNF. CD adult patients needing anti-TNF therapy with CDAI > 150 and at least one diseased-bowel segment on MRI were consecutively included in this multicenter prospective study. All the patients underwent MREC including diffusion-weighted sequences with no bowel cleansing and no rectal enema, before starting therapy, at W12 and W52. The MRI were interpreted independently by two radiologists blinded from clinical data. Clermont score [1] and magnetic resonance index of activity (MaRIA) [2] were calculated according to previous publications. CFREM was defined as CDAI < 150 and CRP < 5 g/L and faecal calprotectin <250 with no switch of anti-TNF agents and no bowel resection. MRI remission was defined as no segmental MaRIA > 11 or no segmental Clermont score > 12.5 and deep MRI remission as no segmental MaRIA > 7 or no segmental Clermont score >8.4.

Results: Overall, 64 CD patients were enrolled in the study. Nine patients were primary non-reponders and left the study before the second MRI. Among the included patients, 41.4% were active smokers and 22.0% previously underwent intestinal resection. CD location was ileal, colonic and ileocolonic in 48.3%, 8.6% and 43.1%, respectively. Overall, 65.5% received concomitant immunosuppressive therapies. In addition, 46.6% and 53.4% of the patients were treated with infliximab and adalimumab, respectively. We assessed the variation of MRI parameters between baseline and W12 in patients achieving CFREM at W52 compared to those who did not among 55 CD patients. In univariate analysis, five factors evaluated at W12 were predictors of CFREM at W52: disappearances of ulcerations (OR = 6.4, p = 0.05), of oedema (OR = 3.3, p = 0.05), of enlarged mesenteric lymph nodes (OR = 5.9, 0.041), or of sclerolipomatosis (OR = 12, p = 0.03), and 10%-increase of ADC (OR = 4.3, p = 0.02). Using several multivariate models, we defined transmural response at W12 as at least one factor among the three following factors: disappearance of ulcerations, increase of ADC (ΔADC > 10 %), and disappearance of at least one extra-enteric sign (sclerolipomatosis OR enlarged mesenteric lymph nodes). Transmural response predicted CFREM at W52 in 18%, 53%, 67% and 100% of the patients when respectively none, one, two or three criteria were achieved at W12. Using ROC curves, we identified that 25%-decrease of Clermont score or MaRIA index at W12 were the best variations of these scores to predict CFREM at W52. All the MRI endpoints (Table 1) evaluated at W12 were highly predictive of CFREM at W52. In addition, transmural reponse (AUC = 0.66, Se = 71.4%, Spe = 60.0%, NPV = 75.0%, PPV = 55.6%) and MRI response according to Clermont score (AUC = 0.77, Se = 64.3%, Spe = 90.0%, NPV = 78.3%, PPV = 81.3%) or MaRIA (AUC = 0.84, Se = 78.6%, Spe = 90.0%, NPV = 85.7%, PPV = 85.7%) evaluated at W12 were highly predictive of deep MRI remission at W52.

Conclusion: MRI is a reliable tool to monitor therapeutic response in ileocolonic CD. Our short-term MRI endpoints are highly predictive of CFREM or transmural healing at W52, supporting their use in daily practice and clinical trials.

Disclosure of Interest: A. Buisson: No conflict of interest related to this work. I declare consulting fees for Takeda, Abbvie and Hospira; lecture fees for Takeda, Abbvie, Hospira, MSD, Ferring, Vifor pharma, Sanofi-Aventis.

M. Reymond: None related to this work Lecture fees for Abbvie.

All other authors have declared no conflicts of interest.

References

1. Hordonneau et al. Am J Gastroenterol 2014

2. Rimola et al. Gut 2009

OP234 EFFICACY OF ENDOSCOPIC PLACEMENT OF A DRUG-ELUTING PLATFORM WITH INFLIXIMAB FOR THE TREATMENT OF MUCOSAL LESIONS IN A RAT MODEL OF EXPERIMENTAL COLITIS

R. Bartolí 1 , I. Bon 2 , J. Boix 3 , V. Moreno De Vega 3 , N. D. De La Ossa 4 , I. Marín 3 , V. Lorenzo-Zúñiga 3

1 IGTP/CIBERehd, Badalona/Spain

2 IGTP, Badalona/Spain

3 Endoscopy Unit, University Hospital Germans Trias, Badalona/Spain

4 Pathology Department, University Hospital Germans Trias, Badalona/Spain

Contact E-mail Address: rbartolisole@gmail.com

Introduction: Refractory mucosal lesions in Inflammatory Bowel Dissease (IBD) patients are an important clinical challenge. Biological therapies have changed the way of treating these patients. Endoscopic administration of these drugs (targeted therapy) could decrease this refractory active inflammation by providing important clinical benefits. We have developed a new hydrogel (TriBio) with triple biological activity (bioadhesive, biocompatible and bioactive) that can acts as drug-eluting platform (patent pending).

Aims & Methods: The aim of this study was to evaluate the utility of endoscopic administration of 2 mL of TriBio platform with infliximab® (0.5 mg/mL), as a shield, in a rat model of TNBS-induced colitis. Colitis was induced by intrarectal administration of 30 mg TNBS to 24 Sprague-Dawley male rats (Day 0). At day 3, animals were randomized in three groups (n = 8, each) to receive: a) TriBio-Infliximab, b) TriBio or c) saline. Macroscopic follow-up (colonoscopy) was assessed at days 6 and 12. Afterwards, animals were sacrificed and colon was resected, weighted and histologically evaluated (1–4 scale). Ponderal evolution and appearance of stool were recorded.

Results: The treatment with TriBio-Infliximab significantly improved the clinical condition of the animals (weight evolution, and stool appearance). Similarly, the weight of the colon was also lower in animals treated with TriBio-infliximab when compared to controls (TriBio & saline). Histologic score also showed that TriBio-infliximab treatment significantly reduced the ulcer and the presence of necrosis and fibrosis. Table 1

Conclusion: Endoscopic placement of infliximab associated to a drug-eluting platform solves inflammatory lesions in experimental colitis. These results may open a new way to manage patients with refractory lesions.

Disclosure of Interest: R. Bartolí: The author declares the authorship of the patent

J. Boix: The authors declares the authorship of the patent

V. Lorenzo-Zúñiga: The authors declares the authorship of the patent

All other authors have declared no conflicts of interest.

OP235 FINAL RESULTS ON EFFICACY AND SAFETY OF BIOSIMILAR INFLIXIMAB AFTER ONE-YEAR: RESULTS FROM A PROSPECTIVE NATIONWIDE COHORT

K.B. Gecse 1 , Z. Vegh 1 , Z. Kurti 1 , M. Rutka 2 , K. Farkas 2 , P.A. Golovics 1 , B.D. Lovasz 1 , L. Gonczi 1 , J. Banai 3 , L. Bene 4 , B. Gasztonyi 5 , T. Kristof 6 , L. Lakatos 7 , P. Miheller 8 , F. Nagy 2 , K. Palatka 9 , M. Papp 9 , A. Patai 10 , A. Salamon 11 , T. Szamosi 3 , Z. Szepes 2 , G.T. Toth 12 , A. Vincze 13 , T. Molnar 2 , P.L. Lakatos 1

1 1st Department Of Medicine, Semmelweis University, Budapest/Hungary

2 First Department Of Internal Medicine, University of Szeged, Szeged/Hungary

3 Military Hospital – State Health Centre, Budapest/Hungary

4 1st Department Of Medicine, Peterfy Hospital, Budapest/Hungary

5 2nd Department Of Medicine, Zala County Hospital, Zalaegerszeg/Hungary

6 2nd Department Of Medicine, B-A-Z County and University Teaching Hospital, Miskolc/Hungary

7 Department Of Internal Medicine, Csolnoky Ferenc Regional Hospital, Veszprem/Hungary

8 Second Department Of Internal Medicine, Semmelweis University, Budapest/Hungary

9 Department Of Gastroenterology, University of Debrecen, Debrecen/Hungary

10 Department Of Medicine And Gastroenterology, Markusovszky Hospital, Szombathely/Hungary

11 Department Of Gastroenterology, Tolna County Teaching Hospital, Szekszard/Hungary

12 Department Of Gastroenterology, Janos Hospital, Budapest/Hungary

13 1st Department Of Medicine, University of Pecs, Pecs/Hungary

Contact E-mail Address: lorantgonczi@gmail.com

Introduction: Biosimilar infliximab CT-P13 received positive CHMP recommendation in June 2013 for all indications of the originator product. It has been previously shown that CT-P13 is effective and safe in inducing remission in inflammatory bowel diseases (IBD).

Aims & Methods: We report here final results from a prospective nationwide IBD cohort. A prospective, nationwide, multicentre, observational cohort was designed to examine the efficacy and safety of CT-P13 infliximab biosimilar in the induction and maintenance treatment of Crohn’s disease (CD) and ulcerative colitis (UC). Demographic data were collected and a harmonized monitoring strategy was applied. Clinical remission, response and biochemical response was evaluated at week 14, 30 and 54. None of the patients had received infliximab within 12 months prior to initiation of the biosimilar infliximab. Safety data was registered.

Results: 353 consecutive IBD (209 CD and 144 UC) patients were included of which 229 patients reached the week 54 endpoint. The age at disease onset was 24/28 years (median, IQR: 19–34 and 22–39) in CD and UC patients, respectively. 31/41% of CD patients had colonic/ileocolonic disease location, 43.5% had complicated disease behaviour, 39% had perianal disease, while 56.2% of UC patients had extensive colitis. 23/19% of patients had received previous anti-TNF therapy in CD and UC, respectively. 60/51% of CD/UC patients received concomitant immunosuppressives at baseline. 49, 53, 48% and 86, 81 and 65% of CD patients reached clinical remission and response by week 14, 30 and 54, respectively. Remission and response rates were 56, 41, 43% and 74, 66 and 50% in UC patients. Previous anti-TNF exposure was associated with decreased clinical efficacy in both CD and UC. Mean CRP decreased significantly both in CD and UC by week 14, which was maintained throughout the 1-year follow-up. 31 (8.8%) patients had infusion reactions, 32 (9%) patients had infections and 1 death occurred.

Conclusion: Final results from this prospective nationwide cohort confirm that CT-P13 is effective and safe in inducing and maintaining remission in both CD and UC. Efficacy was influenced by previous anti-TNF exposure, no new safety signals were detected.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP236 EFFICACY OF HEPATITIS B VIRUS VACCINATION IN NEWBORNS EXPOSED TO ANTI-TNF ALPHA IN UTERO

A. De Lima-Karagiannis 1 , S. Kanis 1 , J.C. Escher 2 , C.J. Van Der Woude 1

1 Gastroenterology And Hepatology, Erasmus MC University Medical Center, Rotterdam/Netherlands

2 Department Of Pediatrics, Erasmus MC University Medical Center, Rotterdam, Netherands, Rotterdam/Netherlands

Contact E-mail Address: a.delima@erasmusmc.nl

Introduction: Neonates exposed to maternal anti-TNF alpha treatment in utero are born with clinically significant anti-TNF alpha levels that can still be detected throughout the first months of life. 1, 2 Adults treated with anti-TNF alpha agents have been reported to respond inadequately to the hepatitis B virus (HBV) vaccine compared to adults not treated with anti-TNF alpha. 3–5 Since 2011, HBV vaccination is included in the Dutch National Vaccination Programme. The efficacy of the HBV vaccination is unclear in children that have been exposed to anti-TNF alpha in utero. The objective of this study was to compare anti-HBs levels following routine HBV vaccination in anti-TNF alpha-exposed children versus non-exposed children.

Aims & Methods: We performed a cross-sectional, controlled cohort study at a single, tertiary referral center. Study enrollment took place from 2014 until 2017. Pregnant women treated with anti-TNF alpha until at least the second trimester for Inflammatory Bowel Disease (IBD) and their subsequent children were recruited from the IBD preconception outpatient clinic. Pregnant women treated with other medication than anti-TNF alpha for IBD and their subsequent children were eligible as controls. Women were not eligible for participation in case of HBV infection. Adherence to the Dutch National Vaccination Programme was mandatory for participation in this study (Routine HBV vaccination (Engerix-B Junior, rDNA vaccine) at 6 weeks, 3, 4 and 11 months). A venous blood sample was obtained from the children one month after final HBV vaccination. Anti-HBs levels were measured by ELISA.

Results: Anti-HBs levels at 12 months did not differ between the anti-TNF alpha exposed (n = 15) and the control group (n = 12) (>1000 IU/L vs >1000 IU/L, p = 0.59). All children were successfully immunised against HBV, defined as anti-HBs>10 IU/L. Median anti-TNF alpha levels determined in cord blood at birth were 2.5 ug/mL (IQR: 0.40–11.01 ug/mL). There were no differences in birth outcomes, growth and infections in the first year of life between the anti-TNF alpha exposed and the control group.

Conclusion: This study suggests that children born with detectable anti-TNF alpha levels can be effectively vaccinated against HBV.

Disclosure of Interest: All authors have declared no conflicts of interest.

References

1. de Lima A, Zelinkova Z, van der Ent C, Steegers EA, van der Woude CJ. Tailored anti-TNF therapy during pregnancy in patients with IBD: maternal and fetal safety. Gut . May 12 2015.

2. Julsgaard M, Christensen LA, Gibson PR, et al. Concentrations of Adalimumab and Infliximab in Mothers and Newborns, and Effects on Infection. Gastroenterology . Jul 2016;151(1):110–119.

3. Gisbert JP, Villagrasa JR, Rodriguez-Nogueiras A, Chaparro M. Efficacy of hepatitis B vaccination and revaccination and factors impacting on response in patients with inflammatory bowel disease. Am J Gastroenterol. Oct 2012;107(10):1460–1466.

4. Andrade P, Santos-Antunes J, Rodrigues S, Lopes S, Macedo G. Treatment with infliximab or azathioprine negatively impact the efficacy of hepatitis B vaccine in inflammatory bowel disease patients. J Gastroenterol Hepatol . Nov 2015;30(11):1591–1595.

5. Jiang HY, Wang SY, Deng M, et al. Immune response to hepatitis B vaccination among people with inflammatory bowel diseases: A systematic review and meta-analysis. Vaccine . Apr 09 2017.

OP237 STRUCTURE AND BIOLOGICAL ACTIVITY OF INFLIXIMAB PRODUCTS

C. Lee 1 , M. Jeong 1 , J. Lee 1 , S. Seo 1 , S. Cho 1 , W. Zhang 2 , O. Jaquez 3

1 Samsung Bioepis Co., Ltd., Incheon/Korea, Republic of

2 Biogen, Inc., Cambridge/United States of America

3 Biogen, Inc., Zug/Switzerland

Contact E-mail Address: conrad.lee@samsung.com

Introduction: As biosimilars are entering the market, evaluation of the quality of these products is needed as differences in manufacturing process may lead to differences in critical quality attributes, which affect efficacy. Thus, major biological activities of reference infliximab and of two biosimilars (SB2 and CT-P13) were determined.

Aims & Methods: More than 30 structural, physicochemical, and biological attributes of the infliximab products were evaluated. Structural comparison was performed by multiple assays including peptide mapping using mass spectrometry and hydrogen/deuterium exchange (HDX). TNF-α neutralisation activity was measured by a luciferase reporter gene assay. The percentages of galactosylated, afucose plus high mannosylated, and charged glycan were determined. FcγRIIIa binding activity in surface plasmon resonance, AlphaScreen-based binding assay, and cell-based binding assay were assessed. Antibody-dependent cell-mediated cytotoxicity (ADCC) activity in a NK92-CD16a cell line and in peripheral blood mononuclear cells (PBMCs) were determined.

Results: Analytical similarity of SB2 was demonstrated through extensive characterisation studies. For example, the primary structure and higher-order structure of the reference infliximab and SB2 were similar. In the comparison of three infliximab products, the relative potency was similar for all 3 products. In N-glycan analysis, as compared with the reference infliximab, a lower percentage of charged glycan with SB2 was noted, and a higher percentage of galactosylated glycan and a lower percentage of afucose plus high mannosylated glycans with CT-P13 were noted. The percentage of the relative FcγRIIIa binding affinity by all 3 methods was lower with CT-P13 as compared with the reference infliximab. The percentage of the relative ADCC activity in the NK92-CD16a cell line was lower with CT-P13 and higher with SB2 as compared with the reference infliximab but was similar for all 3 products in PBMCs.

Conclusion: Comparison of the three infliximab products showed that there was no difference in most quality attributes. FcγRIIIa binding and ADCC activity showed differences that were correlated with the N-glycan profile, but the differences were not demonstrated in the physiologically more relevant condition.

Disclosure of Interest: C. Lee: Employee of Samsung Bioepis

M. Jeong: Employee of Samsung Bioepis

J. Lee: Employee of Samsung Bioepis

S. Seo: Employee of Samsung Bioepis

S. Cho: Employee of Samsung Bioepis

W. Zhang: Employee of Biogen

O. Jaquez: Employee of Biogen

OP238 BODY WEIGHT AND RAPID CLEARANCE DETERMINE EARLY FORMATION OF ANTI-DRUG ANTIBODIES AGAINST INFLIXIMAB

W. Reinisch 1 , A. Eser 1 , S. Schreiber 2 , H.C. Kwon 3 , D.R. Mould 4

1 Gastroenterologie Und Hepatologie, Medical University of Vienna Gastroenterology and Hepatology, Vienna/Austria

2 Uksh, Universität Kiel UKSH Medizinische Abt. I - UKSH, Universität Kiel UKSH Medizinische Abt. I; Kiel/DE, Kiel/Germany

3 Celltrion Inc., Yeonsu-gu, Incheon/Korea, Republic of

4 Projections Research Inc, Phoenixville PA/United States of America

Contact E-mail Address: walter.reinisch@meduniwien.ac.at

Introduction: Anti-drug antibodies (ADA) arise during treatment with Infliximab (IFX). ADA accelerate drug clearance (CL), rendering IFX ineffective (1). Delineation of risk factors for ADA formation and early identification of ADA offer opportunities to attenuate ADA response.

Aims & Methods: A 2-part modeling approach was undertaken to 1) develop a semi-mechanistic conditional on ADA+ pharmacokinetics (PK)/pharmacodynamics (PD) model and 2) identify predictors of early ADA formation. PK data obtained from Celltrion Study 1331 (2, 3) investigating originator and biosimilar IFX in RA patients were evaluated. The PK/PD model by Chen (4), using Nonmem 7.3, was modified: 1) A 2-compartment linear model was fitted to the PK data from the first 2 doses (MOD1), 2) PK and ADA were modeled simultaneously with the PK part of the model fixed to the MOD1 estimates, 3) a zero-inflated Poisson distribution linked predicted ADA to a non-negative integer reflecting ADA levels as suggested by Bonate (5) (MOD2). ADA formation was implemented by introducing putative doses into an empirical ADA depot in a saturable fashion starting at the 3rd IFX dose. The model included a variable time lag before ADA was introduced into the central PK compartment, where it associated with IFX in a 1st order fashion to form an IFX-ADA complex, eliminated by a 1st order process, or was eliminated as free ADA. The incidence of ADA was modeled with logistic regression using baseline predictors (weight (WT), albumin, sex, methotrexate dose, presence of immunosuppressants, and serum glucose) and the estimated CL from MOD1 using Fisher scoring and SAS proc logistic (MOD3).

Results: MOD1 estimated IFX elimination half-life was 8.4 days. Predicted CL increased by 6, 10, and 1.7% as weight increased, albumin decreased, and C-reactive protein (CRP) increased by 10 kg, 1G/dL, and 5 nmol/L, respectively. Unexplained between subject variability (BSV) expressed as coefficient of variation (CV) in CL was 42%. MOD2 indicated variable time to the 1st appearance of ADA (median time = 87 days, 95% CI 74–103 days), with high BSV (CV = 144%). Rising ADA titers associated with decreasing trough levels (TL), given stable albumin, WT, and CRP. For a ADA+ patient, 5 mg/kg dosing at weeks 0, 2, 6, 14, TLs were undetectable by the 5th dose. Simulations using MOD2 suggested that appropriate dose adjustments may be able to overcome low ADA titers to restore response. The ADA formation incidence model (MOD3) identified CL and WT as the only predictors of ADA formation. The odds ratios (95% Wald based confidence intervals (CI) for 0.1 L/day and 10 kg increases in CL and WT were 1.78 (1.50, 2.12) and 1.19 (1.06, 1.33), respectively. Mean IFX CL for ADA+ and ADA- subjects were 0.364 L/day (probability (Pr) of SC = 0.67) and 0.264 L/day (Pr of SC = 0.49).

Conclusion: 3-part modeling identified baseline WT and CL as predictors of ADA formation. A transit model for the combined PK/PD from ADA+ patients described ADA titers that rose after a lag time with increasing elimination of IFX resulting in unmeasurable TLs. Strategies of early rapid CL estimates are needed to guide dosing or measures targeting reduction of ADA production.

Disclosure of Interest: W. Reinisch: Consultant for Celltrion

S. Schreiber: Consultant for celltrion

H.C. Kwon: Employee of Celltrion Inc.

D.R. Mould: President of Projections Research Inc., consulting company for the pharmaceutical industry

All other authors have declared no conflicts of interest.

References

1. Chirmule N, Jawa V, Meibohm B. Immunogenicity to therapeutic proteins: impact on PK/PD and efficacy. AAPS J . 2012 Jun;14(2):296–302.

2. Yoo DH, Hrycaj P, Miranda P, et al. A randomised, double-blind, parallel-group study to demonstrate equivalence in efficacy and safety of CT-P13 compared with innovator infliximab when coadministered with methotrexate in patients with active rheumatoid arthritis: the PLANETRA study. Ann Rheum Dis . 2013 Oct;72(10):1613–20.

3. Yoo DH, Racewicz A, Brzezicki J, et al. A phase III randomized study to evaluate the efficacy and safety of CT-P13 compared with reference infliximab in patients with active rheumatoid arthritis: 54-week results from the PLANETRA study. Arthritis Res Ther . 2016 Apr 2;18:82.

4. Chen, X., Hickling, T., Kraynov, E. et al. A Mathematical Model of the Effect of Immunogenicity on Therapeutic Protein Pharmacokinetics. AAPS J (2013) 15: 1141.

5. Bonate PL, Sung C, Welch K, et al. Conditional modeling of antibody titers using a zero-inflated poisson random effects model: application to Fabrazyme. J Pharmacokinet Pharmacodyn . 2009;36(5):443–59.

TUESDAY, OCTOBER 31, 201714:00-15:30

OPTIMISING YOUR COLONOSCOPY PRACTICE - ROOM 7.1____________________

OP239 RELATED FACTORS TO THE QUALITY OF COLON CLEANSING

C. Mangas 1 , E. Santana Rocamora 1 , A. Suárez González 2 , I. Portillo Villares 3 , A. Seoane 4 , M. Ponce 5 , P. Diez 6 , E. Quintero Carrion 7 , M. Herraiz 8 , M. Pellisé Urquiza 9 , Á. Ferrández Arenas 10 , V. Hernández 11 , Á.E. Pizarro Moreno 12 , R. Jover 1

1 Hospital General Universitario de Alicante, Alicante/Spain

2 Servicio De Aparato Digestivo, Hospital Universitario Central de Asturias, Oviedo/Spain

3 Hospital Universitario de Donostia, San Sebastián/Spain

4 Hospital del Mar-Parc de Salut Mar Barcelona, Barcelona/Spain

5 Hospital Universitari i Politecnic de la Fe, Valencia/Spain

6 Gastroenterology, Hospital Universitario Rio Hortega, Valladolid/Spain

7 Gastroenterology, Hospital Univ. de Canarias, Santa Cruz de Tenerife/Spain

8 Clinica Universitaria de Navarra, Pamplona/Spain

9 Gastroenterology, Hospital Clinic Barcelona, Barcelona/Spain

10 Hospital Clínico Universitario Lozano Bleza, Zaragoza/Spain

11 Instituto de Investigación Biomédica, Xerencia de Gestión Integrada de Vigo, Vigo/Spain

12 Gastroenterology, Hospital Virgen del Rocio, Sevilla/Spain

Contact E-mail Address: cmangassanjuan@gmail.com

Introduction: An adequate colon cleansing is needed for the fullfilment of quality indicators of colonoscopy.

Aims & Methods: The aim of this study was to evaluate which factors are related with colonic cleansing quality. A total of 6323 colonoscopies performed between January and October 2016 were prospectively included in the QUALISCOPIA project, an observational, multicenter and prospective study, developed in 12 centers in Spain. Inadequate cleansing was considered when the Boston Scale score is 0/1 in any of the segments. Variables such as indication for the colonoscopy, sex, age, type of bowel preparation, time of the examination and the time between the last dose of bowel preparation and colonoscopy have been analyzed.

Results: Inadequate cleansing was presented in the 14.1% of the patients. In the multivariate analysis (Table 1) we observed that the indication of colonoscopy influences cleanliness. Regarding the indication of the procedure, inadequate cleansing was observed in 18.4% of the patients with gastrointestinal symptoms (p-value<0.001, aOR1.7, 95%CI 1.3–2.1); 14.6% of patients with post-polypectomy surveillance (p-value<0.001, aOR2.4, 95%CI 2.0–2.9) and 10.6% of patients with direct screening (p-value=0.111, aOR1.3, 95%CI 0.9–1.8) compared with positive fecal immunochemical test, were inadequate cleansing was seen in 8.8% of colonoscopies with this indication. Moreover, inadequate cleansing was more frequently in males (p-value = 0.048, aOR1.3, 95%CI 1.1–1.5) and in patients ≥60 years (p-value = 0.007, aOR1.2, 95%CI 1.1–1.5). Regarding the length of delay between the last dose of bowel preparation and the start of colonoscopy, we observed that a delay longer than 7 h was associated with inadequate cleansing (p-value<0.001, aOR1.8, 95%CI 1.5–2.5), nevertheless, a delay longer than 4 h did not show this association (p-value = 0.174, aOR1.1, 95%CI 0.9–1.4). On the other hand, the type of bowel preparation had no effect on the cleansing quality.

Conclusion: The indication of colonoscopy, sex, age, and time between the last dose of bowel preparation and colonoscopy longer than 7 h are factors that are independently related to the quality of colonic cleansing.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP240 IMPROVEMENT OF COLONOSCOPY PREPARATION BY AN AUTOMATED 4-DAY PATIENT GUIDANCE BY SMS; RESULTS FROM THE PERICLES-II STUDY

B. M. Walter 1 , P. Klare 2 , K. Strehle 2 , J. Aschenbeck 3 , L. Ludwig 4 , N. Dikopoulos 4 , B. Neu 5 , S. Delius 2

1 Klinik Für Innere Medizin I, University Hospital Ulm, Ulm/Germany

2 Ii. Medizinische Klinik, MRI der TU München, München/Germany

3 Facharzt für Innere Medizin Versorgungsschwerpunkt Gastroenterologie, Berlin/Germany

4 Gastroenterologische Schwerpunktpraxis, Dornstadt/Germany

5 Medizinische Klinik Ii, Klinik Landshut-Achdorf, Landshut/Germany

Contact E-mail Address: benjamin.walter@uniklinik-ulm.de

Introduction: Participation in colon-cancer screening is still low in Europe and worldwide. Especially bowel preparation is reported to be the most unpleasant burden. Despite the fact that bowel preparation is a major cornerstone of quality of colonoscopy, in a certain proportion of patients bowel preparation is still insufficient. Problems with dietary recommendations and problems taking the purgatives are reported very often in these cases. Among our patients usage of mobile phone has increased rapidly in the last years. Therefore using this new medium for improvement of colonoscopy preparation has to be considered.

Aims & Methods: To optimize patients' guidance in colonoscopy preparation an easy-to-access solution for all mobile phones by short message service (SMS) covering the 4 days prior colonoscopy was used in a prospective, randomized multicenter study. In comparison to other approaches not only laxative intake but a complete patient guidance over the last four days before colonoscopy was served by the SMS system. 500 (250/250) participants with appointment for out-patient colonoscopy were randomized to regular colonoscopy preparation (control group) or SMS supported colonoscopy preparation. The control group received information about colonoscopy preparation orally and by a leaflet as regularly done by gastroenterologists. The SMS supported group additionally received information regarding dietary and general recommendations time axis adjusted to the colonoscopy appointment by an automated SMS system starting 4 days prior colonoscopy preparation. Level of bowel cleanliness was measured by BBPS. Patients' satisfaction with bowel preparation procedure was analyzed by a questionnaire.

Results: Participants of the SMS supported colonoscopy preparation had a significant higher BBPS score (7.6 vs. 6.1; p < 0.0001) in comparison to regular colonoscopy preparation. All regions of the colon, especially the right colon had higher BBPS scores in SMS supported patients. Overall patient satisfaction with bowel preparation was higher in the SMS supported group.

Conclusion: SMS supported colonoscopy preparation by an automated 4-day guidance improved bowel cleanliness. Patient guidance covering the last four days before colonoscopy was highly accepted by the patients. We conclude further that the usage of a simple tool as SMS for optimizing colonoscopy preparation could improve CRC-Screening participation.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP241 A RANDOMIZED CONTROLLED TRIAL COMPARING WATER ASSISTED AND AIR INSUFFLATION COLONOSCOPY WITHOUT SEDATION

R. Azevedo , C. Leitão, H. Ribeiro, J. Pinto, F. Pereira, A. Caldeira, R. Sousa, E. Pereira, J. Barros, A. Banhudo

Gastroenterology, Amato Lusitano Hospital, Castelo Branco/Portugal

Contact E-mail Address: richardazevedo13@gmail.com

Introduction: Water-assisted colonoscopy is gaining increasing popularity as an alternative method to reduce patients’ discomfort and need for sedation in unsedated and minimally sedated patients. Previous studies have shown that water-aided colonoscopy is superior to air insufflation in attenuating insertion pain.

Aims & Methods: We conducted a patient-blinded, randomized controlled trial with head-to-head comparison of these two methods to evaluate the effectiveness of water-assisted colonoscopy in reducing discomfort and pain in patients without sedation and to determine its influence on other colonoscopy quality indicators compared to the conventional method. A total of 127 outpatients were randomized to either water-aided insertion and air insufflation during withdrawal [Water] or standard air insufflation during both insertion and withdrawal [Air]. The primary outcome was the improvement of patient intraprocedural pain (pain score), evaluated using a questionnaire (score 1 to 10).

Results: Baseline characteristics of the two groups were comparable; 64 patients were included in the Water group and 63 in the Air group. Patients in the Water group reported less intraprocedural pain than those in the Air group (3.52 ± 2.29 vs. 5.10 ± 2, 01 p < 0.01), despite lower levels of anxiety prior to the examination (score 1–5) in the Air group (1.89 ± 0.88 vs. 2.27 ± 1.16 p < 0.05). There were no differences in the quality of bowel preparation (median of 8 for the two arms, according to the Boston Bowel Preparation Scale), cecal intubation time and withdrawal time (15.61 ± 6.74 vs. 16.83 ± 6.55 minutes; 11.23 ± 3.42 vs. 11.90 ± 5.91 minutes, p > 0.05), as well as polyp detection rate (40.6 vs. 39.7%, p > 0.05) in the Water vs. Air group. There were no major complications in both groups.

Conclusion: Water-assisted colonoscopy seems to be a safe and effective alternative to conventional colonoscopy without sedation, being associated with less intraprocedural pain and not influencing other performing measures of colonoscopy. Based on this evidence, the use of water-assisted colonoscopy should be encouraged.

Disclosure of Interest: All authors have declared no conflicts of interest.

References

1. Jun WU, Bing HU. Comparative effectiveness of water infusion vs air insufflation in colonoscopy: a meta-analysis. Colorectal Dis . 2013;15(4):404–409. doi:10.1111/j.1463-1318.2012.03194.x.

2. Ishaq S, Neumann H. Water assisted colonoscopy: A promising new technique. Dig Liver Dis . 2016;48(6):569–570. doi:10.1016/j.dld.2016.03.005.

3. Cadoni S, Leung FW. Water-Assisted Colonoscopy. Curr Treat Options Gastroenterol . 2017;15(1):135–154. doi:10.1007/s11938-017-0119-1.

OP242 NEW GENERATION FULL-SPECTRUM VERSUS STANDARD FORWARD-VIEWING COLONOSCOPY: A MULTICENTER, RANDOMIZED CONTROLLED, TANDEM COLONOSCOPY TRIAL

K. Hotta 1 , T. Kudo 2 , Y. Saito 3 , H. Ikematsu 4 , Y. Takeuchi 5 , M. Shimatani 6 , K. Kawakami 7 , N. Tamai 8 , K. Yoshimura 9 , H. Ishikawa 10 , K. Imai 1 , Y. Mori 11 , T. Matsuda 3 , S. Kudo 2

1 Division Of Endoscopy, Shizuoka Cancer Center, Nagaizumi/Japan

2 Digestive Disease Center, Showa University Northern Yokohama Hospital, Yokohama/Japan

3 Endoscopy Division, National Cancer Center Hospital, Tokyo/Japan

4 Endoscopy Division, National Cancer Center Hospital East, Kashiwa/Japan

5 Department Of Gastrointestinal Oncology, Osaka International Cancer Institute, Osaka/Japan

6 The Third Department Of Internal Medicine, Kansai Medical University, Hirakata/Japan

7 Second Department Of Internal Medicine, Osaka Medical Collage, Osaka/Japan

8 Department Of Endoscopy, The Jikei University School of Medicine, Tokyo/Japan

9 Kanazawa University Hospital, Innovative Clinical Research Center, Kanazawa/Japan

10 Department Of Molecular-targeting Cancer Prevention, Kyoto Prefectural University of Medicine, Kyoto/Japan

11 Northen Yokohama Hospital, Showa University Northern Yokohama Hospital, Yokohama/Japan

Contact E-mail Address: k.hotta@scchr.jp

Introduction: Standard forward-viewing (SFV) colonoscopy was proved to have more than 20% adenoma miss rate based on meta-analysis of tandem colonoscopy trials 1) . Previous model of full-spectrum endoscopy (FUSE) was proved to improve the adenoma miss rate compared to SFV colonoscopy by a multicenter, randomized tandem colonoscopy trial 2) . However, recent another randomized trial did not prove a significant efficacy of FUSE compared to SFV colonoscopy with regard to the adenoma detection rate 3) .

Aims & Methods: Aim of this study was to compare the new generation FUSE with SFV colonoscopy. A multicenter, randomized controlled, tandem colonoscopy trial was conducted in eight Japanese institutions between February 2016 and January 2017. Patients aged 40–75 years referred for colorectal cancer screening, positive fecal immunological test, or polyp surveillance underwent same-day, back-to-back tandem colonoscopy with the new generation FUSE (330°) and SFV colonoscope (140–170°). Randomization was stratified by gender, age, indication and institution. Primary endpoint was the adenoma miss rate via per-protocol, per-patient analysis. Secondary endpoints included the polyp miss rate and the adenoma detection rate. This trial is registered with University Hospital Medical Information Network (UMIN), number UMIN000020448.

Results: A total of 344 patients were enrolled and finally 319 patients were included in the per-protocol analyses: 159 (50%) were randomly assigned to receive FUSE first, and 160 (50%) to receive SFV first. Per-lesion analysis, the adenoma miss rate was significantly lower in patients in the FUSE first than in those in the SFV first: 60 (20.5%) of 293 vs 103 (30.7%) of 335 adenomas were missed ( P < .0035). Per-patient analysis, the adenoma miss rates was significantly lower in patients in the FUSE first than in those in the SFV first: 11.7 (8.0–15.4) % vs 22.9 (17.5–28.3) % ( P < .001). The polyp miss rate via per-patient analysis was also significantly lower in the FUSE first than in the SFV first: 13.9 (10.0–17.7) % vs 26.8 (21.3–32.4) % ( P < .001). The adenoma detection rate was significantly superior in patients in the FUSE first than in those in the SFV first: 62.9 (54.9–70.4) % vs 49.4 (41.4–57.9) % ( P = .018). Cecal intubation rates (%), mean cecal intubation and withdrawal time (min) of FUSE and SFV were 98.2 and 99.1 ( P = .50), 7.5 and 4.7 ( P < .001), 8.4 and 7.9 ( P < .001), respectively.

Conclusion: New-generation FUSE improved not only adenoma miss rate but also adenoma detection rate compared with SFV colonoscopy.

Disclosure of Interest: All authors have declared no conflicts of interest.

References

1. van Rijn JC, et al. Am J Gastroenterol 2006; 101:343–50

2. Glalnek IM, et al. Lancet Oncol 2014; 15: 353–60

3. Hassan C, et al. Gut 2016 Aug 9(Epub ahead of print)

OP243 PERFORMANCE COMPARISON OF FULL-SPECTRUM VERSUS FORWARD-VIEWING COLONSCOPY: A RANDOMIZED CONTROLLED TRIAL

M. Geyer 1 , L. Dominik 2 , F. Bannwart 3

1 Gastroenterologie Wettingen, Wettingen/Switzerland

2 Ludwig-Maximilians University, Munich/Germany

3 Medica Laboratories, Zurich/Switzerland

Contact E-mail Address: geyer@gastroenterologie-wettingen.ch

Introduction: Technology of colonoscopy is constantly evolving. New full-spectrum colonoscopes (FUSE) with 330°angle of view showed a significantly lower adenoma miss rate (7% vs 41%) to standard forward-viewing endoscopes (FVE). The objective of the present investigator-initiated randomized controlled trial was to assess the utility of this new technique regarding polyp detection rate as well as duration of the procedure in daily practice.

Aims & Methods: From March 2015 trough December 2016 patients referred to ambulant colonoscopy were randomly assigned to either a colonoscopy with high definition FVE Pentax i10 or FUSE instruments. 974 patients were allocated to FUSE and 882 to FVE. All procedures were performed by one experienced endoscopist.

Results: 51% of the FUSE and 52% of the FVE patients were female, mean age were 64 (CI 62–66) and 66 years (CI 63–70), respectively. 36% of the FUSE and 30% of the FVE patients were screening, 56 vs 61% were surveillance colonoscopies. 7 vs 8% had a positive family history for CRC. There was no significant difference for all baseline characteristics. Adenoma detection rate (ADR) was 51% for all FUSE cases vs 53% in FVE (ns = not significant). Mean adenoma per colonoscopy (APC) were 1.1 in FUSE vs 1.2 in FVE (ns). In the whole FUSE group 1.8 polyps per patients were found overall increasing to 1.9 with newer FUSE generation and 1. 9 with Lumos (tissue enhancement technology from Endochoice) compared to 1.8 in FVE (ns). 96 to 95% of the polyps were sessile lesions; 84.4 vs 83.7% below 5 mm of size, 12.8 vs 12.5 % between 5–9 mm and 3.2 respectively 3.8% bigger than 1 cm. 34.2 vs 34.1% were right sided, 21.9 vs 20.2% located in the tansverse colon. 48% of the extracted FUSE polyps and 50% of the polyps in the FVE group were tubular adenomas, 0.6 vs 1.2% were villous, 17.5% vs 23.6% serrated (SSA) adenomas and 15 respectively 11.8% were hyperplastic polyps. In 0.7% a CRC and in 0.02% an anal carcinoma was found in the FUSE group vs 0.8% CRCs in the FVE group. There was no significant difference in histology. Time to ileum was with 5.3 min (CI 5.0–5.5) slightly faster with FUSE (overall) even more pronounced with the at that time newest FUSE generation (gen2) and a mean time of 5.0 min (CI 4.7–5.3) compared to 5.5 min (CI 5.2–5.7) with the FVE (p = 0.02). Withdrawal time was significantly shorter with FUSE with a time of 15.8 min (CI 15.3–16.3) in FUSE and 19.1 min (CI 16.8–21.4) in FVE (p = 0.01). Time for intervention was identical in both groups (3.3 (CI 2.8–3.4) vs 3.4 min (CI 2.8–3.6); ns). Depending on FUSE generation the overall examination time gain was 3 to 4.1 min (p < 0.05).

Conclusion: Our randomized controlled trial with the largest FUSE examined patient cohort in the literature revealed significantly shorter examination time compared to conventional high definition colonoscopy with equal adenoma detection rates for both types of instruments. Due to the wider field of view (330° for FUSE endoscopes) polyps might be detected faster and easier during the withdrawal, resulting in the same high adenoma detection rate of 51 up to 52% for FUSE compared to 53% for FVE but with significantly shorter pullback time.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP244 IMPLEMENTATION OF AN OPTICAL DIAGNOSIS STRATEGY FOR DIMINUTIVE POLYPS INCLUDING SESSILE SERRATED LESIONS: TRAINING AND LONG-TERM QUALITY ASSURANCE

J. L. a. Vleugels 1 , M.G. w. Dijkgraaf 2 , Y. Hazewinkel 1 , P. Fockens 1 , E. Dekker 1 , O.B.O.T. Discount Study Group 1

1 Gastroenterology And Hepatology, Academic Medical Center, Amsterdam/Netherlands

2 Clinical Research Unit, Academic Medical Center, Amsterdam/Netherlands

Contact E-mail Address: j.l.vleugels@amc.uva.nl

Introduction: Narrow band imaging (NBI) allows real-time differentiation of diminutive (1–5 mm) polyp histology during endoscopy. Before this practice can be implemented in daily practice, guidelines endorse ≥90% negative predictive value (NPV) for neoplastic histology in the rectosigmoid and ≥90% agreement in surveillance intervals for high-confidence predictions. This study aimed to train endoscopists in optical diagnosis of diminutive polyps with NBI and to determine whether these endoscopists can achieve and maintain the prior thresholds.

Aims & Methods: In this prospective multicentre study, endoscopists accredited for colonoscopies in FIT-positives within the Dutch bowel cancer screening program were trained in optical diagnosis with our validated NICE-WASP module [1]. This module includes optical differentiation of sessile serrated lesions. Trained endoscopists were required to meet predefined thresholds in image-based and real-time tests before entering the continuation phase. In this phase, endoscopists recorded histology predictions and confidence levels of all polyps in consecutive FIT-positive colonoscopies for 1 year. Endoscopists were randomized to receive feedback or no feedback on their performance. Primary outcome was whether endoscopists could maintain a NPV ≥90% for neoplastic histology in the rectosigmoid for high-confidence predictions, either with or without regular interim performance feedback. NPV was determined by comparing predicted with actual histology outcome. Neoplastic histology was defined as adenomatous and sessile serrated lesion histology. For surveillance interval agreement, prediction was based on the combination of high-confidence predictions and histology outcome of low-confidence predictions and polyps sized >5 mm. Generalized estimated equation analyses were used and adjusted for clustering of polyps per patient and per endoscopist.

Results: Of 39 endoscopists initially attending the training sessions, 27 (69%) qualified after a median number of 3 tests (range 2–5). The pooled NPV for predicting neoplastic rectosigmoid histology during the real-time tests was 94.1% (95% confidence interval (CI) 86.1–97.6). In the continuation phase, these 27 endoscopists performed 3, 144 colonoscopies in which 4, 504 diminutive polyps were removed. Of these, 73.5% were predicted with high-confidence and 40.4% were located in the rectosigmoid. The pooled NPV for predicting neoplastic histology in the rectosigmoid at the end of the continuation phase was 90.8% (95% CI 88.6–92.6). The NPV in the feedback group was 91.7% (95% CI 88.2–94.2) and 89.6% (95% CI 85.2–92.8) in the observation group (p = 0.93). The pooled surveillance interval agreement was 95.4% (95% CI 94.0–96.6), and did not differ between the feedback and observation group (96.4% versus 94.1%, p = 0.10). Individually, 17 (63%) endoscopists achieved ≥ 90% NPV for predicting neoplastic rectosigmoid histology, 24 (89%) achieved ≥90% surveillance interval agreement and 16 (59%) achieved both. High-confidence predictions and use of high-definition scopes were independently associated with accurate histology prediction.

Conclusion: Using a validated training module including sessile serrated lesions, a selected group of endoscopists achieved and maintained a pooled NPV and surveillance interval agreement of at least 90% over the course of 1 year. Providing regular interim feedback did not lead to differences in those endpoints. This study design can be used as a template for safe implementation of an optical diagnosis strategy in daily practice ( NCT02516748 ).

Disclosure of Interest: P. Fockens provides ongoing consultancy to Cook, Olympus, Medtronic, and Fujifilm.

E. Dekker has equipment on loan from Olympus Europe and Fujifilm, has received a research grant from Olympus Europe and Fujifilm, and consulted for Tillotts Pharma (one time).

All other authors have declared no conflicts of interest.

Reference

1. IJspeert JEG, Bastiaansen BAJ, van Leerdam ME, et al. Development and validation of the WASP classification system for optical diagnosis of adenomas, hyperplastic polyps and sessile serrated adenomas/polyps. Gut 2016;65:963–970.

TUESDAY, OCTOBER 31, 201714:00-15:30

H. PYLORI : FROM PATHOPHYSIOLOGY TO THE CLINIC - ROOM E2____________________

OP245 LONG-TERM EFFECTS OF H. PYLORI ERADICATION ON MOLECULAR ALTERATIONS RELATED TO GASTRIC CARCINOGENESIS

J. Watari 1 , Y. Michigami 1 , C. Ito 1 , K. Hara 1 , T. Yamasaki 1 , T. Okugawa 1 , T. Kono 1 , K. Tozawa 2 , T. Tomita 2 , Y. Ohda 1 , T. Oshima 1 , H. Fukui 1 , H. Miwa 1

1 Division Of Gastroenterology, Department Of Internal Medicine, Hyogo College of Medicine, Nishinomiya/Japan

2 Gastroenterology, Hyogo College of Medicine, Hyogo/Japan

Contact E-mail Address: watarij@hyo-med.ac.jp

Introduction: A meta-analysis showed that H. pylori eradication seems to reduce gastric cancer (GC). However, a study from Japan showed that even after an H. pylori infection is cured and gastric inflammation is eliminated, the risk of the development of GC remains, and the risk increases in individuals with precancerous conditions such as atrophic mucosa (AM) and intestinal mucosa (IM). Indeed, GC has occurred to some degree during a long-term follow-up in patients treated for H. pylori eradication. In addition, the roles of a number of genetic and epigenetic alterations have been reported to be involved in GC and precancerous conditions of the stomach.

Aims & Methods: To clarify the molecular changes due to H. pylori eradication, we evaluated differences in molecular alterations related to carcinogenesis in background mucosa with and without GC before and after H. pylori eradication. We enrolled 78 consecutive patients and divided them into three groups: the chronic gastritis patients with long-term follow-up (≥3 yrs) after H. pylori eradication (AG group, n = 30), the patients who developed intramucosal early GC after eradication (≥3 yrs) (GC group, n = 27), and the H. pylori -positive chronic gastritis patients (control group, n = 21). The H. pylori status was analyzed in each patient by both Giemsa staining and serum H. pylori -IgG antibody measurement. Biopsy specimens were obtained from the stomach's antrum, angulus, and corpus. DNA was separately extracted from the AM and IM via laser capture microdissection. Genetic instability was evaluated at five loci based on the Bethesda panel; we assessed the CpG island methylator phenotype (CIMP) and the methylation status at seven tumor-related genes, including CDH1, CDKN2A, hMLH1, MINT1, MINT31, MGMT, and RUNX3, by conducting a methylation-sensitive high-resolution melting analysis. CIMP was defined as ≥3/7 methylated markers using the seven-marker CIMP panel.

Results: The mean duration after H. pylori eradication was 6.0 ± 3.1 years (range 3–13 years) in the AG group and 7.0 ± 4.5 years (3–20 years) in the GC group; thus there was no significant difference between groups. The incidence of CIMP and methylation at CDH1 (p < 0.0001), CDKN2A (p = 0.006), MINT1 (p < 0.0001), and MINT31 (p < 0.0001) genes was significantly lower in the AG group compared to the controls. H. pylori eradication was associated with a significant reduction of CDH1 (odds ratio [OR] 0.13, p = 0.02), MINT1 (OR 0.03, p = 0.002), MINT31 (OR 0.08, p = 0.006) in the AM. In contrast, no significant differences in the molecular alterations were seen in the IM between the AG and control groups. The incidence of CIMP in both the AM and IM was significantly higher in the GC group compared to the AG group (p = 0.06 and p = 0.002, respectively). The incidence of molecular alterations was significantly higher in the AM compared to the IM.

Conclusion: In the patients with ≥3 yrs' follow-up after H. pylori eradication, an alteration of molecular events (especially CpG island hypermethylation) in the AM but not the IM may be an important factor in the reduction of GC incidence. In addition, CIMP in the AM and IM may be a surrogate marker of gastric cancer.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP246 CLINICAL CHARACTERISTICS OF HELICOBACTER PYLORI NAÏVE NON-CARDIAC GASTRIC ADENOCARCINOMA

S. Suzuki 1 , N. Uedo 1 , M. Arao 1 , T. Iwatsubo 1 , H. Nakahira 1 , M. Kato 1 , Y. Tounai 1 , K. Hamada 1 , Y. Yamasaki 1 , N. Matsuura 1 , S. Sichijo 1 , T. Kanesaka 1 , S. Yamamoto 1 , T. Akasaka 1 , N. Hanaoka 1 , Y. Takeuchi 1 , K. Higashino 1 , R. Ishihara 1 , Y. Tomita 2 , H. Iishi 1

1 Gastrointestinal Oncology, Osaka International Cancer Institute, Osaka/Japan

2 Department Of Pathology, Osaka International Cancer Institute, Osaka/Japan

Contact E-mail Address: syo_suzuki@med.miyazaki-u.ac.jp

Introduction: Helicobacter pylori ( H. pylori ) infection is strongly associated with development of non-cardiac gastric cancer, and gastric adenocarcinoma occurred in patients naïve to H. pylori infection is very rare. In this study, we investigated the clinical characteristics of non-cardiac gastric adenocarcinoma that developed in H. pylori uninfected patients who underwent endoscopic resection.

Aims & Methods: A total of 2221 gastric neoplasia in 1707 patients that were removed by ESD or EMR between January 2010 and May 2016 at our hospital were included. Patients were excluded if they were not evaluated H. pylori infection status, and were diagnosed with tumors other than adenocarcinoma. H. pylori uninfection was defined as condition that fulfilled all following criteria: 1) negative result from at least one of the H. pylori test: serum antibodies (<3U/ml), urea breath test and stool antigen tests, 2) no endoscopic finding of gastric mucosal atrophy, and 3) no histological finding of grandular atrophy and intestinal metaplasias in the surrounding mucosa of the resected specimen. Clinical characteristics including age, sex, tumor location, size, macroscopic type, histological type, and depth, presence of ulceration and curative resection rate were compared between H. pylori -uninfected and –infected gastric adenocarcinoma. For differentiated type adenocarcinoma in the uninfected group, mucin phenotype was compared between the lesions in the infected group that were matched by age, sex, tumor location and size. Mucin phenotype was classified into gastric (G-), intestinal (I-), and gastrointestinal (GI-) types according to immunohistological staining with MUC5AC, MUC6, CD10 and MUC2.

Results: Finally, 1, 430 non-cardiac gastric adenocarcinoma in 1111 patients were analyzed in this study. 18 (1.3%) out of 1430 lesions were diagnosed as H. pylori uninfected gastric adenocarcinoma. Mean age of patients with H. pylori uninfected gastric adenocarcinoma was significantly younger than that of those with H. pylori infected gastric adenocarcinoma (63 vs. 70 years old, p < 0.001). Undifferentiated type was more frequent in the H. pylori uninfected gastric adenocarcinoma (44%) than in the H. pylori infected gastric adenocarcinoma (5.8%). Among 10 differentiated type H. pylori uninfected gastric adenocarcinoma, 70% (7/10) located in upper third of the stomach, while 51% (675/1330) of differentiated type H. pylori infected gastric adenocarcinoma located in the lower third (p < 0.05). There was no statistical difference for other variables. Of the 10 differentiated type H. pylori uninfected gastric adenocarcinoma, 5 (50%) were G-type and 5 (50%) were GI-type lesions. Of the 30 matched differentiated type H. pylori infected gastric adenocarcinoma, G-type lesions, were only 2 (6.7%, p < 0.05) and 26 (86.7%) were GI-type and 2 (6.7%) were I-type, respectively.

Conclusion: The prevalence of H. pylori uninfected gastric adenocarcinoma was low (1.3%). H. pylori uninfected gastric adenocarcinoma has different characteristics from infected gastric adenocarcinoma in terms of histological type, location of the tumor and mucin phenotype. It is important to bear these differences in mind when we make diagnosis of early gastric cancer in H. pylori uninfected patients.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP247 EPIGENETIC SILENCING OF AN AUTOPHAGY GENE BY HELICOBACTER PYLORI FACILITATES CARCINOGENIC TRANSFORMATION OF GASTRIC EPITHELIAL CELLS

J. Sualeh Muhammad 1 , S. Nanjo 2 , T. Ando 2 , S. Yamashita 3 , T. Ushijima 3 , T. Sugiyama 2

1 Biological And Biomedical Sciences, The Aga Khan University, Karachi/Pakistan

2 University of Toyama, Toyama/Japan

3 National Cancer Center Research Institute, Tokyo/Japan

Contact E-mail Address: dr.jibran@live.com

Introduction: Helicobacter pylori ( H. pylori ) infection is known to induce epigenetic silencing, that is DNA methylation of the promoter region of various genes, leading to silencing of those genes. Impairment of autophagy via methylation silencing induces DNA damage leading to genetic instability and carcinogenesis. For the first time in this study, we aimed to identify the role of H. pylori infection in inducing DNA methylation and silencing of host autophagy-related (Atg) genes. Further, it was evaluated whether silencing of specific autophagy gene will lead to impairment of autophagy leading to promotion of gastric carcinogenesis.

Aims & Methods: We obtained gastric mucosae from 41 gastric cancer patients and from 11 healthy volunteers (8 H. pylori -uninfected and 3 H. pylori -infected). Methylation microarray and quantitative methylation-specific polymerase chain reaction (qMSP-PCR) were used to assess the methylation statuses of 34 Atg genes. Further, quantitative reverse transcription PCR (qRT-PCR) was used to analyze mRNA expression of specific Atg genes. De-methylation assay was performed using an enzyme, 5Aza-dC. Later, gene knock-down was performed by siRNA transfection. To assess tumorigenic properties, cell proliferation, migration, and invasion assays were performed using normal rat gastric epithelial cells. Western blotting of LC3 was performed to assess autophagy.

Results: We found that MAP1LC3A variant 1 (MAP1LC3Av1) and ULK2 were specifically methylated in H. pylori -infected mucosae and gastric cancer tissues, identified by methylation microarray analysis. Data from qMSP, qRT-PCR, and de-methylation assay confirmed methylation silencing of MAP1LC3Av1 in two gastric cancer cell lines. Knock-down of MAP1LC3Av1 from rat normal gastric epithelial cells, which were deprived of serum, showed inhibition of autophagy, an increased cell proliferation, increased cell migration, and increased cell invasion. Furthermore, analyses of human gastric tissue sample showed that MAP1LC3Av1 was methylated and silenced in 23.3% of gastric cancerous mucosae and 40% of non-cancerous mucosae with H. pylori infection.

Conclusion: MAP1LC3Av1 is an essential gene for normal function of autophagy and H. pylori -induced methylation silencing of MAP1LC3Av1 impairs autophagy, promoting a carcinogenic transformation of gastric mucosa. Results of this study highlight how H. pylori -associated epigenetic changes in infected host cells, such as methylation silencing of Atg genes, are likely to play a significant role in gastric cancer development and the progression of the precancerous cascade. Therefore, in future chemoprevention may be achieved against H. pylori -associated gastric cancer with by using de-methylating agents.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP248 THE EPITHELIAL-MESENCHYMAL TRANSITION PROCESS OF NORMAL EPITHELIUM INFECTED BY HELICOBACTER PYLORI . ROLE OF FIBROBLASTS AND CANCER-ASSOCIATED PROTEINS

G. Krzysiek-Maczka , A. Ptak-Belowska, A. Targosz, M. Strzalka, U. Szczyrk, T. Brzozowski

Physiology, Jagiellonian University Medical College, Cracow/Poland

Contact E-mail Address: gracjana.krzysiek-maczka@uj.edu.pl

Introduction: Major human gastrointestinal pathogen Helicobacter pylori (Hp) colonizes the gastric mucosa causing inflammation and severe complications including gastroduodenal ulcers, MALT lymphoma, or even cancer but the role of fibroblasts in the pathogenesis of Hp in the stomach has been little studied. Normal stroma contains few fibroblasts, especially myofibroblasts, but their number rapidly increases in the reactive stroma surrounding inflammatory region and neoplastic tissue. The interaction between Hp and fibroblasts and the contribution of Hp-infected fibroblasts to the epithelial-mesenchymal transition (EMT) process of gastric epithelium in Hp-infected mucosa has been little explored.

Aims & Methods: We determined the effect of co-incubation of cultured rat gastric fibroblasts with alive Hp strain expressing cagA+, vacA+ compared with Hp (cagA-, vacA-) strain on the transdifferentiation of fibroblasts into myofibroblasts associated with Hp-induced inflammation and neoplasia. We also attempted to examine whether differentiated fibroblasts possess characteristics of cancer associated fibroblasts (CAF) able to induce epithelial mesenchymal transition (EMT) of normal rat gastric epithelial cells (RGM-1 cell line). Gastric mucosal samples were harvested from 8-week-old Spraque-Dowley rats and cultured to obtain the sub-confluent fibroblasts. The isolated fibroblasts were infected with 1 × 10 9 per dish of live Hp (ATCC 700824, cagA+, vacA+) or for comparison, with Hp (cagA-, vacA-) and incubated in humidified atmosphere for 3 h, 24 h and 48 h. At respective times, Hp (cagA+ vacA+) increased mRNA expression of α-SMA, collagen I, HSP-70 and Hif1α. After co-incubation with live Hp, fibroblasts were harvested for determination of the protein expression for α-SMA and HSP-70, by Western Blot analysis.

Results: We found that fibroblasts co-cultured with Hp (cagA+, vacA+) strongly upregulated protein expression α-SMA and HSP-70. In clear contrast, the co-incubation with Hp (cagA- vacA-) failed to significantly alter the expression of mRNA for α-SMA, collagen I, HSP-70 and Hif1α. The extension of the time of incubation of fibroblasts with selected Hp (cagA+ vacA+) strain up to 72 h revealed a strong signals for the mRNA expression of CAFs markers including α-SMA, FAP, Fsp, SDF, IL-6, IL-8, HGF, THFβ, collagen I and III and tenascin C. Interestingly, after insert co-culture of differentiated fibroblasts with RGM-1 cells from 24 h up to 96 h, the E-cadherin mRNA expression was significantly decreased starting from 48 h. The parallel increase in the expression of Twist and Snail mRNAs was observed already after 24 h, along with the overexpression of TGFβRII, HGFR and FGFR mRNA. The increased expression of mRNA for N-cadherin, vimentin, α-SMA, Fsp, Fap VEGF and integrin β1 has been observed in RGM1 cells after insert of co-culture of differentiated fibroblasts.

Conclusion: We conclude that 1) the Hp strain encoding for cagA+ vacA+ cytotoxins, but not Hp strain (cagA-vacA-) increased the differentiation of fibroblasts into myofibroblasts mediated by an overexpression of HSP-70 protein, and 2) Hp strain expressing cagA+, vacA+ may induce the differentiation of fibroblasts associated with expression of CAFs markers, likely to initiate at least, partial EMT process in RGM-1 cell line with insert co-culture.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP249 HELICOBACTER PYLORI INFECTION IS AN INDEPENDENT RISK FACTOR OF EARLY AND ADVANCED COLORECTAL NEOPLASM

S.J. Lee , S.H. Kim, T.J. Kim, E.R. Kim, S.N. Hong, D.K. Chang, Y.H. Kim

Internal Medicine, Samsung Medical Center, Seoul/Korea, Republic of

Contact E-mail Address: puhaha78677867@gmail.com

Introduction: The role of Helicobacter pylori ( H. pylori ) in the development of colorectal neoplasm remains controversial. We examined the association between H. pylori infection and colorectal neoplasm in a large sample of healthy participants who underwent screening colonoscopy.

Aims & Methods: A cross-sectional study of 8916 men, who participated in a regular health screening examination that included an H. pylori -specific immunoglobulin G antibody test and colonoscopy, was conducted to evaluate the association between H. pylori and colorectal neoplasm.

Results: Multivariable analyses adjusted for age, body mass index, smoking status, alcohol intake, regular exercise, regular aspirin use, and family history of colorectal cancer showed that the odds ratio (OR) [95% confidence interval (CI)] for any adenoma and advanced neoplasm was 1.32 (1.07–1.61) and 1.90 (1.05–3.56) in participants with H. pylori infection and without H. pylori infection, respectively. The association persisted after further adjustment for inflammatory markers or metabolic variables including fasting blood glucose, triglycerides, high-density lipoprotein-cholesterol, and low-density lipoprotein-cholesterol. Regarding the location, a positive association was confined to cases with proximal adenomas, and was observed similarly in all the evaluated subgroups.

Conclusion: In a large-scale study, carefully controlled for confounding factors, involving asymptomatic participants without a history of colonoscopy, H. pylori infection was significantly associated with the risk of any colorectal adenoma and advanced colorectal neoplasm. Prospective studies are necessary to determine whether H. pylori eradication can reduce this risk.

Disclosure of Interest: All authors have declared no conflicts of interest.

References

1. Everhart JE. Recent developments in the epidemiology of Helicobacter pylori. Gastroenterol Clin North Am 2000;29:559–78.

2. Ernst PB, Peura DA, Crowe SE. The translation of Helicobacter pylori basic research to patient care. Gastroenterology 2006;130:188–206; quiz 12–3.

3. Suerbaum S, Michetti P. Helicobacter pylori infection. N Engl J Med 2002;347:1175–86.

4. Goni E, Franceschi F. Helicobacter pylori and extragastric diseases. Helicobacter 2016;21 Suppl 1:45–8.

5. Edwards BK, Ward E, Kohler BA, Eheman C, Zauber AG, Anderson RN, Jemal A, Schymura MJ, Lansdorp-Vogelaar I, Seeff LC, van Ballegooijen M, Goede SL, Ries LA. Annual report to the nation on the status of cancer, 1975–2006, featuring colorectal cancer trends and impact of interventions (risk factors, screening, and treatment) to reduce future rates. Cancer 2010;116:544–73.

6. Haggar FA, Boushey RP. Colorectal cancer epidemiology: incidence, mortality, survival, and risk factors. Clin Colon Rectal Surg 2009;22:191–7.

7. Stegeman I, de Wijkerslooth TR, Stoop EM, van Leerdam ME, Dekker E, van Ballegooijen M, Kuipers EJ, Fockens P, Kraaijenhagen RA, Bossuyt PM. Colorectal cancer risk factors in the detection of advanced adenoma and colorectal cancer. Cancer Epidemiol 2013;37:278–83.

8. Inoue I, Mukoubayashi C, Yoshimura N, Niwa T, Deguchi H, Watanabe M, Enomoto S, Maekita T, Ueda K, Iguchi M, Yanaoka K, Tamai H, Arii K, Oka M, Fujishiro M, Takeshita T, Iwane M, Mohara O, Ichinose M. Elevated risk of colorectal adenoma with Helicobacter pylori-related chronic gastritis: a population-based case-control study. Int J Cancer 2011;129:2704–11.

9. Zhang Y, Hoffmeister M, Weck MN, Chang-Claude J, Brenner H. Helicobacter pylori infection and colorectal cancer risk: evidence from a large population-based case-control study in Germany. Am J Epidemiol 2012;175:441–50.

10. Chen YS, Xu SX, Ding YB, Huang XE, Deng B. Helicobacter pylori Infection and the risk of colorectal adenoma and adenocarcinoma: an updated meta-analysis of different testing methods. Asian Pac J Cancer Prev 2013;14:7613–9.

OP250 HELICOBACTER PYLORI INFECTION ALLEVIATES THE ALLERGIC SYMPTOMS OF ATOPIC DERMATITIS IN A MOUSE MODEL VIA GENERATION OF CD4 + CD25 + FOXP3 + T CELLS

Q. Xue 1 , W. J. Tong 2 , X. Li 2

1 Gastroenterology, Peking University People's Hospital, Beijing/China

2 Gerontology, Peking university people's hospital, Beijing/China

Contact E-mail Address: xueqian0719@163.com

Introduction: Increasing attention was paid to the protective function of Helicobacter pylori ( H.pylori ) on some allergic diseases. Epidemiological studies showed that there was an inverse relationship between H.pylori infection and allergic diseases including asthma, allergic rhinitis, food allergy. Atopic dermatitis (AD) is a kind of chronic inflammatory skin disease associated with allergy and inheritance tendency. The clinical manifestations include pruritis, xerosis and eczematous dermatitis, which affecting the quality of life seriously. The atopic dermatitis is usually accompanied with asthma and allergic rhinitis. Whether H.pylori infection had the similar protective effect on AD was unknown. The aim of this study was to evaluate the association between H.pylori infection and AD, and explore the mechanism.

Aims & Methods: The C57BL/6 mice models of H. pylori infection & AD was induced by epicutaneous sensitization with calcipotriol after infection with H. pylori by gavage. The CD4 + CD25 + Foxp3 + Tregs cells in blood, spleen and mesenteric lymph nodes (MLN) were analysed by flow cytometry. The expression of Foxp3 + in dermal tissues was detected by immunohistochemistry. The anti- and pro-inflammatory cytokines were also investigated at mRNA level by real-time PCR in dermal tissue. The CCR4 + CD4 + CD25 + Foxp3 + Tregs cells in gastric lymph nodes, MLN, blood, spleen and cervical lymph nodes were measured by flow cytometry.

Results: Compared with H. pylori negative & AD group, the degree of skin lesions such as hyperemia, scale, erythema and ear swelling were lower in the H. pylori infection & AD group; the Serum IgE levels decreased significantly in H. pylori infection & AD group (2730.00 ± 1076.98 IU/ml vs 4922.22 ± 1275.00 IU/ml, P = 0.002). The percentages of CD4 + CD25 + Foxp3 + Tregs cells in peripheral blood and the numbers of Foxp3 + cells per HPF in dermal tissue increased significantly in H.pylori infection & AD groups (P = 0.016, P = 0.018). IL-10 and TGF-β mRNA relative expression upregulated (P = 0.034; P = 0.004), and IL-4 mRNA relative expression downregulated (P = 0.023) in dermal issue in H. pylori infection & AD groups. CCR4 is an important skin-homing marker. We found H. pylori infection and atopic dermatitis could induce CCR4 + CD4 + CD25 + Foxp3 + Tregs expansion in gastric lymph nodes, spleen, blood, MLN and cervical lymph nodes synchronously by time.

Conclusion: H. pylori infection could alleviate AD symptom by inducing the amplification of CD4 + CD25 + Foxp3 + Tregs cells in peripheral blood, and did increase the expression of IL-10, TGF-β and inhibite the expression of IL-4 in dermal tissue. Atopic dermatitis may chemoattracte CCR4 + Tregs cells migrating to the skin.

Disclosure of Interest: All authors have declared no conflicts of interest.

TUESDAY, OCTOBER 31, 201714:00-15:30

PANCREATIC CANCER: RISK FACTORS AND SCREENING - ROOM E3____________________

OP251 INCREASING MORTALITY FROM PANCREATIC CANCER IN PORTUGAL – AN EPIDEMIOLOGICAL ANALYSIS OF 25 YEARS

P. Marques Da Costa 1 , R.T. Marinho 2 , H. Cortez-Pinto 1 , L. Costa 3 , J. Velosa 1

1 Gastroenterology And Hepatology Department, Hospital de Santa Maria, Lisboa/Portugal

2 Gastroenterology Clinic, Faculdade de Medicina, Universidade de Lisboa, Lisboa/Portugal

3 Oncology Department, Hospital de Santa Maria, Lisboa/Portugal

Contact E-mail Address: pedroavmcosta@gmail.com

Introduction: Pancreatic cancer is the 5 th leading cause of death by cancer in Europe. With a mortality that mostly overlaps its incidence, this cancer type is predicted to become increasingly prevalent as a result of population aging and high prevalence of known risk factors (e.g. smoking, alcohol, obesity).

Aims & Methods: We aimed at describing the mortality trends through the past 25 years in the Portuguese population (around 10.3 million habitants). For this purpose, we analysed the data published by the Portuguese National Statistical Institute, regarding the cause of death attributed to malignant pancreatic neoplasia (ICD10-C25; ICD9/8 -157) from 1991 to 2015. Data were further sub analysed by sex, age, and geographic area. Crude mortality rates (MR) represent deaths per 100.000 habitants. Age-standardised rates (ASR) were calculated using the revised (2013) standard European population. Logistic regression with jointpoint analysis was used to predict expected mortality rates by 2030.

Results: A total of 25,449 deaths from malignant pancreatic neoplasia were recorded between 1991 (n = 701) and 2015 (n = 1415). The number of deaths displayed an average annual percent change (AAPC) of 2.8 (CI:2.6–3.1, p < 0.0001). Overall, crude MR demonstrated an exponential growth (AAPC = 2.7 CI:2.3–3.0; p < 0.001) between 1991 (MR = 7.5) and 2015 (MR = 13.68). A higher annual percent change (APC) was recorded from 2006–2015 (APC = 3.8 CI:3.0–4.6); in relation to 1991–2006 (APC = 2.0 CI:1.5–2.4). As for ASR, a 29.5% increase was observed from 1991 (ASR = 6.1) to 2015 (ASR = 7.9). Assuming growth trends remain similar through the next 15 years, mortality from pancreatic cancer is predicted to reach 2131 annual deaths by 2030, corresponding to a 35.5% increase. Virtually all deaths (99%) occurred in patients over the age of forty. People aged 70–74 exhibited the highest ASR (ASR 70–74 = 1.09). ASR increased equally among all age groups. Male patients showed a higher mean ASR when compared to females (9.49 ± 3.2 vs 5.18 ± 0.4 p < 0, 001). They also displayed an ASR growth rate that was approximately 5 times higher than females (AAPC male = 4.5 CI:3.9–5.1 Vs AAPC female = 0.9 CI:0.6–1.2, p < 0.001). Regional differences were observed: the two provinces of Alentejo (ASR = 12.8 ± 2.9) and Azores archipelago (ASR = 17.05 ± 3.0) demonstrated significantly higher ASR.

Conclusion: In Portugal, pancreatic cancer mortality increased 29% throughout the past 25 years. This seems unrelated to population aging and may reflect an impressive rise in incidence. Sex and regional differences were noted with male patients and habitants living in Alentejo and Azores provinces exhibiting significantly higher mortality from pancreatic cancer.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP252 ADHERENCE TO FOOD GUIDELINES OF THE WORLD CANCER RESEARCH FUND & AMERICAN INSTITUTE FOR CANCER RESEARCH AND PANCREATIC CANCER RISK

J. Fest 1 , R. Ruiter 2 , M. A. Ikram 2 , C. H.j. Van Eijck 1 , J. C. Kiefte-De Jong 3 , B. H. Stricker 2

1 Surgery, Erasmus Medical Centre, Rotterdam, Rotterdam/Netherlands

2 Epidemiology, Erasmus Medical Centre, Rotterdam/Netherlands

3 Global Public Health, Leiden University College The Hague, Rotterdam/Netherlands

Contact E-mail Address: j.fest@erasmusmc.nl

Introduction: Pancreatic cancer is one of the most lethal cancers, it has an increasing incidence and limited treatment options. Prevention of this cancer might be the key in lowering the burden of this disease. Two well-known modifiable risk factors are smoking and BMI. For other lifestyle factors, such as diet, there is limited or inconsistent evidence for the association with pancreatic cancer. The World Cancer Research Fund (WCRF) and American Institute for Cancer Research (AICR) have developed guidelines for the prevention of cancer in general. It is known that adherence to these guidelines results in a lower risk of colorectal and breast cancer, however to what extend this applies to pancreatic cancer is unknown.

Aims & Methods: The aim of this study was to assess whether adherence to the WCRF & AICR guidelines is associated with a lower risk of pancreatic cancer. This study was embedded in the Rotterdam Study, a longstanding, prospective and population-based cohort study. Data on dietary intake were collected at baseline, through a frequent food questionnaire and interview by a dietician. We constructed an adherence score, based on the WCRF/AICR recommendations on weight management, foods and drinks that promote weight gain, plant and animal foods, alcoholic drinks, and use of dietary supplements. A higher score corresponds with greater adherence and an hypothesised lower risk of pancreatic cancer. We used Cox Proportional Hazard Models to estimate the association between the adherence score and pancreatic cancer risk.

Results: For 9778 (65.5%) participants dietary data was available. During a median follow-up time of 11.9 years, 77 patients developed pancreatic cancer. Adherence to the WCRF/AICR recommendations was analysed continuously and after stratification into quartiles. Greater adherence was associated with a reduced risk of pancreatic cancer, however not significantly (HR continuously : 0.82, 95%CI: 0.64–1.04). Stratified analysis showed a significant effect for the third quartile (HR: 0.44, 95%CI: 0.22–0.88) with a P -value for trend over the quartiles of 0.028. This effect persisted after excluding all participants with less than two years of follow-up, ensuring the effect was not due to yet undetected disease. Further analysis of the separate recommendations showed that the overall effect was driven by refraining from taking dietary supplements (HR: 0.54, 95% CI: 0.34–0.84).

Conclusion: Greater adherence to the World Cancer Research Fund and American Institute for Cancer Research guidelines for diet and lifestyle might be associated with lower risk of pancreatic cancer. Promoting these recommendations to the general population could help reduce pancreatic cancer incidence. However definitive results should follow from pooled analyses of multiple, large and longstanding prospective cohorts to secure more power.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP253 SURVEILLANCE FOR PANCREATIC CANCER IN HIGH-RISK INDIVIDUALS: FIRST-ROUND SCREENING RESULTS OF A MULTICENTRIC ITALIAN PROGRAM

S. Paiella 1 , G. Capurso 2 , G. Butturini 3 , R. Pezzilli 4 , S. Carrara 5 , M. Falconi 6 , M. Signoretti 2 , M. Di Leo 5 , I. Frigerio 3 , C. Bassi 1 , A. Zerbi 7

1 General And Pancreatic Surgery Department, Pancreas Institute, University of Verona, Verona/Italy

2 Digestive & Liver Disease Unit, Ii, Medical School Univesity “Sapienza”, S. Andrea Hospital, Rome/Italy

3 Hpb Unit, Clinica Pederzoli spa, Peschiera del Garda/Italy

4 Sant'orsola Malpighi Hospital, Pancreatic Unit, Bologna/Italy

5 Department Of Gastroenterology, Humanitas Research Hospital, Endoscopic Unit, Rozzano/Italy

6 San Raffaele University Hospital, Pancreatic Surgery Department, Milan/Italy

7 Humanitas Research Hospital, Pancreatic Surgery Department, Rozzano/Italy

Contact E-mail Address: salvatore.paiella@univr.it

Introduction: The early diagnosis of cancer can help reduce mortality. Surveillance programs on high-risk individuals (HRI) proved to be able to detect premalignant lesions or early pancreatic adenocarcinoma (PDAC). Currently, surveillance programmes on HRI are based on findings from endoultrasonography and/or MRI. These imaging techniques proved to be able to diagnose malignant or pre-malignant both on syndromic and familiar cases. The aim of our study was to provide the first registry-based Italian experience on HRI enrolled in a surveillance program for pancreatic cancer.

Aims & Methods: The multicentric surveillance program includes: individuals with familial pancreatic cancer (FPC) defined as those with 3 first-, second- or third-degree relatives with PDAC or individuals with 2 relatives with PDAC with at least 1 first-degree relative; BRCA 1/2 or p16 mutation carriers with at least 1 first- or second-degree relative diagnosed with PDAC; subjects suffering from hereditary pancreatitis or Peutz-Jegher syndrome. The surveillance program consists of an annual magnetic resonance cholangiopancreatography (MRCP).

Results: Seventy-eight subjects were enrolled from September 2015 to February 2017, by six high-volume pancreatic Institutions. The mean age was 50 years (range 26–79). Sixty-seven (86%) subjects had FPC, 9 were syndromic HRI (11.5%) and 2 (2.5%) subjects suffered from hereditary pancreatitis. MRCP detected pancreatic cysts in 14 HRI (17.9%, 12 FPC- and 2 syndromic-HRI) and features of chronic pancreatitis in 2 (2.5%). Twelve branch duct-IPMNs (mean diameter 9 mm, range 3–16) and 1 serous cystadenoma were identified. Of note, a patient with a MD-IPMN with high-grade dysplasia (Figure) has been considered for surgical resection. Two suspected solid lesions were identified at MRCP, not further confirmed at endoultrasonography.

Conclusion: At the time of the first-round screening program in Italy, the rate of diagnosed malignant or pre-malignant lesions on HRI is lower than expected. MRCP diagnosed pancreatic cystic neoplasms in 17.9% of subjects. This might be due to the low rate of syndromic HRI and/or to a low mean age compared to other series and/or to the less strict criteria of definition of FPC. The diagnostic yield for lesions with an indication for surgery is currently 1.2%.

Disclosure of Interest: All authors have declared no conflicts of interest.

References

Canto MI, International Cancer of the Pancreas Screening (CAPS) Consortium summit on the management of patients with increased risk for familial pancreatic cancer, GUT 2013. Bartsch D, Refinement of screening for familial pancreatic cancer, GUT 2016.

OP254 THE ROLE OF CYSTIC PRECURSOR LESIONS IN THE DEVELOPMENT OF PANCREATIC DUCTAL ADENOCARCINOMA IN CDKN2A-P16-LEIDEN MUTATION CARRIERS

I. Ibrahim 1 , M. Wasser 2 , Y. Wu 3 , A. Inderson 1 , W. De Vos Tot Nederveen Cappel 4 , H. Morreau 2 , F. Hes 2 , R.A. Veenendaal 1 , H. Putter 2 , S. Feshtali 2 , A. Van Mil 2 , N. Gruis 2 , R. Tollenaar 5 , W. Bergman 2 , B. Bonsing 2 , H. Vasen 1

1 Gastroenterology, Leiden University Medical Center, Leiden/Netherlands

2 Leiden University Medical Center, Leiden/Netherlands

3 West Suffolk Hospital, Bury St. Edmunds/United Kingdom

4 Isala Clinics, Zwolle/Netherlands

5 Surgical Oncology, Leiden University Medical Centre, Leiden, Netherlands, Leiden/Netherlands

Contact E-mail Address: isaura_ibrahim@hotmail.com

Introduction: CDKN2A-p16-Leiden mutation carriers have a 15–20% risk of developing pancreatic ductal adenocarcinoma (PDAC). Surveillance of these carriers increased the survival but did not prevent all cancer deaths. Understanding of the natural course of PDAC might further improve the surveillance program.

Aims & Methods: The aim of the study was to evaluate the role of cystic precursor lesions (PRL) and the growth rate of PDAC. Since 2000, a large cohort of CDKN2A-p16-Leiden mutation carriers has participated in the annual MRI-surveillance program. We compared the frequency of cystic PRL in this group with that of controls who underwent MRI-scanning for symptoms of liver-biliary tract disorders. We also evaluated whether cystic PRL increase in size and develop into PDAC. Finally, we calculated the growth rate of screen-detected PDAC.

Results: Cystic PRL were found in 52 (25%) of 205 mutation carriers compared to 19 (19%) of 100 controls (P = 0.22). Growth of PRL was observed in six mutation carriers (12%). Five (9.7%) of 52 mutation carriers with PRL and eight (7.0%) of 114 mutation carriers without PRL developed PDAC (P = 0.56). The growth rate of PDAC was 21 mm per year. A reduction of the surveillance interval to 6 months would increase the detection of early tumors from 58% to 92%.

Conclusion: Cystic PRL play a minor role in the development of PDAC in CDKN2A-p16-Leiden mutation carriers. More intensive surveillance is only recommended for patients with large cystic PRL. Independent of the presence of cystic PRL, the surveillance interval may be reduced to 6 months, if studies show this approach to be cost-effective.

Disclosure of Interest: All authors have declared no conflicts of interest.

References

1. Goldstein AM, Fraser MC, Struewing JP, et al. Increased risk of pancreatic cancer in melanoma-prone kindreds with p16INK4 mutations. N Engl J Med 1995; 333:970–4.

2. Vasen HF, Gruis NA, Frants RR, et al. Risk of developing pancreatic cancer in families with familial atypical multiple mole melanoma associated with a specific 19 deletion of p16 (p16-Leiden). Int J Cancer 2000;87:809–11.

3. Hruban RH, Adsay NV, Albores-Saavedra J, et al. Pancreatic intraepithelial neoplasia: a new nomenclature and classification system for pancreatic duct lesions. Am J Surg Pathol 2001;25:579–86.

4. Sipos B, Frank S, Gress T, et al. Pancreatic intraepithelial neoplasia revisited and updated. Pancreatology 2009;9:45–54.

5. Tanaka M, Fernandez-del Castillo C, Adsay V, et al. International consensus guidelines 2012 for the management of IPMN and MCN of the pancreas. Pancreatology 2012;12:183–97.

6. Vasen H, Ibrahim I, Ponce CG, et al. Benefit of Surveillance for Pancreatic Cancer in High-Risk Individuals: Outcome of Long-Term Prospective Follow-Up Studies From Three European Expert Centers. J Clin Oncol 2016;34:2010–9.

7. Vasen HF, Wasser M, van Mil A, et al. Magnetic resonance imaging surveillance detects early-stage pancreatic cancer in carriers of a p16-Leiden mutation. Gastroenterology 2011;140:850–6.

OP255 CHARACTERIZATION OF GENETIC ALTERATIONS IN PANCREATIC CANCER HIGH-RISK POPULATION

G. Rosner , E. Scapa, E. Santo, M. Ben-Yehoyada

Gastroenterology, Tel-Aviv Sourasky Medical Center, Tel-Aviv/Israel

Contact E-mail Address: guyr@tlvmc.gov.il

Introduction: Pancreatic cancer (PC) is a leading cause of cancer death worldwide. Despite modern treatment, 90% of patients die within one year of diagnosis. At early stages, surgical treatment is most beneficial, however, early diagnosis is rare, and most PC cases are confirmed as being locally invasive or metastatic. Inherited predisposition to pancreatic cancer is prevalent in 10% of PC cases. These include characterized genetic conditions such as the hereditary breast and ovarian cancer syndrome (HBOC), Lynch syndrome, familial adenomatous polyposis (FAP), Peutz-Jeghers syndrome (PJS), familial atypical multiple mole melanoma syndrome (FAMMM) and hereditary pancreatitis (HP). However, about 85% of PC cases with strong family history are still uncharacterized.

Aims & Methods: We have recruited 120 high-risk PC individuals for genetic screening and clinical surveillance. Forty individuals fulfilled criteria for familial pancreatic. For all individuals, germ line DNA was extracted from whole blood and analyzed for the BRCA1 and 2 mutations. Whole Exome Sequencing (WES) technique (Illumina HiSeq platform) was used to screen families with high prevalence to PC for pathogenic germline mutations. Candidate genetic variants were analyzed for their pathogenic potential through familial genetic segregation analysis. Endoscopic ultrasound (EUS) was used to correlate the genetic findings to the clinical phenotype.

Results: We screened 10 informative families and performed segregation analysis. Out of these families we have discovered several possible pancreatic cancer candidates' point mutations in well-established as well as in unreported genes. Whole exome sequencing (WES) revealed wide variety of genetic changes in cancer related genes including KLLN, HMMR, GATA5, MSR1 and KDR genes.

Conclusion: PC development is relatively slow, making it ideal for screening of high-risk individuals. Therefore, identifying this high-risk population is crucial for better surveillance and early detection of pancreatic cancer.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP256 DETECTION OF PANCREATIC CANCER BY URINE ELECTRIC NOSE ANALYSIS, A PROOF-OF-CONCEPT STUDY, 80 CASES

S. Nissinen 1 , A. Roine 2 , L. Hokkinen 3 , T. Rantanen 4 , N. Oksala 2

1 Gastroenterology, Kuopio University Hospital, KYS/Finland

2 Surgery, Tampere University Hospital, Tampere/Finland

3 Technology, University of Tampere, Tampere/Finland

4 Surgery, Kuopio University Hospital, KYS/Finland

Contact E-mail Address: samuli.nissinen@kuh.fi

Introduction: The prognosis of early stage pancreatic cancer has improved yet there is no feasible screening tool in clinical use. Recent studies have shown that an electronic nose can detect volatile organic compounds from urine and can discriminate between cancer patients and healthy controls.

Aims & Methods: The aim of this study was to determine if pancreatic cancer can be detected non-invasively from a urine sample by an electric nose (FAIMS, Field Asymmetric Ion Mobility Spectrometer). Pancreatic cancer patients were recruited in two centers, Seinäjoki Central Hospital and Kuopio University Hospital, between January 2014 and June 2016. Cancer patients provided a urine sample at the time of the diagnosis. Controls were patients undergoing hernia reparation or cholecystectomy and were recruited in the same centers during the same time period. They provided a urine sample before their operation. 100 ml of midstream urine was stored in −70C and thawed and warmed up to room temperature for analysis in random order with FAIMS. FAIMS analyses volatile compounds released from the sample, producing an ion mobility spectrum. The resulting spectrums were analyzed by linear discriminant analysis and cross-validated by leave-one-out cross-validation (LOOCV).

Results: 80 patients with pancreatic cancer, 40 with acute pancreatitis, 16 with chronic pancreatitis and 14 patients with suspected pancreatic lesion and 44 controls were recruited. The mean age of the pancreatic cancer patients was 70. 49% were females, 29% had stage IB-IIB, 71% stage III-IV cancer and 26% underwent the Whipple procedure or radical pancreatectomy. Patients who died had 16.9 months mean survival time and the mean follow-up time for survivers was 57 months (25–87 months). FAIMS signal data was identified to detect differences between cancer and control samples. The test detected pancreatic cancer with 81% sensitivity and 68% specificity. We combined patients with pancreatic cancer and premalign pancreatic lesions into one group and compared it to controls. Sensitivity was 83% and specificity 63%.

Conclusion: We found that the urine of pancreatic cancer patients has distinct volatile compounds that can be detected by FAIMS, which can distinguish pancreatic cancer patients from controls. It may also be able to detect premalign pancreatic lesions. This investigation was the first to test the ability of electric nose detect pancreatic cancer from urine samples. Measurement is quick and easy to perform, its costs are low and most importantly it is non-invasive. FAIMS has potential to be a screening tool for pancreatic cancer.

Disclosure of Interest: A. Roine: Owner of Olfactomics ltd, a company that develops clinical applications of eNose technology

N. Oksala: Owner of Olfactomics ltd, a company that develops clinical applications of eNose technology

All other authors have declared no conflicts of interest.

TUESDAY, OCTOBER 31, 201714:00-15:30

CARCINOGENESIS AND TUMOUR PROGRESSION IN GI CANCER - ROOM B5____________________

OP257 HINOS PROMOTES A CD24+CD133+ LIVER CANCER STEM CELL PHENOTYPE AND TUMOR PROGRESSION THROUGH A TACE/ADAM17 DEPENDENT NOTCH SIGNALING PATHWAY

R. Wang

Department Of Gastroenterology And Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan/China

Contact E-mail Address: 1765106711@qq.com

Introduction: Hepatocellular carcinoma (HCC) is closely associated with chronic inflammation caused by viral hepatitis, alcoholic or non-alcoholic steatohepatitis, and other conditions leading to chronic inflammation and hepatocyte regeneration 1 . These long-term processes include an accumulation of genetic and/or epigenetic changes, alterations of the liver tumor microenvironment, and generation of liver cancer stem cells (LCSCs) 2 . Growing evidence supports the concept that tumor initiation can be driven by cancer stem cell (CSCs) subsets that are responsible for tumor relapse, metastasis, and chemotherapy-resistance 3 . Therefore, identification of CSC markers as well as signaling pathways activated in LCSCs could advance the development of liver cancer diagnosis and treatment strategies. The inducible nitric oxide synthase (iNOS) is associated with more aggressive solid tumors, including hepatocellular carcinoma (HCC). Notch signaling in cancer stem cells promotes cancer progression and requires Notch cleavage by ADAM (a disintegrin and metalloprotease) proteases. We hypothesized that iNOS/NO promotes Notch1 activation through ADAM17/TACE activation in liver cancer stem cells (LCSC) leading to a more aggressive cancer phenotype.

Aims & Methods: Primary human HCC were subjected to immunohistochemistry (IHC) for the expression CD24, CD133, iNOS, activated ADAM17/TACE or activated Notch. CD24 + CD133+ cells isolated from HCC cell lines or from human tumors were assessed in vitro and in vivo (Xenograft tumor model in mice) for stem-like properties and growth characteristics. Lentiviral-based short hairpin RNA (LV-shRNA) and LV-iNOS were used to knockdown or overexpress hiNOS in LCSCs, respectively. Activation of the Notch signal pathway was detected by a CSL-luciferase reporter in CD24 + CD133+ cells after iNOS overexpression, or the inhibition of iNOS (1400W) or TACE (TAPI-2). Immunoprecipitation experiments were carried to assess the interaction between TACE and iRhom2 or TACE and Notch intracellular domain (NICD). We evaluated the relationship of hiNOS and NICD with clinic-pathological features using a liver cancer tissue microarray (TMA).

Results: Expression of stem cell markers, CD24 and CD133 in the tumors of patents with HCC was associated greater iNOS expression and worse outcomes. The expression of iNOS in CD24 + CD133+ liver cancer stem cells (LCSC), but not CD23-CD133- LCSC, promoted Notch1 signaling and stem-ness characteristics in vitro and in vivo as well as accelerated HCC initiation and tumor formation in the mouse xenograft tumor model. Lentiviral-based short hairpin RNA (shRNA)-mediated iNOS knockdown or iNOS activity inhibition using BYK191023 significantly suppressed CD24 + CD133+ LCSCs stem-ness characteristics in vitro and in vivo . Furthermore, up-regulation of iNOS expression in LCSCs led to TACE and iRhom2 phosphorylation in a cyclic GMP (cGMP)/protein kinase G (PKG)-dependent manner. Immunoprecipitation experiments show that the physical binding between TACE and iRhom2 increased significantly when iNOS was overexpressed. Kaplan-Meier analysis showed that high hiNOS and NICD expression were significantly associated with aggressive behavior of HCC and decreased survival in patients.

Conclusion: These findings link iNOS to Notch1 signaling in CD24 + CD133 + LCSC through the activation of ADAM17/TACE and identify a mechanism for how iNOS contributes to progression of CD24 + CD133 + HCC.

Disclosure of Interest: All authors have declared no conflicts of interest.

References

1. Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell 2010;140:883–99.

2. Magee JA, Piskounova E, Morrison SJ. Cancer stem cells: impact, heterogeneity, and uncertainty. Cancer Cell 2012;21:283–96.

3. Ishizawa K, Rasheed ZA, Karisch R, et al. Tumor-initiating cells are rare in many human tumors. Cell Stem Cell 2010;7:279–82.

OP258 AUTOPHAGY INHIBITS PROTUMORAL EFFECTS INDUCED BY COLIBACTIN-PRODUCING COLORECTAL CANCER-ASSOCIATED ESCHERICHIA COLI

C. Lucas 1 , G. Dalmasso 1 , M. Bonnet 1 , P. Sauvanet 1 , D. Pezet 1 , N. Barnich 1 , P. Rosenstiel 2 , R. Bonnet 3 , H. T.T. Nguyen 1

1 Université Clermont Auvergne, Inserm U1071, INRA USC2018, M2iSH, Clermont-Ferrand/France

2 Institute Of Clinical Molecular Biology, University of Kiel, Kiel/Germany

3 Laboratoire Bacteriologie, CHU Hopital G. Montpied, Clermont-Ferrand/France

Contact E-mail Address: cecily.lucas@uca.fr

Introduction: The mucosa of patients with colorectal cancer (CRC) is abnormally colonized by Escherichia coli strains, which frequently harbor the pathogenic pks genomic island responsible for the synthesis of the genotoxin colibactin. Colibactin-producing E. coli induce DNA damage and enhance tumorigenesis in CRC mouse models. Autophagy, cellular process allowing the degradation of cytoplasmic contents via the lysosomal pathway, plays a crucial role in the maintenance of homeostasis and is implicated in various human diseases including cancer.

Aims & Methods: This study aimed at investigating the role of autophagy in host responses to infection with the CRC-associated E. coli strains. mRNA expression levels of autophagy genes in the colonic mucosal biopsies from CRC patients were determined by qRT-PCR. Autophagy induction was assessed by Western blot and immunofluorescent labelling of LC3. DNA damage was assessed by Western blot analysis and immunofluorescent labelling of phospho-H2AX. Recruitment of the DNA repair protein RAD51 into the nucleus, which is required for DNA damage repair, was examined by Western blot analysis of nuclear extract and immunofluorescent staining. Intestinal epithelial HCT116 cells, APC Min/+ mice deficient for Atg16l1 in intestinal epithelial cells (APC Min/+ /ATG16L1 ΔIEC ) and the control mice (APC Min/+ /ATG16L1 f/f ) were infected with the pks-harboring E. coli strains (pks+ E. coli ).

Results: mRNA expression levels of many autophagy genes were increased in the tumors compared to the adjacent mucosa from CRC patients. In particular, their expression was higher in the mucosa colonized with pks+ E. coli compared with those colonized with E. coli strains without pks island (pks- E. coli ). Infection of HCT116 cells with the pks+ E. coli strains resulted in autophagy activation, and this was dependent on the presence of the pks island. Using autophagy-deficient HCT116 cells infected with the pks + E. coli reference strain 11G5 or its isogenic mutant defective for pks, we showed that autophagy was required to decrease colibactin-induced DNA damage by recruiting RAD51 into the nucleus and thereby activating the DNA damage repair. Autophagy deficiency increased colonic tumorigenesis induced by infection with the pks+ E. coli 11G5 strain in APC Min/+ mice.

Conclusion: Autophagy is induced in intestinal epithelial cells infected with the CRC-associated pks+ E. coli strains, and a functional autophagy is necessary to limit the protumoral effects of pks+ E. coli on infected cells.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP259 INTERPLAY BETWEEN CD80 SIGNALLING AND MISMATCH REPAIR GENES EXPRESSION IN THE EARLY STAGES OF COLONIC CARCINOGENESIS

A. Kotsafti 1 , M. Scarpa 1 , M. Fassan 2 , S. Morgan 3 , A. Porzionato 4 , C. Marchiori 5 , P. Brun 4 , I. Angriman 6 , M. Rugge 7 , C. Castoro 8 , I. Castagliuolo 2 , M. Scarpa 1

1 Esophageal And Digestive Tract Surgical Unit, Regional Centre For Esophageal Disease, Veneto Institute of Oncology (IOV-IRCCS), Padova/Italy

2 University of Padova, Padova/Italy

3 Barnsley Hospital NHS Foundation Trust, Barnsley/United Kingdom

4 Dept. Of Molecular Medicine, University of Padova Dept. of Molecular Medicine, Padova/Italy

5 Department Of Molecular Medicine, University of Padua, Padova/Italy

6 Dept. Of General Surgery, University of Padova, Padova/Italy

7 Pathology, Medical School of the Padova University, Padova/Italy

8 Venesto Institute of Oncology, Padova/Italy

Contact E-mail Address: andromachi.kotsafti@iov.veneto.it

Introduction: Several studies and meta-analysis demonstrated that patients with mismatch repair (MMR) genes deficient colorectal cancer (CRC) have a more favourable stage-adjusted prognosis. A possible mechanism is that in tumor with MMR defects T-cells, macrophages, and natural killers, infiltration might be increased enhancing immune surveillance mechanisms [1]. In fact, a higher density of tumor infiltrating lymphocytes was associated with better disease free survival in cases with defective versus intact MMR [2, 3]. CRC with MMR genes deficiency showed a higher CD80 expression, and in vitro silencing of MSH2, MLH1 and MSH6 significantly increased CD80+ cell rate [4]. However, the precise role of CD80 signalling and its effect on MMR genes expression colonic carcinogenesis remain unclear.

Aims & Methods: The aim of this work was to investigate whether the modulation of CD80 signalling may influence the expression of MMR genes in a mouse model of early colorectal carcinogenesis. C57BL/6 mice received azoxymethane (AOM) i.p. at a dose of 10 mg/kg body weight weekly for 6 weeks to induce dysplasia and then sacrificed four or six months after the first AOM injection to perform histology, flow cytometry analysis and immunohistochemistry of colonic mucosa. Some WT mice received i.p. a monoclonal antiCD80 or antiCTLA4 antibody following AOM administration. Immunohistochemistry for MLH1, MSH2 and MSH6 was carried on. Non parametric statistics was performed.

Results: Low-grade dysplasia (LGD) extension was to about 20% of the colon mucosa at 4 and 6 months after AOM treatment in the AOM group and in the AOM-antiCD80 antibody while it dropped at less than 5% in the AOM-antiCTLA4 group (p < 0.001). High grade dysplasia (HGD) extension peaked in AOM-antiCD80 group (p = 0.018). The frequency of mice with low expression of MLH1 was significantly lower in the AOM-antiCD80 group (23.1%) compared to the AOM one (78.5%) (p = 0.007). Similarly, the frequency of mice with low expression of MSH2 was significantly higher in the AOM-antiCD80 group (30.7%) compared to the AOM one (85.7%) (p = 0.006) Curiously enough, the frequency of mice with low expression of MSH6 was significantly higher in the AOM group (71.4%) compared to either AOM-antiCD80 (0%) or AOM-antiCTLA4 (0%) groups (p < 0.001). (p = 0.014).

Conclusion: Lack of functional CD80 in colonic mucosa is associated to extended LGD and to the presence of HGD whereas enhancing CD80 function with antiCTLA4 antibody drastically decrease LGD extension and make HGD disappear. CD80 inhibition is associated to a high expression of MLH1, MSH2 and MSH6 suggesting a possible interplay between CD80 and MMR genes expression. Unexpectedly, MSH6 expression seemed enhanced even in case of CD80 stimulation suggesting a more complex regulation.

Disclosure of Interest: All authors have declared no conflicts of interest.

References

1. Dunn GP, Koebel CM, Schreiber, R.D. Interferons, immunity and cancer immunoediting. Nat Rev Immunol 2006;6:836–848.

2. Dolcetti R, Viel A, Doglioni C, Russo A, Guidoboni M, Capozzi E, Vecchiato N, Macrì E, Fornasarig M, Boiocchi M. High prevalence of activated intraepithelial cytotoxic T lymphocytes and increased neoplastic cell apoptosis in colorectal carcinomas with microsatellite instability. Am J Pathol . 1999;154:1805–1813.

3. Sinicrope FA, Rego RL, Garrity-Park MM, Foster NR, Sargent DJ, Goldberg RM, Wiesenfeld M, Witzig TE, Thibodeau SN, Burgart LJ. Alterations in cell proliferation and apoptosis in colon cancers with microsatellite instability. Int J Cancer . 2007; 120:1232–1238.

4. Scarpa M, Ruffolo C, Canal F, Scarpa M, Basato S, Erroi F, Fiorot A, Dall'Agnese L, Pozza A, Porzionato A, Castagliuolo I, Dei Tos AP, Bassi N, Castoro C. Mismatch repair gene defects in sporadic colorectal cancer enhance immune surveillance. Oncotarget . 2015 Dec 22;6(41):43472–82. doi: 10.18632/oncotarget.6179.

OP260 BETA-6-INTEGRIN SERVES AS A NOVEL SERUM TUMOR MARKER AND THERAPEUTIC TARGET FOR COLORECTAL CARCINOMA

S. Bengs 1 , E. Becker 1 , M. R. Spalinger 1 , T. Raselli 1 , S. Kasper 1 , S. Lang 1 , K. Atrott 1 , C. Mamie 1 , N. Britzen-Laurent 2 , L. Von Boehmer 3 , A. K.R. Knuth 4 , A. Tuomisto 5 , M. J. Mäkinen 5 , P. Hruz 6 , M. Turina 7 , A. Rickenbacher 7 , H. Petrowsky 7 , A. Weber 7 , P. Frei 7 , S. Vavricka 1 , M. Halama 7 , R. S. Croner 8 , J. Christoph 9 , G. Jenkins 10 , D. Sheppard 11 , M. Stürzl 2 , M. Fried 1 , G. Rogler 1 , M. Scharl 1

1 Division Of Gastroenterology And Hepatology, University Hospital Zürich, Zürich/Switzerland

2 University of Erlangen, Erlangen/Germany

3 The Rockefeller University, New York/United States of America

4 Hamad Medical Corporation, Doha/Qatar

5 University of Oulu, Oulu/Finland

6 Department Of Gastroenterology And Hepatology, Department Of Biomedicine, University of Basel, Basel/Switzerland

7 University Hospital Zürich, Zürich/Switzerland

8 University Hospital Magdeburg, Magdeburg/Germany

9 University of Erlangen, Tennenlohe/Germany

10 University of Nottingham, Nottingham/United Kingdom

11 University of California, San Francisco, San Francisco/United States of America

Contact E-mail Address: michael.scharl@usz.ch

Introduction: Colorectal cancer (CRC) is the third most common malignancy and one of the leading causes of cancer-related deaths worldwide. The need for novel biomarkers and therapeutic strategies for CRC is obvious and the identification of such markers and targets might significantly improve prognosis of CRC patients. β 6 -integrin (ITGB6) is a marker for cells undergoing epithelial-to-mesenchymal transition and has been associated with many epithelial tumors, such as CRC, lung cancer, breast cancer or pancreatic cancer. ITGB6 serves as a cell surface receptor for matrix proteins, such as fibronectin, and activates matrix degrading enzymes, such as matrix metalloproteinases 2 and 9 as well as TGF-beta. Previous studies identified a possible role for the ITGB6 in CRC pathogenesis.

Aims & Methods: The aim of this study was to investigate whether ITGB6 might serve as a novel serum marker and therapeutic target in CRC patients. We used serum samples of 19 healthy volunteers and 269 CRC patients including 53 patients with metastatic CRC. A follow-up cohort consisted of 19 CRC patients (n = 11 without lymph node metastasis, n = 4 with lymph node metastasis and n = 4 with liver metastasis) serum samples were collected pre-surgery (−3 to −1 days), post-surgery (2 to 6 days) and during follow-up visits (visit 1: 3 to 20 weeks; visit 2: 80 weeks). Wild-type and Itgb6-deficient mice were treated with 0.5–1.0% DSS for 7 days in drinking water followed by a recovery period of 14 days over three cycles. 10 mg azoxymethane (AOM) was administered by i.p. injection six times. ITGB6 serum levels were determined by ELISA.

Results: We detected ITGB6 in the serum of CRC patients (range 0–10 ng/ml) and found that a cut-off of ≥2 ng / mL ITGB6 predicts metastatic disease in 100% of respective patients. An ITGB6 serum level above 2 ng/ml was also associated with a significantly worse prognosis compared to patients with a ITGB6 serum level below 2 ng / mL . By comparing ITGB6 and CEA levels we found that ITGB6 above the cut-off of 2 ng / mL predicts metastatic disease with a higher accuracy as CEA. In a separate follow-up cohort (n = 19), after surgical R0 resection of the colon tumor and concomitant liver metastasis, ITGB6 serum levels declined to zero. Of note, we found that ITGB6 serum levels also declined after removal of the primary tumor in the colon and indicate treatment response to chemotherapy. ITGB6 serum levels rise again when liver metastases were newly diagnosed or tumor progression occurred. In this regard, ITGB6 serum levels were much more reliable as CEA levels. By immunohistochemistry, ITGB6 staining was strongly detectable in the tumor tissue. However, ITGB6 serum levels correlated clearly better with disease course as ITGB6 mRNA or protein levels in tumor tissue. In a colitis-associated colon tumor model, deficiency of Itgb6 protects mice from development of colon tumors in vivo. By endoscopy and histology, we found a significant number of colon tumors in DSS/AOM treated wild-type mice, but no tumors in treated Itgb6 deficient mice.

Conclusion: This is the first study showing ITGB6 levels in patients’ sera. Our findings provide evidence that ITGB6 can serve as a novel serum biomarker for diagnosis and prognosis of advanced CRC, as a marker for tumor surveillance, relapse and treatment response as well as a therapeutic target for CRC treatment. In summary, our findings suggest that using targeted therapy in patients with high levels of ITGB6 may be a novel treatment option for CRC patients.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP261 RESPONSIBLE GENES FOR CHARACTERISTICS OF THE INDUCED CANCER STEM-LIKE SPHERE CELLS OF HEPATOCELLULAR CARCINOMA

R. Tsunedomi 1 , K. Yoshimura 2 , M. Nishiyama 1 , S. Matsukuma 1 , S. Kanekiyo 1 , Y. Tokumitsu 1 , S. Tomochika 1 , Y. Tokuhisa 1 , M. Iida 1 , K. Sakamoto 1 , N. Suzuki 1 , S. Takeda 1 , S. Yamamoto 1 , S. Yoshino 3 , S. Hazama 4 , T. Ueno 5 , H. Nagano 1

1 Dept. Of Gastroenterological, Breast And Endocrine Surgery, Yamaguchi University, Graduate School of Medicine, Ube/Japan

2 Exploratory Oncology Research And Clinical Trial Center, National Cancer Center of Japan, Chuo-ku/Japan

3 Oncology Center, Yamaguchi University, Ube/Japan

4 Dept. Of Trans. Res. And Dev. Ther. Against Cancer, Yamaguchi University, Faculty of Medicine and Health Sciences, Ube/Japan

5 Dept. Of Digestive Surgery, Kawasaki Medical School, Kurashiki/Japan

Contact E-mail Address: tsune-r@yamaguchi-u.ac.jp

Introduction: Cancer stem cells are thought to play important roles in carcinogenesis, recurrence, metastasis, and therapy-resistance. So far, we revealed that poorly-differentiated hepatocellular carcinoma (HCC) has potential that convert to cancer stem-like cell (CSLC), which responsible for metastasis and chemoresistance.

Aims & Methods: In this study, we examined the target to develop the therapy against intrahepatic recurrence of HCC after surgery. A unique medium supplemented with neural survival factor-1 was used for the induction of CSLCs. The human HCC cell lines SK-HEP-1 and HuH-7 were used as sphere-forming and non-sphere-forming cells, respectively. Frozen clinical specimens of 10 pair of HCC and liver tissue were used. Liver metastatic potential was examined by injection of the cells to immune-deficient mice spleen. Cell viability was measured by MTS assay. Comprehensive analyses for mRNA, microRNA, and protein expressions were performed by strand-specific RNA-seq, DNA chip, and iTRAQ-labeled 2D-LC-MS/MS, respectively. The mRNA and protein levels were examined by real-time PCR and flow cytometry analyses. To targeted-gene knock-down, specific small interfering RNAs were used.

Results: Poorly differentiated HCC derived SK-HEP-1 cells efficiently formed sphere cells (SK-sphere), but well-differentiated HCC-derived HuH-7 did not. SK-sphere showed more CD44 variant-positive cells compared to parental SK-HEP-1 cells. Interestingly, SK-sphere showed 2.3-folds higher PD-L1 expression than SK-HEP-1. In the liver-metastatic mouse model, SK-sphere cells showed 3.6-fold more frequent liver metastasis compared to parental cells ( P = 0.02). The cell viability of SK-spheres was significantly higher than that of SK-HEP-1 cells in the presence of several anti-cancer drugs (1.7- to 7.3-fold, each P < 0.05). RNA-seq analysis followed by Gene Set Enrichment Analysis showed epithelial-mesenchymal transition (EMT) and hypoxia were significantly enriched in the sphere cells. As regards EMT, increased expression of Vimentin and Snail were observed in SK-sphere cells compared to parental cells. It was also observed that down-regulation of let-7a-5p microRNA and up-regulation of HMGA2 expressions in SK-sphere cells. Regarding chemoresistance, ABCG2 and HIF1alpha expressions were significant higher in SK-sphere than in SK-HEP-1, and significant lower ROS production was observed in SK-sphere cells. As a result of integrated analysis with cell lines and clinical specimens, a geneA encoding one of small GTPase was identified as an up-regulated gene in both CSLC and poor prognostic HCC. The knock-down of geneA promoted conversion from sphere cells to adherent cells. Furthermore, the cell viability of the geneA knock-down cells were significantly lower than that of mock transfected cells in the sphere induction medium supplemented with doxorubicin.

Conclusion: Our novel method successfully induced CSLCs, SK-sphere, which showed increased metastatic potential and chemoresistace. It was suggested that EMT and hypoxia were responsible for those SK-sphere characteristics. Furthremore, the up-regulation of geneA might be responsible for properties of cancer stem-like cells.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP262 IN VIVO EFFICACY OF LOCAL THERAPY WITH ADHESIVE WAFER CONTAINING ANTICANCER DRUG IN AN ORTHOTOPIC PANCREATIC CANCER MOUSE MODEL

E. Lee 1 , J.H. Maeng 1 , Y.H. Nan 1 , K. Kim 1 , S. Jeong 2 , D.H. Lee 2

1 Utah-Inha DDS and Advanced Therapeutics Research Center, Incheon/Korea, Republic of

2 Division Of Gastroenteroloy, Department Of Internal Medicine, Inha University School of Medicine, Incheon/Korea, Republic of

Contact E-mail Address: eunhye.lee@unidds.com

Introduction: Pancreatic cancer (PC) has the highest mortality rate of all the major cancers. It is the only leading cancer killer with a 5-year survival rate still in the single digits and the survival rate has not improved in the last 40 years. And less than 10% of patients are candidates for surgical resection at the time of diagnosis. Endoscopic ultrasonography-guided fine-needle injection (EUS-FNI) is an attractive minimally invasive delivery system with potential applications in local (intratumoral) against PC. EUS-FNI has demonstrated its feasibility and safety in delivery of meditation, this procedure has attracted attention as a method of antitumor-agent delivery such as anticancer drug, alcohol, gene, and dendritic cells as well as radioactive seeds. Recently Levy et al. in Mayo Clinic reported EUS-guided fine-needle injection of gemcitabine for locally advanced and metastatic pancreatic cancer. Gliadel® Wafer is chemotherapeutic wafer implant that is a biodegradable polymer implant loaded with the chemotherapeutic agent (BCNU) approved by the U.S. Food and Drug Administration (FDA) for during surgery of malignant brain glioma.

Aims & Methods: The objectives of this study are to confirm in vivo efficiency of adhesive wafer containing chemotherapeutic agent (gemcitabine or paclitaxel). Adhesive wafer consists of the two kinds of polymer matrix of Glycosaminoglycan and polyamine and chemotherapeutic agent are distributed in this wafer. Orthotopic PC model induced by local injection of AsPc-1 tumor cells into the tail of the pancreas. Adhesive wafer containing gemcitabine or paclitaxel was directly applied in the surface of pancreatic cancer and free gemcitabine or paclitaxel was administered by single intratumoral (I.T.) injection as positive control. We compared the anti-tumor efficiency of adhesive wafer containing gemcitabine or paclitaxel and that of intratumoral injection of free drug (positive control) in the orthotropic PC mouse model.

Results: The mean tumor volume of adhesive wafer containing gemcitabine or paclitaxel treating groups shows significantly supressed than positive control group. The metastasis scores of non-treating group, vehicle, adhesive wafer containing gemcitabine or paclitaxel, and positive control groups were 1.80, 1.83, 1.00 and 1.67, respectively. These results demonstrate that adhesive wafer containing gemcitabine or paclitaxel for local chemotherapy is more effective than intratumoral injection of free drug in orthotopic PC mouse model.

Conclusion: This study provides the first in vivo application of the adhesive wafer containing gemcitabine or paclitaxel for the local treatment of pancreatic cancer. We confirmed that higher antitumor effects of adhesive wafer containing paclitaxel and gemcitabine than intratumoral injection of free drug in orthotopic PC mouse model. These results indicate that adhesive wafer containing chemotherapeutic agents is one of new candidates for local chemotherapy of PC.

Disclosure of Interest: All authors have declared no conflicts of interest.

TUESDAY, OCTOBER 31, 201715:45-17:15

MULTIDISCIPLINARY MANAGEMENT OF COMPLICATED LUMINAL CROHN'S DISEASE - HALL 6____________________

OP263 PATIENT-REPORTED OUTCOMES WITH UPADACITINIB IN SUBJECTS WITH MODERATELY TO SEVERELY ACTIVE CROHN’S DISEASE: PHASE 2 RESULTS FROM CELEST STUDY

L. Peyrin-Biroulet 1 , E. Louis 2 , E.V. Loftus Jr 3 , N. Tundia 4 , M. Fuldeore 4 , A. Lacerda 4 , J. Enejosa 4 , A. Pangan 4

1 Nancy University Hospital, Les Nancy/France

2 University Hospital CHU of Liège, Liège/Belgium

3 Mayo Clinic College of Medicine, Rochester/United States of America/MN

4 AbbVie Inc., North Chicago/United States of America/IL

Contact E-mail Address: peyrinbiroulet@gmail.com

Introduction: Upadacitinib (UPA) is an oral selective Janus kinase 1 inhibitor that is being assessed for treatment in subjects with Crohn’s disease (CD). The effects of UPA on patient-reported outcomes (PROs) were evaluated in a phase 2 dose-ranging study.

Aims & Methods: M13-740 (Celest study; NCT02365649 ) was designed to evaluate the efficacy and safety of multiple doses of UPA. Subjects with moderately to severely active CD with inadequate response or intolerance to immunosuppressants or tumour necrosis factor alpha inhibitors were randomly assigned in a 1:1:1:1:1:1 ratio to double-blind induction therapy with placebo (PBO) or UPA at 3, 6, 12 or 24 mg twice daily (BID) or 24 mg once daily (QD) for 16 weeks, followed by a blinded extension therapy for 36 weeks. PROs assessed were the Inflammatory Bowel Disease Questionnaire (IBDQ), and EuroQol (EQ-5D) and Work Productivity and Activity Impairment (WPAI) questionnaires. Herein, analyses of within-group changes from baseline to week 16 are presented. Percentage of subjects whose improvements met or exceeded the minimum clinically important differences (MCID) in IBDQ score (defined as increase ≥16 points) from baseline to week 16 or who achieved IBDQ remission (IBDQ score ≥170) at week 16 were determined. Change from baseline to week 16 was calculated using mixed-effects model for IBDQ total score and analysis of covariance for EQ-5D visual analogue score (VAS) and WPAI scores. Missing data were reported using non-responder imputation (NRI) and last observation carried forward (LOCF) methods.

Results: Celest enrolled 220 subjects with mean age of 41 years, mean CD duration of 13 years and mean CDAI of 303; 57% were female and 96% had failed or were intolerant to tumour necrosis factor alpha inhibitors. At baseline, overall mean IBDQ score was 116, EQ-5D VAS was 49.8, and WPAI was 61%. At week 8, clinically meaningful improvements in IBDQ MCID were observed in 53–62% of subjects in all UPA dose groups, except the 3 mg BID group. At week 16, UPA was associated with dose-related increases in the percentage of patients achieving IBDQ remission (Table). Significantly more subjects achieved the MCID for the IBDQ score in all UPA dose groups vs PBO with a plateaued response to UPA at 6 mg BID. Significant improvement from baseline in mean EQ-5D VAS at week 16 was observed for both the 6 mg and 24 mg BID doses vs PBO. Activity impairment was significantly reduced for the 6 mg and 24 mg BID doses vs PBO. Overall work impairment was significantly reduced for the 24 mg dose vs PBO.

Table. Patient-Reported Outcome Results

Conclusion: Subjects with active and refractory CD treated with 16 weeks of UPA showed clinically meaningful and early improvements in health-related quality of life, had better work performance, and were better able to perform daily activities compared with subjects on PBO.

Disclosure of Interest: L. Peyrin-Biroulet: Consulting: Merck, Abbvie, Janssen, Genent, Mitsubishi, Ferring, Norgine, Tillots, Vifor, Therakos, Pharmacosmos, Pilège, BMS, UCB, Hospira, Celltrion, Takeda, Biogaran, Boerhinger-Ing, Lilly, Pfizer, HAC, Index, Amgen, Sandoz, Forward, Celgene …

E. Louis: Educational Grants: MSD, Abbvie, Takeda; Speaker fees: Abbvie, Ferring, MSD, Chiesi, Mitsubishi Pharma, Hospira, Janssen, Takeda. Advisory Board: Abbvie, Ferring, MSD, Takeda, Hospira, Mitsubishi Pharma, Celltrion, Prometheus

E.V. Loftus Jr: Consulting: AbbVie, Takeda, Janssen, UCB, Amgen, Pfizer, Eli Lilly, Mesoblast, CVS Caremark. Research support: AbbVie, Takeda, Janssen, UCB, Amgen, Pfizer, Genentech, Receptos, Gilead, Celgene, Seres, MedImmune, Robarts Clinical Trials

N. Tundia: Employee: AbbVie; Stockholder: AbbVie

M. Fuldeore: Employee: AbbVie; Stockholder: AbbVie

A. Lacerda: Employee: AbbVie; Stockholder: AbbVie

J. Enejosa: Employee: AbbVie; Stockholder: AbbVie

A. Pangan: Employee: AbbVie; Stockholder: AbbVie

Acknowledgements & Funding Statement: Financial support for the study and medical writing services (Joann Hettasch, Fishawack Group, Conshohocken, PA) was provided by AbbVie. AbbVie participated in interpretation of data, review, and approval of the abstract. All authors contributed to development of the abstract and maintained control over final content.

OP264 FECAL MICROBIOTA TRANSPLANT FOR CROHN’S DISEASE: A PROSPECTIVE, RANDOMIZED STUDY IN CHINESE POPULATION

Z. Yang , X. Wang, C. Bu

Department Of Gastroenterology, Third Xiangya Hospital, Central South University, Changsha/China

Contact E-mail Address: 823480936@qq.com

Introduction: Crohn’s disease (CD) is an inflammatory bowel disease (IBD), characterized by chronic, recurrent, uncontrolled and idiopathic immune-mediated inflammation that can affect any sites along the whole length of the gastrointestinal tract. CD impairs health-related quality of life (HRQoL) and the incidence of CD continues to rise in low-incidence areas, including China. The precise aetiology of IBD is unclear; however, the intestinal microbiota has been proved to play an important role in the pathogenesis of IBD. Patients with CD usually present with an overall drop in gastrointestinal microbiota species richness and alternation in the abundance of several taxa. Such conditions are potentially amenable to biologic therapies. Fecal microbiota transplant(FMT) infusion of a fecal suspension from a healthy individual into the gastrointestinal tract of a patient to restore the intestinal homeostasis. During the past several years FMT is a highly effective therapy for recurrent Clostridium difficile infection (CDI). However, few case series have reported the effects of FMT for CD and the results were mixed. We carried out this trial to investigate the outcomes of FMT for CD and to analyse the factors correlated with curative effect.

Aims & Methods: Several case series have reported the effects of FMT for CD. We assessed the efficacy and safety of FMT for patients with CD in a prospective, randomized study trial. Patients with active CD (n = 31) were assigned to groups. Prospective study conducted at The Third Xiangya Hospital of Central South University form From January 2014 through March 2016. Patients with active CD (n = 31) were randomized assigned to receive FMT by either gastroscopy or colonoscopy (200 g Qualified stool sample was mixed with sterile saline buffer). Fresh fecal suspension was generated from a related healthy volunteer or a prescreened standard donor. Patients were followed by physical examination and laboratory tests of peripheral blood on weeks 1, 2, 4, 6 and 8 after the transplant. Extraction donor and CD patient fecal in DNA, analysis by Illuminal sequencing platform. For patients who didn't get clinical remission after a single FMT, a second transplant will be taken one week later. The primary end point was clinical remission of CD (Crohn's disease activity index less than 150 score or CDAI decrease more than 100 score) at week 8. Secondary endpoint was safety, assessed by adverse effects related to the therapy.

Results: In 14 of 31 patients received FMT by colonoscopy and 13 by gastroscopy. Clinical remission was achieved in 15 patients (55.6%) after a single FMT. 12 patients received a second transplant and 3 obtaining clinical remission. Resulting in an overall clinical remission rate of 66.7%. At week 8 compared to who didn’t get a clinical remission, patients with clinical remission have lower CDAI (420 vs 200, P<0.05), less times of daily diarrhea (6 vs 4, P<0.05). Adverse effects of FMT were all mild and self-limited. There was no significant difference in adverse events between groups. Operational Taxonomic Units (OTU) analysis shows that CD patient have a lower OTU number than donor (117 vs 258, P<0.05). CD patients also have a lower abundance of Bacteroides, Roseburia, Phascolarctobacterium Eubacterium, and higher abundance of Bilophila, Streptococcus, Clostridium, Paraprevotella.

Conclusion: FMT is effective in treating CD, with satisfactory short-term effects and no severe adverse effect. CD patients have a drop of microbiota species richness and alternation in the abundance.

Disclosure of Interest: All authors have declared no conflicts of interest.

References

1. Rossen NG, Fuentes S, van der Spek MJ, et al., Findings From a Randomized Controlled Trial of Fecal Transplantation for Patients With Ulcerative Colitis. Gastroenterology , 2015. 149(1): 110–118.e4.

2. Moayyedi P, Surette MG, Kim P T, et al., Fecal Microbiota Transplantation Induces Remission in Patients With Active Ulcerative Colitis in a Randomized Controlled Trial. Gastroenterology , 2015. 149(1): 102–109.e6.

3. van Nood E, Vrieze A, Nieuwdorp M et al., Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med , 2013. 368(5): 407–15.

TUESDAY, OCTOBER 31, 201715:45-17:15

CASE FINDING AND SURVEILLANCE OF BARRETT'S OESOPHAGUS - ROOM C1____________________

OP265 A NOVEL, INTERACTIVE WEB-BASED EDUCATIONAL TOOL IMPROVES DETECTION AND DELINEATION OF BARRETT’S OESOPHAGUS RELATED NEOPLASIA (BORN): THE BORN PROJECT

J.J. G. h.m. Bergman 1 , O. Pech 2 , K. Ragunath 3 , D. Armstrong 4 , G. Tytgat 1 , J. Dent 5 , L. Lundell 6 , M. Vieth 7 , P. Sharma 8

1 Gastroenterology & Hepatology, Academic Medical Centre - Gastroenterology & Hepatology, Academic Medical Centre; Amsterdam/NL, Amsterdam/Netherlands

2 Klinik Für Gastroenterologie Und, Krankenhaus Barmherzige Brüder Klinik für Gastroenterologie und Interventionelle Endoskopie - Klinik, Regensburg/Germany

3 Endoscopy & Gastroenterologist Wolfson Digestive Diseases Centre, Queens Medical Centre campus Nottingham University Hospitals, Nottingham/United Kingdom

4 Gastroenterology, McMaster University, Ontario/Canada

5 Royal Adelaide Hospital Gastroenterology and Hepatology, Adelaide, SA/Australia

6 Department Of Gastroenterology, Karolinska University Hospital, Stockholm/Sweden

7 Abt. Pathologie, Klinikum Bayreuth Abt. Pathology, Bayreuth/Germany

8 Gastroenterology, University of Kansas School of Medicine Dept. of Gastroenterology, Leawood/United States of America

Contact E-mail Address: j.j.bergman@amc.uva.nl

Introduction: Endoscopic detection and delineation of neoplasia is crucial for the surveillance and treatment of Barrett’s oesophagus.

Aims & Methods: High-quality HD-videos were obtained from pts with BORN (endoscopically visible lesion with HGD/EAC) or with non-dysplastic (ND) BO. For BORN videos, 3 experts independently delineated lesions throughout the video using software developed specifically for the project. The mean AND/OR-ratio of each pair of experts was used to denote agreement on delineated frames. All videos and frames with an agreement ratio ≤0.25, were reviewed in consensus after which the experts repeated delineation independently. In Phase I, 68 assessors from the US and Europe scored 4 sets of 20 videos. The order of sets and the order of videos within each set were randomized for each assessor. Assessors were classed as: Trainees: fellows in training; Junior: board certified ≤2 yrs of practice; Senior: board certified ≥5 yrs in practice. Assessors paused the video when a BORN lesion was visible, marked their preferred biopsy position and then delineated the entire lesion using the BORN software. After each set, assessors were guided through mandatory, tailored feedback based on their scores and the experts’ delineations. After Phase I, BORN videos with no apparent contribution to the learning process (either a perfect score at baseline (“too easy”) or poor performance throughout the 4 sets (“too difficult”) were excluded. This condensed version of the training module, again consisting of 4 sets, was then validated in Phase II by 121 new assessors from Canada (19), Germany (20), the Netherlands (33), United Kingdom (28), and United States (21). Outcome parameters: (1) Detection score: percentage of BORN lesions with a biopsy mark positioned within “the sweet spot” (i.e. area delineated by all 3 experts). (2) Delineation score: percentage of the sweet spot delineated by the assessor. (3) Relative delineation score: mean agreement of the assessor with the 3 experts divided by the mean agreement amongst experts.

Results: In Phase 1, detection scores and delineation scores significantly increased over the 4 sets. There were no significant differences between trainees, juniors and seniors. In Phase II, detection and delineation again significantly increased over the 4 sets yet with an even higher increase in outcome parameters compared to Phase I (Table 1). Again, there were no significant differences between trainees, juniors and seniors or between countries.

Conclusion: We have developed and validated a unique interactive web-based teaching tool that significantly improves the detection and delineation of BORN. This improvement was found to be robust and significant in endoscopists with a range of experience and country of practice.

Disclosure of Interest: J.J.G.H.M. Bergman: Research support: Olympus, Fujifilm, Erbe, Ninepoint Medical, C2 therapeutics, Cernostics, Interpace, Lumen-R. Speakers fee: Olympus, Fujifilm, WATTS-3D. Research support, speakers fee and financial support for training programs: Medtronic, Boston Scientific

O. Pech: Speaker honorarium: Olympus, Fujifilm, Boston Scientific, AbbVie, Falk Foundation, Norgine

K. Ragunath: Olympus: consultancy, research support and educational grants Pentax: research support COOK: Educational grants and research support Boston Scientific: Educational grants, consultancy Medtronics: educational grants ERBE: educational grants

D. Armstrong: AbbVie, Allergan, Boston Scientific, ConMed Canada, Cook Canada, Janssen, Intercept, Lupin, Medtronic, Olympus Canada, Pentax Medical, Pendopharm, Pfizer, Shire Canada, Takeda *Due to max. amount of characters no description possible

M. Vieth: Honorarium: FALK, Olympus, Shire

All other authors have declared no conflicts of interest.

OP266 MANAGEMENT OF PATIENTS WITH BARRETT’S OESOPHAGUS: A COST-EFFECTIVENESS ANALYSIS

A. Omidvari 1 , S. Kroep 1 , I. Lansdorp-Vogelaar 1 , A. Ali 2 , W. D. Hazelton 3 , E. Richmond 4 , C. Y. Kong 2 , J. H. Rubenstein 5 , G. Luebeck 3 , C. Hur 2 , J. Inadomi 6

1 Public Health, Erasmus MC, Rotterdam/Netherlands

2 Institute For Technology Assessment, Massachusetts General Hospital, Boston/United States of America/MA

3 Program In Computational Biology, Fred Hutchinson Cancer Research Center, Seattle/United States of America

4 Division Of Cancer Prevention, National Cancer Institute, Rockville/United States of America

5 Division Of Gastroenterology, University of Michigan, Ann Arbor/United States of America

6 Division Of Gastroenterology, Department Of Medicine, University of Washington, Seattle/United States of America

Contact E-mail Address: a.omidvari@erasmusmc.nl

Introduction: Barrett’s oesophagus (BO) is a known precursor to oesophageal adenocarcinoma (OAC). Surveillance and/or treatment of BO patients is recommended by various clinical practice guidelines, but prior analyses indicated that surveillance of non-dysplastic BO is not cost-effective. However, those studies largely predated the advent of widespread use of endoscopic therapy.

Aims & Methods: This study aimed to determine the optimal management strategy of BO patients through a cost-effectiveness analysis. We used the MIcrosimulation SCreening Analysis (MISCAN) model of OAC to simulate a hypothetical cohort of US males with BO at age 60 who were followed over their life-time under 203 different management strategies. In the first strategy (natural history) no BO patients received endoscopic surveillance or treatment. In all other strategies, BO patients with high-grade dysplasia received endoscopic therapy and then underwent intensive surveillance. For patients with low-grade or no dysplasia, treatment and/or surveillance strategies were varied. An incremental cost-effectiveness analysis was performed to specify the optimal management strategy using a willingness-to-pay threshold of $100,000 per quality-adjusted life-year (QALY).

Results: In the natural history strategy, 68 OAC cases were diagnosed and 50 patients died of OAC per 1000 BO patients. The total cost in this strategy was $3,995,560. Surveillance with endoscopic therapy for BO patients with high-grade dysplasia reduced OAC incidence to 19–54 cases depending on the intensity of surveillance but also increased costs to $4,-292,995–15,531,773. Strategies that also provided endoscopic therapy of patients with low-grade dysplasia reduced OAC cases to 17–55, however total costs increased to $4,396,760–15,906,455. The optimal management strategy was to offer surveillance every 3 years to BO patients without dysplasia; surveillance every 6 months within the first year of diagnosis of patients with low-grade dysplasia and annually thereafter; and endoscopic therapy of patients with high-grade dysplasia. The surveillance stop age of BO patients in the optimal strategy was 80 years. This strategy prevented 64% of OAC cases at an incremental cost-effectiveness ratio of $97,918 per QALY (Table 1).

Conclusion: Our findings indicate that BO patients without dysplasia should undergo surveillance every three years, and that treatment of BO patients with low-grade dysplasia may not be cost-effective. The optimal surveillance interval for these patients is 6 months in the first year and annually thereafter. Surveillance should stop at age 80.

Disclosure of Interest: All authors have declared no conflicts of interest.

TUESDAY, OCTOBER 31, 201715:45-17:15

POTENTIAL FUTURE TARGETS IN IBD - ROOM A3____________________

OP267 MIR-9 INHIBITS GROWTH OF INTESTINAL EPITHELIAL CELLS AND PROMOTES EPITHELIAL-MESENCHYMAL TRANSITION IN HUMAN CROHN’ S DISEASE AND MURINE COLITIS

Y. Zhao , R. Shi

Department Of Gastroenterology, Zhongda Hospital Southeast University, Nanjing/China

Contact E-mail Address: misszhaoye@126.com

Introduction: Emerging evidence suggests that loss of intestinal epithelial cells (IECs) acts as one of the major contributors to the pathogenesis of Crohn’s disease (CD) [1, 2] . Therefore, maintaining the intact of epithelium plays pivotal roles in improving pathophysiology and clinical outcomes of CD [3] . We have previously shown that miR-9 is markedly decreased in colon tissues of CD patients, however, its biological function remains elusive [4] .

Aims & Methods: In this study, we further investigated the impact of miR-9 in maintaining intact of intestinal epithelium during the pathogenetic process of CD. miR-9 expression was assayed in isolated IECs and inflamed colon samples of 2, 4, 6-trinitrobenzene sulfonic acid (TNBS)-induced and CD patients by qRT-PCR and miRNA in situ hybridization. The levels of SMAD nuclear interacting protein 1(SNIP1) and epithelial-mesenchymal transition (EMT) biomarkers were examined by dual immunofluorescence staining and western blot analysis. The influence of differently expressed miR-9 on its putative target genes, SMAD nuclear interacting protein 1(SNIP1) and CDH1, was investigated in colonic epithelia cells and colitis models. The role of miR-9 was further studied in the experimental colitis mice by intracolonic administration of miR-9 precursors or inhibitors.

Results: We found that miR-9 expression was significantly upregulated in IECs isolated from inflamed colon tissues of CD patients and 2, 4, 6-trinitrobenzene sulfonic acid (TNBS)-induced colitis mice, when compared with negative controls. Interestingly, the genes of SNIP1, cyclin D1 and E-cadherin were downregulated significantly and correlated inversely to miR-9, while the genes of Vimentin was positively correlated to miR-9 in CD patients. Further study demonstrated that miR-9 cooperatively suppressed SNIP1 and CDH1 expression at posttranscriptional levels in colonic cells. In addition, upregulation of miR-9 suppressed colonic cell proliferation via suppressing SNIP1-mediated cyclin D1 expression, induced EMT by targeting CDH1, and vice versa. Moreover, downregulation or upregulation of miR-9 in TNBS-induced colitic colon alleviated or aggravated experimental colitis, respectively.

Conclusion: Our study reveals the mechanism that miR-9 inhibits growth of IECs, promotes EMT and thereby affects intestinal epithelial homeostasis. Blockade of miR-9 in vivo may serve as a potential therapeutic intervention for CD.

Disclosure of Interest: All authors have declared no conflicts of interest.

References

1. Luissint AC, Parkos CA, Nusrat A. Inflammation and the Intestinal Barrier: Leukocyte-Epithelial Cell Interactions, Cell Junction Remodeling, and Mucosal Repair. Gastroenterology . 2016; 151(4): 616–632.

2. Peterson LW, Artis D. Intestinal epithelial cells: regulators of barrier function and immune homeostasis. Nat Rev Immunol . 2014; 14(3): 141–153.

3. Odenwald MA, Turner JR. The intestinal epithelial barrier: a therapeutic target? Nature reviews Gastroenterology & hepatology . 2017; 14(1): 9–21.

4. Zhao Y, Ma T, Chen W, Chen Y, Li M, Ren L, Chen J, Cao R, Feng Y, Zhang H, Shi R. MicroRNA-124 Promotes Intestinal Inflammation by Targeting Aryl Hydrocarbon Receptor in Crohn's Disease. Journal of Crohn's & colitis . 2016; 10(6): 703–712.

OP268 TARGETING NAD IMMUNOMETABOLISM AS NOVEL THERAPEUTIC STRATEGY IN IBD

R. R. Gerner 1 , V. Klepsch 2 , K. Arnhard 3 , T. E. Adolph 1 , S. Macheiner 1 , C. Grander 1 , N. Hermann-Kleiter 2 , H. Oberacher 3 , G. Baier 2 , H. Tilg 4 , A.R. Moschen 5

1 Internal Medicine, Innsbruck Medical University, Innsbruck/Austria

2 Division Of Translational Cell Genetics, Innsbruck Medical University, Innsbruck/Austria

3 Institute Of Legal Medicine, Innsbruck Medical University, Innsbruck/Austria

4 Department Of Medicine, Innsbruck Medical University - Department of Medicine, Innsbruck Medical University; Innsbruck/AT, Innsbruck/Austria

5 Christian Doppler Laboratory for Mucosal Immunology, Innsbruck/Austria

Contact E-mail Address: romana.gerner@i-med.ac.at

Introduction: Nicotinamide−phosphoribosyl transferase (NAMPT, also referred to as PBEF or Visfatin) is indispensable for the cellular NAD supply by catalysing the rate-limiting step of the NAD salvage pathway . Upon inflammation, NAMPT upregulation counteracts an increased cellular NAD turnover mediated by NAD-depleting enzymes. These display an important mechanistic link between inflammatory, metabolic and transcriptional pathways and NAD metabolism. NAMPT is strongly upregulated in IBD patients, however, its functional impact still remains unclear.

Aims & Methods: In this study we investigated the efficacy of NAMPT inhibition by the small molecule inhibitor FK866 as a novel treatment strategy in intestinal inflammation. NAMPT enzymatic activity was blocked in the dextran sulfate sodium (DSS) model of colitis and the azoxy−methane (AOM)/DSS model of colitis-associated cancer. Mucosal NAD levels and its metabolites were determined by HPLC. FK866 was tested on the differentiation and polarization of human and mouse primary macrophages. Further, lamina propria mononuclear cells (LPMNC) from IBD patients were treated ex vivo with FK866, dexamethasone or infliximab and assayed for cytokine release.

Results: NAMPT blockade resulted in mucosal NAD depletion that was consequently associated with reduced abundances and activities of the NAD-dependent enzymes PARP1, Sirt6 and CD38. FK866 particularly decreased colonic infiltration of inflammatory monocytes, macrophages and activated T cells. FK866 treatment was associated with an altered monocyte/macrophage biology and skewed macrophage polarization by reducing CD86, MHC-II and IL-6 and promoting CD206 and IL-10. Importantly, in lamina propria mononuclear cells from IBD patients, FK866 also effectively supressed cytokine release.

Conclusion: Our data highlight NAD immunometabolism as an important source for mucosal immunity and propose FK866-mediated NAMPT blockade as a promising therapeutic approach in acute intestinal inflammation.

Disclosure of Interest: All authors have declared no conflicts of interest.

References

Moschen AR, Kaser A, Enrich B, Mosheimer B, Theurl M, Niederegger H, et al. Visfatin, an adipocytokine with proinflammatory and immunomodulating properties. Journal of immunology . 2007;178(3):1748–58.

Hasmann M, Schemainda I. FK866, a highly specific noncompetitive inhibitor of nicotinamide phosphoribosyltransferase, represents a novel mechanism for induction of tumor cell apoptosis. Cancer research . 2003;63(21):7436–42.

Starr AE, Deeke SA, Ning Z, Chiang CK, Zhang X, Mottawea W, et al. Proteomic analysis of ascending colon biopsies from a paediatric inflammatory bowel disease inception cohort identifies protein biomarkers that differentiate Crohn's disease from UC. Gut . 2016.

OP269 BALANCING JAK/STAT-SIGNALING WITH TOFACITINIB IN MONOCYTES OF HEALTHY CONTROLS AND IBD PATIENTS

F. Cordes 1 , E. Lenker 2 , T. Weinhage 2 , D. Bettenworth 2 , G. Varga 2 , D. Foell 2

1 Department Of Medicine B, University Hospital Münster, Münster, Germany;, Münster/Germany

2 Department Of Pediatric Rheumatology And Immunology, University Children’s Hospital Münster, Münster/Germany

Contact E-mail Address: annafriederike.cordes@ukmuenster.de

Introduction: Monocytes are bridging natural and acquired immunity. Information about JAK signaling in monocytes is scarce especially in an inflammatory milieu. JAK-inhibition is a promising new anti-inflammatory treatment option. However, JAK/STAT activation may be involved both in pro- and anti-inflammatory monocyte programs. We have shown that GM-CSF-activated regulatory monocytes (GMaM) induce Treg-differentiation in co-cultures with naive T-cells in vitro 1 . Inflammatory T-cells produce high amounts of GM-CSF in vivo, not leading to anti-inflammatory monocytes, likely because of pro-inflammatory cytokines in the environment. We used JAK-inhibitor Tofacitinib to explore mechanisms that block pro-inflammatory pathways and still allow anti-inflammatory functions in monocytes.

Aims & Methods: Primary monocytes from peripheral blood of healthy human donors were isolated and phenotyped by FACS analysis after treatment with GM-CSF and JAK-inhibitor Tofacitinib. Monocytes were co-cultured with autologous naïve T-cells and differentiation of Foxp3 + regulatory T-cells was evaluated by FACS. Furthermore, primary monocytes from IBD patients with active disease were used to investigate JAK/STAT signaling and inhibition. JAK1 activation (represented by IFNγ-induced phospho-STAT1), JAK2 activation (represented by GM-CSF-induced phospho-STAT5), and JAK3 activation (represented by IL-4-induced phospho-STAT6) was analyzed by FACS. Non-toxic dosages of 1 to 1000 nM of Tofacitinib were used.

Results: We aimed to define the dose of JAK inhibition that keeps JAK2 activity (GM-CSF-induced pSTAT5) intact. Upon stimulation with 10–100 nM Tofacitinib, we detected GM-CSF-induced phospho-STAT5 while phospho-STAT1 and phospho-STAT6 were blocked. Concentrations above 100 nM Tofacitinib led to inhibition of GM-CSF-induced CD39-, CD206-, CD209 -expression. 10–100 nM Tofacitinib allowed CD39-, CD206-, CD209-expression and IL-10 release while TNFα was still blocked. Co-culture of GMaM and T-cells resulted in increased differentiation of Foxp3 + Treg that was even enhanced when 10 nM Tofacitinib was used. Investigation of JAK/STAT activation in monocytes from IBD patients revealed a lower increase after stimulation compared to healthy controls. Furthermore, TNFα expression was not inhibited in monocytes obtained from IBD patients using the same dosage of Tofacitinib which significantly inhibited TNFα expression in healthy controls (10–100 nM).

Conclusion: In summary, Tofacitinib (10–100 nM) facilitates GM-CSF-induced reprogramming of monocytes to anti-inflammatory cells. This could not be confirmed in monocytes from active IBD patients as blockage with similar doses did not inhibit pro-inflammatory cytokine expression. Thus, pro-inflammatory activation in IBD does depend on more complex interplays of multiple factors and solely blocking JAK/STAT activation by Tofacitinib cannot fully restore the GMaM phenotype.

Disclosure of Interest: All authors have declared no conflicts of interest.

Reference

1. Dabritz J, Weinhage T, Varga G , et al. Reprogramming of monocytes by gm-csf contributes to regulatory immune functions during intestinal inflammation. J Immunol 2015; 194: 2424–38.

OP270 CHROMOFUNGIN, CGA47-66 DERIVED PEPTIDE, PROMOTES ALTERNATIVELY ACTIVATED MACROPHAGES, SUPPRESSES CLASSICALLY ACTIVATED MACROPHAGES AND IMPROVES EPITHELIAL BARRIER FUNCTIONS DURING COLITIS

N. Eissa 1 , L. Kermarrec 1 , C.N. Bernstein 2 , J. Ghia 1

1 Department Of Immunology, College Of Medicine, Faculty Of Health Sciences University Of Manitoba, University of Manitoba, Winnipeg/Canada/MB

2 Internal Medicine Section Of Gastroenterology, University of Manitoba, Winnipeg/Canada

Contact E-mail Address: noureissa@live.com

Introduction: Chromogranin-A (ChgA) is a prohormone secreted by neuroendocrine and immune cells and is elevated in inflammatory bowel disease (IBD) and can generate several peptides. ChgA has eight exons and Chromofungin (CHR: ChgA 47–66 ), a peptide with cardioprotective and antinociceptive effects, is encoded from Exon-IV. IBD is characterized by an imbalance in the activation of proinflammatory and anti-inflammatory signaling pathways, altered functions of macrophages, intestinal tight junction (TJ) barrier and intestinal epithelial cells. Moreover, the nuclear transcription factor kappa B (NF-κB) signaling, a master regulator of genes transcription, is dysregulated leading to perpetuate inflammation.

Aims & Methods: We aimed to study the activity of CHR, CgA Exon-IV, in colonic tissues of patients with active ulcerative colitis (UC) and underlying mechanisms in dextran sulfate sodium (DSS)-colitis, macrophages and human colonic epithelial cells. Expression of Exon-IV and its correlation with classical activated macrophages (CAMs) markers ( IL1B, IL6, TNFA, SLAM7, TLR4, CD120B) , alternative activated macrophages (AAMs) markers (IL10, TGFB, MR, CMYC, CD1B), NFKB, and TJ proteins (Claudin-1 ( CLDN1 ), zonula occludens-1 ( ZO1 ), E-cadherin ( ECADH ), occludin ( OCLD ))) were determined in human colonic tissues. Colitis was induced in C57BL/6 mice by administration of DSS (5%, 5 days). Preventive CHR (2.5 mg/kg/day) treatment or vehicle started 1 day before colitis induction and lasted for 5 days. Disease activity index, macroscopic score, histological score and serum C-reactive protein were evaluated. Mouse colonic CAMs, AAMs markers and TJ proteins were assessed using ELISA/RT-qPCR. CHR (200 ng/ml) treated naïve peritoneal macrophages were exposed for 6 h to LPS (100 ng/ml) to promote CAMs, or to IL-4/IL-13 (20 ng/ml) to promote AAMs. CAMs and AAMs markers were quantified. To gain more mechanistic insights, phosphorylated NF-κB levels were quantified in mice colonic mucosa and CAMs using Western Blot. In vitro chemotaxis activity of CHR (200 ng/ml) on naïve macrophages were assessed by transwell migration assay using MCP-1 (30 ng/ml) as a chemoattractant. Caco-2 epithelial cells were treated with CHR (1, 10, 100 nM/ml) for 24 h in the presence or absence of LPS (1μg/ml, 24 h) and proliferation, viability migration and TJ proteins were quantified by proliferation, MTT assay, wound healing and RT-qPCR . Moreover, to confirm CHR specificity, Scrambled CHR peptide was used as negative control for in-vivo and in-vitro experiments to show that a specific sequence rather than the amino acid composition is critical for CHR activity.

Results: mRNA expression of Exon-IV, AAMs and TJPs was decreased while CAMs and NF-κB activation were increased in UC patients compared to control, and Exon-IV expression correlated positively with AAMs, TJPs and negatively with CAMs & NFKB . Experimentally, CHR reduced the severity of colitis. In colitic CHR treated group, CRP, colonic Il6, Il1b, Tnfa , and CAMs markers ( Mcp1, Mip1a, Mip1b ) were decreased. Conversely, AAMs markers ( Il10, Arg1, Cmyc ) were increased. In vitro , CHR-conditioned CAMS expressed less Il6, Il1b, Tnfa, Mip1a, Mip1b, but more Cmyc when compared to LPS control condition. CHR-conditioned AAMs expressed more Arg1 when compared to IL-4/IL-13 control condition. CHR treatment reduced intracellular NF-κB activation in colitic mice and CAMs compared to controls. Moreover, CHR treatment decreased macrophages migration, increased epithelial cells proliferation, viability, migration and upregulated the expression levels of TJ proteins. Interestingly, CHR specificity and activity were verified by finding that scrambled CHR peptide did not modify the course of colonic inflammation, NF-κB activation, and the macrophages and epithelial cell barrier functions.

Conclusion: CHR treatment attenuates the severity of colitis and the inflammatory process via the modulation of macrophages’ functions, maintaining TJ barrier integrity and diminishing NF-κB activation. Targeting CHR may represent a promising new direction in the search for therapeutic targets and biomarkers associated with IBD.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP271 A ROLE FOR THE NADPH OXIDASES NOX1 AND P22PHOX IN VEO-IBD

S. Lipinski 1 , F. Tran 2 , B. Petersen 2 , S. Stengel 3 , M. Barann 3 , M. Jentzsch 1 , A. Franke 4 , S. Schreiber 5 , P. Rosenstiel 3

1 Institute of Clinical Molecular Biology, Kiel/Germany

2 Cell Biology, Institute of Clinical Molecular Biology, University of Kiel, Kiel/Germany

3 Institute Of Clinical Molecular Biology, University of Kiel, Kiel/Germany

4 Institute Of Clinical Molecular Biology, Kiel University, Kiel/Germany

5 University Hospital Schleswig-Holstein, Department for Internal Medicine, Schittenhelmstr. 12, 24105, Kiel/Germany

Contact E-mail Address: f.tran@ikmb.uni-kiel.de

Introduction: NOD2 is one of the most known IBD risk factors which has been well characterized genetically and functionally. In brief, NOD2 is a PAMP-recognizing receptor which mediates NK-kB-dependent signals upon stimulation with muramyl dipeptide (MDP). In previous studies we have shown that the production of ROS as a host defense mechanism is controlled by NOD2. Further, members of the group of the ROS-producing NADPH oxidases seem to play a critical role as they have been identified as novel molecular interactors of NOD2. Interestingly, a pediatric patient with very early onset IBD (Crohn's disease) who received whole genome sequencing harbours genetic variants in NOX1 and CYBA, two genes coding for two NADPH oxidases.

Aims & Methods: In this study, we aimed to investigate the role of the NADPH oxidases NOX1 and CYBA/p22phox in the context of ROS-mediated antimicrobial defense and their impact on the pathogenesis of chronic intestinal inflammation. In a DSS colitis model, we investigated the expression of NOX1 and CYBA/p22phox. In brief, wild type C57BL/6 mice received 2% DSS for 5 days before receiving regular drinking water. Intestinal epithelial cells were then detached from lamina propria using commercial dissociation kits. To functionally characterize the gene mutation in NOX1 and CYBA, we generated plasmids harbouring wild type (wt) and mutant (mu) variants found in the pediatric IBD case described. HEK293 cells were then transfected with NOX1/CYBA wt- or mu-vectors and production of ROS were measured using cDCFH assay. To evaluated the role of these variants in ROS-dependent bacterial clearance, HEK293 and Caco-2 cells were transfected with NOX1/CYBA wt and ko vectors or siNOX1, respectively, and then an infection with Listeria monocytogenes was performed. A Gentamicin protection assay (GPA) was then performed and colony forming units (CFU) were counted to determine intracellular bacterial survival rate. Furthermore, a luciferase assay for NF-kB activation was performed after knockdown of p22phox.

Results: In murine DSS colitis model, expression of CYBA/p22phox is upregulated in both epithelium and lamina propria, indicating an important role in intestinal inflammation. Overexpression of wt variants of NOX1 and CYBA led to increased production of ROS in HEK293 cells, whereas ROS production was ameliorated in cells overexpressing mu NOX1 and CYBA variants. Also, NOX1 and CYBA wt overexpression reduced bacterial survival in a GPA dramatically, indicating the inportance of NOX1 and CYBA in ROS-dependent intracellular bacterial clearance. On the contrary, overexpression of the patient's mutant variants of NOX1 and CYBA in HEK293 and Caco-2 cells led to less bacterial clearance and thus the count of CFU was significantly higher vs the wt variants. Vice versa knockdown of NOX1 is associated with higher bacterial cytoinvasion and decreased NF-kB activation.

Conclusion: NOX1 and p22phox are key modulators of ROS-dependent host defense against microbial pathogens. As potential interactors of NOD2 these oxidases may play crucial role in pathogenesis in very early onset IBD. However, further studies need to be performed to elucidate the role of NOX1 and p22phox.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP272 A NOVEL ORAL DOMAIN ANTIBODY TO TUMOUR NECROSIS FACTOR (TNF), ENGINEERED TO BE STABLE TO INTESTINAL PROTEASES, RESULTS IN HIGH CONCENTRATIONS OF ACTIVE COMPOUND DETECTED IN FAECES OF CROHN’S PATIENTS AFTER ORAL DOSING

J. Robinson 1 , S. Crowe 1 , M. West 1 , T. Carlton 1 , L. Maggiore 1 , G. Whale 1 , J. Ritter 2 , P. Irving 3 , S. Nurbhai 1

1 VHsquared Ltd, Cambridge/United Kingdom

2 Kings College London, London/United Kingdom

3 Dept. of Gastroenterology - Guy's and St Thomas' Hospital, London/United Kingdom

Contact E-mail Address: suhail.nurbhai@vhsquared.com

Introduction: Monoclonal antibodies to TNF have transformed the treatment options for patients with Inflammatory Bowel Disease (IBD). V565 is a novel oral domain antibody (Vorabody) to TNF engineered to be resistant to intestinal proteases. It is 115 amino acids (12.6 kDa) in size and neutralizes TNF in vitro with similar potency to adalimumab. In preclinical testing it has demonstrated in vitro resistance to degradation by intestinal proteases, rapid renal excretion following an intravenous bolus, and minimal absorption and good survival in the GI tract following oral dosing in monkeys. V565 is formulated in enteric coated mini-tablets designed to release active domain antibody at pH ≥6.5.

Aims & Methods: Following earlier demonstration of the safety and tolerability of high single and multiple doses of V565 in healthy volunteers, this study aimed to assess V565 pharmacokinetics following a single oral dose to patients with Crohn’s disease (CD). Six subjects with CD received a single dose of open label V565. Prior to dosing, the diagnosis of CD was confirmed by a gastroenterologist and a clinical assessment of severity was carried out. As this was primarily a pharmacokinetic study, patients were excluded if they required surgery, had a current abscess, a non-inflammatory stricture, or a history of obstruction. Serial blood samples were taken to assess systemic V565 exposure, and all stool samples were collected for up to three days after dosing for detection of faecal V565. In addition, urine was collected from all patients over periods 0–4 h, 4–8 h, 8–12 h and 12–24 h post dose.

Results: Two subjects with CD were dosed with a single 555 mg dose of V565. Following review by the study safety committee a further four subjects were dosed with a single 1665 mg dose of V565. Active V565 was detected in the faeces of all subjects. In the stool samples around 24 h after dosing V565 was detected at concentrations up to 84 µM.

Conclusion: V565, an oral domain antibody to TNF engineered to be resistant to intestinal proteases, resulted in high concentrations of active drug in the faeces of all Crohn’s patients following a single oral dose, demonstrating survival in the human GI tract. No drug was detected in any serum sample. The detection of active V565 in the urine 4–8 h after dosing of a subject with no evidence of enterovesical fistula suggests that V565 can access the lamina propria in the diseased state and that any V565 absorbed is rapidly cleared from the circulation. With this pharmacokinetic profile V565 may be beneficial as a potential oral treatment for IBD.

Disclosure of Interest: J. Robinson: J Robinson is an employee of the Sponsor company

S. Crowe: S Crowe is an employee of the Sponsor company

M. West: M West is an employee of the Sponsor company

T. Carlton: T Carlton is an employee of the Sponsor company

L. Maggiore: L Maggiore is an employee of the Sponsor company

G. Whale: G Whale is an employee of the Sponsor company

J. Ritter: J Ritter was a salaried employee of Quintiles at the time of the study; he has no other significant relationships

P. Irving: Lecture: AbbVie, Warner Chilcott, Ferring, Falk, Takeda, MSD, Janssen, Shire Research Support: MSD, Takeda Advisor: AbbVie, Warner Chilcott, Takeda, MSD, Vifor, Pharmacosmos, Topivert, Genentech, Hospira, Samsung Bioepis, VH2, Janssen, Pfizer

S. Nurbhai: S Nurbhai is an employee of the Sponsor company

TUESDAY, OCTOBER 31, 201715:45-17:15

QUALITY ASSURANCE IN COLONOSCOPY: ROOM FOR IMPROVEMENT? - ROOM B2____________________

OP273 SUSTAINED CHANGE IN COLONOSCOPY PRACTICE 3 YEARS AFTER INTRODUCTION OF QUALITY IMPROVEMENT IN COLONOSCOPY (QIC) BUNDLE

L.J. Neilson 1 , J.E. East 2 , P.T. Rajasekhar 3 , S. Dunn 4 , R. Bevan 5 , S. Paremal 4 , S. Esmaily 5 , C.J. Rees 1

1 Dept. Of Gastroenterology, South Tyneside District Hospital, South Shields/United Kingdom

2 Department Of Gastroenterology, Gastroenterology Unit, John Radcliffe Hospital Oxford/United Kingdom

3 Gastroenterology, North Tyneside District Hospital Dept. of Gastroenterology Northern Region Endoscopy Group, North Shields/United Kingdom

4 Dept. Of Gastroenterology, James Cook University Hospital, Middlesbrough/United Kingdom

5 Gastroenterology, University Hospital of North Tees, Stockton on Tees/United Kingdom

Contact E-mail Address: neilson.laurajane@hotmail.co.uk

Introduction: Adenoma detection rate (ADR) is the most widely used contemporaneous measure of colonoscopy quality. Low ADRs are associated with higher post-colonoscopy colorectal cancer rates and poorer patient outcomes.(1) A study implementing a “bundle” of evidence-based interventions demonstrated practice change and ADR improvement driven by improvements amongst the poorest performing colonoscopists.(2) Interventions were: withdrawal time ≥6 minutes; hyoscine butylbromide use; position change; rectal retroflexion. We assessed whether practice change and ADR improvements were sustained 3 years following intervention.

Aims & Methods: We aimed to identify if changes in colonoscopy practice were sustained three years following the initial "bundle" implementation. Data were collected from the original study sites, including ADR and hyoscine butylbromide (Buscopan) use. Hyoscine butylbromide usage rate was used as a marker for uptake of the bundle implementation. Comparisons were made with baseline data collected for 3 months prior to bundle implementation and for a duration of 9 months following completion. Sustainability data were collected for 6 months, 3 years following implementation. Data were compared globally, by endoscopy unit and by quartile, where colonoscopists were ranked by baseline ADR. Multilevel logistic regression analyses were undertaken.

Results: 12 endoscopy units housed within 8 UK NHS Trusts participated. Global analyses included data from a total of 184 colonoscopists and 28615 procedures. Quartile analyses included data from 50 colonoscopists and 14435 procedures. Hyoscine butylbromide use significantly rose and was sustained above baseline globally in all endoscopy units and quartiles. A sustained ADR increase (18.2%) was observed globally. Quartile analyses demonstrated that improvement was most marked in the lowest colonoscopist quartile (Table 1).

Conclusion: A simple, evidence-based intervention changed colonoscopy practice, as evidenced by increased Hyoscine Butylbromide use in all quartiles and endoscopy units. As a result ADR was improved. These effects were sustained 3 years following implementation, suggesting this approach is a feasible and durable means of improving ADR, particulary in groups with lower ADRs, with minimal resources.

Disclosure of Interest: L.J. Neilson: Research post previously partly funded by Aquilant endoscopy

J.E. East: Clinical advisory board: Lumendi, Boston Scientific Research support: Olympus, Cosmo Pharmaceuticals

P.T. Rajasekhar: Previous travel and speaking grant for Olympus invited talk

S. Dunn: Dr Dunn previously undertook a research post funded by Aquilant Endoscopy.

R. Bevan: Dr Bevan has previously been awarded a competitive travel grant by Cook Endoscopy.

C.J. Rees: Colin Rees has received research grants from ARC medical, Olympus Medical, Aquilant endoscopy, Norgine, travel grants from Boston scientific and Cook medical and speaking grants from Norgine and Olympus

All other authors have declared no conflicts of interest.

References

1. Corley DA et al. Adenoma Detection Rate and Risk of Colorectal Cancer and Death. N Engl J Med 2014;370(14):1298–306

2. Rajasekhar PT et al. A multicenter pragmatic study of an evidence-based intervention to improve adenoma detection: the Quality Improvement in Colonoscopy (QIC) study. Endoscopy 2015;47(3):217–24

OP274 VARIATION BETWEEN PATHOLOGICAL MEASUREMENT AND ENDOSCOPIC ESTIMATED SIZE OF COLONIC POLYPS

C. Atalaia Martins , P. Marcos, S. Barbeiro, A. Fernandes, A. Santos, L. Eliseu, C. Gonçalves, I. Cotrim, H. Vasconcelos

Gastrenterology, Centro Hospitalar de Leiria, Leiria/Portugal

Contact E-mail Address: catarinatalaiamartins@gmail.com

Introduction: Current guidelines about post-polypectomy colonoscopy surveillance take in count size, number, villous component and high-grade dysplasia of resected polyps to stratify patients’ risk and determine surveillance intervals. Regarding size, 10 millimeters is the cut-off to classify an adenoma as an advanced adenoma. Polyp size is visually estimated during the colonoscopy. Is a two-dimensional subjective evaluation with significant variability among endoscopists. The pathological size results from the measurement with a ruler after excision and fixation with formalin. Is not consensual what measurement should be consider to determine surveillance colonoscopy: endoscopic or pathological.

Aims & Methods: The aim of this study was to evaluate variation between colonic polyp size reported by the endoscopist and its pathological size. All colonoscopies performed by 7 experienced colonoscopists during a 12-month period in our center were retrospectively analyzed. The inclusion criteria were (1) adenomatous polyps excised in a single specimen; (2) not fragmented during retrieval; (3) exact documentation of endoscopic estimated size and resection method. The exclusion criteria (1) polyps greater than 25 millimeters; (2) unclear size (not reported or reported imprecisely); (3) more than one polyp placed in the same recipient after retrieval; (4) patients with inflammatory bowel disease and (5) history of colorectal cancer. Statistical analysis was performed with SPSS v.23 (descriptive and inferential statistics: Chi-2, ANOVA and Kruskal-Wallis).

Results: A total of 3997 colonoscopies were analyzed and 573 polyps were included (507 patients: 58.3% male, mean age 65 years old) corresponding to 82 polyps per endoscopist. Polyps morphology (Paris classification): 71.4% were sessile (0-Is), 20.1% were pedunculated (0-Ip), 5.4% were subpenduculated (0-Isp) and 3.2% were flat elevated (IIa). Method of excision was hot snare polypectomy in 68.2%, biopsy forceps in 16.2%, cold snare polypectomy in 10.8% and endoscopic mucosal resection (EMR) in 4.7%. In 62.1% the endoscopist overestimated polyp size when compared with pathological size; in 8.7% with a difference greater than or equal to 5 millimeters. Overestimation was significatively more frequent in EMR technique (70.4% vs. 48.4% in biopsy forceps; p = 0, 025) as well as overestimation greater than or equal to 5 millimeters (37% vs. 10.2% in hot snare polypectomy vs 0% in cold snare polypectomy and biopsy forceps, p = 0.001). Table 1 resumes the pathological-endoscopic variation based on the method of excision.

Conclusion: There is a considerable variability between the endoscopic estimated size and pathological size. In our study endoscopists tend to overestimate the polyp size. The overestimation was more evident in EMR, suggesting that larger polyps are probably more overestimated than smaller ones. The pathological-endoscopic variation is significantly correlated with each endoscopist.

Disclosure of Interest: All authors have declared no conflicts of interest.

References

1. Eichenseer PJ., Dhanekula R., Jakate S. et al. Endoscopic mis-sizing of polyps changes colorectal cancer surveillance recommendations. Dis Col Rectum 2013; 56: 315–321.

2. Rubio C.; Grimelius L, Lindholm et al. Reliability of the reported size of removed colorectal polyps. Anticancer Res 2006; 26: 4895–4900.

3. Turner J., Wright M., Morgan M. et al. A prospective study of the accuracy and concordance between in-situ and postfixation measurements of colorectal polyp size and their potential impact upon surveillance. Gastrointest Endosc 2014; 80: 652–659

4. Moug SJ, Vernall N., Saldanha J. Endoscopists’ estimation of size should not determine surveillance of colonic polyps. Colorectal Dis 2010; 12: 646–650.

OP275 SHOULD WE RESECT AND DISCARD SMALL AND DIMINUTIVE POLYPS?

S. Mifsud 1 , E. L. Schembri 1 , M. Muscat 1 , P. Ellul 1

1 Medicine, Mater Dei Hospital, Msida/Malta

Contact E-mail Address: pierre.ellul@gov.mt

Introduction: Small (6–9 mm) and diminutive (1–5 mm) colonic polyps are frequently encountered during colonoscopy. Diminutive polyps rarely have advanced histological features. 1 To date histology is the gold standard for polyp assessment. However, data has demonstrated inter-observer histo-pathological disagreement ranging from 0.84 to 0.98 in differentiating between adenomas and hyperplastic polyps. 2 Due to the relatively high prevalence and clinical insignificance of small left-sided hyperplastic polyps, there is a substantial—and unwarranted—cost burden associated with the removal and pathologic examination of these lesions. In an era characterized by limited economic resources, the resect-and-discard strategy would lead to substantial cost-saving due to the elimination of pathology fees. 1 Furthermore, this strategy could allow patients to learn the timing of their next colonoscopy before being discharged, thus avoiding the psychological impact of waiting for a definitive diagnosis and surveillance plan.

Aims & Methods: The aim of this study was to identify the histological features of diminutive and small polyps and verify the possible role in the introduction of the resect-and-discard strategy in routine clinical practice. Patients who underwent polypectomy in 2016 were identified through our endoscopy database and those who had polyps <1 cm were recruited.

Results: 156 patients (females - 55%) were identified. The mean age was 58.4 years (50–75 years). There were 282 polyps of which 183 (64.9%) were diminutive as shown in Table 1. 69.8% (n = 197) of all polyps were left sided and 58.8% (n = 116) of these were hyperplastic. Meanwhile only 13.3% of right sided polyps were hyperplastic. This difference in histology was statistically significant (p < 0.0001). Adenocarcinoma was found in 2 left sided polyps (both 9 mm in size). Table 1

Conclusion: This data demonstrates that left-sided diminutive polyps (<5 mm) identified at endoscopy are likely safe to resect and discard. However, small polyps (>5 mm) warrant histological assessment as they may harbour carcinoma. Furthermore, accurate endoscopist analysis of size and pit pattern is of paramount importance in the management of colonic polyps.

Disclosure of Interest: All authors have declared no conflicts of interest.

References

1. Wilson A. Optical diagnosis of small colorectal polyps during colonoscopy: When to resect and discard? Best Practice and Research Clinical Gastroenterology. 2015;29(4):639–649.

2. Radaelli F. The Resect-and-Discard Strategy for Management of Small and Diminutive Colonic Polyps. Gastroenterology & Hepatology . 2013;9(5):305–308.

OP276 APPROPRIATE INTERVALS TO LOOK FOR LOCAL RECURRENCE AFTER ENDOSCOPIC TREATMENT OF COLORECTAL NEOPLASMS

Y. Komeda 1 , H. Kashida 1 , T. Sakurai 1 , T. Nagai 1 , S. Matsui 1 , M. Kudo 2

1 Department Of Gastroenterology And Hepatology, Kindai University Faculty of Medicine, Osaka/Japan

2 Gastroenterology And Hepatology, Kindai University, Osaka/Japan

Contact E-mail Address: y-komme@mvb.biglobe.ne.jp

Introduction: Appropriate intervals for repeat endoscopy to look for a possible local recurrence after endoscopic resection have not been established.

Aims & Methods: The aims of this study were to clarify clinicopathological characteristics of recurrent tumors after endoscopic resection and to determine appropriate follow-up intervals for repeat colonoscopy. The objects were 4236 colorectal lesions which were treated with endoscopic resection at our hospital from January 2010 to December 2015. Patients with inflammatory bowel disease, patients with polyposis were excluded from the study. The breakdown of therapeutic method was ESD: 375, EMR (including piecemeal EMR): 3390, and polypectomy (including cold polypectomy, hot biopsy): 471. The endoscopic reports and medical charts were retrospectively analyzed.

Results: Local recurrence occurred in 31 lesions (0.7% 31/4236). Male:female ratio was 24:7. There was no speicific tendency concirning. Original size of the tumor was 30 mm in average (6–80). Median period between the initial resection and the recurrence was 6 months (2–15). Re-recurrence was encounterd in 8 patients (8/31, 26%), but curative treatment was finally achieved with additional endoscopic treatment including EMR, ESD, polypectomy, hot biopsy, and APC or their combination. In cases where the initial resection was complete en-bloc resection, there was no recurrence. The recurred lesion was completely cured when it was treated with ESD. All patients with local recurrence were those in whom the treatment had resulted in piecemeal resection or in complete resection with tumor positive margin. Most of the recurrent lesions were endoscopically treatable except for 2 invasive lesions. Our recommendation for the interval before repeat colonoscopy: a. 1–3 months in cases with piecemeal resection >5 pieces (high risk for recurrence). b. 4–6 months in cases with piecemeal resection <4 pieces (moderate risk for recurrence). c. 6 months in cases with en-bloc resection for cancer. d. At least 12 months after en-bloc resection for adenoma (very low risk for recurrence).

Conclusion: The interval before a repeat colonoscopy after endocopic resection for colorectal neopalsms should be determined based on the number of pieces (one, <4, or >5) and on the completeness of the resection (positive or free margin).

Disclosure of Interest: All authors have declared no conflicts of interest.

Reference

Local recurrence after endoscopic resection for large colorectal neoplasia: a multicenter prospective study in Japan. Oka S, et al. Am J Gastroenterol . 2015.

OP277 OPTICAL DIAGNOSIS OF T1 COLORECTAL CANCER AMONGST ACCREDITED ENDOSCOPISTS IN A NATIONWIDE BOWEL CANCER SCREENING PROGRAM

J. L.a. Vleugels 1 , L. Koens 2 , Y. Hazewinkel 1 , P. Fockens 1 , E. Dekker 1 , O.B.O.T. Discount Study Group 1

1 Gastroenterology And Hepatology, Academic Medical Center, Amsterdam/Netherlands

2 Pathology, Academic Medical Center, Amsterdam/Netherlands

Contact E-mail Address: j.l.vleugels@amc.uva.nl

Introduction: Endoscopic recognition of early stage colorectal cancer (CRC) is of increasing importance due to the worldwide implementation of CRC screening programs. Accurate optical diagnosis of early stage CRCs (T1 CRCs) can guide treatment strategies. So far, little is known about the identification and endoscopic removal of T1 CRCs in a fecal immunochemical test (FIT)-based screening program. The aim of this study was to examine whether endoscopists performing colonoscopies in a FIT-based screening program are able to identify T1 CRCs correctly and to describe the treatment approaches towards these T1 CRCs.

Aims & Methods: In a prospective multicentre study, endoscopists accredited for FIT-positive colonoscopies within the Dutch bowel cancer screening program were trained in optical diagnosis with our validated NICE-WASP module. A total of 27 endoscopists completed the training successfully and entered the prospective study, in which the endoscopists as well as pathologists reported their findings in a predefined structure. Endoscopists recorded endoscopic diagnosis (adenoma, hyperplastic polyp, sessile serrated lesion and CRC) of every lesion in all consecutive FIT-positive colonoscopies for the Dutch screening program during one year. Two by two contingency tables were created to calculate sensitivity and specificity. T1 CRC was defined as CRC confined to the submucosa without invasion of the muscularis propria at histopathological evaluation.

Results: Between February 2015 and February 2017, 27 endoscopists recorded histology predictions during 3, 622 FIT-positive colonoscopies. During these colonoscopies, 287 patients (7.9%) were diagnosed with CRC. Overall, sensitivity of optical diagnosis of CRC was 76.0% (95% CI; 70.7–80.8) and specificity 99.7% (95% CI 99.6–99.8). In 107 (37%) patients with CRC, a total of 110 T1 cancers were detected (table 1). T1 CRCs had a median size of 20 mm (range 6–100 mm) and were predominantly located in the rectosigmoid (83%). Of these 110 T1 cancers, 41 (37%) were correctly predicted as CRC. Of these 41 correctly diagnosed CRCs, 18 were removed endoscopically en 23 were referred for surgical treatment because of suspicion of invasive cancer (N = 16), non-lifting sign (N = 4) or preference for TEM (N = 3). Of the 69 non-recognized T1 CRCs, 67 were endoscopically removed and 2 were referred for surgical treatment because of their size. Piecemeal removal was performed in 15 unrecognized T1 cancers and the remaining 52 were removed en-bloc. After histopathological evaluation, resection margins showed invasive growth in 13 non-recognized T1 cancers and in 17 cases resection margins could not be assessed. In 43 patients, an additional colonoscopy had to be performed to mark the previous endoscopic resection site of the T1 cancer after histology outcome. In total, adjuvant surgical treatment was required in 3 (7%) patients with recognized T1 CRCs compared to 29 (42%) of patients with non-recognized early stage cancers.

Conclusion: In a prospective study in which endoscopists were trained in optical diagnosis, approximately two-thirds of the T1 CRCs were not recognized during consecutive FIT-positive colonoscopies leading to suboptimal use of endoscopic and surgical treatment options. Training in structured lesion assessment is needed to improve endoscopic recognition of T1 CRCs and ensure optimal treatment strategies ( NCT02516748 ).

Disclosure of Interest: P. Fockens: P. Fockens provides ongoing consultancy to Cook, Olympus, Medtronic, and Fujifilm.

E. Dekker: Dekker has equipment on loan from Olympus Europe and Fujifilm, has received a research grant from Olympus Europe and Fujifilm, and consulted for Tillotts Pharma (one time).

All other authors have declared no conflicts of interest.

OP278 TIME TO POLYPECTOMY COMPETENCY IN THE UK: RETROSPECTIVE ANALYSIS OF 1633 DOPYS FROM 131 TRAINEES

A. Rajendran 1 , S. Thomas-Gibson 2 , P. Bassett 3 , R. Rameshshanker 2 , P. Dunckley 4 , N. Sevdalis 1 , A. Haycock 5

1 Centre Of Implementation Science, Kings' College London, London/United Kingdom

2 Imperial College London, London/United Kingdom

3 Stats Consultancy, Amersham/United Kingdom

4 Gloucestershire Royal Hospital, Gloucester/United Kingdom

5 Wolfson Endoscopy Unit, St. Marks Hospital Wolfson Endoscopy Unit, London/United Kingdom

Contact E-mail Address: arun.rajendran@kcl.ac.uk

Introduction: Directly Observed Polypectomy Skills (DOPyS) is a validated tool used to assess polypectomy technique 1 . In the UK, trainees are certified as competent in Level 1 (<1 cm) & Level 2 (1–2 cm) polypectomy if they achieve overall scores 3 or 4 in their last 4 consecutive DOPyS, alongside other key performance indicators. It is envisaged that all independent endoscopists should be competent in Level 2 polypectomy 2

Aims & Methods: The aim was to examine time & association of procedure intensity for level 1 (provisional) & level 2 polypectomy (full certification). Procedure intensity (PI) was defined as the "average number of lower gastrointestinal procedures per month performed by the trainee". Retrospective data was extracted from the JETS database (Jan 2009 to Sept 2015) on 131 trainees (1633 DOPyS) from the time of their first DOPyS (1st DOPyS) up to achieving provisional & full certification. As not all trainees achieved full certification, the analysis was performed using survival analysis methods. Data from trainees who didn’t achieve each type of certification were statistically censored at the time of last measurement. Cox regression was used to examine PI association with the time to achieving certification. Kaplan-Meier graphs were used to show the proportion of trainees who achieved certification at different points in time.

Results: The analysis showed that: · 38% of trainees had reached provisional certification by one year, 74% by two years, 94% by three years, & 99% by four years of the 1st DOPyS. · 5% of endoscopists had reached full certification after one year, 33% after two years, 50% by three years and 87% after four years from 1st DOPyS There was some evidence that PI at 1st DOPyS was associated with time to provisional (P = 0.06) and time to full certification (P = 0.08). A higher baseline PI was associated with a higher probability of obtaining polypectomy competency/certification in a shorter timescale A five-unit increase in baseline PI was associated with a 25% increase in the chance of obtaining provisional & 17% increase in obtaining full certification status at any time.

Conclusion: In the UK, the majority (94%) of trainees achieve level 1 polypectomy competency within 3 years of 1st DOPyS, but only 50% achieve Level 2 polypectomy competency in the same time. Increasing procedure intensity (PI) to an average of >10 procedures/month may shorten the learning curve to polypectomy competency/full certification. Current data collection only allows the estimation of learning curve by time and DOPyS documented & not the number of polypectomies performed. There is ongoing work to establish the learning curve based on number of polypectomies.

Disclosure of Interest: All authors have declared no conflicts of interest.

References

1. Gupta, S., et al., Validation of a novel method for assessing competency in polypectomy. Gastrointest Endosc , 2012. 75(3): p. 568–75.

2. JAG, T. Colonoscopy certification pathway. 2011 03/08/2015]; Available from: http://www.thejag.org.uk/downloads/JAG Certification for trainees/Colonoscopy application criteria and process.pdf.

TUESDAY, OCTOBER 31, 201715:45-17:15

EMERGING BIOMARKERS IN GI CANCER MEDICINE - ROOM B3____________________

OP279 NOVEL COMBINATION OF CIRCULATING MICRORNAS FOR DETECTION OF EARLY GASTRIC CANCER

S. Abe 1 , J. Matsuzaki 2 , K. Sudo 3 , I. Oda 1 , H. Katai 3 , K. Kato 3 , J. Kawauchi 4 , S. Takizawa 4 , H. Sakamoto 5 , F. Takeshita 2 , S. Niida 6 , Y. Saito 1 , T. Ochiya 5

1 Endoscopy Division, National Cancer Center Hospital, Tokyo/Japan

2 Division Of Molecular And Cellular Medicine, National Cancer Center Research Institute, Tokyo/Japan

3 National Cancer Center Hospital, Tokyo/Japan

4 Toray Industries, Kamakura/Japan

5 National Cancer Center Research Institute, Tokyo/Japan

6 National Center for Geriatrics and Gerontology, Aichi/Japan

Contact E-mail Address: seabe@ncc.go.jp

Introduction: A combination of the detection of serum anti- Helicobacter pylori antibody and measurement of the level of serum pepsinogens has been used in screening for early gastric cancer (EGC). However, there are several issues which need to be improved. MicroRNAs (miRNAs) circulating in peripheral blood have been reported to be potentially useful for detecting cancer. The aims of this study are 1) to identify specific serum miRNAs and establish the discriminant model for EGC detection, 2) to validate the miRNAs and the discriminant model using a large cohort.

Aims & Methods: This retrospective study included 1417 serum samples of patients with EGC stored at the National Cancer Center Biobank between 2008 and 2012. In addition, 5051 serum samples of non-cancer patients stored at the National Center for Geriatrics and Gerontology Biobank and healthy volunteers who were recruited in the Toray Industries and the Yokohama Minoru Clinic between 2010 and 2015 were used as control. miRNA expression profiles of whole serum samples were comprehensively evaluated using highly sensitive microarray analysis with DNA chip (3D-Gene®) which was designed to detect 2555 miRNA sequences registered in miRBase release 20. Diagnostic models were constructed using the expression levels of several miRNAs in the discovery cohort and the diagnostic performances of the model were evaluated in the validation cohort.

Results: Patients and lesions characteristics of gastric cancer were as follows; male/female = 1001/416, median age (range) = 66 (20–90), stage IA/IB/II = 1349/58/10, differentiated-type/undifferentiated-type/special type = 811/588/18. The discovery cohort included 708 patients with EGC and 708 non-cancer controls. A diagnostic model for EGC detection constructed by a combination of the five miRNAs (miRNA A, B, C, D, and E) had a sensitivity of 99% and specificity of 97% with 0.99 of area under curve (AUC). The validation cohort included 709 patients with EGC and 4343 non-cancer controls. The diagnostic model could accurately discriminate EGC from the three kinds of non-cancer cohorts with a sensitivity of 99% and a specificity of 97% with 0.99 of AUC. The diagnostic accuracies of the model were equivalent among the stage (sensitivities of 98%, 100% and 100% in IA, IB and II respectively) and major histological types (sensitivities of 98%, 99%, and 100% in differentiated-type, undifferentiated-type, and special types, respectively).

Conclusion: Novel combination of serum miRNAs could be useful diagnostic biomarkers to detect EGC detection with high accuracy. Further prospective studies are warranted to confirm the diagnostic performance of the model.

Disclosure of Interest: K. Kato: I have the following financial relationships to disclose. corporate-sponsored research, ONO, Shionogi, MSD

J. Kawauchi: Employee of Toray Industries, Inc.

S. Takizawa: Employee of Toray Industries, Inc.

T. Ochiya: I have the following financial relationships to disclose. Kyowa Medex, Kewpie Corporation, Takeda, Rohto Pharmaceutical Co., Ltd.,

Japan Atherosclerosis Research Foundation, Inter Stem, BioMimetics Sympathies

All other authors have declared no conflicts of interest.

OP280 CIRCULATING TUMOR DNA FOR MONITORING COLORECTAL CANCER – RELATIONSHIP TO TISSUE METHYLATION, CANCER CHARACTERISTICS AND COMPLETENESS OF RESECTION

G. Young 1 , E. Symonds 2 , D. Murray 3 , S. Pedersen 3 , S. Byrne 1 , P. Rabbitt 4 , R. Baker 3

1 FCIC, Flinders University, Adelaide/Australia

2 Bowel Health Service, Repatriation General Hospital, Daw Park/Australia

3 Clinical Genomics P/L, Sydney/Australia/NSW

4 Lyell McEwin Hospital, Adelaide/Australia

Contact E-mail Address: graeme.young@flinders.edu.au

Introduction: BCAT1 and IKZF1 are frequently methylated in colorectal cancer (CRC) tissue and are detectable in blood as cell-free tumour-derived DNA (ctDNA) [1]. Better markers for adequacy of initial therapy would allow identification of subjects at high risk for recurrence or in need of extended initial therapy such as addition of or prolongation of chemotherapy. A prospective correlative biomarker study in CRC was conducted to explore how these ctDNA biomarkers might aid management of patients diagnosed with CRC and to better understand how detection of such ctDNA relates to cancer characteristics, methylation in tissue, and completeness of surgical resection of the primary cancer.

Aims & Methods: Patients with invasive CRC were followed for at least 12 months after surgical resection of the primary cancer. Blood collected at diagnosis and after surgery was assayed for presence of methylated BCAT1 and IKZF1. The level of methylation of the two markers was also determined in surgically removed cancer and adjacent non-neoplastic tissue. Modelling by logistic regression was used to compare patient and cancer characteristics, including location, size, stage, and morphology, as well as surgical pathology, between those positive or negative for either marker in plasma. The primary outcome for comparison was complete surgical resection (clear margins, absence of distant metastases and lack of apical node involvement as a strong suspicion of residual disease).

Results: Of 189 cases with peri-diagnostic blood collected, 91 cases also had matched tissue samples and 93 cases had at least one post-surgical blood sample available for marker assay. ctDNA was detected in the blood of 119/189 (63.0%) of cases at diagnosis and was significantly more likely to be detected with later stage and distal location (all p < 0.01). The mean BCAT1 and IKZF1 methylation in cancer tissues were 48.0% and 60.5% (respectively), compared to 6.8% and 0.4% in non-neoplastic tissues (each p < 0.0001). Detectable methylation of either marker was seen in 90/91 (98.9%) cancer tissues. Tissue methylation levels in cancer were not concordant with detection in blood or affected by any of the aforementioned variables affecting ctDNA detection. A finding of a post-surgical ctDNA positive result was most strongly associated with incomplete surgical resection (OR 31.2, 95% CI 3.4–291.2). Thirty-five of the 47 (74.5%) ctDNA-positive CRC patients at diagnosis who provided a post-surgical sample became negative after surgery, most within 3–4 months. Of the 12/47 cases who remained ctDNA positive after surgery, incomplete surgical resection was observed in 5/12 (41.7%) compared to 1/35 (2.9%) who became negative (p = 0.003, Fisher Exact test). In all 93 cases providing a post-surgery blood sample, incomplete surgical resection or strong suspicion of residual disease was more likely in those returning a positive ctDNA result than in those with a negative result (5/17, 29.4%, vs 1/76, 1.3%, p = 0.001).

Conclusion: BCAT1 and IKZF1 methylation are common events in CRC and presence of methylated ctDNA in blood is dependent on cancer stage (AJCC and TNM) at diagnosis rather than whether or not these markers are methylated in cancer tissue, which is near ubiquitous. Following primary cancer resection, a positive ctDNA result is associated with a significantly higher likelihood of incomplete surgical resection. Consequently, this test has the potential to allow dynamic monitoring of tumour bulk. Detection of methylated BCAT1/IKZF1 DNA in blood appears clinically useful for assessing adequacy of initial therapy and potential for recurrence.

Disclosure of Interest: G. Young: Paid consultant of Clinical Genomics P/L.

D. Murray: I am a paid employee of Clinical Genomics P/L.

S. Pedersen: I am a paid employee of Clinical Genomics P/L.

R. Baker: I was a paid employee of Clinical Genomics P/L at the time the study was conducted.

All other authors have declared no conflicts of interest.

Reference

1. Young GP, et al. A cross-sectional study comparing a blood test for methylated BCAT1 and IKZF1 tumor-derived DNA with CEA for detection of recurrent colorectal cancer. Cancer Medicine . 2016; 5:2763–2772

TUESDAY, OCTOBER 31, 201715:45-17:15

RANDOMISED CONTROLLED TRIALS IN FUNCTIONAL LOWER GI DISORDERS - ROOM 7.1____________________

OP281 PRELIMINARY RESULTS OF A RANDOMISED CONTROLLED TRIAL ON HYPNOTHERAPY FOR IRRITABLE BOWEL SYNDROME (THE IMAGINE STUDY)

C. Flik 1 , Y. R. Van Rood 2 , W. Laan 1 , A. Smout 3 , B.L. a.m. Weusten 4 , P. Whorwell 5 , N.J. De Wit 6

1 Julius Center, University Medical Centre Utrecht Julius Centre Health Sciences and Primary Care, Utrecht/Netherlands

2 Psychiatric Policlinic, Leids University Medical Centre, Leiden/Netherlands

3 Department Of Gastroenterology And Hepatology, Academic Medical Center - Department of Gastroenterology and Hepatology, Academic Medical Center; Am, Amsterdam/Netherlands

4 Dpt. Of Gastroenterology And Hepatology, Universy Medical Center Utrecht, Utrecht/Netherlands

5 Medicine, University of Manchester Wythenshawe Hospital, Manchester/United Kingdom

6 Julius Center For Health Sciences And Primary Care, UMC Utrecht Julius Center for Health Sciences and Primary Care, Utrecht/Netherlands

Contact E-mail Address: c.e.flik@umcutrecht.nl

Introduction: Irritable Bowel Syndrome (IBS) is a common functional gastro-intestinal disorder, characterized by abdominal pain, discomfort and altered bowel habits, often accompanied by symptoms of bloating and distension. In general the efficacy of drug therapies is limited. Although individual hypnotherapy was demonstrated to be cost-effective for secondary care patients with IBS, implementation in primary care is limited due to lack of therapists. Therefore group sessions of hypnotherapy may better facilitate large scale implementation, but the non-inferiority of group application needs to be established first.

Aims & Methods: We designed the IMAGINE-study to assess the overall benefit of hypnotherapy as well as to compare the efficacy of individual versus group hypnotherapy in the treatment of IBS. We designed a randomized placebo-controlled trial with 354 primary and secondary care patients (aged 18–65) with IBS (Rome-III criteria). Patients were randomly allocated to either 6 bi-weekly sessions of individual hypnotherapy, 6 bi-weekly sessions of group hypnotherapy or 6 bi-weekly sessions of educational supportive therapy in a group (placebo), with a follow-up of 9 months post treatment for all patients. Thirteen hospitals in different parts of The Netherlands collaborated in this study. The primary endpoint was the percentage of patients with adequate relief (AR) of IBS symptoms after 12 months. AR was defined as 3 or 4 weeks out of 4 weeks adequate relief from IBS complaints. Secondary efficacy parameters were changes in the IBS symptom severity, quality of life, cognitions, psychological complaints, self-efficacy as well as direct and indirect costs of the condition. Hypnotherapy was expected to be more effective than the control therapy, and group hypnotherapy was expected not to be inferior to individual hypnotherapy (<15% difference).

Results: Follow-up will be finished by the end of 2017. We present the preliminary results after three months. Of the 354 randomized patients, 150 patients were allocated to individual hypnotherapy, 150 to group hypnotherapy and 54 patients to the educational support group therapy. Of these patients 79.6%, 81.3% and 84% respectively completed 6 sessions of therapy, all within 3 months after start. Of those who completed the therapy 40.4% of the patients in the individual hypnotherapy, 33.7% of the patients in the group-hypnotherapy and 17.1% (p = 0.041) of the patients in the educational support group had adequate relief of symptoms after 3 months.

Conclusion: After 3 months of treatment hypnotherapy is more effective in patients with IBS than placebo. Group administration of hypnotherapy is not inferior to individual hypnotherapy. Group sessions may stimulate large-scale implementation.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP282 INDIVIDUAL VERSUS GROUP HYPNOTHERAPY FOR IBS: A RANDOMIZED CONTROLLED TRIAL

J. Lövdahl 1 , O.S. Palsson 2 , G. Ringström 1 , H. Törnblom 3 , M. Simrén 4

1 Internal Medicine & Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg/Sweden

2 Dept. Of Medicine, University of North Carolina, Chapel Hill, Chapel Hill, NC/United States of America/NC

3 Dept Of Gastroenterology And Hepatology, Sahlgrenska Academy Faculty of Medicine, Gothenburg/Sweden

4 Dept Of Internal Medicine, Sahlgrenska University Hospital - Dept of Internal Medicine, Sahlgrenska University Hospital; Gothe, Gothenburg/Sweden

Contact E-mail Address: jenny.lovdahl@vgregion.se

Introduction: Gut-directed hypnotherapy, delivered individually or in groups, improve symptoms in patients with irritable bowel syndrome (IBS). Using group hypnotherapy for IBS would increase cost-effectiveness of this treatment, but only one very small parallel comparison between individual and group hypnotherapy has been published.

Aims & Methods: We aimed to evaluate and compare the effectiveness of hypnotherapy for IBS delivered in individual versus group format. We included 119 IBS-patients (mean age 41, 19–70 years; 87 women) with symptoms refractory to standard management, who were randomized to receive individual or group hypnotherapy. They attended eight sessions based on the North Carolina Hypnotherapy Protocol (Palsson) delivered by one nurse specialized in hypnotherapy, during a period of twelve weeks. The groups consisted of 5–8 patients. IBS symptom severity was assessed by the IBS Severity Scoring System (IBS-SSS), and subjective health was evaluated by the Short Health Scale (SHS), at baseline and after the 12 week hypnotherapy treatment period, at visit 8. A reduction of IBS-SSS ≥ 50 compared with baseline at visit 8 was considered a response to treatment.

Results: Sixty-one patients received individual treatment, 58 patients hypnotherapy in groups. Eleven patients (4 individual, 7 group) did not complete the treatment, but were included in the ITT-analysis. Groups were comparable at baseline regarding age, gender, IBS symptom severity (IBS-SSS) and subjective health (SHS). At the end of the treatment (visit 8) the patients in both groups reported improvement of IBS symptoms, as well as subjective health (SHS) (table 1). Improvement was observed for all five IBS-SSS domains (pain intensity, pain frequency, bloating severity, bowel habit dissatisfaction and daily life interference) (p < 0.001), as well as for all four subjective health domains of SHS (symptom burden, daily function, disease-related worry and general well-being) (p < 0.001). There were no differences between the treatment arms in regard to improvement in IBS-symptoms (p = 0.16) or subjective health (p = 0.17). Sixty-nine percent of the individual hypnotherapy patients met the responder criterion at the end of treatment, compared to 57% of group hypnotherapy patients (p = 0.25).

Conclusion: Both individual and group hypnotherapy is effective and relieves IBS symptoms and improves subjective health in patients with IBS. Although the proportion of responders was larger among the patients who received individual therapy, no statistically significant differences in overall improvement in GI symptoms were seen between treatment arms. Group hypnotherapy may therefore be a way to deliver effective IBS hypnotherapy at less cost. Further investigation regarding possible predictors of response to the different treatments could facilitate the choice of the most adequate treatment for each patient.

Disclosure of Interest: O.S. Palsson: Received research grants from Ironwood Pharmaceuticals, Takeda Pharmaceuticals, and Salix Pharmaceuticals and the Rome Foundation.

H. Törnblom: Has served as Consultant/Advisory Board member for Almirall and Allergan as a speaker for Tillotts, Takeda, Shire and Almirall.

M. Simrén: Has received unrestricted research grants from Danone and Ferring Pharmaceuticals, and served as a Consultant/Advisory Board member for AstraZeneca, Danone, Nestlé, Menarini, Almirall, Allergan, Albireo, Glycom and Shire

All other authors have declared no conflicts of interest.

OP283 EFFECT OF LACTOBACILLUS PARACASEI CNCM I-1572 ON SYMPTOMS, GUT MICROBIOTA, SHORT CHAIN FATTY ACIDS, AND IMMUNE ACTIVATION IN PATIENTS WITH IRRITABLE BOWEL SYNDROME: A RANDOMIZED CLINICAL TRIAL

C. Cremon 1 , S. Guglielmetti 2 , A.M. Castellazzi 3 , W. Fiore 4 , M. Bellini 5 , M. Cicala 6 , M.R. Barbaro 7 , L. Bellacosa 1 , V. Stanghellini 8 , G. Barbara 7

1 University Of Bologna, St. Orsola-Malpighi Hospital, Bologna/Italy

2 Department Of Food, Environmental And Nutritional Sciences, University of Milan, Milan/Italy

3 University of Pavia, Pavia/Italy

4 Sofar spa, Trezzano Rosa/Italy

5 Ospedale Di Cisanello Pisa, Pisa/Italy

6 Gastroenterologia, Università Campus Bio Medico, Roma/Italy

7 Dept. Medical And Surgical Sciences, University of Bologna Dept. of Medical and Surgical Sciences, Bologna/Italy

8 Department Of Digestive System, University of Bologna Policlinico S. Orsola-Malpighi Internal Med. & Gastroenterology - Department of, Bologna/Italy

Contact E-mail Address: cesare.cremon@aosp.bo.it

Introduction: Several lines of evidence suggest the contribution of intestinal microbiota in the pathophysiology of irritable bowel syndrome (IBS). This provides a proof of concept evidence of an implication of intestinal bacteria-host interactions in the pathophysiology and symptom generation of IBS.

Aims & Methods: To assess the effects of Lactobacillus paracasei CNCM I-1572 on clinical and gut microbiota-related factors in irritable bowel syndrome (IBS). We conducted a multicenter, randomized, double-blind, cross-over, 18-week, placebo-controlled, pilot trial assessing the effect of Lactobacillus paracasei CNCM I-1572 on symptoms, gut microbiota composition, fecal short chain fatty acid (SCFA), immunoglobulin A, and cytokines in patients with IBS. The intestinal microbial ecosystem was characterized by 16 S rRNA gene profiling.

Results: A total of 40 patients with IBS were enrolled from five Italian centers. Although better results were obtained with Lactobacillus paracasei CNCM I-1572, there was not a statistically significant improvement with active probiotic vs. placebo for all the clinical efficacy variables investigated. Interestingly, active probiotic, but not placebo, induced a significant increase in Lactobacillus (P = 0.011) and a significant reduction in Ruminococcus (P = 0.042), dominated by taxa related to Ruminococcus bromii and Ruminococcus callidus . Lactobacillus paracasei Lactobacillus paracasei CNCM I-1572, but not placebo, induced a significant increase in the SCFAs acetate (P = 0.021) and butyrate (P = 0.047) and a significant reduction in the pro-inflammatory cytokine interleukin-15 (P = 0.042).

Conclusion: This pilot study shows that Lactobacillus paracasei CNCM I-1572 is able to modulate gut microbiota structure and function and reduce immune activation in IBS, even if it was not statistically superior to placebo in symptom relief. If Lactobacillus paracasei CNCM I-1572 is effective in the management of IBS symptoms, this should be demonstrated in well-powered ad hoc studies. ClinicalTrials.gov Identifier: NCT02371499 .

Disclosure of Interest: All authors have declared no conflicts of interest.

OP284 PATIENT-REPORTED OUTCOMES WITH NALDEMEDINE LONG-TERM TREATMENT OF OPIOID-INDUCED CONSTIPATION (OIC) IN SUBJECTS WITH CHRONIC NON-CANCER PAIN

J. Tack 1 , M. Camilleri 2 , B. Cai 3 , T. Yamada 3 , J.C. Arjona Ferreira 3

1 Gastroenterology, University of Leuven, University Hospital Gasthuisberg, Leuven/Belgium

2 Mayo Clinic, Mayo Clinic Dept. of Gastroenterology Charlton Bldg., Rm. 8-110, Rochester, MN/United States of America

3 Shionogi Inc, New Jersey/United States of America

Contact E-mail Address: jan.tack@med.kuleuven.ac.be

Introduction: Opioid use for the treatment of chronic pain is associated with constipation. Symptoms of OIC significantly affect quality of life. The efficacy and safety profile of naldemedine (NAL), a peripherally-acting µ-opioid receptor antagonist, as a treatment for OIC has been demonstrated in multiple phase 3 studies of up to 52-week duration.

Aims & Methods: To assess the long-term effect of NAL on Patient Assessment of Constipation Symptoms (PAC-SYM) and Quality of Life (PAC-QOL). Methods: In a randomized double-blind placebo (PBO)-controlled 52-week study, subjects 18 to 80 years of age, having ≤4 spontaneous bowel movements (SBM) over 2 weeks and ≤3 SBMs in a given week, were randomized 1:1 to received NAL 0.2 mg once daily or PBO for 52 weeks. Subjects were either not on laxatives or on a stable laxative regimen for the study duration. Subjects with gastrointestinal (GI) abnormalities or taking drugs that could affect GI motility were excluded. Primary endpoints were change from baseline in the frequency of BM/week over the 52 weeks’ treatment, and PAC-SYM and PAC-QOL scores at weeks 12, 24, 36, and 52. They were analyzed using mixed model repeated measures.

Results: A total of 1246 subjects were randomized (n = 623 in each group). Subjects were 63.3% female and 79.7% white. Treatment with NAL led to a significantly (P ≤ 0.0001) greater increase in the frequency of bowel movements (BM)/week from baseline to each assessed time point (NAL 3.70, 3.77, 3.88, and 3.92 vs PBO 2.42, 2.77, 2.88, and 2.92 BM/week, at weeks 12, 24, 36, and 52, respectively). Treatment with NAL significantly improved (P < 0.0001) the mean overall PAC-SYM score from baseline for all assessed time points (weeks 2, 12, 24, 36, and 52) compared with PBO (NAL −1.15, −1.11, −1.16, −1.21, and −1.22; PBO −0.81, −0.86, −0.87, −0.85, and −0.98, respectively). Similarly, NAL treatment significantly improved (P < 0.0001) the mean overall PAC-QOL score from baseline for all assessed these time points compared with PBO (NAL −1.14, −1.19, −1.19, −1.22, and −1.24; PBO −0.75, −0.83, −0.86, −0.82, and −0.94, respectively). Treatment with NAL for 52 weeks was generally well tolerated; the most frequently reported adverse events were abdominal pain, diarrhea, and nausea.

Conclusion: Treatment with NAL 0.2 mg once daily significantly improved the frequency of BM over 52 weeks. Treatment with NAL also significantly improved symptoms of OIC as assessed by PAC-SYM, and quality of life as assessed by PAC-QOL, relative to PBO, and was generally well tolerated for up to 52 weeks.

Disclosure of Interest: J. Tack: advisory board to Shionogi Ltd in the past

M. Camilleri: advisory board to Shionogi Inc. in the past

B. Cai: Employee of Shionogi Inc.

T. Yamada: employee of Shionogi Inc

J.C. Arjona Ferreira: employee of Shionogi Inc

OP285 RANDOMIZED CLINICAL TRIAL OF FOUR TREATMENTS FOR FAECAL INCONTINENCE AMONG ADULT COMMUNITY-DWELLING WOMEN: ASSESSMENT OF INDIVIDUAL EFFICACY OF ANORECTAL PHYSIOLOGY, THE IMPACT ON CLINICAL SEVERITY AND ON QUALITY OF LIFE

L. Mundet 1 , L. Rofes 1 , O. Ortega 1 , P. Clavé 1

1 Gastrointestinal Physiology Laboratory, Hospital de Mataró, Mataró/Spain

Contact E-mail Address: lluismundetp@gmail.com

Introduction: Faecal incontinence (FI) is a prevalent condition with a major impact on quality of life (QoL). Currently four treatments are being used in clinical practice: Kegel exercises (K), biofeedback (BF) electrostimulation (ES) and transcutaneous neuromodulation (NM). Results in the literature are discordant and lack methodological rigour making scientific evidence weak 1–3 .

Aims & Methods: The aim of this study is to assess the efficacy of these four treatments on community-dwelling women and their impact on anorectal physiology, on clinical severity and on QoL. This is a randomized control trial. Patient physiology was studied with anorectal manometry and endoanal ultrasonography; clinical severity was assessed with Cleveland and St. Mark’s scales, and QoL with the Faecal Incontinence Quality of Life (FIQL) and the EuroQol’s EQ5D questionnaires. Urinary incontinence (UI) was also evaluated by means of International Consultation on Incontinence (ICIQ) score. Patients were randomized and assigned to K (control), BF+K, ES+K or NM+K, given active treatment for a 3-month period, and then evaluated again with identical tests and parameters to identify changes.

Results: Sample was of 152 women with a mean age of 61.09 ± 12.17 years. Clinical severity improved for all treatment arms (Cleveland score pre and post-treatment: 10.92 ± 4.14 – 7.46 ± 4.42 for the K group, 12.08 ± 3.27 – 7.08 ± 5.39 for the BF + K group, 11.54 ± 3.7 – 5.85 ± 4.71 for the ES + K group, and finally 12.35 ± 3.96 – 6.73 ± 4.41 for the NM + K arm; all differences p < 0.001). Severity improvement between treatments was not statistically significant. Symptoms of patients with UI assigned to K and NM + K improved, with an initial and final ICIQ index of 11.5 ± 5.61 – 8.3 ± 6.48 for the K group, and 10.14 ± 5.17 – 7.36 ± 5.76 for the NM + K group; p < 0.05). QoL scores improved for all four treatments, especially in the coping and embarrassment subscales (p < 0.001). Mean resting pressure of anal canal improved minimally but significantly in the patients in the K and ES + K groups (pre – post-treatment: 50.91 ± 20.88 – 56.75 ± 22.64 mmHg and 52.73 ± 24.46 – 56.32 ± 25.06 mmHg; p < 0.01). Maximal pressure of voluntary contraction improved significantly in the patients with BF + K, ES + K and NM + K (26.93 ± 19 – 38.99 ± 22.88 mmHg, 29.83 ± 24.83 – 39.09 ± 28.45 mmHg, 28.69 ± 25.58 – 38.44 ± 29.50 mmHg; p < 0.01). Patients with non-effective voluntary contraction pressure profiles (low endurance) changed to effective profiles when treated with BF + K and ES + K (20 to 28 patients with effective profiles in the BF + K group and 23 patients to 34 in the NM + K), with differences being statistically significant, p < 0.01. Regarding perception after rectal distention, statistically significant changes at the first perception threshold were observed in the BF + K (23.61 ± 15.7 – 16.67 ± 5.85 ml), ES + K (22.89 ± 12.5 – 18.74 ± 6.5 ml), and NM + K groups (19.21 ± 8.5 – 16.05 ± 4.95 ml). Other thresholds that changed after rectal distension in the patients in the K arm were tenesmus (64.85 ± 24.38 – 55.94 ± 27.46 ml) and urgency (106.4 ± 46.76 – 92.26 ± 43.26 ml); p < 0.05. The minimum rectal distension volumes from which the recto-anal inhibitory reflex was initiated decreased in NM-treated patients, 19.41 ± 6.48 – 16.67 ± 5.95 before and after treatment, respectively; p < 0.01).

Conclusion: The treatments available for treating IF have similar efficacy in terms of decreased clinical severity and improved QoL, but affect distinct pathophysiological aspects. Further knowledge of the effects of different treatments on the physiology of the individual may lead the way to selecting the most appropriate treatment for each patient phenotype.

Disclosure of Interest: All authors have declared no conflicts of interest.

References

1. Norton C, Whitehead WE, Bliss DZ, Harari D, Lang J. Management of fecal incontinence in adults. Neurourology and urodynamics 2010;29:199–206. Epub 2009/12/22.

2. Norton C, Cody JD. Biofeedback and/or sphincter exercises for the treatment of faecal incontinence in adults. Cochrane Database Syst Rev 2012;7:CD002111. Epub 2012/07/13.

3. Horrocks EJ, Thin N, Thaha MA, Taylor SJ, Norton C, Knowles CH. Systematic review of tibial nerve stimulation to treat faecal incontinence. The British journal of surgery 2014;101:457–468.

OP286 THE EFFECT OF ZESPRI GREEN KIWIFRUIT ON DIGESTIVE FUNCTIONS IN CONSTIPATED PATIENTS: A MULTICENTRE, RANDOMIZED, CONTROLLED, SINGLE-BLIND, CROSS-OVER STUDY

C. Cremon 1 , J. Ansell 2 , I. Pagano 1 , B. Kuhn-Sherlock 3 , L. Drummond 4 , M.R. Barbaro 5 , E. Capelli 5 , L. Belacosa 1 , V. Stanghellini 1 , G. Barbara 1

1 University Of Bologna, St. Orsola-Malpighi Hospital, Bologna/Italy

2 Zespri International Ltd, Mt Maunganui/New Zealand

3 BKS Consulting, Hamiton/New Zealand

4 Drummond Food Science Advisory Ltd, Leeston/New Zealand

5 Dept. Medical And Surgical Sciences, University of Bologna Dept. of Medical and Surgical Sciences, Bologna/Italy

Contact E-mail Address: cesare.cremon@aosp.bo.it

Introduction: Digestive discomfort, including constipation, is a common condition throughout the world. Gastrointestinal discomfort and bowel habit are two target areas for potential health claims for foods identified by EFSA. Green kiwifruit is often used as natural food for the relief of constipation.

Aims & Methods: We performed a multicentre, randomised, controlled, single-blind, cross-over clinical trial to assess the effect of green kiwifruit on digestive and gut health functions. As a part of an international study which involved three sites around the world using the same protocol (New Zealand, Italy, and Japan), we enrolled three cohorts of participants: 20 healthy controls, 20 patients with functional constipation (FC) and 20 patients with irritable bowel syndrome with constipation (IBS-C), according to Rome III criteria. The study duration was a total of 16 weeks; 2-week lead in, 4-week first intervention, 4 week washout, 4-week second intervention, and final 2-week follow-up. The cross-over design was completed using kiwifruit intervention (2 green kiwifruit per day [Actinidia deliciosa var. Hayward]), compared to a positive control intervention of psyllium (7.5 g of psyllium per day). The primary outcome measure was quantification of complete spontaneous bowel movement (CSBM). Secondary outcome measures included additional stool frequency measures (spontaneous bowel movements [SBM], complete bowel movements [CBM], bowel movements [BM]), the Gastrointestinal Symptom Rating Scale (GSRS), the IBS-QoL questionnaire, together with objective measures of gastrointestinal transit times using Smart Pills. Faecal sample collection was required for immune measures and DNA extraction to microbial analysis.

Results: The primary outcome measure (quantification of CBSM) was found to be significantly improved by kiwifruit as compared with psyllium. In particular, analysing the data for all the constipated patients, we showed that the test product, kiwifruit, is effective and adequately rules out an unacceptable loss of the control effect. Interestingly, better results were obtained in patients with FC as compared with IBS-C. Similar results were obtained for all the analysed secondary outcome measures, suggesting the non-inferiority of kiwifruit in comparison with psyllium.

Conclusion: In this study we demonstrated the efficacy and safety of kiwifruit as a food intervention for the relief of constipation and associated symptoms in patients with FC and IBS-C, using validated outcome measures. As empiric therapy should begin with a fibre supplement in constipated patients, including psyllium, also kiwifruit should be considered in these patients. ClinicalTrials.gov Identifier: NCT02888392 .

Disclosure of Interest: All authors have declared no conflicts of interest.

TUESDAY, OCTOBER 31, 201715:45-17:15

AUTOIMMUNE AND CHOLESTATIC LIVER DISEASES: NOVELTIES - ROOM E2____________________

OP287 SURROGATE MARKERS FOR DISEASE PROGRESSION AND RISK FOR BILIARY NEOPLASIA IN PRIMARY SCLEROSING CHOLANGITIS

M.A. A. Färkkila 1 , H. Mustonen 2 , K. Jokelainen 1 , J. Arola 3 , H. Alfthan 4

1 Clinic Of Gastroenterology, Helsinki University and Helsinki University Hospital, Helsinki/Finland

2 Surgery, Helsinki University Hospital, HUS/Finland

3 Pathology, Helsinki University Hospital, HUS/Finland

4 Clinical Chemistry, Helsinki University Hospital, HUS/Finland

Contact E-mail Address: martti.farkkila@hus.fi

Introduction: Primary sclerosing cholangitis [PSC] is a chronic inflammatory disease of biliary epithelium leading to strictures intra- and extrahepatic bile ducts and finally to cholestasis and secondary biliary cirrhosis (1). The chronic inflammation is associated with increased proliferation of biliary epithelial cells and a markedly increased risk of biliary dysplasia and cholangiocarcinoma [CCA](2), SIR ranging from 161 to 973 (2–3), with the lifetime risk around 10% (4–5). CCA is the most common reason for death among patients with PSC (6, 7). Several serum surrogate markers (8) have been developed to predict the risk for liver cirrhosis, transplantation free survival or death, such as decrease of P-ALP during UDCA therapy (9), IL-8 (10), and ELF® (11). However, all of these are very late endpoints and not suitable for monitoring bile duct inflammation, progression of bile duct disease or development of risk of biliary dysplasia, before development of CCA.

Aims & Methods: To evaluate the role of serum surrogate markers or they combinations and biliary calprotectin and grade of inflammation to predict the progression of the PSC based on changes in sequential ERC’s examinations and biliary dysplasia detected by brush cytology. In total, 425 patients with confirmed PSC referred for ERC for diagnosis and surveillance of the disease were included (166 females, 259 males), mean age 39.8 ± 13.6 y. Of all the patients 72% had IBD. After cannulation of the common bile duct bile sample was aspirated using balloon catheter and immersed immediately in liquid nitrogen (−196 o C) and then stored in −80 o C. Brush cytology (BC) was collected both from extra- and intrahepatic bile ducts for Papanicolau staining for grading dysplasia and inflammation. Neutrophilic inflammation in BC was evaluated semi quantitatively (0 = neutrophils/epithelial cells <0.05, 1 = neutrophils/epithelial cells 0.05–0.4, 2 = neutrophils/epithelial cells >0.4). Bile concentrations of calprotectin were analyzed using ELISA method. Liver function tests were taken at the time of ERC. ERC findings were scored according to modified Amsterdam score, [Helsinki score] (12). Based on sequential ERC-examinations and scores an ERC-load/burden was calculated and likewise summary variable for serum ALP, AST, ALT, GT, IgG, IgG4, Ca19–9, CEA and biliary calprotectin and neutrophils in BC in relation to time were calculated.

Results: During the mean follow-up of 6 years, 20 patients were referred for liver transplantation, and biliary dysplasia or CCA was diagnosed in 29 patients. Serum and biliary surrogate markers for disease progression (ERC score ≤ 4 vs >4) based on sequential ERC findings and the surrogate markers predicting development of biliary dysplasia and CCA are shown in table.

Conclusion: Of serum surrogate markers, log[AST], log[ALP], the sum of log[ALT + AST + ALP + GT] and biliary calprotectin >20 and neutrophils in BC (>1) turned out to be best predictors for PSC progression based on ERC-score in sequential examinations. Risk for development of biliary dysplasia or CCA is associated with ERC score load, biliary calprotectin (>0.2) and log[AST] and log[ALP], and also the sum of log[ALT + AST + ALP + GT]. These variables are useful for monitoring progression of bile duct changes, response for therapy and individual risk stratification for dysplasia in PSC patients

Disclosure of Interest: All authors have declared no conflicts of interest.

References

1. Hirschfield GM, et al. Lancet . 2013;382:1587–99.

2. Bergquist A, et al. J Hepatol . 2002;36:321–327.

3. Manninen P, et al. Scand J Gastroenterol . 2015;50:423–8

4. Boberg KM, et al. Scand J Gastroenterol 2002; 37: 1205–11.

5. Claessen MM. J Hepatol . 2009;50:158–64.

6. de Valle et al. Liver Int . 2012;32:441–8

7. Lewis JT, et al. Am J Surg Pathol . 2010;34:27–34.

8. Ponsioen CY, et al. Hepatology 2016;63:1357 −67

9. de Vries EM, et al. Liver Int . 2016;36:1867–75

10. Vesterhus M, et al. J Hepatol . 2017 Feb 2.

11. deVries EM et al. Liver Int . 2017 Mar 7.

12. Boyd S, et al. Endoscopy . 2016;48:432–9.

OP288 DURABLE RESPONSE IN THE MARKERS OF CHOLESTASIS THROUGH 24 MONTHS OF OPEN-LABEL EXTENSION STUDY OF OBETICHOLIC ACID IN PRIMARY BILIARY CHOLANGITIS

M. Trauner 1 , F. Nevens 2 , P. Andreone 3 , G. Mazzella 3 , S. Strasser 4 , P. Invernizzi 5 , J.P. h. Drenth 6 , P. Pockros 7 , J. Regula 8 , A. Floreani 9 , S. Hohenester 10 , V. Luketic 11 , M. Shiffman 12 , K. Van Erpecum 13 , V. Vargas 14 , C. Vincent 15 , B. Hansen 16 , C. Bowlus 17 , L. Macconell 18 , E. Smoot Malecha 18 , D. Shapiro 18

1 Department Of Gastroenterology And Hepatology, Department Of Internal Medicine Iii, Medical University of Vienna, Vienna/Austria

2 UZ Leuven, Leuven/Belgium

3 Universitaria di Bologna, Bologna/Italy

4 Royal Prince Alfred Hospital, Camperdown/Australia/NSW

5 University of Milan-Bicocca, Milan/Italy

6 Gastroenterology And Hepatology, Radboud University Nijmegen Medical Centre - Gastroenterology and Hepatology, Radboud University Nij, Nijmegen/Netherlands

7 Scripps Clinic, La Jolla/United States of America/CA

8 Cancer Centre, Warsaw/Poland

9 Surgery, Oncology And Gastroenterology, Università di Padova, Padova/Italy

10 Department Of Medicine Ii, Liver Center Munich, Munich/Germany

11 McGuire DVAMC, Richmond/United States of America/VA

12 Liver Institute of Virginia, Newport News/United States of America/VA

13 UMC Utrecht, Utrecht/Netherlands

14 Hospital Vall d’Hebron, Barcelona/Spain

15 Centre Hospitalier Universitaire de l’Université de Montréal-, Montreal/Canada

16 Toronto General Hospital, Toronto Centre for Liver Disease, Toronto/Canada/ON

17 University of California, Davis, Sacramento/United States of America/CA

18 Intercept Pharmaceuticals, Inc., San Diego/United States of America/CA

Contact E-mail Address: michael.trauner@meduniwien.ac.at

Introduction: Obeticholic Acid (OCA) is a selective and potent farnesoid X receptor agonist indicated for treatment of primary biliary cholangitis (PBC). POISE is a 12-month double-blind (DB), placebo (PBO)-controlled, Phase 3 PBC study including an open-label extension (OLE). Patients who completed the DB phase were eligible to participate in the OLE.

Aims & Methods: The purpose of the OLE is to assess safety and the durability of OCA on markers of cholestasis. Key POISE inclusion criteria: PBC diagnosis, ALP ≥1.67x ULN and/or total bilirubin >ULN to <2x ULN, stable UDCA dose or unable to tolerate UDCA. During the DB phase, 216 patients were randomized and dosed to: daily PBO, n = 73; OCA 5–10 mg (titration after 6 months based on response and tolerability), n = 70; or OCA 10 mg, n = 73. In the OLE, all patients were initially treated with OCA 5 mg regardless of DB treatment with the option to increase to OCA 10 mg after 3 months based on response and tolerability.

Results: 193 of 198 (97%) patients completing the DB phase of the trial enrolled in the OLE and 166 patients have reached 24 months of the OLE: PBO, n = 52; OCA 5–10 mg, n = 57; OCA 10 mg, n = 57. After 12 months in the DB phase patients who received OCA had significant reductions in ALP, GGT, ALT and AST (Table 1) compared to patients who received PBO; improvement was durable through 24 months of the OLE. Patients who received OCA during the DB phase had significant reductions in total bilirubin at 12 months DB when compared to PBO. Patients who received PBO during the DB phase and who initiated OCA during the OLE had significant reductions in markers of cholestasis at 24 months, with the exception of total bilirubin. Pruritus was the most common adverse event (AE) associated with OCA. Overall incidence of pruritus in OCA groups during the DB phase (55–68%) was reduced during the OLE (21–37%), with comparable incidence to that in DB PBO patients (38%). During the OLE, 22 (11%) patients discontinued treatment: 4 (2%) for pruritus; 7 (4%) for other AEs; 1 (<1%) for death unrelated to OCA, and 10 (5%) for other reasons.

Conclusion: OCA treatment improves liver biochemistry, most notably ALP and GGT, which is sustained through 24 months of treatment in the OLE. Pruritus was the most common AE, but its occurrence appeared to lessen with longer treatment.

Disclosure of Interest: M. Trauner: Advisor: Albireo, Falk, Genfit, Gilead, Intercept, MSD, Novartis, Phenex Grants: Albireo, Falk Pharma, Gilead, Intercept, MSD, Takeda Speaker: Falk Foundation, Gilead, MSD, Roche Travel grants: Falk Foundation, Gilead, Roche

F. Nevens: Consulting: MSD, CAF, Intercept, Gore, BMS, Abbvie, Novartis, Durect, Janssens-Cilag, Ono Pharma, Promethera Biosciences; Grant/Research Support: Ferring, Roche, Astellas, Novartis, Janssen-Cilag, Abbvie

P. Andreone: Advisory Committees or Review Panels: Janssen-Cilag, Gilead, MSD/Schering-Plough, Abbvie, Intercept; Speaking and Teaching: Gilead, BMS

S. Strasser: Honoraria for advisory boards/speaker fees: Gilead, AbbVie, Bristol Myers-Squibb, MSD, Norgine, Bayer, Sirtex, Astellas

P. Invernizzi: Grant/Research Support: Intercept, Consult/Advisor: Intercept Sponsored Lectures: Galmed, Trendfull Development

P. Pockros: Intercept, Gilead, AbbVie, Merck, BMS, Genfit, Beckman: research grants to Scripps Health. Speaking and education to PJP.: Intercept, Gilead, Merck, AbbVie

S. Hohenester: Lecture fees: Intercept, Falk Travel grants: Gilead

V. Luketic: Sponsored Clinical Trials:AbbVie, BMS, Exalenz, Genfit, Intercept, Lumena/Shire, Merck Consulting:Genfit Advisory:GSK

M. Shiffman: Abbvie, BMS, Conatus, CymaBay, Exalenz, Galectin, Genfit, Gilead, Intercept, Immuron, Merck, NGMBio, Novartis, Shire, Bayer, Daiichi Sankyo, Optum Rx

K. van Erpecum: Advisory Committees or Review Panels: Bristol Meyers Squibb, Abbvie, Janssen Cilag, Gilead; Consulting: abbvie; Grant/Research Support: abbvie, gilead, Janssen Cilag

C. Vincent: Investigator for Intercept, GSK and Novartis and advisory board for Intercept

B. Hansen: Dr. Hansen reports grant support and personal fees from Intercept Pharmaceuticals, personal fees from Janssen Pharmaceuticals, and Grant Support from Roche

C. Bowlus: Research: Intercept Pharmaceuticals, NGM Biosciences, Gilead, Takeda, BMS, GlaxoSmithKline, Galectin Therapeutics, CymaBay, TARGET Pharmasolutions Advisory Board: Intercept Pharmaceuticals, GSK, Takeda Speakers Bureau: Intercept Pharmaceuticals

L. MacConell: Dr. MacConell is an employee and stock shareholder of Intercept Pharmaceuticals

E. Smoot Malecha: Dr. Smoot Malecha is an employee and stock shareholder of Intercept Pharmaceuticals.

D. Shapiro: Dr. Shapiro is an employee and stock shareholder of Intercept Pharmaceuticals

All other authors have declared no conflicts of interest.

OP289 DIFFERENTIAL EFFECTS OF FXR OR TGR5 ACTIVATION IN CHOLANGIOCARCINOMA PROGRESSION

O. Erice 1 , I. Labiano 2 , A. Arbelaiz 1 , A. Santos-Laso 1 , P. Munoz-Garrido 1 , A. Caro-Maldonado 2 , N. Martin-Martin 2 , A. Carracedo 3 , E. Lozano 4 , J.J. Marin 4 , C.J. O'Rourke 5 , J.B. Andersen 5 , J. Llop 6 , V. Gomez-Vallejo 6 , D. Padro 6 , A. Martin 6 , M. Marzioni 7 , L. Adorini 8 , M. Trauner 9 , L. Bujanda Fernández De Piérola 2 , M.J. Perugorría 10 , J.M. Banales 1

1 Liver And Gastrointestinal Diseases, Biodonostia Research Institute- Donostia University Hospital- UPV/EHU, San Sebastián/Spain

2 Cic Biogune, Bizkaia Technology Park, Derio/Spain

3 Ciberonc, Carlos III National Institute of Health, Madrid/Spain

4 Experimental Hepatology And Drug Targeting (hevefarm), Biomedical Research Institute of Salamanca (IBSAL), Salamanca/Spain

5 Department Of Health And Medical Sciences, Biotech Research and Innovation Centre (BRIC)- University of Copenhagen, Copenhagen/Denmark

6 Molecular Imaging Unit, CIC biomaGUNE, San Sebastián/Spain

7 Department Of Gastroenterology, Università Politecnica delle Marche, Ancona/Italy

8 Intercept Pharmaceuticals, New York/United States of America/NY

9 Department Of Gastroenterology And Hepatology, Department Of Internal Medicine Iii, Medical University of Vienna, Vienna/Austria

10 Ikerbasque, Basque Foundation for Science, Bilbao/Spain

Contact E-mail Address: jesus.banales@biodonostia.org

Introduction: Cholangiocarcinomas (CCAs) are aggressive tumors with poor outcome due to late diagnosis and refractory nature. CCAs may arise under certain cholestatic conditions, where intrahepatic accumulation of bile acids may facilitate a co-carcinogenic effect by triggering cholangiocyte proliferation and inflammation, and by reducing FXR-dependent chemoprotection.

Aims & Methods: The differential activation of the bile acid receptors FXR or TGR5 was evaluated in CCA progression. FXR and TGR5 expression was determined in two different cohorts of CCA patients (i.e. Denmark and Spain), as well as in CCA cells and normal human cholangiocytes in culture. An orthotopic model of human CCA was established in immunodeficient mice and tumor growth was monitored by magnetic resonance imaging (MRI) under chronic administration of selective FXR or TGR5 agonists, i.e. obeticholic acid (OCA) or INT-777 (Intercept Pharmaceuticals; 0.03% in chow for 2 months), respectively. The differential effects of FXR or TGR5 activation were evaluated on proliferation, apoptosis, migration and mitochondrial energetic metabolism (i.e. Seahorse Bioscience) in CCA cells in vitro .

Results: FXR is downregulated and TGR5 upregulated in human CCA tissue compared to normal surrounding liver tissue in both human cohorts. FXR correlates with tumor differentiation, whereas TGR5 correlates with perineural invasion. TGR5 expression is increased in perihilar vs intrahepatic CCAs. In vitro , FXR is downregulated and TGR5 upregulated in human CCA cells compared to normal human cholangiocytes. In mice with orthotopic implants of human CCA tumors, chronic administration of OCA inhibited the tumor growth compared to untreated control animals; this was accompanied by decreased expression of proliferation (i.e. PCNA , Ki67 ), biliary (i.e. CK19 ) and epithelial (i.e. ZO -1) markers within the tumors. In contrast, chronic administration of INT-777 in vivo showed no effects on CCA tumor growth. In vitro , OCA inhibited CCA cell proliferation and migration, associated with decreased mitochondrial energetic metabolism, and did not affect apoptosis. In contrast, INT-777 stimulated proliferation and migration of CCA cells, associated with increased mitochondrial energetic metabolism.

Conclusion: Activation of FXR inhibits, whereas TGR5 may promote, CCA progression through regulation of proliferation, migration and mitochondrial energetic metabolism. Regulation of FXR and/or TGR5 activities may represent potential novel therapeutic strategies for CCA.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP290 THE ROLE OF PNPLA3 (RS738409 C>G P.I148M) ALLELE DOSE ON BILE ACID COMPOSITION IN PRIMARY SCLEROSING CHOLANGITIS (PSC)

M.A. A. Färkkila 1 , A. Tenca 1 , H. Kautiainen 2

1 Clinic Of Gastroenterology, Helsinki University and Helsinki University Hospital, Helsinki/Finland

2 Unit Of Primary Health Care, Helsinki University, Helsinki University/Finland

Contact E-mail Address: martti.farkkila@hus.fi

Introduction: PSC is chronic cholestatic liver disease characterized by inflammation and strictures of intra- and extrahepatic bile ducts. Several pathogenetic mechanisms have been suggested, such as toxic bile acids-induced inflammation and fibrosis biliary epthelium. Ursodeoxycholic acid (UDCA), the most hydrophilic bile acid, has widely been used to treat PSC with reduction of cholestatic liver enzymes. PNPLA3 (patatin-like phospholipase domain containing 3) encodes carbohydrate-regulated lipogenic and/or lipolytic enzymes in liver. The PNPLA3 rs738409 C>G p.I148M has been associated with steatosis and fibrosis in various liver disease and increased risk for development of liver cirrhosis and hepatocellular cancer (1), and in increased risk of bile duct stenosis in male PSC patients (2). Survival free of liver transplantation is reduced in male PSC patients with development of dominant strictures in carriers of PNPLA3 I148M variant (2).

Aims & Methods: To evaluate the allele dose effect of PNPLA3 variant on clinical manifestation, biliary bile acid composition, and impact on UDCA content in bile in a PSC patient population from a single center. In total, 220 patients with confirmed PSC from the patient registry of Helsinki University Hospital were enrolled into the study. The diagnosis of PSC was based on elevation of P-ALP, ERC and liver biopsy typical for PSC. All the patients had a colonoscopy performed. ERC findings were scored according to modified Amsterdam score. After cannulation the common bile duct with papillotomy knife with guide wire a bile sample was aspirated using balloon catheter. Blood samples were drawn at the time of ERC for analysis of live enzymes. PNPLA3 variants were analyzed with TaqMan PCR method. The total bile acids, cholesterol and phospholipids were analyzed by gas-liquid chromatography and the content of individual bile acids: deoxycholic (DCA), chenodeoxycholic (CDCA), cholic acid (CA), lithocholic (LCA) and UDCA were analyzed. The amount of bile acids were expressed as molar percentages (mM%) or mg of total bile acids.

Results: Of the 220 patients 122 (55.5%) had the wild type (CC), 80 (36.3%) were heterozygous (CG) and 18 (8.2%) were homozygous for the mutation (GG). The PNPLA3 rs738409 C>G p.I148M variant (GG) was much more commen in males and AST values tend to be higher in patients with GG-allele. Both secondary bile acid contents were were reduced in relation to allele dose of PNPLA3 variant. A summary of the results is presented in the table. Table. Clinical characteristics and bile acid composition in PSC patients in relation to allele dose of PNPLA3 variant

Conclusion: The allele dose of PNPLA3 did not have any significant impact on clinical manifestations of PSC, cholesterol, total bile acid or phospholipid composition in UDCA-naïve patients. However, in patients homogenous for the mutation (GG), there was a statistically significant linearity for lower content of secondary bile acids: deoxy- and lithocholic acid, the most toxic ones, reversed by UDCA therapy.

Disclosure of Interest: All authors have declared no conflicts of interest.

References

1. Trepo E et al. J Hepatol . 2016 Mar 30. pii: S0168–8278(16)30084-8. doi: 10.1016/j.jhep.2016.03.011

2. Friedrich K, et al. PLoS ONE 8(3): e58734. doi:10.1371

OP291 CLINICAL EFFECT AND SAFETY OF ENDOSCOPIC RADIOFREQUENCY ABLATION FOR UNRESECTABLE EXTRAHEPATIC CHOLANGIOCARCINOMA, A PROSPECTIVE STUDY

J. Yang 1 , Y. Zhou 1 , Q. Lou 1 , W. Gu 1 , X. Zhang 1

1 Gastroenterology, Hangzhou First People's Hospital, Hangzhou/China

Contact E-mail Address: yjf-1976@163.com

Introduction: Endoscopic placement of biliary stents to relieve jaundice is the main palliative treatment for unresectable extrahepatic cholangiocarcinoma (EHCC) [1] . It were reported endoscopic biliary radiofrequency ablation (RFA) could prolong the stent patency, which may also be beneficial to improve the patient survival. However, the available evidence is still insufficient for majority of studies were retrospective case series [2–3] .

Aims & Methods: The aim of this study is to explore the clinical effect and safety of RFA in patients with unresectable EHCC. 59 Patients with unresectable EHCC were enrolled and randomly underwent either RFA combined with biliary stenting (RFA + stent group, n = 29) or biliary stent only (stent group, n = 30). The overall survival time, stent patency period and postoperative complication were collected.

Results: With follow-up of 43 months, the mean overall survival was significantly longer in the RFA+ stent group than in the stent group (13.8 vs. 8.4 months, P < 0.001). The mean stent patency period of the RFA + stent group was also significantly longer than that of the stent group (6.9 vs. 3.5 months, P = 0.02). There was no significant difference in the incidence of postoperative complications between the two groups [6.9% (2/29) vs 10% (3/30), P = 0.67].

Conclusion: Endoscopic RFA combined with stenting can significantly prolong the EHCC patients' survival and stent patency period without increasing the incidence of adverse events. This approach can be considered as a safe and effective palliative treatment for unresectable EHCC.

Disclosure of Interest: All authors have declared no conflicts of interest.

References

1. Razumilava N, Gores GJ. Cholangiocarcinoma. Lancet 2014;383:2168–79.

2. Steel AW, Postgate AJ, Khorsandi S, et al. Endoscopically applied radiofrequency ablation appears to be safe in the treatment of malignant biliary obstruction. Gastrointest Endosc 2011;73:149–53.

3. Laquiere A, Boustiere C, Leblanc S, et al. Safety and feasibility of endoscopic biliary radiofrequency ablation treatment of extrahepatic cholangiocarcinoma. Surg Endosc 2015.

OP292 PREDNISONE DOSAGE AND CHANCE OF REMISSION IN PATIENTS WITH AUTOIMMUNE HEPATITIS: AN INTERNATIONAL MULTICENTER COHORT STUDY

S. Pape 1 , T. J. Gevers 1 , I. F. Mustafajev 1 , F. F. Van Den Brand 2 , C. M. Van Nieuwkerk 2 , G. Bouma 2 , J.M. Vrolijk 3 , J. Hartl 4 , A. W. Lohse 4 , C. Schramm 4 , J.P.h. Drenth 1

1 Gastroenterology And Hepatology, Radboud University Medical Center, Nijmegen/Netherlands

2 Gastroenterology And Hepatology, VU University Medical Center, Amsterdam/Netherlands

3 Gastroenterology And Hepatology, Rijnstate Hospital, Arnhem/Netherlands

4 I. Department Of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg/Germany

Contact E-mail Address: Simon.Pape@radboudumc.nl

Introduction: Current treatment of autoimmune hepatitis (AIH) consists of induction therapy with prednisone followed by azathioprine maintenance therapy. The EASL (European Association for Study of the Liver) Clinical Practice Guidelines on AIH advise a prednisone dose ranging from 0.50 to 1 mg/kg/day. It is not known whether lower doses might be equally effective. We hypothesized that lower doses of prednisone would not lower the chance of achieving biochemical remission.

Disclosure of Interest: All authors have declared no conflicts of interest.

Aims & Methods: We investigated the effect of low-dose versus high-dose prednisone induction therapy in AIH on biochemical remission in a multicenter cohort, using chart review data from centers in Amsterdam, Nijmegen, Arnhem (The Netherlands) and Hamburg (Germany). Patients were eligible in case of an established AIH diagnosis according to the International Autoimmune Hepatitis Group criteria, were ≥18 years old at time of diagnosis and received induction treatment with prednisone. The primary outcome was biochemical remission, defined as a normal alanine transferase (ALT) serum level (<45 U/l) at 24 weeks after initiation of therapy. Patients were split into a high- and a low-dose group using the EASL guideline cut-off of 0.50 mg/kg/day prednisone starting dose. We performed log-binomial regression to determine differences in outcome between the high and low-dose prednisone group, with correction for center and confounders: baseline ALT, maintenance therapy and use of prednisone at week 24. Risk ratios (RR) with 95% confidence intervals were calculated.

Results: A total of 517 patients was identified and 234 patients were included in our primary analysis. Main reasons for exclusion were missing data on prednisone dosages or ALT levels at primary endpoint (n = 250) or overlap syndromes (n = 33). Most patients (77%) were female and mean age at diagnosis was 52.5 years (SD 17.5). The low-dose group consisted of 98 patients while 136 patients received high-dose prednisone. Baseline transaminases (ALT 403 U/l vs. 717 U/l, p < 0.01; AST 387 U/l vs. 611 U/l, p < 0.01) and bilirubin (52.1 µmol/l vs. 85.2 µmol/l, p = 0.04) were significantly higher in the high-dose group. More patients in the low-dose group had cirrhosis at presentation compared to the high-dose group (29% vs. 16% p = 0.02). In the low-dose group, 74% of patients started with maintenance therapy during the first 24 weeks compared to 82% in the high-dose group. Maintenance therapy consisted mainly of azathioprine in both groups. Biochemical remission at week 24 (median 25.9 weeks (range 16 – 36)) was similar in the low- and high-dose group: 66.3% versus 66.9% and remained similar after correction for confounders (RR 1.01 (0.81 – 1.27) p = 0.91).

Conclusion: Our data shows that prednisone starting dosages below the EASL guideline threshold of 0.50 mg/kg/day can be effective in achieving biochemical remission in AIH.

Disclosure of Interest: All authors have declared no conflicts of interest.

References

EASL Clinical Practice Guidelines: Autoimmune hepatitis. J Hepatol . 2015 Oct;63(4):971–1004

Lamers MM, van Oijen MG, Pronk M, et al. Treatment options for autoimmune hepatitis: a systematic review of randomized controlled trials. J Hepatol 2010;53:191–8.

Alvarez F, Berg PA, Bianchi FB et al. International Autoimmune Hepatitis Group Report: review of criteria for diagnosis of autoimmune hepatitis. J Hepatol . 1999 Nov;31(5):929–38.

Manns MP, Czaja AJ, Gorham JD, Krawitt EL, Mieli-Vergani G, Vergani D, et al. Diagnosis and management of autoimmune hepatitis. Hepatology 2010;51:2193–2213.

TUESDAY, OCTOBER 31, 201715:45-17:15

FROM PREVENTION TO THERAPY OF OESOPHALO-GASTRIC CANCER - ROOM E3____________________

OP293 LONG-TERM ASPIRIN AND RISK OF GASTRIC CANCER AFTER H. PYLORI ERADICATION: A POPULATION-BASED STUDY WITH PROPENSITY SCORE ANALYSIS

K.S. Cheung 1 , A.Y. Wong 2 , E.W. Chan 2 , L. Chen 3 , I.C. Wong 4 , W.K. Leung 1

1 Department Of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, Hong Kong/Hong Kong PRC

2 Center For Safe Medication Practice And Research, Department Of Pharmacology And Pharmacy, The University of Hong Kong, Hong Kong/Hong Kong PRC

3 Department Of Medicine, The University of Hong Kong, Hong Kong/Hong Kong PRC

4 UCL School Of Pharmacy, University College London, London/United Kingdom

Contact E-mail Address: mongolhorse2002@gmail.com

Introduction: Individuals are still at risk of gastric cancer (GC) development despite successful eradication of H. pylori (HP) infection. Although aspirin has been shown to reduce the GC risk in previous studies, the results were not stratified by HP status and the role of aspirin in subjects with prior HP eradication remains unknown.

Aims & Methods: We determined the effects of long-term aspirin on GC risk in a large population-based cohort of subjects who had received HP eradication. This was a retrospective cohort study based on a territory-wide healthcare database of Hong Kong. All adult subjects who had received an outpatient prescription of clarithromycin-based triple therapy between January 2003 and December 2012 were included. The observation period commenced from the date of triple therapy prescription and was censored at the date of diagnosis of gastric cancer, death, or end of the study. Prescriptions of aspirin before HP eradication or after the censored date were excluded in the analysis. We also excluded subjects with failed HP eradcation and those with GC diagnosis within 12 months of HP therapy. We determined the hazard ratio (HR) of GC with aspirin use by Cox proportional hazards model with propensity score adjustment of different baseline characteristics, comorbidities and use of concurrent medications.

Results: During a median follow-up of 7.4 years, 169 (0.27%) of the 63,605 eligible HP infected patients who had successful HP eradication developed GC (median time from HP therapy to GC development: 4.7 years). Aspirin use, defined as ≥weekly use, was associated with a significantly reduced risk of GC development (HR 0.30, 95% CI: 0.15–0.61). Subgroup analysis showed the risk reduction was confined to non-cardia (HR 0.25, 95% CI: 0.11–0.58) but not cardia GC. The risk of GC decreased with increasing frequency, duration and dose of aspirin (all p-trend <0.001) ( Table ).

Conclusion: Long-term aspirin use was associated with a frequency-, dose- and duration-related decrease in GC risk in subjects after successful HP eradication.

Disclosure of Interest: W.K. Leung: WKL has received honorarium for attending advisory board meetings of Takeda and Abbott Laboratories.

All other authors have declared no conflicts of interest.

OP294 GASTRIC INTESTINAL METAPLASIA IS SIGNIFICANTLY ASSOCIATED WITH POST ENDOSCOPY NON-CARDIA GASTRIC CANCER

Y. Snir 1 , A. Vilkin 1 , R. Gingold Belfer 1 , D. Boltin 2 , O. Sneh Arbib 1 , I. Feldhamer 3 , Y. Niv 2 , I. Dotan 4 , Z. Levi 2

1 Dept. Of Gastroenterology, Rabin medical center, Petah Tikva/Israel

2 Sackler Faculty Of Medicine, Tel Aviv University, Tel Aviv/Israel

3 Clalit health services headquarter, Tel Aviv/Israel

4 Sackler Faculty Of Medicine, Rabin Medical Center, Petah Tikva/Israel

Contact E-mail Address: snir01@gmail.com

Introduction: Evidence suggests that the presence of gastric intestinal metaplasia (GIM) is involved in the pathogenesis of Non-Cardia Gastric Cancer (NCGC). Yet, the role of GIM in the occurrence of post endoscopy cancer is scarce.

Aims & Methods: We aimed to determine the incidence of post endoscopy NCGC and assess whether the presence of GIM is associated with its occurrence. Subjects with no previous cancer undergoing upper endoscopy at a tertiary referral center of the Clalit Health Services (CHS) HMO were included. NCGC was detected through the National Cancer Registry. Demographic data was extracted from the CHS database and pathology data including presence of GIM (with or without dysplasia) and extent (focal/extensive) were reviewed. Covariate data included age, sex, body mass index, smoking status, proton pump inhibitors use, triple therapy for helicobacter pylori , comorbidity index. Cox proportional Hazard Ratios (HR) model along with 95% Confidence Interval (CI) was calculated.

Results: Between 01.2004 to 12.2013, 34, 391 subjects (55% females; mean age 60.2 ± 17.5 years) underwent upper endoscopy. At baseline, 1406 (4.1%) had GIM:1360 without dysplasia, 46 with low grade dysplasia (LGD). During a median follow-up of 52 months [interquartile range (IQR) of 28–82 months], 25 cases of NCGC occurred (0.07%):13/32, 985 without GIM, 10/1360 with GIM without dysplasia, and 2/46 with GIM-LGD. The rate (cases/10 5 ) of post endoscopy NCGC for subjects with GIM and LGD, GIM without dysplasia, and without GIM was 1031, 163 and 8.5, respectively (P < .001). Eight cancers (32%) occurred within 12 months from endoscopy, 11 cancers (44%) within 12–36 months of endoscopy and 6 (24%) after 36 months. Among subjects with GIM without dysplasia, 7/10 developed NCGC within 36 month. Compared to subjects without GIM, the presence of GIM with and without dysplasia was significantly associated with NCGC at follow-up, HR 73.5 (CI% 16.3–331) and 14.23 (CI 6.1–32.8), respectively. Among subjects with GIM without dysplasia, extensive GIM was associated with NCGC, HR 7.63 (95% CI 1.96–29.8).

Conclusion: GIM is significantly associated with post endoscopy NCGC. This finding highlights the importance of GIM as a marker for identifying subjects at risk. Health policy makers may take these finding into consideration in future guidelines regarding biopsies during upper endoscopy and GIM surveillance.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP295 ROLE OF MIR-20B-5P, MIR-451A-5P AND MIR-1468-5P IN GASTRIC CANCER

G. Streleckiene 1 , J. Kupcinskas 1 , S. Juzenas 1 , R. Gedgaudas 1 , V. Salteniene 1 , A. Link 2 , M. Leja 3 , G. Kiudelis 1 , L. Jonaitis 1 , R. Lukosevicius 1 , R. Inciuraite 1 , G. Hemmrich-Stanisak 4 , M. Hübenthal 4 , A. Franke 5 , P. Malfertheiner 6 , L. Kupcinskas 1 , J. Skieceviciene 1

1 Institute For Digestive Research, Lithuanian University of Health Sciencies, Kaunas/Lithuania

2 Gastroenterology, Otto-von-Guericke University of Magdeburg, Magdeburg/Germany

3 Digestive Diseases Centre Gastro, University of Latvia, Riga/Latvia

4 Institute Of Clinical Molecular Biology, Christian-Albrechts-University Kiel, Kiel/Germany

5 Institute Of Clinical Molecular Biology, Kiel University, Kiel/Germany

6 Hepatologie Und Infektiologie, Universiätsklinikum Magdeburg, Magdeburg/Germany

Contact E-mail Address: greta.streleckiene@gmail.com

Introduction: MicroRNAs (miRNAs) are an evolutionarily conserved group of small noncoding RNAs that post-transcriptionally regulate gene expression and play important role in a variety of physiological and pathological processes. The aim of this study was to compare miRNA expression profiles in paired gastric cancer (GC) and adjacent normal GC tissues (GCadj) with control gastric tissues (N) from healthy individuals. We further aimed to evaluate the functional role of deregulated miR-20b-5p, miR-451a-5p and miR-1468-5p and their target genes in GC cell lines.

Aims & Methods: To investigate the role of miRNAs in GC, small RNA-sequencing (RNA-seq) analysis was performed using Illumina next generation sequencer (NGS) sequencer HiSeq 2500. In total, 20 paired GC tumorous and adjacent to tumor tissue samples as well as 26 healthy control tissue samples were sequenced. Based on sequencing results in the next stage of analysis we selected three deregulated miRNAs: miR-20b-5p, miR-451a-5p, and miR-1468-5p for functional analysis. Potential target genes of these miRNAs were determined using bioinformatical prediction tools. For target genes experimental analysis GC cell cultures (AGS, MKN28) were used. Target gene expression level was determined by qRT-PCR comparing cells transfected with negative control and miRNA inhibitor or mimic.

Results: 110 differentially expressed miRNAs were identified in GC group compared to HC group, 72 of which were up-regulated and 38 were down-regulated. 32 differentially expressed miRNAs were identified in GCadj group compared to HC group, 25 of which were up-regulated and 7 were down-regulated. Sequencing data analysis revealed that miR-145a-5p and miR-1468-5p were significantly downregulated when comparing GC tissues and healthy controls, while GC and GC adjacent tissue comparison showed significant differences only in miR-1468-5p profile (p < 0.05). After bioinformatics analysis five potential target genes were selected for miR-20b-5p ( EREG , FAT4 , IRF1 , TXNIP , PTEN ), two for miR-451a-5p ( CAV1, ADAM28 ) and three for miR-1468-5p ( TNFa , DNMT1 , CITED2 ). Experimental target genes analysis revealed that IRF1 , TXNIP , and PTEN gene expression level increased after miR-20b-5p inhibition, CAV1 gene expression decreased after forced overexpression of miR-451a-5p. CITED2 gene expression level decreased after miR-1468-5p forced overexpression in GC cell cultures.

Conclusion: MiRNA profiles determined by NGS in gastric tissues show a distinct deregulation pattern in GC, GCadj and healthy control tissues. Cell lines analysis shows that miR-20b-5p may potentially target IRF1 , TXNIP and PTEN , miR-1468 - CITED2 , miR-451a-5p - CAV1 genes and thus mediate gastric carcinogenesis.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP296 AMOTL1 IS INVOLVED IN HIPPO PATHWAY BY PROMOTING YAP1 NUCLEAR LOCALIZATION TO DRIVE GASTRIC CARCINOGENESIS

Y. Zhou 1 , T. Huang 1 , J. Zhang 1 , C.C. Wong 2 , Y. Dong 2 , A.S. l. Cheng 3 , J. Yu 2 , K.F. To 1 , W. Kang 1

1 Anatomical & Cellular Pathology, the Chinese University of Hong Kong, Hong Kong PRC

2 Institute Of Digestive Disease, Partner State Key Laboratory Of Digestive Disease, Chinese University of Hong Kong, Hong Kong PRC

3 School Of Biomedical Sciences, Chinese University of Hong Kong, Hong Kong PRC

Contact E-mail Address: zyhjoe@gmail.com

Introduction: AMOTL1 (Angiomotin-like protein 1), a member of Motin family, is associated with the tight junction between cells. However, its functional role has been reported contradictorily in multiple cancer types and its Hippo-involvement during gastric carcinogenesis remains uninvestigated.

Aims & Methods: We seek to elucidate the functional role of AMOTL1 and comprehensively reveal its regulatory mechanisms during gastric carcinogenesis. Mass spectrometry analysis was applied to identify AMOTL1 as one of the YAP1 binding partners, which was further confirmed by co-immunoprecipitation. Immunofluorescence was performed to confirm the localization of YAP1 after AMOTL1 knockdown or overexpression. The mRNA and protein expression levels of AMOTL1 were examined by qRT-PCR and Western blot. The correlation of AMOTL1 expression with other clinical parameters was checked by immunohistochemistry on the tissue microarray. The biological function of AMOTL1 in GC was determined by MTT proliferation, monolayer colony formation, cell invasion assays through siRNA-mediated knockdown.

Results: When using YAP1 as a bait, mass spectrometry revealed that AMOTL1 was listed in the key binding partners of YAP1. Knocking down AMOTL1 inhibited YAP1 translocation from cytoplasm to the nucleus and promoted YAP1 degradation through ubiquitination. In primary samples, AMOTL1 is found to be highly expressed in primary GC (P = 0.007, GENT) as well as in paired GC tissues compared with adjacent non-tumorous controls (P = 0.012, NCBI/GEO/ GSE63089 ). AMOTL1 upregulation also indicated poor survival among GC patients (overall survival, HR = 1.542, P = 0.007, n = 394, TCGA cohort; first progression survival, HR = 2.230, P < 0.001, n = 512, NCBI/GEO/ GSE14210 , GSE15459 , GSE22377 , GSE29272 , GSE51105 and GSE62254 ). More importantly, overexpression of AMOTL1 was correlated with worse clinical outcomes of patients in advanced stage (overall survival, HR = 1.555, P = 0.025, n = 205, TCGA cohort), which was further verified by gene set enrichment analysis (GSEA) that AMOTL1 expression was positively associated with upregulation of advanced-GC-related genes (ES = 0.775, NES = 1.953, P = 0.025, n = 300, NCBI/GEO/ GSE62254 ). Both univariate and multivariate Cox Regression analyses suggested that AMOTL1 upregulation predicted poor survival independently (univariate analysis, P = 0.016; multivariate analysis, P = 0.022). In vitro experiments revealed that siAMOTL1 led to reduction of cell growth (P < 0.001), colony formation (P < 0.001) and invasion (P < 0.001), suggesting its oncogenic role during gastric carcinogenesis. Finally, AKT and MAPK signalling pathways were confirmed to be the main downstream of AMOTL1 in GC, which showed good concordant with the driver oncogenic role of YAP1.

Conclusion: AMOTL1 is abundantly expressed in GC tissues and its overexpression indicates poor outcomes. The accumulation of AMOLT1 in GC promotes the growth and invasive ability of tumour cells. AMOTL1 exhibits an oncogenic role in gastric carcinogenesis through stabilization and facilitating the nucleus transportation of YAP1, thus to activate AKT and MAPK singling. Our findings demonstrate that AMOTL1 is involved in Hippo pathway and it might serve as a potential therapeutic target for GC.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP297 PERIOPERATIVE CHEMOTHERAPY WITH DOCETAXEL, OXALIPLATIN AND FLUOROURACIL/LEUCOVORIN (FLOT) VERSUS EPIRUBICIN, CISPLATIN AND FLUOROURACIL OR CAPECITABINE (ECF/ECX) FOR RESECTABLE GASTRIC OR GEJ ADENOCARCINOMA (FLOT4-AIO): A RANDOMIZED PHASE 3 TRIAL

N. Homann 1 , H. Schmalenberg 2 , H. Kopp 3 , G.M. Haag 4 , K.B. Luley 5 , W. Schmiegel 6 , G. Folprecht 7 , S. Probst 8 , N. Prasnikar 9 , P. Thuss-Patience 10 , W. Fischbach 11 , J. Trojan 12 , M. Koenigsmann 13 , C. Pauligk 14 , T.O. Goetze 14 , T.W. Kraus 15 , A. Battmann 16 , S.P. Moenig 17 , W. Bechstein 12 , T. Gaiser 18 , A. Tannapfel 19 , E. Jäger 20 , M. Schuler 21 , U. Lindig 22 , M. Pohl 6 , S. Kasper 21 , R.D. Hofheinz 18 , S. Al-Batran 14

1 Department Of Internal Medicine II, Academic Teaching Hospital Wolfsburg, Wolfsburg/Germany

2 IV. Medizinische Klinik, Krankenhaus Dresden-Friedrichstadt, Dresden/Germany

3 Medical Center II, University Hospital, Tuebingen/Germany

4 Department Of Medical Oncology, National Center for Tumor Diseases, Heidelberg University Hospital, Heidelberg/Germany

5 UKSH Campus Luebeck, Lübeck/Germany

6 Ruhr-University Bochum, Bochum/Germany

7 University Hospital Carl Gustav Carus, Dresden/Germany

8 Klinikum Bielefeld, Bielefeld/Germany

9 Klinikum Ludwigsburg, Ludwigsburg/Germany

10 Charité Universitätsmedizin Berlin, Berlin/Germany

11 Klinikum Aschaffenburg, Aschaffenburg/Germany

12 University Hospital Frankfurt, Frankfurt/Germany

13 MediProjekt Gesellschaft für Medizinstatistik und Projektentwicklung, Hannover/Germany

14 Institute Of Clinical Cancer Research (ikf), UCT-university Cancer Center, Krankenhaus Nordwest, Frankfurt/Germany

15 Klinik Für Allgemein-, Viszeral- Und Minimal Invasive Chirurgie, Krankenhaus Nordwest, Frankfurt/Germany

16 Department Of Pathology, Krankenhaus Nordwest, Frankfurt/Germany

17 Service De Chirurgie Viscéral, Hôpitaux Universitaires de Genève, Geneve/Switzerland

18 University Medical Center Mannheim, Mannheim/Germany

19 Pathological Institute, Ruhr University Bochum, Bochum/Germany

20 Clinic For Oncology And Hematology, Krankenhaus Nordwest, Frankfurt/Germany

21 University Hospital Essen, Essen/Germany

22 University Hospital Jena, Jena/Germany

Contact E-mail Address: nils.homann@klinikum.wolfsburg.de

Introduction: The MAGIC trial established perioperative (periop) epirubicin, cisplatin, and 5-FU (ECF) as a standard treatment for patients (pts) with operable esophagogastric cancer, but survival continues to remain poor. FLOT4 ( NCT01216644 ) is a multicenter, randomized, investigator-initiated, phase 3 trial. It compares the docetaxel-based triplet FLOT with the anthracycline-based triplet ECF/ECX as a periop treatment for pts with resectable gastric or GEJ adenocarcinoma.

Aims & Methods: Eligible pts of stage ≥cT2 and/or cN+ were randomized to either 3 preoperative and 3 post-operative 3-week cycles of ECF/ECX (epirubicin 50 mg/m2, cisplatin 60 mg/m 2 , both d1, and 5-FU 200 mg/m 2 as continuous infusion or capecitabine 1250 mg/m2 orally d1-21) or 4 pre-operative and 4 post-operative 2-week cycles of FLOT (docetaxel 50 mg/m2, oxaliplatin 85 mg/m 2 , leucovorin 200 mg/m 2 , and 5-FU 2600 mg/m 2 as 24-hour infusion, all d1). The primary endpoint was overall survival (OS; 80% power; HR of 0.76; 2-sided log-rank test at 5% type I error). Funded by Deutsche Krebshilfe.

Results: Between Aug 2010 and Feb 2015, 716 pts (360 ECF/ECX; 356 FLOT) were randomly allocated. Baseline characteristics were similar between arms (overall, male 74%; median age 62; cT3/T4 81%; cN+ 80%; GEJ 56%). 91% and 37% of pts with ECF/ECX and 90% and 50% with FLOT completed planned pre-operative and post-operative cycles, respectively. Median follow-up was 43 mon. 369 pts died (203 ECF/ECX; 166 FLOT). FLOT improved OS (mOS, 35 mon with ECX/ECF vs. 50 mon with FLOT; HR 0.77 [0.63–0.94]; p = 0.012). 3y OS rate was 48% with ECF/ECX and 57% with FLOT. FLOT also improved PFS (mPFS, 18 mon with ECX/ECF vs. 30 mon with FLOT; HR 0.75 [0.62–0.91]; p = 0.004). Periop complications were 50% with ECF/ECX and 51% with FLOT. 30- and 90-day mortality was 3% and 8% with ECF/ECX and 2% and 5% with FLOT. There was more G3/4 nausea and vomiting with ECF/ECX and more G3/4 neutropenia with FLOT.

Conclusion: Periop FLOT improved outcome in patients with resectable gastric and GEJ cancer compared to periop ECF/ECX and is new standard therapy in this setting.

Disclosure of Interest: N. Homann: consulting or advisory role Sanofi, Roche, Amgen, Cellgene, Lilly

H. Schmalenberg: Consulting/Advisory Role: Lilly, Baxalter; Research Funding: Sanofi; Travel: Merck.

G.M. Haag: advisory role: Sanofi

K.B. Luley: travel, accomodation, expenses: Ipsen, Novartis, Sanofi

W. Schmiegel: adviser: Aicuris, Amgen, Apceth, AstraZeneca, Indivumed, Merck Serono, and Roche; speaker’s fees: Abbott, Falk Foundation, GSB, Lilly, MCI, Medcongress, Pfizer, Sanofi Aventis, Siemens Healthcare, Merck Serono, and Roche

P. Thuss-Patience: consulting: Roche, Lilly, BMS, MSD, Nordic, Pfizer; research grant: Novartis; travel, accomodations, expenses: Roche, Merck, TEVA

M. Koenigsmann: honoraria: Novartis, Celgene; consulting: Novartis, Celgene; travel, accomodation, expenses: Novartis

M. Schuler: adviser: AstraZeneca, Boehringer Ingelheim, BMS, Celgene, Lilly, Novartis, and Roche; speaker’s fees: Alexion, Boehringer Ingelheim, BMS, Celgene, Lilly, and Novartis; research grants Boehringer Ingelheim, BMS, and Novartis

S. Al-Batran: adviser for Merck, Roche, Celgene, Lilly, and Nordic Pharma; speaker’s fees fromRoche, Celgene, Lilly, and Nordic Pharma; research grants from Sanofi, Merck, Roche, Celgene, Vifor, Medac, Hospira, and Lilly.

All other authors have declared no conflicts of interest.

OP298 TUMOR-ASSOCIATED MACROPHAGES AS NOVEL TARGETS FOR IMMUNOTHERAPY IN ESOPHAGEAL ADENOCARCINOMA

S. Calpe , S. Hoefnagel, S. Bouchmal, C. Del Sancho-Serra, D. Straub, K.K. Krishnadath

CEMM, Academic Medical Center Amsterdam, Amsterdam/Netherlands

Contact E-mail Address: s.calpe@amc.uva.nl

Introduction: It has been shown that immune modulation e.g., by inhibition of the T-cell cancer interaction, can greatly improve cancer response. Tumor-associated-macrophages (TAMs) are other key immunological players within the tumor microenvironment which can present both tumor-promoting and tumor-suppressive functions (1). Although several anti-TAM therapies reduce tumor growth and metastasis in preclinical cancer models (2), strategies that aim at specifically eliminating the protumoral TAMs are lacking.

Aims & Methods: This study aimed at identifying specific pro-tumoral TAM populations within the tumor microenvironment of esophageal adenocarcinoma (EAC) and elucidate their potential therapeutic value. EAC is a highly aggressive cancer that presents high intratumoral heterogeneity and dismal prognosis. To determine whether TAM infiltration is associated to low survival and high recurrence in EAC, we analyzed the transcriptomes of 73 EAC by RNAseq of pre-treatment biopsy specimens. As opposed to the publicly available TGCA database, this unique database is composed of a cohort of patients homogeneously treated with standardized treatment, which facilitates the identification of novel treatment targets as well as predictive biomarkers. The ConsensusClusterPlus tool and Gene set enrichment analyses within the computational R platform, were used to determine whether markers that define specific TAM subpopulations could be used as prognostic factors, theraputic targets and/or identify different EAC subgroups.

Results: Clustering of the EAC tumors using specific TAM markers, resulted in the identification of two molecular subtypes of EAC tumors. Gene Set enrichment analyses demonstrated that whereas one group was enriched by metabolic genes, the other group presented an “immune-like” signature and correlated significantly with worse survival. Markers that specifically define immunosuppressive, angiogenic, and stem cell promoting TAMs were highly expressed in these cancers, together with genes involved in leukocyte migration as well as the STAT-JAK signaling pathways. Not surprisingly, this group was also significantly enriched with malignant genes involved in stem cell and epithelial proliferation, epithelial cell migration, EMT and angiogenic factors. In particular, three TAM-specific markers were identified within this “immune-like” group: MARCO, CD80 and ANG2. Immunohistochemistry analyses validated their expression at the protein level. Most importantly, patients with elevated expression of one of these genes presented significantly worse survival.

Conclusion: In sum, we have demonstrated that a subset of EAC patients present an “immune-like” molecular signature which is associated to poor survival. These EAC tumors are characterized by the presence of various subpopulations of pro-tumoral TAMs that promote malignancy such as epithelial proliferation and migration as well as angiogenesis. In particular, three TAM genes (MARCO, CD80 and ANG2) were elevated in these patients and found to be significantly associated to worse survival. Although further experiments are warranted to define their exact prognostic and therapeutic value, our findings might have important clinical implications for EAC. They have illustrated the importance of the role of pro-tumoral TAMs in EAC and have identified a subgroup of patients with aggressive tumors that might benefit from novel tailored immunotherapies directed against pro-tumoral TAMs.

Disclosure of Interest: All authors have declared no conflicts of interest.

References

1. Noy R, Pollard JW. Tumor-associated macrophages: from mechanisms to therapy. Immunity . 2014 Jul 17;41(1):49–61.

2. Petty AJ, Yang Y. Tumor-associated macrophages: implications in cancer immunotherapy. Immunotherapy . 2017 Mar;9(3):289–302.

TUESDAY, OCTOBER 31, 201715:45-17:15

NERVES & BARRIER FUNCTION IN HEALTH & DISEASE - ROOM B5____________________

OP299 ESTROGEN RECEPTOR BETA STIMULATION CONTROLS ENTERIC NEURON AND GLIAL CELL PROLIFERATION IN VITRO AND IN VIVO

F. D'Errico 1 , G. Goverse 1 , Y. Dai 2 , W. Wu 2 , E. Labeeuw 1 , P. J. Gomez-Pinilla 1 , M. Stakenborg 1 , M. Warner 2 , A. Di Leo 3 , J. Gustafsson 2 , G. Matteoli 1

1 Translational Research Center For Gastrointestinal Disorders, KU Leuven, Leuven/Belgium

2 Center For Nuclear Receptors And Cell Signaling, University of Houston, Houston/United States of America

3 Emergency And Organ Transplantation, University of Bari, Bari/Italy

Contact E-mail Address: francescaderrico@hotmail.it

Introduction: A subpopulation of enteric glial cells has the capacity to behave like enteric neuronal stem/progenitor cells (ENSCs) and can reconstitute the enteric neuron pool upon damage. Thus, favoring ENSC differentiation can be considered as a novel therapeutic approach to treat gastrointestinal motility disorders resulting from neuronal loss. In this context, accumulating evidence has shown that estrogens via the activation of the estrogen receptor beta (ER-β) may play a role in stimulating neuronal proliferation and survival in the central nervous system. Although it has been shown ER-β is expressed in the myenteric plexus both by enteric neurons and glial cells, there is no data concerning its possible role in intestinal neurogenesis.

Aims & Methods: Therefore, the aim of this study was to demonstrate if the selective ER-β agonist, LY3201, can act on ENSC-like glial cells to enhance their capacity to generate neurons in case of neuronal damage or loss. To study the effect of LY3201 on murine enteric ganglia in vitro, the muscularis externa of C57Bl/6J mice (8–10 weeks old) was enzymatically digested to isolate myenteric ganglia. After 7 days of incubation with placebo or different concentrations of LY3201 (1, 10, 100 and 1000 nM), cells were stained for glial cell (SOX10, GFAP), progenitor (SOX10, SOX2) and neuronal markers (HuC/D, NF). Moreover, the effect of LY3201 was evaluated in vivo by implanting pellets releasing 0, 119 mg LY3201 over a period of 7 days in two murine models of enteric neuronal damage: topical application of 0.1% benzalkonium chloride (BAC) on the serosa of the ileum and high fat diet (HFD; 60% kcal from fat) for 12 weeks. The number of HuC/D + neurons in the myenteric plexus was assessed by immunofluorescence.

Results: In vitro , different concentrations of LY3201 were tested in myenteric ganglionic cultures showing an increased number of glial cells (SOX10 + GFAP + SOX2- cells) mainly at a concentration of 100 nM (Vehicle: 1130 ± 234; LY3201: 5444 ± 528 per mm 2 ). Interestingly, after blocking glial cell proliferation with an anti-mitotic agent [cytosine arabinoside (AraC)], LY3201 significantly increased the percentage of differentiated neurons (HuC/D + NF + SOX10- cells) (Vehicle 18 ± 3%; LY3201 41 ± 7%) suggesting that in response to LY3201 some glial cells with preserved ENSC capacity are able to give rise to neurons. In vivo , LY3201 treatment for 7 days was able to significantly reduced the myenteric plexus area with neuronal loss compared to the vehicle after BAC treatment (Vehicle: 2, 5 ± 2 mm 2 versus LY3201: 8, 5 ± 3 mm 2 ). In line, LY3201 treatment for 7 days after a HFD resulted in an increased number of myenteric neurons compared to the control group (Vehicle: 510 ± 35; LY3201: 776 ± 49 per mm 2 ).

Conclusion: Here, we demonstrated that the selective ER-β agonist, LY3201, can promote neurogenesis in the damaged myenteric plexus by favoring differentiation of ENSCs into mature enteric neurons. Overall, our study demonstrated that selective ER-β agonists may hold potential as a novel therapeutic approach to treat gastrointestinal motility disorders.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP300 CD90+ SUBPOPULATION OF FIBROBLASTS AS A MESENCHYMAL STEM CELL NICHE IN THE COLON

O. N. Karpus 1 , B. F. Westendorp 1 , J. J. Koster 2 , S. Meisner 1 , V. Muncan 1 , M. E. Wildenberg 3 , G.R. Van Den Brink 4

1 Tytgat Institute For Liver And Intestinal Research, Academic Medical Center, Amsterdam/Netherlands

2 Department Of Oncogenomics And Emma Children's Hospital, Academic Medical Center, Amsterdam/Netherlands

3 Tytgat Institute, AMC Amsterdam, Amsterdam/Netherlands

4 Dept. Of Gastroenterology, Academisch Medisch Centrum, Amsterdam/Netherlands

Contact E-mail Address: karpus.olga@gmail.com

Aims & Methods: We aimed to find a specific fibroblast subpopulation in mouse colon that is able to support stem cell growth and can be visualised by a membrane staining. Primary fibroblasts isolated from Gli1Cre-ZsGreen mouse colons were flow-sorted based on gp38 positivity and Gli1 expression (Gli1 − , Gli1 dim and Gli1 high ). The ability to support organoid growth by fibroblasts was accessed by measurement of organoids perimeter in co-cultures of flow-sorted fibroblasts and organoids in growth factors reduced medium. Sorted cells were further characterized by microarray analysis and results were confirmed by qPCR. Based on microarray results few membrane markers were chosen and an expression pattern of these markers was studied by immunofluorescent and in situ hybridisation tissue staining. New candidate subpopulations were flow-sorted again and characterized by qPCR and co-cultures with organoids.

Introduction: The intestinal epithelium renews every 3–5 days and this process is fully dependent on stem cells. Stem cell potential is strictly defined by its microenvironment – the stem cell niche – which provide all signals required for stem cell maintenance and differentiation. Cell cultures developed from a single stem cell – so called organoids – still requires addition of growth factors such as EGF, R-spondin1 and Noggin. Local fibroblasts may help to support stem cells by producing these missing factors. Vast heterogeneity of fibroblasts can be found in various organs and these subpopulations exert different functions. Not much is known about markers for fibroblast subpopulations in intestine. Recent studies showed expression of the membrane marker podoplanin (gp38) (1) and transcription factor Gli1 (2) by all intestinal fibroblasts.

Results: We observed differential expression of Gli1 in gp38+ intestinal fibroblasts. gp38 + Gli1 high fibroblasts were able to support stem cell growth in vitro. Using membrane markers upregulated in Gli1 high fibroblasts we identified several new markers expressed by all colon fibroblasts (such as Itga9, Sdc2 and Sdc3) and two markers that showed a differential expression (Itga8 and CD90). Itga8 stained mostly smooth muscle cell layer in a colon and does not contribute to the stem cell niche. CD90+ cells located in close proximity to stem cells, supported stem cell growth and express crucial stem cell growth factors such as Grem1, Wnt2b and R-spondin3. We also identified semaphorins class 3 (Sema3) members - Sema3a, Sema3b, Sema3c, Sema3d - expressed by CD90+ fibroblasts. Treatment of organoids with recombinant Sema3a increased organoid growth. Alternatively, blocking of Sema3 binding to its receptor Nrp2 by using recombinant Nrp2 reduced organoid growth in co-cultures with CD90+ fibroblasts.

Conclusion: We identified CD90 as a marker for mouse colon fibroblasts located in close proximity to stem cells. This subpopulation supported stem cell growth and expressed crucial stem cell growth factors such as Grem1, Wnt2b and R-spondin3. Moreover we found an additional protein family, class 3 semaphorins (Sema3), which is expressed by CD90+ fibroblasts and able to increase organoid growth.

Disclosure of Interest: All authors have declared no conflicts of interest.

References

1. Stzepourginski I, Eberl G, Peduto L An optimized protocol for isolating lymphoid stromal cells from the intestinal lamin apropria. J Immunol Methods . 2015 Jun; 421: 14–9.

2. Lee JJ, Rothenberg ME, Seeley ES, Zimdahl B, Kawano S, Lu WJ, et al. Control of inflammation by stromal Hedgehog pathway activation restrains colitis. Proc Natl Acad Sci U S A . 2016. E7545-E7553

OP301 INDIAN HEDGEHOG SUPPRESSES A STROMAL CELL DRIVEN INTESTINAL IMMUNE RESPONSE

B. F. Westendorp 1 , N.V. j.a. Büller 1 , O. N. Karpus 1 , W. A. Van Dop 1 , J. J. Koster 2 , R. Versteeg 2 , P. J. Koelink 1 , C. Snel 1 , S. Meisner 1 , J. J.t.h. Roelofs 3 , A. Uhmann 4 , E. Ver Loren Van Themaat 5 , J. Heijmans 1 , H. Hahn 4 , V. Muncan 1 , M. E. Wildenberg 1 , G.R. Van Den Brink 1

1 Tytgat For Liver And Intestinal Research, Academic Medical Center, Amsterdam/Netherlands

2 Department Of Oncogenomics And Emma Children's Hospital, Academic Medical Center, Amsterdam/Netherlands

3 Department Of Pathology, Academic Medical Center, Amsterdam/Netherlands

4 Department Of Human Genetics, University Medical Center Göttingen, Göttingen/Germany

5 Max Planck Institute for Plant Breeding Research, Köln/Germany

Contact E-mail Address: b.f.westendorp@amc.uva.nl

Introduction: Upon intestinal epithelial damage, a dual response is required to restore homeostasis. While wound repair responses ensure restoration of the epithelial integrity, rapid recruitment and activation of the immune system is essential to limit impact of harmful luminal content. Indian Hedgehog (Ihh) is an epithelial factor that functions as a critical sensor in this process and loss of Ihh results in increased epithelial repair. Signaling occurs in a paracrine manner, as the receptor for Ihh is only expressed in the mesenchyme, but the exact Hedgehog target cell has remained elusive.

Aims & Methods: The aim of this project was to further elucidate the nature of this target cell in the context of intestinal inflammation. Gene expression profiles were determined in Villin-CreERT2-Ihh fl/fl and Rosa26-CreERT2-Ptch fl/fl animals. Sensitivity to DSS induced colitis was tested in Villin-CreERT2-Ihh fl/fl , Gli-CreERT2-Smo fl/fl , LysM-Cre-Smo fl/fl and CD11c-Cre- Smo fl/fl animals. To characterize the Hedgehog target cell, Gli1-CreERT2-Rosa26-ZsGreen animals were analyzed by immunofluorescence, flow cytometry and quantitative PCR.

Results: Loss of intestinal Hedgehog signaling resulted in a rapid increase in expression of inflammation related genes, accompanied by increased influx of immune cells. Animals deficient in general intestinal Hedgehog signaling (Villin-CreERT2-Ihh fl/fl and Gli-CreERT2-Smo fl/fl ) were more sensitive to DSS colitis. In contrast, animals lacking the receptor Smoothened in the myeloid compartment (LysM-Cre-Smo fl/fl and CD11c-Cre-Smo fl/fl ) did not show altered sensitivity, suggesting a non-myeloid target cell. Indeed, Hedgehog responsive cells expressed gp38, smooth muscle actin and desmin, indicating a fibroblastic nature. Ihh signaling inhibited expression of chemokine CXCL12 in fibroblasts in vitro and in vivo, thereby impairing the recruitment of immune cells.

Conclusion: We show that epithelium-derived Indian Hedgehog signals exclusively to fibroblasts in the intestine. Loss of Ihh leads to a rapid immune response with upregulation of fibroblast-derived CXCL12, and migration of immune cells into the lamina propria.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP302 SEMAPHORIN-3E PLAYS A ROLE IN TIGHT JUNCTION EPITHELIAL BARRIER MAINTENANCE IN PATIENTS WITH ACTIVE ULCERATIVE COLITIS

L. Kermarrec 1 , N. Eissa 1 , C.N. Bernstein 2 , J. Ghia 2

1 Department Of Immunology, College Of Medicine, Faculty Of Health Sciences University Of Manitoba, University of Manitoba, Winnipeg/Canada

2 Internal Medicine Section Of Gastroenterology, University of Manitoba, Winnipeg/Canada

Contact E-mail Address: laetitia.kermarrec@umanitoba.ca

Introduction: Patients with ulcerative colitis (UC) patients reveal a dysfunction of tight junction barrier and immune dysregulation. A defective tight junction (TJ) barrier is a key pathogenic factor in the causation and progression of UC by allowing increased antigenic permeation especially gut-derived bacterial lipopolysaccharides (LPS). Semaphorins (Sema) and their receptors plexins (PLX) are novel regulators of epithelia in health and disease. This study aimed to investigate the activity of Sema3E in human subjects with active UC and its effects on the intestinal epithelial cells functions.

Aims & Methods: mRNA levels of Sema3E and its correlation with tight junction proteins (TJPs); Claudin-1 (CLDN1), zonula occludens-1 (ZO-1), E-cadherin (ECADH), occludin (OCLD) and mucosal healing mediator (Krupple Like Factor (KLF)-5) were quantified in colonic tissues of active UC and healthy subjects. Sema3E receptor (PLX D1R) expression level was quantified by immunocytochemistry/RT-qPCR in Caco2 epithelial cell line and cells were treated with Sema3E recombinant protein (100 ng/ml) for 24 h and proliferation, metabolism and migration were assessed by proliferation assay, MTT assay and wound healing assay respectively. Moreover, Caco-2 cells were pretreated with Sema3E recombinant protein (100 ng/ml) for 24 h then challenged with LPS (1μg/ml) for 24 h and TJPs and KLF-5 were quantified by RT-qPCR.

Results: Sema3E level is reduced in UC patients and has strong positive correlation with TJPs; CLDN-1 (r = 0.54, P = 0.03), ZO-1 (r = 0.53, P = 0.03), ECADH (r = 0.60, P = 0.01), OCLDN (r = 0.64, P = 0.008) and KLF-5 (r = 0.52, P = 0.03). Plexin D1R is expressed by Caco2 epithelial cells and Sema3E treatment accelerated significantly the epithelial cells migration when compared to control group. No significant changes on epithelial cells proliferation, metabolism and viability were detected. However, when compared to LPS-induced inflammation, Sema3E treatment increased the expression levels of TJPs and KLF-5.

Conclusion: Sema3E has a critical role in UC pathogenesis through regulation of the intestinal epithelial cells migration and epithelial barrier integrity via the modulation of tight junction protein and mucosal healing mediators. These findings may lead to improved therapeutic strategies in the treatment of UC by restoring Sema3E level in UC patients.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP303 ENDOPLASMIC RETICULUM STRESS INCREASES TRYPSIN-3 ACTIVITY IN ENTEROCYTES AND ALTERS BARRIER FUNCTION

N. Sola Tapias , A. Denadai-Souza, C. Rolland-Fourcade, C. Blanpied, G. Dietrich, C. Bonnart, A. Edir, C. Rolland, C. Deraison, N. Vergnolle, F. Barreau

Digestive Health Research Institute (IRSD), INSERM UMR-1220, Toulouse/France

Contact E-mail Address: nrasola@gmail.com

Introduction: Ulcerative Colitis (UC) is a chronic relapsing inflammatory bowel disease (IBD) with mucosal ulcerations. Excessive induction of endoplasmic reticulum stress (ERS), enhanced proteolytic activity and intestinal barrier disruption have been described in the colon mucosa of UC patients; however associated links between these features had not been described yet.

Aims & Methods: We evaluated the link between ERS and trypsin proteolytic activity (serine protease) in human enterocytes and its impact on intestinal barrier function. Colonic biopsies were taken during routine endoscopy from 12 UC patients and 19 controls. Biopsy supernatants were used to quantify Trypsin-like activity. In parallel, human intestinal Caco-2 cell line was cultured in a transwell system and stimulated with thapsigargin (10 µg/mL) to induce ERS. Supernatants were collected at 6 h and 24 h to quantify Trypsin-Like Activity by enzyme assay. Activity-based probe (ABP) were used to identify specifically the active trypsin-like proteases present in Caco2- supernatants. Paracellular permeability, IL-8 and antimicrobial peptides (AMP) genes were measured to study the impact of proteases on intestinal barrier function. Serine protease inhibitor (AEBSF), and antagonists of protease-activated receptors (PAR) -2 and -4 were used to elucidate the mechanism of action of epithelial proteases.

Results: Trypsin-Like Activity was significantly higher in biopsies from UC patients compared to controls, p = 0.0157. Thapsigargin enhanced trypsin-like activity in Caco2 cells at 6 hours at the apical side of the transwell. ABP assay identified a unique band at 33 KDa in ERS-induced Caco-2 supernatants. This band showed, specificity for trypsin-3. mRNA expression of PRSS-3 (trypsin-3 gene) was increased only at 24 hours after stimulation. In UC patients, immunochemistry of colonic biopsies showed that Trypsin-3 was detectable mainly in epithelial cells, and up-regulated compared to biopsies from healthy controls. In Caco-2 cells, ERS induction was linked to increased paracellular permeability, IL-8 release and AMP (HBD1, HBD2, MUC2, MUC5) dys-regulation. Protease inhibitor AEBSF inhibited thapsigargin-induced increased paracellular permeability and AMP dys-regulation, while, IL-8 increase was aggravated. In Caco-2, mRNA expression of PAR2 and 4 was increased after thapsigargin-induced ERS, and PAR4 levels were restored to basal in the presence of AEBSF. Increased paracellular permeability associated to ERS was reduced after treatment with PAR-2 or -4 antagonists.

Conclusion: Our data showed that in intestinal epithelial cells, ERS increased serine protease activity, which is responsible for altered barrier function and dys-regulated AMP expression. We identified PAR2 and PAR4 activation as mechanisms of ERS-induced barrier dysfunction, and Trypsin-3 as a candidate protease overexpressed upon ERS, and in UC patients epithelium.

Disclosure of Interest: All authors have declared no conflicts of interest.

References

Tewart S. Cao, Inflamm Bowel Dis 2015 Paolo Biancheri et al. Cell Tissue Res 2013 E Hyun, N Vergnolle et al. Gut 2008

OP304 INTESTINAL EPITHELIAL BARRIER DYSFUNCTION IN PATIENTS WITH CHRONIC INTESTINAL PSEUDO-OBSTRUCTION

E. Boschetti 1 , V. Bertakis 1 , T.M.P.B. Karunaratne 1 , A. Accarino 2 , C. Malagelada 3 , F. Azpiroz 4 , R. Cogliandro 5 , E. Bonora 6 , P. Clavenzani 5 , U. Volta 7 , G. Caio 5 , A. Gori 8 , V. Stanghellini 9 , R. De Giorgio 10

1 Medical And Surgical Sciences, University of Bologna, Bologna/Italy

2 Dygestive System Research Unit, University Hospital Vall D'Hebron, Barcelona/Spain

3 Digestive And Liver Diseases, Hospital Vall d`Hebron, Barcelona/Spain

4 Gastroenterology Department, University Hospital General Vall d'Hebron - Gastroenterology Department, University Hospital General, Barcelona/Spain

5 University of Bologna, Bologna/Italy

6 University of Bologna Dept. of Gynaecology Unit of Medical Genetics, Bologna/Italy

7 Dep. Of Medical And Surgical Sciences, Policlinic S. Orsola - Malpighi University of Bologna, Bologna/Italy

8 Dimec, Università di Bologna, Bologna/Italy

9 Department Of Digestive System, University of Bologna Policlinico S. Orsola-Malpighi Internal Med. & Gastroenterology - Department of, Bologna/Italy

10 Dept. Of Medical Surg. Science, University of Bologna Dept. of Clinical Medicine, Bologna/Italy

Contact E-mail Address: elisa.boschetti@unibo.it

Introduction: Chronic intestinal pseudo-obstruction (CIPO) is a rare condition characterized by a severe impairment of gut motility responsible for recurrent episodes of intestinal sub-occlusion and severe digestive symptoms in the absence of mechanical causes. Neuro-interstitial cells of Cajal (ICC)-muscular abnormalities represent the main pathogenetic mechanism explaining gut dysfunction, however other factors, i.e. intestinal epithelial barrier (IEB) abnormalities, may contribute to symptoms and clinical manifestations in CIPO patients. In this study we analyzed the protein expression of the major components of tight junctions (TJs), i.e. occludin, two selected claudins (Cln4 and Cln5) and zonula occludens-1 (ZO-1), as markers of IEB integrity in patients with CIPO. Moreover, based on published evidence we investigated the expression of vasoactive intestinal polypeptide (VIP) as neuronal mediator involved in the regulation of IEB.

Aims & Methods: This study was aimed to clarify the molecular abnormalities responsible for IEB dysfunction in patients with CIPO. A number of n = 28 clinically and histopathologically characterized CIPO patients (15F; age range: 16–75 yrs) entered the study and were subdivided according to the underlying structural alterations detectable at histopathology: specifically, n = 7 with an apparently normal (AN) neuro-muscular layer; n = 11 with inflammatory (INF) changes throughout the neuro-muscular wall and n = 10 with degenerative alterations (DEG). Patients (n = 8; 3F, 48–73 yrs) undergoing elective surgery for uncomplicated neoplastic diseases served as control group. The immunohistochemical techniques used in this study have been performed according to standardized and widely validated protocols. CIPO and control jejunal full thickness biopsies were processed to assess protein expression using western blot. To identify occludin oligomerization, western blot was carried out in low-reducing conditions.

Results: Compared to controls, total occludin protein showed a marked decrease in CIPO pts (P < 0.05). Moreover, occludin oligomers, an index of occludin assembly in rafts TJs, were detected only in 19% of CIPO patients while all controls showed normal oligomerization (P < 0.0001). Cln4, Cln5, ZO-1 and VIP expression did not change in CIPO vs. controls. The analysis of CIPO subgroups vs. controls indicated that total occludin decreased selectively in AN (P < 0.05) and INF (P < 0.05) CIPO subgrousps, whereas ZO-1 and VIP were downregulated only in DEG (P < 0.05 and P < 0.01).

Conclusion: IEB integrity was altered in patients with CIPO as identified by occludin expression abnormalities. Particularly the atypical occludin oligomerization is indicative of TJ dysfunction which increases the possibility of noxious agents passing through the intestinal wall in these patients. Subgroup analysis showed that different molecular mechanisms disrupt the IEB in CIPO patients. Barrier dysfunction in AN and INF is occludin dependent, while in DEG is ZO-1-dependent likely influenced by VIP downregulation. IEB altered molecular mechanisms represent molecular targets for development of diagnostic markers/therapeutic interventions.

Disclosure of Interest: All authors have declared no conflicts of interest.

References

Knowles CH et al. Acta Neuropathol 2009;118: 271–301. Knowles CH et al. Gut 2010;59: 882–7.

Cummins P.M. Molecular and Cellular Biology 2012; 32: 242–250. McCffrey G. et al. J. Neurochem 2009; 110: 58–71.

TUESDAY, OCTOBER 31, 201715:45-17:15

ABSTRACTS ON FIRE: HEPATOBILIARY AND PANCREATIC MALIGNANCIES: FROM BENCH TO BEDSIDE - HOTSPOT____________________

OP305 PREOPERATIVE ENDOSCOPIC VERSUS PERCUTANEOUS TRANSHEPATIC BILIARY DRAINAGE IN RESECTABLE PERIHILAR CHOLANGIOCARCINOMA: A MULTICENTER RANDOMIZED CONTROLLED TRIAL

E. Roos 1 , R.J. S. Coelen 1 , J. K. Wiggers 1 , E. A. j. Rauws 2 , O. M. Van Delden 3 , B. Groot Koerkamp 4 , J. N. m. Ijzermans 4 , C.H.j. Van Eijck 4 , J. De Jonge 4 , R. J. Porte 5 , C. Buis 5 , C. H. Dejong 6 , V. Van Woerden 6 , D.J. Gouma 1 , M.G.h. Besselink 1 , O.R.c. Busch 1 , M.G.w. Dijkgraaf 7 , T. M. Van Gulik 1

1 Surgery, Academic Medical Center, Amsterdam/Netherlands

2 Gastroenterology, Academic Medical Center, Amsterdam/Netherlands

3 Radiology, Academic Medical Center, Amsterdam/Netherlands

4 Surgery, Erasmus MC, Rotterdam/Netherlands

5 Surgery, University Medical Center Groningen, Groningen/Netherlands

6 Surgery, Maastricht University Medical Center and NUTRIM School for Translational Research, Maastricht/Netherlands

7 Clinical Research Unit, Academic Medical Center, Amsterdam/Netherlands

Contact E-mail Address: eva.roos@amc.uva.nl

Introduction: Liver surgery in perihilar cholangiocarcinoma (PHC) is associated with high postoperative morbidity and mortality, primarily due to biliary obstruction caused by the tumor. Preoperative biliary drainage is used to treat jaundice and optimize the patients’ clinical condition. However, biliary drainage itself is also associated with complications that might deteriorate the patient’s condition and worsen outcomes. Consensus is lacking on whether endoscopic or percutaneous biliary drainage should be preferred.

Aims & Methods: This multicenter randomized controlled trial with an “all-comers’’ design (DRAINAGE trial) compared two drainage approaches in patients with presumed, potentially resectable PHC requiring major hepatectomy. Patients with obstructive jaundice and a bilirubin level above 50 μmol/L were randomly assigned to undergo either endoscopic (EBD) or percutaneous transhepatic biliary drainage (PTBD). Primary outcome were severe preoperative complications between randomization and surgery. The secondary outcomes encompassed the success of biliary drainage and postoperative morbidity and mortality. Total sample size required was 106 patients. All procedures were performed by experienced interventional radiologists and gastroenterologists. PTBD remained in situ postoperatively whereas EBD was removed intra-operatively.

Results: From June 2013 through June 2016, a total of 54 patients were randomly assigned to EBD (27 patients) or PTBD (27 patients), without differences in baseline characteristics. The data safety and monitoring board advised to terminate the trial based on a higher perioperative mortality rate in the PTBD group. Prior to surgery, 3 (11%) patients died in the PTBD group versus 0 in the EBD group). After surgery, 8/19 (42%) patients died in the PTBD group versus 2/21 (5%) in the EBD group (of whom 1 was a crossover of EBD to PTBD) (P = 0.002). Initial technical or therapeutic failure occurred more often in the EBD group: 5 (18%) versus 2 (7%). Cross-over from EBD to PTBD due to insufficient drainage or technical failure occurred in 15 patients (54%) of the EBD group. Preoperatively the percentage of patients with more than one complication was comparable between groups 22 (78%) versus 21 (81%). The number of patients with more than one severe complication (Clavien-Dindo 3 or higher) was 21 (78%) in the EBD group versus 18 (67%) in the PTBD group. Post-surgery the amount of patients with more than one complication was comparable 14/22 (64%) in the EBD group versus 14/20 (70%) in the PTBD group. Cause of death was most often a combination of an infectious or vascular complication and subsequent liver failure and multi organ failure.

Conclusion: EBD is advised in patients with resectable PHC requiring biliary drainage since PTBD increased mortality. PTBD should only be used if EBD fails.

Disclosure of Interest: All authors have declared no conflicts of interest.

References

Van der Gaag NA, Kloek JJ, de Castro SMM, Busch ORC, van Gulik TM, Gouma DJ. Preoperative biliary drainage in patients with obstructive jaundice: History and current status. J Gastrointest Surg 2009, Apr;13(4):814–20.

Farges O, Regimbeau JM, Fuks D, Le Treut YP, Cherqui D, Bachellier P, et al. Multicentre european study of preoperative biliary drainage for hilar cholangiocarcinoma. Br J Surg 2013, Jan;100(2):274–83.

Kloek JJ, van der Gaag NA, Aziz Y, Rauws EAJ, van Delden OM, Lameris JS, et al. Endoscopic and percutaneous preoperative biliary drainage in patients with suspected hilar cholangiocarcinoma. J Gastrointest Surg 2010, Jan;14(1):119–25.

Van der Gaag NA, Rauws EAJ, van Eijck CHJ, Bruno MJ, van der Harst E, Kubben FJGM, et al. Preoperative biliary drainage for cancer of the head of the pancreas. N Engl J Med 2010, Jan 14;362(2):129–37.

Olthof PB, Coelen RJS, Wiggers JK, Besselink MGH, Busch ORC, van Gulik TM. External biliary drainage following major liver resection for perihilar cholangiocarcinoma: impact on development of liver failure and biliary leakage. HPB 2016 Apr; 18(4); 348–53.

OP306 IMPACT OF THE PREOPERATIVE GD-EOB-DTPA-ENHANCED MRI ON PROGNOSIS AFTER HEPATECTOMY IN THE PATIENTS WITH HEPATOCELLULAR CARCINOMA

M. Tada , E. Hatano, T. Okada, Y. Asano, N. Uyama, K. Suzumura, I. Nakamura, Y. Kondo, S. Hai, H. Sueoka, H. Iwama, A. Kurimoto, R. Ito, H. Nishida, K. Iida, J. Fujimoto

Hepato-biliary-pancreatic Surgery, Hyogo Medical Collage, Nishinomiya/Japan

Contact E-mail Address: ruhasama519@gmail.com

Introduction: Preoperative 3D simulation images prepared from MD-CT have become essential for safe accomplishment of hepatectomy. On the other hand, Gd-EOB-DTPA-enhanced MRI (EOB-MRI) has been reported to be useful for accurate diagnosis for liver tumor, because it has advanced diagnostic ability for detection of early stage hepatocellular carcinoma (HCC) in patients with cirrhosis of the liver. However, depending on the circumstances of each medical institution, it is often difficult to perform preoperative EOB-MRI.

Aims & Methods: The purpose of this study is to clarify the clinical impact of EOB-MRI as a preoperative examination for hepatectomy. From 2009 to 2016, 342 patients with HCC who underwent curative hepatectomy were enrolled in this study. The patients were divided into the two groups; preoperative EOB-MRI positive and negative groups consisting of the patients who received EOB-MRI within 60 days before the operation or not, respectively, simply because it was dependent on the availability. Preoperative enhanced CT was performed in all cases. In addition to CT, 203 patients received EOB-MRI before hepatectomy. We compare prgonosis of patients who had preoperative EOB-MRI with those who didn’t. Patients who had died of other disease were excluded. Log-rank test and Kaplan-Meier curves were used for survival analysis, and logistic regression analysis was used for Multivariate analysis. Significance was defined as P < 0.05.

Results: The patient age was 68.9 ± 9.9 years. Male and female were 255 and 87. Stage I/II/III/IV were 45/68/60/30 cases, and 16/48/50/25 cases in EOB-MRI positive and negative groups, respectively. There was no significant difference. The median of relapse-free survival with/without EOB-MRI: 895/637 days, the 3-year relapse-free survival rate with/without EOB-MRI: 48.7/39.7% (p = 0.11), but recurrence within 90 days with/without EOB-MRI: 5.4/15.8% (p = 0.0015). The 5-year survival rates with/without EOB-MRI were 77.8%/69.5%, with a significant difference (p = 0.044). Multivariate analysis on Child score, anatomical hepatectomy, tumor number, surgical margin, preoperative EOB-MRI as an early recurrence factor within 90 days revealed that preoperative EOB-MRI was an independent early recurrence factor. [Child score(Odds ratio 1.16, 95%CI 0.43–3.17, P = 0.77), anatomical hepatectomy (Odds ratio 1.02, 95%CI 0.55–1.86, P = 0.95), tumor number(Odds ratio 1.46, 95%CI 0.81–2.63, P = 0.20), surgical margin(Odds ratio 0.33, 95%CI 0.06–1.76, P = 0.20), preoperative EOB-MRI(Odds ratio 2.43, 95%CI 1.23–4.83, P = 0.01)]

Conclusion: The early recurrence within 90 days after surgery was significantly less in EOB-MRI positive group, probably because EOB-MRI has high ability of diagnosis for small tumor in the remnant liver. The preoperative EOB-MRI would contribute to the determination of appropriate resection range and the accompanying improvement of treatment outcomes.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP307 SAFETY AND EFFICACY OF TAE AND SIRT IN NET PATIENTS

L. Van , A. Veenendaal 1 , M. Braat 2 , K. Meier 3 , W. Samsom 1 , M. Verbeek 4 , G. Vriens 5 , W. Valk 6 , M. Prevoo 3 , M. Lam 2 , Tesselaar 1

1 Medical Oncology, Netherlands Cancer Institute, Amsterdam/Netherlands

2 Nuclear Medicine, UMC Utrecht, Utrecht/Netherlands

3 Radiology, Netherlands Cancer Institute, Amsterdam/Netherlands

4 Gastroenterology, Netherlands Cancer Institute, Amsterdam/Netherlands

5 Surgery, UMC Utrecht, Utrecht/Netherlands

6 Endocrinology, UMC Utrecht, Utrecht/Netherlands

Contact E-mail Address: l.v.veenendaal@nki.nl

Introduction: Transarterial embolization (TAE) and Selective Internal Radiation Therapy (SIRT) are effective liver-directed treatments in patients with liver metastases of a neuroendocrine tumour (NET). However, differences between TAE and SIRT have scarcely been investigated.

Aims & Methods: The aim of the study is to compare safety and efficacy of TAE and SIRT. Consecutive patients with histologically confirmed well differentiated NET who underwent TAE or SIRT for liver dominant disease in our NET-expert centre during 2004–2016 were analysed. Toxicity and response were evaluated per procedure during 3 months of follow up. Toxicity were all clinical and laboratory adverse events graded according to CTCAE v4.03. Radiological response was defined according to RECIST 1.1 and/or mRECIST. Clinical response was defined as a decrease in use of somatostatin analogues, diarrhoea or flushes. Biochemical response was defined as >50% decrease in Chromogranin A.

Results: Eighty-seven patients (40 males) with a median age of 60 years underwent 123 procedures (90 TAE/33 SIRT). The majority had a gastroentero-pancreatic NET (94%).

There was imbalance between the 2 groups: in the TAE group 56% had a small bowel NET and 15% a pancreatic NET, whereas this was 28% respectively 34% in the SIRT group. Furthermore, 61% of the patients who underwent TAE had a functional NET, this was 46% in the SIRT group.

Clinical toxicities encountered in the entire cohort were; pain; fever; nausea; vomiting; fatigue; pleural infusion and hepatic infection. Grade 3/4 toxicity occurred in 81% and 24% in the TAE and SIRT-group, respectively; mainly temporary elevated liver enzymes with TAE and one treatment-related death after SIRT, due to ‘radioembolization-induced liver disease’ (REILD). A significant higher clinical response was seen after TAE vs SIRT (88% vs 67%). Biochemical response and radiological overall response rate were comparable; 24% vs 18% respectively 40% vs 45% for TAE vs SIRT. An overall (clinical, biochemical or radiological) response was seen in 86% vs 72% TAE vs SIRT respectively (ns). Progressive disease was seen in the minority of the procedures; 3 after TAE vs 9% after SIRT.

Conclusion: Both TAE and SIRT are safe and effective in treating NET-patients with liver metastases. After TAE more grade 3/4 toxicity occurs, mainly postprocedural elevated liver enzymes, but a higher clinical response is seen as well. SIRT shows less toxicity, although one treatment-related death occurred. REILD is potentially lethal, but occurs rarely (<1%). No significant difference in biochemical and radiological response was seen between TAE and SIRT. Individual patient characteristics should be taken into account in deciding which treatment is preferred.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP308 GEMCITABINE AND PLATINUM-BASED CHEMOTHERAPY FOR THE FIRST-LINE TREATMENT OF HEPATOCHOLANGIOCARCINOMA: AN AGEO MULTICENTER RETROSPECTIVE STUDY

M. Salimon 1 , C. Prieux-Klotz 2 , D. Tougeron 3 , T. Lecomte 4 , M. Caulet 4 , T. Matysiak Budnik 1 , V. Hautefeuille 5 , M. Tiako-Meyo 6 , A. Zaanan 6 , Y. Touchefeu 1

1 IMAD, Department of Gastroenterology, University Hospital, Nantes/France

2 Department of Gastroenterology, Cochin University Hospital, Paris/France

3 Gastroneterology, Poitiers unversity hospital, Poitiers/France

4 Department of Gastroenterology, Tours University Hospital, Tours/France

5 Department of Gastroenterology, Amiens University Hospital, Amiens/France

6 Department of Gastroenterology, Hôpital Européen Georges Pompidou, Paris/France

Contact E-mail Address: maeva.salimon@chu-nantes.fr

Introduction: Hepatocholangiocarcinoma (cHCC-ICC) is a rare primary hepatic tumor combining features of both, cholangiocarcinoma (ICC) and hepatocellular carcinoma (HCC). Only few data exist on prognosis and chemosensitivity of cHCC-ICC.

Aims & Methods: The main objective of this retrospective, multicenter study was to evaluate the overall survival (OS), progression free survival (PFS) and prognostic factors in advanced, unresectable cHCC-ICC treated by gemcitabine plus platinum based chemotherapy as a first line systemic treatment. Data from patients treated for an unresectable cHCC-ICC by gemcitabine and platinum based chemotherapy in six French university hospitals between 2008 and June 2016, were retrospectively collected. The diagnosis of cHCC-ICC was based on histological analysis or, in case of typical histology of ICC or HCC, on discordant CT-Scan findings and/or tumor marker (alpha-fetoprotein, carbohydrate antigen 19–9, carcinoembryonic antigen) serum levels suggesting the other histology . Response rates were defined by RECIST 1.1 criteria. OS and PFS were estimated by Kaplan-Meier method. Prognostic factors were analyzed by Log-rank test in univariate analysis and by Cox model in multivariate analysis with p ≤ 0.05 considered as significant difference. Statistical analysis was performed using Graph Pad Prism 6.

Results: Forty patients were included (70% men, median age 66 years [extremes 32–88]). cHCC-ICC was histologically proven in 55% of cases. At diagnosis, twenty-three (57.5%) of patients had at least one metastatic synchronous lesion. Twenty-nine (72.5%) patients were treated by gemcitabine (gem) and oxaliplatine (GEMOX), 9 (22.5%) by GEMOX plus bevacizumab, 2 (5%) by gem + cisplatine. Eighteen patients (45%) received second line of systemic treatment (FOLFIRI (n = 7), Capecitabine (n = 4), LV5FU2 (n = 2), LV5FU2-Cisplatine (n = 1), Cyclophosphamide (n = 1), Sutent (n = 1), Sorafenib (n = 1) and anti-PDL1 therapy (n = 1)). In the first line, patients received a median of 10 cycles of chemotherapy (extremes 1–28). RECIST criteria were reported in 35 patients. Among them, 9 patients (25.7%) had partial response, 18 patients (51.4%) had stable disease, and 8 patients (22.8%) had tumor progression at first CT scan evaluation. Median PFS and median OS were 9.0 and 15.4 months, respectively. No significant difference was observed according to treatment. In multivariate analysis, significant poor prognostic factors for OS were: positive serology for hepatitis B virus and/or C virus (HR = 1.35 IC95% [1.13–13.24], p = 0.031), serum bilirubin level >30 µmol/L (HR = 1.66 IC95% [1.57–17.54], p = 0.007, and ECOG score ≥ 2 (HR = 2.46 IC95%[2.23–61.75], p = 0.04).

Conclusion: These data suggest a chemosensitivity of cHCC-ICC to gemcitabine plus platinum-based chemotherapy. These results need to be confirmed in a prospective study.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP309 SQLE DRIVES HEPATOCARCINOGENESIS AND IS A THERAPEUTIC TARGET IN NONALCOHOLIC FATTY LIVER DISEASE-ASSOCIATED HEPATOCELLULAR CARCINOMA

D. Liu 1 , C.C. Wong 1 , H. Chen 1 , L. Fu 2 , L. Zhao 1 , C. Li 1 , J. Jy Sung 1 , J. Yu 1

1 Institute of Digestive Disease and Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Shatin/Hong Kong PRC

2 Shenzhen Key Laboratory of Translational Medicine of Tumor and Cancer Research Centre, School of Medicine, Shenzhen University, Shenzhen., Shenzhen/China

Contact E-mail Address: liudb526@gmail.com

Introduction: Due to the obesity epidemic, nonalcoholic fatty liver disease-associated hepatocellular carcinoma (NAFLD-HCC) is an emerging malignancy worldwide. However, the underlying mechanisms and targeted therapy of NAFLD-HCC are still largely unclear. Using transcriptome sequencing, squalene epoxidase (SQLE), a rate limiting enzyme in cholesterol biosynthesis, was identified to be up-regulated in NAFLD-HCC.

Aims & Methods: We aimed to evaluate the biological function of SQLE in NAFLD-HCC, and assess the therapeutic efficacy of targeting SQLE in NAFLD-HCC. SQLE expression was determined by qPCR and western blot. Biological function of SQLE was assessed in vivo using hepatocyte-specific Sqle transgenic mice. Therapeutic efficacy of terbinafine, a SQLE inhibitor, was determined in NAFLD-HCC cell lines in vitro , and nude mice and Sqle-transgenic mice models in vivo .

Results: We performed transcriptome sequencing analysis of 18 paired NAFLD-HCC and adjacent normal tissues. SQLE was a top outlier gene and it was overexpressed in 16 out of 17 paired NAFLD-HCC samples. SQLE mRNA up-regulation was validated in an independent cohort of 27 paired NAFLD-HCC and adjacent normal samples (P = 0.01). In two obesity-induced NAFLD-HCC mice models, Sqle was also up-regulated. We next investigated the biological function of SQLE in vivo. Wild-type and hepatocyte-specific Sqle transgenic mice were injected with a single dose of diethylnitrosamine (DEN) and fed a high fat-high cholesterol diet (HFHC). At 25 weeks of age, spontaneous HCC formation was observed in 9 out of 10 Sqle mice, but only in 2 out of 10 wild type mice (p = 0.003). Sqle tg mice also developed a higher tumor multiplicity (p < 0.01). Histological examination confirmed the formation of HCC in the livers of Sqle tg mice. Consistent with the formation of HCC, α-fetoprotein (AFP), serum AST and ALT were higher in Sqle tg mice. Intraparenchymal pericellular fibrosis, as determined by Sirius Red staining, was highly elevated in Sqle tg mice. Collectively, these data demonstrated that SQLE exacerbated HFHC diet-induced liver inflammation and accelerated HCC formation in mice. Finally, we tested the therapeutic efficacy of terbinafine, a FDA-approved SQLE inhibitor, in the treatment of NAFLD-HCC. Terbinafine inhibited the cell proliferation NAFLD-HCC cell lines in vitro and suppressed the growth of tumor xenografts in nude mice. In DEN-injected and HFHC diet-fed Sqle tg mice, terbinafine treatment reduced tumor incidence (4/9 mice vs 8/9 mice in control) and multiplicity (P = 0.021). These results indicate that therapeutic targeting of SQLE is a promising approach for the treatment of NAFLD-HCC.

Conclusion: We established SQLE as an oncogene in NAFLD-HCC. SQLE promotes HCC in NAFLD-HCC cells and Sqle tg mice. SQLE inhibitor terbinafine confers a clear therapeutic benefit in cell lines and animal models of NAFLD-HCC, corroborating SQLE as a therapeutic target in this subset of HCC.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP310 A XENOTRANSPLANTATION APPROACH USING HUMAN PLURIPOTENT STEM CELL-DERIVED PANCREATIC ORGANOIDS

M. Hohwieler 1 , Z. Xiaofeng 2 , P.C. Hermann 1 , L. Perkhofer 1 , T. Seufferlein 1 , B. Böhm 2 , Y. Ali 2 , A. Kleger 1

1 Internal Medicine, Universitätsklinik Ulm, Ulm/Germany

2 Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore/Singapore

Contact E-mail Address: alexander.kleger@uni-ulm.de

Introduction: Exocrine/ductal pancreatic differentiation from human pluripotent stem cells is a poorly understood process, albeit various diseases arise from this compartment. We have previosuly designed a straightforward approach to direct human pluripotent stem cells (PSC) toward pancreatic organoids resembling exocrine and ductal progeny. Extensive phenotyping of the organoids not only shows the appropriate marker profile but also ultra-structural and functional hallmarks of human pancreas in the dish (Hohwieler, GUT , 2017).

Aims & Methods: Xenotransplantation assays were applied to systematically transplant pancreatic organoids into immunodeficient mice aiming for the ultimate niche to host a human pancreas in mice.

Results: We systematically compared various PO transplantation niches (pancreas, kidney, anterior eye chamber). Tri-lineage differentiation potential of pancreatic progenitor cells, which gave rise to pancreatic organoids, is shown by immunohistochemistry for amylase, CK19 and insulin. Consequently, detailed immunophenotyping of the grafts was performed. In line with morphological appearance acinar-like cells stained positive for several acinar marker genes such amylase and chymotrypsin C, while ductal structures expressed CK19. To assess the maturity of the grafts, co-staining for acinar and ductal lineage markers with various progenitor cell markers such SOX9, PDX1 and NKX6.1 were performed. These data indicate a developmental stage of a human Carnegie Stage CS20 to CS23. Staining for α-smooth muscle actin (α-SMA) also revealed signs of neovascularisation in the grafts.

Conclusion: Xenotransplantation of human pancreatic organoids into the anterior eye chamber an/or the pancreas might become a future and humanized model system.

Disclosure of Interest: All authors have declared no conflicts of interest.

References

Human pluripotent stem cell-derived acinar/ductal organoids generate human pancreas upon orthotopic transplantation and allow disease modelling. Hohwieler M, Illing A, Hermann PC, Mayer T, Stockmann M, Perkhofer L, Eiseler T, Antony JS, Müller M, Renz S, Kuo CC, Lin Q, Sendler M, Breunig M, Kleiderman SM, Lechel A, Zenker M, Leichsenring M, Rosendahl J, Zenke M, Sainz B Jr, Mayerle J, Costa IG, Seufferlein T, Kormann M, Wagner M, Liebau S, Kleger A. Gut . 2017 Mar;66(3):473–486.

The anterior chamber of the eye is a transplantation site that supports and enables visualisation of beta cell development in mice. Ali Y, Diez J, Selander L, Zheng X, Edlund H, Berggren PO. Diabetologia . 2016 May;59(5):1007–11.

OP311 FEASIBILITY OF WHOLE EXOME SEQUENCING AND GENOMIC PROFILING OF PANCREAS TUMOR TISSUE OBTAINED WITH A NOVEL FORK-TIPPED EUS GUIDED FINE NEEDLE CORE BIOPSY

P. Kandel 1 , A. Nassar 2 , G. Tranesh 2 , C. Graddy 1 , R. Bingham 1 , B. Brahmbhatt 1 , V. Gomez 1 , M. Raimondo 1 , T. Woodward 1 , M.B. Wallace 1

1 Gastroenterology And Hepatology, Mayo Clinic, Jacksonville/United States of America

2 Divison Of Pathology, Mayo Clinic, Jacksonville/United States of America

Contact E-mail Address: kandel.pujan@mayo.edu

Introduction: Endoscopic ultrasound-guided fine need biopsy (EUS-FNB) is an important technique for obtaining core tissue for pathological evaluation. Recent advances in FNB needle devices, such as a fork-tipped design (Shark Core Needle, Medtronic Corp, USA) termed here FNB-SC, has been shown to provide reliable histological material in fewer passes compared with traditional FNA. Precision oncological therapy requires further specific data on tumor DNA mutations. The main aim of this study is to compare the DNA yield and histology yield between EUS-FNB-SC and EUS-FNA needles on first pass and determine if such DNA is sufficient for next generation whole exome sequencing.

Aims & Methods: This is prospective registered ( NCT02678442 #) randomized tandem controlled trial started in May 2016 and is ongoing. Consecutive patients undergoing EUS for a pancreas mass were eligible for inclusion. All patients underwent both conventional EUS-FNA and paired EUS-FNB-SC with the order randomized. A minimum of 1 pass with each needle was obtained for histology. Then 2 nd and 3 rd set of passes (one with each needle) was performed to collect for DNA and RNA extraction. The procedure was performed with rapid onsite evaluation. Each specimen slides were evaluated by cytopathologists, who were blinded to the needle type, for histology yield using standard scoring system (0 = no material, 1–2 cytologic, 3–5 histologic). DNA yield, histology yield and technical characteristics were calculated for both EUS-FNB-SC and EUS-FNA needles.

Results: Per-protocol analysis included 18 patients (males: n = 9 [50%], median age: 64 [45–83] years, with a lesion size of 32 [8–69] mm. Sixty percent of lesions were pancreatic adenocarcinoma (n = 11). The median histology score per pass in EUS-FNA was 2 (sufficient for cytology but not for histology) vs 5 (sufficient for adequate histology) in EUS-FNB-SC group for all lesions Table 1. The amount of histology yield, tumor cellularity, surface of area of FFPE samples, length of core tissue, and adequacy for Foundation Medicine assay obtained on first pass was greater in EUS-FNB-SC group vs EUS-FNA group Table 2. DNA sufficient (using a 1100 ng threshold; Mayo Genomics Core Lab) for whole exome sequencing with first pass on pancreatic adenocarcinoma was obtained from 74% of FNB-SC and 45% of FNA specimens.

Conclusion: In this ongoing study histology yield and DNA yield was higher in EUS-FNB-SC needle compared to EUS-FNA needle. EUS-FNB-SC needles appear capable of DNA acquisition sufficient to guide precision oncological therapy.

Disclosure of Interest: M.B. Wallace: Michael Wallace reports grant support from Boston Scientific, Medtronic, Cosmo pharmaceuticals, and equity interest in iLumen. Dr Wallace is a consultant to Aries Pharmaceuticals and Lumendi Inc.

All other authors have declared no conflicts of interest.

OP312 USEFULNESS OF COMPLEMENTARY PANCREATIC JUICE CYTOLOGY IN AVOIDING UNNECESSARY SURGERY FOR PANCREATIC INTRA-DUCTAL PAPILLARY MUCINOUS NEOPLASM

M. Tag-Adeen 1 , E. Ozawa 1 , K. Ogihara 1 , S. Iwatsu 1 , Y. Akazawa 1 , K. Ohnita 1 , T. Adachi 2 , Y. Sumida 2 , K. Nakao 1

1 Department Of Gastroenterology And Hepatology, Nagasaki University Hospital, Nagasaki/Japan

2 Department Of Surgery, Nagasaki University Hospital, Nagasaki/Japan

Contact E-mail Address: tagmedicine@gmail.com

Introduction: Pancreatic juice cytology (PJC) is important factor for detecting malignancy in pancreatic intra-ductal papillary mucinous neoplasm (IPMN) [1]; however, its routine use was not recommended in the international consensus guidelines (ICG) 2012 for diagnosis of IPMN [2].

Aims & Methods: We aimed to usefulness of pancreatic juice cytology in avoiding unnecessary surgery for IPMN patients in the era of ICG 2012. Medical records of patients who underwent surgery for pancreatic IPMN based on ICG 2012; from January 1; 2012 till December 31; 2016, in Nagasaki university hospital were reviewed. Validation of ICG 2012 was done by comparing preoperative imaging criteria with postoperative histopathologic diagnoses. Patients who underwent preoperative PJC were classified into: high risk stigmata (HRS), worrisome features (WF), and neither HRS nor WF (none criteria)groups, then diagnostic validity of PJC was calculated in each group. Only invasive IPMN was defined as malignant IPMN and indicated as IPMC in this abstract, while benign IPMN and high-grade dysplasia were indicated as non-IPMC. PJC of class III or more was considered as positive. p-value <0.05 was statistically significant.

Results: 52 IPMN patients were subjected to surgery based on ICG 2012 in our center, Malignant IPMN (IPMC) was histopathologically confirmed only in 15 patients (29%). Validation of ICG 2012 revealed: low specificity (8%), low positive predictive value (PPV) (29%), low accuracy (33%), and high false positive rate (FPR); 27% for HRS and 65% for WF. Subsequently, 37 patients (71%) were subjected to unnecessary surgery. Preoperative PJC was done in 33 patients: But it was inadequate in 4 patients who were excluded, The difference in PJC adequacy between IPMN types (branched duct-IPMN or non) was insignificant; p=0.1. Only patients with adequate PJC were included (n=29; 10 IPMC and 19 non-IPMC): 9 with HRS, 17 with WF and 3 without any ICG 2012 criteria. In HRS group (n=9; 3 IPMC and 6 non-IPMC): PJC was negative in 4; all of them were non-IPMC, and it was positive in 5 (3 IPMC and 2 non-IPMC), with 100% sensitivity, 67% specificity, 60% PPV, 100% negative predictive value (NPV), 78% accuracy. In WF group (n=17; 6 IPMC and 11 non-IPMC): PJC was negative in 12 (3 IPMC and 9 non-IPMC), and it was positive in 5 (3 IPMC and 2 non-IPMC), with 50% sensitivity, 82% specificity, 60% PPV, 75% NPV, 71%accuracy. Collectively; patients with HRS and/or WF (n=26; 9 IPMC and 17 non-IPMC): PJC was negative in 16 (3 IPMC and 13 non-IPMC), and positive in 10 (6 IPMC and 4 non-IPMC), with 67% sensitivity, 76% specificity, 60% PPV, 81% NPV and 73% accuracy. So, negative PJC result potentially could help in changing therapeutic decision and avoiding unnecessary surgery for 13/17 (76%) of non-IPMC, adversely 3/9 (33%) of IMPC patients might be subjected to more follow up. On the other hand; positive PJC result has supported imaging findings in 6 IPMC patients, but false positive PJC was obtained in 4 non-IPMC cases. In none criteria group (n=3; 1 IPMC and 2 non-IPMC): PJC was negative in all of them with 0% sensitivity, 100% specificity, 67% NPV and 67% accuracy. Overall diagnostic validity of PJC in 29 patients was: 60% sensitivity, 79% specificity, 60% PPV, 79% NPV and 72% accuracy; p-value 0.03, with FPR (21%) less than that of HRS (32%) and WF (58%) in the same patients, and there was no statistically significant difference in its accuracy among IPMN types. Post-ERCP pancreatitis was recorded in 7/33 PJC cases, all were mild and discharged after receiving proper treatment.

Conclusion: PJC is statistically significant predictor for malignant IPMN; and whenever it is used as complementary test to ICG 2012 criteria, it might be useful in improving its diagnostic validity and in avoiding unnecessary surgery.

Disclosure of Interest: All authors have declared no conflicts of interest.

References

1. Rei Suzuki, Nirav Thosani, Srinadh Annangi et al (2014). Diagnostic yield of endoscopic retrograde cholangiopancreatography-based cytology for distinguishing malignant and benign intraductal papillary mucinous neoplasm: Systematic review and meta-analysis. Digestive Endoscopy 26: 586–593.

2. Tanaka M, Ferna´ndez-del Castillo C, Adsay V et al (2012). International consensus guidelines 2012 for the management of IPMN and MCN of the pancreas. Pancreatology 12:183–197.

OP313 COMPARISON OF AMERICAN GASTROENTEROLOGICAL ASSOCIATION, INTERNATIONAL ASSOCIATION OF PANCREATOLOGY, AND AMERICAN COLLEGE OF RADIOLOGY GUIDELINES FOR DIAGNOSIS OF MALIGNANT PANCREATIC CYSTS

M. Mizrahi , T. Kent, K. J. Mortele, J. Moser, J. Tseng, M. Callery, J. Cohen, T. Berzin, D. Pleskow, M. Sawhney

Beth Israel Deaconess Medical Center, Harvard Medical School, Boston/United States of America

Contact E-mail Address: mmizrahi@bidmc.harvard.edu

Introduction: Guidelines published by the American Gastroenterology Association in 2015 (AGA), International Association of Pancreatology in 2006 (Sendai) and in 2012 (Fukuoka), and American College of Radiology 2010 (ACR) are used by clinicians for the management of pancreatic cysts. Guideline recommendations differ from one another and it is not known which guideline is best able to identify patients with malignant pancreatic cysts for surgery.

Aims & Methods: Clinical guidelines were reviewed, and risk-factors associated with malignant cysts were identified. All patients who underwent surgery for mucinous pancreatic cysts between 2002–14 were included, and surgical pathology served as criteria standard. A single expert radiologist, blinded to final cyst pathology, reviewed imaging studies for all study patients. Guidelines were applied to this data to determine their performance in identifying malignant cysts. EUS results were not incorporated.

Results: During study period, 166 patients with mucinous pancreatic cysts underwent surgery. Of these 61 patients (36.7%) had a malignant cyst. Using information from imaging studies, accuracy for malignant cyst diagnosis for clinical guidelines was: 81.3% for AGA, 78.3% for Fukuoka, 63.9% for Sendai, and 51.2% for ACR. The AGA guidelines were more accurate than Sendai guidelines (p = 0.0004), and ACR guidelines (p = 0.0001); but similar to Fukuoka guidelines (p = 0.5). Of the 61 malignant cysts, 31% were missed by AGA guidelines, 34% by Sendai, 25% by Fukuoka, and 10% by ACR guidelines. Final regression model showed that enhancing intra-mural nodule, pancreas duct diameter ≥ 10 mm, and abrupt change in pancreas duct diameter were independent predictors of malignancy.

Conclusion: When only information from radiologic imaging studies was used, AGA and Fukuoka guidelines are more accurate than other guidelines for identifying patients with malignant pancreas cysts.

Disclosure of Interest: All authors have declared no conflicts of interest.

WEDNESDAY, NOVEMBER 01, 201708:30-10:00

PANCREATO-BILIARY EUS: HOW TO DO IT BETTER? - ROOM A1____________________

OP314 LONG-TERM OUTCOMES AND RE-INTERVENTION OF EUS-GUIDED BILIARY DRAINAGE FOR MALIGNANT BILIARY OBSTRUCTION

Y. Nakai 1 , H. Isayama 1 , Y. Ito 2 , H. Yagioka 3 , N. Sasahira 4 , N. Yamamoto 1 , S. Matsubara 1 , H. Kogure 1 , S. Mizuno 1 , N. Takahara 1 , T. Hamada 1 , K. Saito 1 , R. Hakuta 1 , K. Ishigaki 1 , T. Takeda 1 , T. Sato 1 , T. Nakamura 1 , M. Tada 1 , K. Koike 1

1 Gastroenterology, The University of Tokyo, Tokyo/Japan

2 Gastroenterology, Japanese Red Cross Medical Center, Tokyo/Japan

3 Gastroenterology, Tokyo Metropolitan Police Hospital, Tokyo/Japan

4 Gastroenterology, Tokyo Takanawa Hospital, Tokyo/Japan

Contact E-mail Address: ynakai-tky@umin.ac.jp

Introduction: Although EUS-guided biliary drainage (EUS-BD) is increasingly reported as one of treatment options for malignant biliary obstruction (MBO), with a high technical success rate and an acceptable complication rate, its long-term outcomes are not fully discussed. The aim of this multicenter retrospective study is to evaluate long-term outcomes of EUS-BD and clarify the role of re-interventions for stent dysfunction or stent-related complications.

Aims & Methods: Consecutive patients undergoing EUS-BD for unresectable MBO were retrospectively studied. Data on recurrent biliary obstruction (RBO) and other stent-related complications were extracted. Cumulative time to RBO was calculated by a Kaplan-Meier method. Procedures details of re-interventions for RBO and other complications were also described including its route i.e. EUS-BD, transpapillary or percutaneous approach.

Results: Between Aug 2011 and Dec 2016, EUS-BD was performed in 96 pts (EUS-HGS in 82 and EUS-CDS in 14, covered metal stent in 95 and plastic stent in 1) at 4 tertiary referral centers. Biliary drainage prior to EUS-BD had been performed in 54%. The major cause of MBO was pancreatic cancer (52%) and biliary tract cancer (28%). Duodenal invasion (64%) and surgically altered anatomy (25%) were two major reasons for EUS-BD. MBO was distal in 76% and hilar in 24%. A median procedure time was 35 minutes. Technical success rate was 98% with two technical failures (1 stent misplacement and 1 failed insertion of CMS delivery). The incidence of RBO was 36% and a median cumulative time to RBO was 6.8 (95%CI, 4.3–9.7) months. The causes of RBO were non-tumor related (hyperplasia 17%, migration 9%, sludge 5%, reflux 2% and kink 2%), other than de novo stricture (2%). Re-intervention for RBO was successfully performed via EUS-BD route in 89% (31/35). The types of procedures were 22 stent-in-stent, 5 balloon sweep, 3 stent exchange and 1 additional antegrade stenting. Other re-interventions were 2 conversion to transpapillary stenting, 1 conversion from CDS to HGS and 1 PTBD. The incidence of other complications was 29% (5 cholecystitis, 5 cholangitis, 5 peritonitis, 5 bleeding, 5 abdominal pain, 2 fever and 1 stent misplacement).

Conclusion: The incidence of RBO necessitating re-interventions was not rare in EUS-BD for MBO but re-intervention via EUS-BD route was technically feasible in most cases.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP315 EUS-GUIDED RADIOFREQUENCY ABLATION (RFA) FOR PANCREATIC NEUROENDOCRINE TUMOR (NET) AND PRE-MALIGNANT INTRADUCTAL PANCREATIC MUCINOUS TUMOR (IPMN): FIRST RESULTS OF PROSPECTIVE MULTICENTER STUDY

M. Barthet 1 , M. Giovannini 1 , N. Lesavre 1 , B. Napoléon 2 , C. Boustiere 3 , S. Koch 4 , M. Gasmi 1 , J. Gonzalez 1

1 Gastroenterology And Endoscopy, AP-HM, Marseille/France

2 Hôpital Privé Jean Mermoz, Lyon/France

3 Hopital Saint Joseph, Marseille/France

4 CHRU Minjoz, Besançon/France

Contact E-mail Address: marc.barthet@ap-hm.fr

Introduction: Pancreatic NET and IPMN with worrisome features required surgical resection due to the respective risk of lymph nodes/metastatic widespread or invasive adenocarcinoma. EUS-guided antitumoral treatments, mainly based on alcohol injection, have been recently developped with the risk of acute pancreatitis due to uncontrolled diffusion and poorly evaluated efficacy. The aim of this prospective study was: primary endpoint, to evaluate the safety of EUS-RFA in such pancreatic tumors; secondary endpoint: to assess the efficacy in a one-year follow-up

Aims & Methods: This study was conducted as a prospective multicenter study planned to include 30 patients in a two years period with a one-year follow-up and intermediate results are reported. Patients with NET pancreatic tumor less than 2 cm or with pre-malignant pancreatic cystic tumor (side branches IPMN with worrisome features or mucinous cystadenoma (MCA)) were included if they were not operable or refuse surgery. Since October 2015, all the patients have been included, the last one being in January 2017. They were 16 males and 14 females with a 54.4 years mean age (49–84 years). EUS-RFA was performed with a 18G RFA needle (Starmed, Taewong, Korea) applying a 50 W current until reaching 100 Ohms impedance (white bubbles appearence). Patients were followed with MRI and/or EUS.

Results: 12 patients had 14 NET with a 13.4 mm size (8–20 mm) located in 3 cases to the head, 6 to the body, 1 to the tail, respectively. 18 patients had cystic tumor (17 IPMN, 1 MCA) with a 29.1 mm mean size (9–60 mm) located in 14 cases to the head, 3 to the body, 1 to the tail, respectively. 10 out of them had mural nodes and 4 increased thickness of the cyst wall. The mean duration of hospital stay was 4 days (2–6). 3 complications (10%) occured, two with the first patients included: one mild pancreatitis, one small bowel perforation surgically managed, one pancreatic ductal stenosis endoscopically managed. After these initial patients, the protocol was improved with prophylactic adminstration of NSAID and antibiotics and emptying the cyst fluid content leading to dramatic decrease of further complication (3.5%). Three patients experienced mild abdominal pain without acute pancreatitis successfully managed with paracetamol. 10 patients among 12 with NET and 10 patients among 18 with IPMN had at least 6 months follow-up. In NET patients, 6 had complete necrosis or disappearence, 3 a diameter decrease >50%, 1 failure. In patients with pancreatic cystic tumors, mural nodes diseappared in 7/8 cases followed, and the cystic tumor diseappared in 5/10 cases.

Conclusion: EUS-RFA management of pancreatic NET or pancreatic cystic tumors is safe with a 10% complication rate that could be decreased with an improved prophylactic protocol study. Looking to antitumoral treatment, promising results are yielded by the initial follow-up.

Disclosure of Interest: M. Barthet: Boston Scientific consultant

All other authors have declared no conflicts of interest.

WEDNESDAY, NOVEMBER 01, 201708:30-10:00

SUBMUCOSAL ENDOSCOPY: INDICATIONS, TECHNIQUES AND OUTCOMES - ROOM B2____________________

OP316 LIFE AFTER PERORAL ENDOSCOPIC MYOTOMY (POEM): QUALITY OF LIFE AND ITS ASSOCIATION WITH ECKARDT SCORE

Y. Perbtani 1 , J. Suarez 1 , L. Mramba 1 , D. Yang 1 , P. Draganov 1

1 Medicine, University of Florida, Gainesville/United States of America

Contact E-mail Address: peter.draganov@medicine.ufl.edu

Introduction: Peroral endoscopic myotomy (POEM) is an endoscopic technique for the treatment of achalasia and esophageal spastic disorders. The Eckardt score has been traditionally used as a clinical parameter to assess the efficacy of the procedure. The association between the Eckardt score and health-related quality of life (HRQOL) in POEM patients has not been fully elucidated.

Aims & Methods: (1) To evaluate the effect of POEM on short and long-term QOL and to (2) assess the association between QOL and Eckardt scores over time. Single-center prospective cohort study of consecutive POEM cases at the University of Florida during a 5-year period (2011–2016). Both Eckardt scores and HRQOL measured by the Short Form-36 Health Survey (SF-36) were obtained at baseline, and at various intervals post-POEM (1–3 months; 6–9 months; 12 months and beyond). The SF-36 form consists of 8 dimensions, which include: General Health; Bodily Pain; Social Functioning; Emotional Well-Being; Energy/Fatigue; Role limitation due to emotional problems; Role limitation due to physical health and Physical functioning. These eight domains were then grouped into two separate composite scores of overall physical and mental health. Comparison of means scores of Eckardt, Dysphagia and HRQOL were originally described using a univariate linear regression. Pairwise comparisons of means by visit were corrected for multiple testing using Bonferroni method. The association between Eckardt scores and HRQOL were performed by using a Linear mixed model analysis.

Results: POEM was performed in 143 consecutive patients (54% male; mean age 56.9 ± 17.9 years) by a single gastroenterologist in an endoscopy suite during the study period. Most patients had achalasia type II (82; 57.3%) and 12 (8.4%) had prior surgical myotomy. Mean total procedure time was 73.4 ± 30.2 minutes. Overall, mean Eckardt score decreased from 7.8 ± 2.5 to 0.9 ± 1.4 after POEM (p < 0.001). Composite HRQOL dimension scores improved from baseline and held statistical significance over various follow-up lengths after POEM. Mixed model analysis showed a significant association between Eckardt scores and all HRQOL domains (Table 1).

Conclusion: POEM improves symptoms of achalasia as traditionally assessed by changes in Eckardt score. POEM also improved all dimensions of HRQOL as measured by the SF-36 survey at both short and long-term follow-up. A strong association was seen between Eckardt score and all HRQOL domains. The use of the Eckardt score may be used as a surrogate marker for HRQOL in patients who have undergone POEM for achalasia.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP317 TECHNICAL FEASIBILITY OF ENDOSCOPIC SUBMUCOSAL DISSECTION FOR LOCAL FAILURE AFTER CHEMORADIOTHERAPY OR RADIOTHERAPY FOR ESOPHAGEAL SQUAMOUS CELL CARCINOMA

K. Nakajo 1 , T. Yano 1 , Y. Yoda 1 , K. Hori 1 , K. Takashima 1 , K. Shinmura 1 , Y. Ohno 1 , H. Ikematsu 1

1 Department Of Gastroenterology and Endoscopy, National Cancer Center Hospital East, Kashiwanoha, Kashiwa, CHiba, Japan/Japan

Contact E-mail Address: knakajo@east.ncc.go.jp

Introduction: Endoscopic submucosal dissection (ESD) has been widely accepted as the effectiveness and safe procedure for treatment naïve superficial esophageal squamous cell carcinoma (ESCC). However, there are few reports to evaluate the technical feasibility of ESD for local failure after radiotherapy (RT) for ESCC.after CRT or RT compared with conventional ESD.

Aims & Methods: We aimed to evaluate the technical feasibility of ESD for local failure after RT for ESCC comparing with ESD for RT naïve ESCC or for other primary lesions within RT field. Consecutive patients (pts) who were treated with ESD between December 2009 and August 2016 at our institution were retrospectively investigated. Local failure was defined as a recurrent or a residual tumor just at the post RT primary site. We classified the cohort into 3 groups as follows: A group: pts with local failure, B group: pts with other primary lesions within RT field, C group: pts with radiation naïve superficial ESCC. We comparatively evaluated procedure completion rate, en block resection rate, complete resection rate (en block resection with negative of cancer at the margin), procedure time and incidence of major complications for the assessment of feasibility between three groups.

Results: In total 522 pts with 605 lesions were analyzed, and A group included 25 pts (27 lesions), B group included 16 pts (22 lesions), and C group included 481 pts (556 lesions). The characteristics of pts in A, B, and C group were as follows: the median age (years)=70.5, 73.5, 70. male/female=17/8, 15/1, 417/64. Mean tumor size (±standard deviation) was 15.7 (±9.9) mm, 17.7 (±10) mm, 29.1 (±15) mm, and there was significant differences between A group and C group (P<0.001), and between B group and C group (P<0.001). There were no significant differences in procedure completion rate between three groups (92.6% vs 100% vs 100%). 2 lesions in 2 pts were incomplete of ESD procedure due to severe fibrosis and switched to Photodynamic therapy (PDT). While en block resection rate were similar between 3 groups (96% vs 100% vs 100%), complete resection rate of A group was significantly lower comparing with that of C group (A group vs B group vs C group = 60.0% vs 77.3% vs 80.4%, A group vs C group; P = 0.013). Mean procedure time (±standard deviation) was 63 (±32) minutes, 69 (±27) minutes, 91 (±50) minutes, respectively, and there was significant differences between A group and C group (P = 0.006), and between B group and C group (P = 0.002). Serious complications involving perforation or bleeding required transfusion were not observed in A group and B group, whereas perforation was occurred in 17 cases of C group (2.8%). However, there was no significant difference in the frequency of complications between three groups.

Conclusion: In this study, we showed the technical feasibility of ESD for patients for local failure and for other primary lesions within RT field without major complications compared with conventional ESD. However, it could be technically difficult to complete ESD for local failure after CRT or RT due to severe fibrosis in the submucosal layer in some cases. In such a case, an alternative treatment such as PDT should be considered.

Disclosure of Interest: All authors have declared no conflicts of interest.

WEDNESDAY, NOVEMBER 01, 201708:30-10:00

ENDOSCOPIC MANAGEMENT OF GI BLEEDING: WHAT IS NEW? - ROOM E4____________________

OP318 MULTICENTRE RANDOMISED CONTROLLED TRIAL COMPARING THE EFFICACY AND SAFETY OF ADDING EARLY HEMOSTATIC POWDER APPLICATION TO ENDOSCOPIC AND MEDICAL TREATMENT IN THE MANAGEMENT OF ACUTE VARICEAL BLEEDING IN CIRRHOTIC PATIENTS

M. Ibrahim 1 , A. El-Mikkawy 2 , M. Abdel Hamid 2 , H. Abdalla 2 , A. Lemmers 1 , I. Mostafa 2 , J. Devière 1

1 Gastroenterology, Hepatopancreatology And Digestive Oncology, Erasme Hospital, Université libre de Bruxelles ULB, Brussels/Belgium

2 Gastroenterology And Hepatology, Theodor Bilharz Research Institute, Cairo/Egypt

Contact E-mail Address: mostafa.ibrahim@webgit.net

Introduction: Acute variceal bleeding (AVB) is a severe complication of portal hypertension in patients with liver cirrhosis. Standard therapy includes the administration of vasoactive drugs, antibiotics and endoscopic therapy with band ligation or cyanoacrylate injection. The novel Hemostatic powder “Hemospray®” (Cook Medical, Winston-Salem, NC) has been shown to be effective at short-term follow-up for emergency treatment of AVB in a pilot study (1) as an initial therapy in patients with massive bleeding as a temporary “bridge” until definitive endoscopic treatment.

Aims & Methods: The primary objective was to assess the added value of early Hemospray in combination with standard of care (SOC) medical treatment compared to the SOC in cirrhotic patients with acute variceal bleeding. The primary endpoint was a combined endpoint of clinical hemostasis which was defined as the absence of clinical features of rebleeding from admission till the definitive endoscopy (12–24 h) in both groups and endoscopic hemostasis which was defined as the absence of endoscopic signs of bleeding at the time of the definitive endoscopy (12–24 h). Subjects were randomized in a 1:1 ratio. All subjects in Group 1 (Hemospray® group) were treated by medical treatment plus Hemospray application within 2 hours of admission. The medical treatment was continued till 12–24 h hours after admission when the definitive endoscopy was performed. All subjects in Group 2 (Non-Hemospray) were treated by medical treatment followed by the definitive endoscopy 12–24 hours from admission. Urgent Endoscopy within 60 minutes was performed in any patient who failed to achieve clinical hemostasis within the first 24 hours.

Results: One hundred five patients were randomized for suspected AVB; 19 were excluded due to non-variceal source of bleeding; 86 patients were randomized: group 1 (n = 43), group 2 (n = 43). Severity of liver disease was similar (Child-Pugh class B 49% in both groups, Child-Pugh class C in 19% and 23% in group 1 and 2, respectively. Clinical hemostasis was achieved in 98% in group 1 and 70% in group 2 (P = 0.0005). Hemospray® failed to stop spurter gastric variceal bleeding in 4 patients who were treated by cyanoacrylate injection. Endoscopic hemostasis was achieved in all patients of group 1. Despite the medical treatment, all patients of group 2 had fresh blood into the stomach at the time of endoscopy and 30% of them had to have urgent endoscopy to control relapsing overt hematemesis. A significant improvement on survival at 30 days was observed in the Hemospray group compared to SOC group (93% vs 67%; p = 0.0029). While no difference on survival in the hospitalization period (5 days) (95% vs 91%; p = 0, 3972).

Conclusion: Hemospray ® application at 2 hours of admission improves clinical and endoscopic hemostasis of AVB. This bridge therapy may have an impact on early and 30 days survival of these cirrhotic patients.

Disclosure of Interest: All authors have declared no conflicts of interest.

Reference

Management of acute variceal bleeding using hemostatic powder. United European Gastroenterol J . 2015 Jun;3(3):277–83.

OP319 HIGH EFFICACY OF OTSC AS FIRST-LINE ENDOSCOPIC TREATMENT IN PATIENTS WITH GASTROINTESTINAL BLEEDING: AN ITALIAN MULTICENTRIC EXPERIENCE IN A LARGE COHORT OF PATIENTS

S. Mangiafico 1 , S. Russo 2 , M. Lupo 2 , A. Caruso 1 , G. Grande 3 , F.P. Zito 2 , H. Bertani 4 , R. Conigliaro 4 , A. Pisani 5 , B. Germaná 6 , G. Galloro 7 , L. Pasquale 8 , B. Mangiavillano 9 , G. Bassotti 10 , M. Mutignani 11 , R. Manta 2

1 Aou Modena, Gastroenterology and Digestive Endoscopy Unit, Modena/Italy

2 Interventional Endoscopy, Ospedale s. Agostino Estense Uo di Endoscopia Digestiva, Modena/Italy

3 Digestive Endoscopy - Nocsae Modena, Digestive Endoscopy - NOCSAE Modena, Modena/Italy

4 U.O.C. Gastroenterology and Digestive Endoscopy Unit, Nuovo Ospedale Civile Sant'Agostino Estense, Modena/Italy

5 Gastroenterology Section, Department of Emergency and Organ Transplantation, University of Bari, Bari/Italy

6 San Martino Hospital - Ulss, Gastroenterologic Unit, Belluno/Italy

7 Endoscopy Unit, AOU "Federico II" di Napoli, Naples/Italy

8 Department Of Endoscopy, AZIENDA OSPEDALIERA S.G., Avellino/Italy

9 Gastrointestinal Endoscopy Unit, Humanitas - Mater Domini, Castellanza (VA)/Italy

10 Sofar Osp. Clinicla Gastro Università, Perugia/Italy

11 Diagnostic and Interventional Digestive Endoscopy, Niguarda Ca' Granda Hospital, Milan/Italy

Contact E-mail Address: s.mangiafico@ausl.mo.it

Introduction: The over-the-scope clip (OTSC) is a known endoscopic clipping device designed for tissue approximation, used for endoscopic closure of perforations, leaks, fistulas and for endoscopic hemostasis. Emerging evidences report high efficacy when such device is used both as first-line or rescue endoscopic therapy for acute gastrointestinal bleeding management.

Aims & Methods: Our aim is to report a large series of patients with non-variceal upper and lower gastrointestinal bleeding lesions in whom OTSCs were used as first-line endoscopic treatment. In a retrospective analysis of prospectively collected data in tertiary referral centers, patients undergoing emergency endoscopy for severe acute nonvariceal gastrintestinal bleeding were treated with OTSC as primary first-line therapy. The endoscopic procedures were performed in anaestesiologic-assisted deep sedation, by skilled operators. Technical and clinical success, rate of re-bleeding, blood infusion, days of hospitalization were recorded for each patient.

Results: Over a period of 3 years, from January 2014 to January 2017, we included 201 consecutive patients with mean age 68 years (range 28–89 years). Out of 106/201 patients were treated with the non-traumatic version of the OTSC system while in 95/201 the traumatic clip was preferred. Indications for OTSC treatment included, for the upper gastrointestinal tract, duodeno-jejunal ulcer Forrest 1a (n = 29) and Forrest 1b (n = 35), gastric ulcer Forrest 1a (n = 19) and Forrest 1b (n = 28), Mallory Weiss (n = 19), Dieulafoy's lesion (n = 9), post gastric- ESD bleeding (n = 14); for the lower gastrointestinal tract indications for OTSC treatment included post EMR bleeding (n = 15), post ESD bleeding (n = 12), traumatic rectal ulcer (n = 2), colonic diverticulum (n = 4); 15 patients with upper or lower gastrointestinal tract surgical anastomosis bleeding were also included. Technical success was achieved in all cases 201/201 (100%). Primary haemostasis was achieved in 193/201 patients (96%). In the remaining 8 patients haemostasis was obtained with radiological vascular embolization (n = 5) or surgery (n = 3). Early re-bleeding occurred in 9/201 patients (4%) after 12–24 hours and it was treated with epinephrine injection with or without use of through the scope clips in case of minor oozing from the bleeding site (n = 6) while radiological vascular embolization was required for major bleeding events (n = 3). In these 9 patients median number of packed red cell units transfused was 2 U (1–3 U) whilst it was not needed in patients successfully treated with OTSC. Finally no late re-bleeding was observed in our series and a median length of total hospital stay of 4 days (3–11 days) was required in patients responsive to OTSC treatment.

Conclusion: Our multicenter report has shown that the use of OTSC as first-line therapy in acute high-risk gastrointestinal bleeding appears to be safe and highly effective.

Disclosure of Interest: All authors have declared no conflicts of interest.

References

A new endoscopic over-the-scope clip sys tem for treatment of lesions and bleeding in the GI tract: first clinical experiences. Kirschniak A, Kratt T, Stuker D et al (2007) Gastrointest Endosc 66:162–16

Over-the-scope clip (OTSC) represents an effective endoscopic treatment for acute GI bleeding after failure of conventional techniques Manta R, Galloro G, Mangiavillano B, Conigliaro R, Pasquale L, Arezzo A, Masci E, Bassotti G, Frazzoni M. Surg Endosc . 2013 Sep;27(9):3162–4. doi: 10.1007/s00464-013-2871-1. Epub 2013 Feb 23.

OP320 NEW USE OF LOW-DOSE ASPIRIN AND RISK OF UPPER AND LOWER GASTROINTESTINAL BLEEDING: ASSOCIATIONS BY CASE-FATALITY, HOSPITALISATION STATUS, BLEEDING LOCATION, ASPIRIN DOSE AND DURATION IN A LARGE OBSERVATIONAL STUDY IN THE UNITED KINGDOM

L. Cea Soriano 1 , M. Soriano-Gabarró 2 , A. Lanas 3 , L.A. García Rodríguez 4

1 Complutense University of Madrid, Madrid/Spain

2 Bayer AG, Berlin/Germany

3 University of Zaragoza, Zaragoza/Spain

4 Spanish Centre for Pharmacoepidemiologic Research, Madrid/Spain

Contact E-mail Address: lagarcia@ceife.es

Introduction: There is increasing evidence of the benefits of low-dose aspirin for primary prevention of colorectal cancer (1), in addition to established benefits on cardiovascular prevention. Estimates of the incidence of upper and lower gastrointestinal bleeding are needed to inform adequate benefit–risk assessment.

Aims & Methods: Using The Health Improvement Network primary care database, we estimated the association between new use of low-dose aspirin (75–300 mg/day) and upper/lower gastrointestinal bleeds (UGIB/LGIB) by case-fatality (fatal case = death within 30 days), hospitalization/referral status, bleeding location, and aspirin dose and duration. Among persons aged 40–84 years from 2000–2012 with no previous low-dose aspirin use, 199, 049 new users of low-dose aspirin were identified. Each member was matched to a person free of low-dose aspirin on that day by age, sex, primary care practitioner visits in the previous year and time since study entry. Cohorts (mean age at entry, 64 years) were followed (max. 14 years, median 5.4 years) to identify incident cases of UGIB/LGIB, with validation through manual review of patient records and linkage to hospital data. A nested case–control analysis was conducted using cases and controls from both cohorts. To account for temporal changes in aspirin exposure, an ‘as-treated’ analysis was used. Controls (n = 5000 for UGIB and n = 10,000 for LGIB) were frequency-matched to cases by age, sex and calendar year. Adjusted rate ratios (RRs) with 95% confidence intervals (CIs) were calculated for current low-dose aspirin use (0–30 days before the index date [UGIB/LGIB date for cases, random date for controls]); reference group was never use.

Results: There were 1843 UGIB cases and 2763 LGIB cases; 60% of UGIBs and 28% of LGIBs were hospitalized (remaining cases were referred only). Low-dose aspirin was associated with significantly increased risks of non-fatal UGIB/LGIB, hospitalized as well as referred (but not hospitalized) UGIB/LGIB, but not fatal UGIB/LGIB (Table 1). RRs (95% CI) by UGIB location were 2.33 (1.69–3.21) for duodenal ulcers, 1.94 (1.46–2.58) for gastric ulcers and 1.59 (1.25–2.02) for mucosal erosions; RRs (95% CI) for LGIB were 2.33 (1.96–2.77) for diverticular diseases and 3.09 (2.13–4.50) for polyps. By daily dose of aspirin, RRs (95% CI) for UGIB were 1.58 (1.37–1.83) for 75 mg/day and 2.12 (1.53–2.93) for 150–300 mg/day; estimates for LGIB were 1.98 (1.76–2.24) for 75 mg/day and 1.98 (1.50–2.62) for 150–300 mg/day. Around 95% of low-dose aspirin use was at 75 mg/day. The magnitude of the increased LGIB risk was similar with all durations used, while there was a suggestion of a greater risk of UGIB in the first months after starting treatment: RRs (95% CI) for LGIB were 2.20 (1.74–2.77) for <3 months and 1.96 (1.74–2.21) ≥3 months; and for UGIB were 2.57 (1.93–3.42) for <3 months and 1.54 (1.33–1.78) for ≥3 months.

Conclusion: Use of low-dose aspirin is associated with a significantly increased risk of UGIB/LGIB overall (both hospitalized and referred cases) but not with fatal UGIB/LGIB. Our results also suggest a possible dose–response relationship between low-dose ASA and UGIB but not LGIB.

Disclosure of Interest: L. Cea Soriano: LCS works for CEIFE, which has received research funding from Bayer AG

M. Soriano-Gabarró: MS-G is a full-time salaried employee of Bayer AG

A. Lanas: 'AL has received a research grant from Bayer AG and has served as an advisory board member for Bayer AG

L.A. García Rodríguez: LAGR works for CEIFE, which has received research funding from Bayer AG. LAGR has also received honoraria for serving on advisory boards for Bayer AG.

Reference

1. Patrignani & Patrono. 2016. J Am Coll Cardiol . 2016 Aug 30; 68(9):967–76.

OP321 THE EFFICACY OF POLYGLYCOLIC ACID SHEETS AND FIBRIN GLUE FOR PREVENTING BLEEDING AFTER ENDOSCOPIC SUBMUCOSAL DISSECTION FOR GASTRIC NEOPLASMS (PAGER BUSTER TRIAL): INTENTION TO TREAT ANALYSIS OF A PROSPECTIVE MULTICENTER RANDOMIZED CONTROLLED TRIAL

Y. Kataoka 1 , Y. Tsuji 1 , K. Hirasawa 2 , K. Takimoto 3 , T. Wada 4 , S. Mochizuki 5 , K. Ohata 6 , K. Niimi 7 , S. Ono 1 , S. Kodashima 1 , N. Yamamichi 1 , M. Fujishiro 1 , K. Koike 1

1 Dept. Of Gastroenterology, University of Tokyo, Tokyo/Japan

2 Division Of Endoscopy, Yokohama City University Medical Center, Yokohama/Japan

3 Dept. Of Gastroenterology, National Hospital Organization Kyoto Medical Center, Kyoto/Japan

4 Dept. Of Gastroenterology, Sanraku Hospital, Tokyo/Japan

5 Dept. Of Gastroenterology, Tokatsu-Tsujinaka Hospital, Chiba/Japan

6 Dept. Of Gastroenterology, NTT Medical Center Tokyo, Tokyo/Japan

7 Center For Epidemiology And Preventive Medicine, Graduate School of Medicine, the University of Tokyo, Tokyo/Japan

Contact E-mail Address: saichu_resi_ky@yahoo.co.jp

Introduction: Endoscopic submucosal dissection (ESD) for gastric neoplasms has been established as a standard treatment in many countries. However, post-ESD bleeding is still one of the major complications which are impossible to completely prevent. Recently there have been some reports about the endoscopic tissue shielding method with polyglycolic acid (PGA) sheets and fibrin glue for the mucosal defect after ESD. In our pilot study we have demonstrated that this method may reduce the risk of post-ESD bleeding, but there have been no reports which provide strong evidence concerning this issue to date.

Aims & Methods: This is a prospective multicenter open-label RCT conducted in six hospitals across Japan to investigate the efficacy of the PGA shielding method for preventing post-ESD bleeding. Out of scheduled gastric ESD patients, those with a high-risk for post-ESD bleeding were enrolled in this study. High-risked patients were defined as follows: 1) those expected to undergo large mucosal resection (≥40 mm) or 2) those with regular intake of antithrombotic agents. Before ESD the patients were allocated to PGA group or non-PGA group at a ratio of 1:1 by a minimization method through a web-based system. The enrolled patients in both groups received proton pump inhibitor for 4 weeks from the day before ESD, and underwent coagulation of visible vessels on the ESD–induced ulcer floor. And then, in the PGA group, PGA sheets were placed onto the ulcer floor and stuck with fibrin glue. 2 days after ESD, soft diet was started. Post-ESD bleeding was defined as follows: 1) hematemesis, melena or a hemoglobin decrease ≥2.0 g/dL and 2) emergency endoscopy revealed active bleeding or accumulated blood in the stomach. When a patient presented with post-ESD bleeding, endoscopic hemostasis was performed. The primary endpoint was the post-ESD bleeding rate.

Results: A total of 68 patients were assigned to the PGA group and 72 patients to the non-PGA group. After excluding 3 patients (the ESD cessation: 2, consent withdrawal: 1), 67 patients in the PGA group and 70 in the non-PGA group were included in the intention to treat analysis. Post-ESD bleeding occurred in 3 patients (4.5%) in the PGA group and 4 (5.7%) in the non-PGA group. There was no significant difference between the two groups (P = 1.000). Concerning the date of bleeding onset, in the non-PGA group post-ESD bleeding tended to occur later than in the PGA group (11.7 ± 2.6, 3.0 ± 3.6, respectively). All the post-ESD bleeding cases were successfully treated by endoscopic hemostasis. Univariate analysis revealed significant risk factors for post-ESD bleeding: tumor location of lesser curvature (P = 0.045) and intake of multiple antithrombotic agents (P = 0.031). As for the complications other than post-ESD bleeding, one delayed perforation and one pyloric stenosis occurred in the non-PGA group.

Conclusion: The present study could not demonstrate a significant effect of the PGA shielding method on the prevention of post-ESD bleeding although this method has the possibility of preventing late-phase bleeding.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP322 SIGNIFICANT REDUCTION OF POSTINTERVENTIONAL HAEMORRHAGE AFTER RESECTION OF LARGE DUODENAL ADENOMAS BY THE USE OF A HEMOSTATIC POWDER?

T. Mueller , M. Knabe, J. Wetzka, C. Ell, A. May

Medical Clinic II, Sana Klinikum Offenbach, Offenbach/Germany

Contact E-mail Address: bbc2@gmx.net

Introduction: Against the background of the relatively high rates of relevant bleedings after endoscopic resection depending on the size of the duodenal adenoma, the value of a hemostatic powder was examined.

Aims & Methods: This is a prospective, randomized study with (Group A) and without (Group B) administration of a hemostatic powder after resection. Only large duodenal adenomas with a size ≥20 mm were included. The resection was performed by means of a snare after prior injection. Intraprocedural bleedings were treated by injection and coagulation. Post-interventional Hb-control and an EGD on the following day were documented, whereby bleeding stigmata (Forrest IIc-Ia) were recorded. The sample size calculation showed 21 patients per arm with a reduction in bleeding by one third. Minor bleeding was defined as Hb decrease less than 2 g/dl and bleeding stigmata during wound control the next day. The major bleeding was defined as Hb drop ≥2 g/dl.

Results: Between December 2014 to February 2017, 39 suitable patients were presented, 38 patients (14 ♀; 24 ♂, average age 65 years) of which were randomized. Two patients dropped out of the study. The etiology of adenomas was sporadic in 66%, and 34% had FAP. The average adenoma size was 33 ± 11 mm (20–60 mm). The localization of the duodenal adenomas was 32% suprapapillary, 26% at the papillary level, and 42% infrapapillary. In each case 18 patients received either a hemostatic powder or not. In group A patients (with hemostatic powder) a minor hemorrhage was detected in 9/18 and a major hemorrhage in 2/18. In the group B (without hemostatic powder) a minor hemorrhage occurred in 4/18 and major hemorrhage in 3/18 patients. After an interim analysis, the study was terminated prematurely if the effect of the hemostatic powder was missing.

Conclusion: By applying a hemostatic powder no significant reduction of relevant post-bleeding after endoscopic resection of large duodenal adenomas ≥20 mm can be achieved.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP323 EFFECT OF PROPHYLACTIC CLIP APPLICATION FOR THE PREVENTION OF POSTPOLYPECTOMY BLEEDING IN LARGE PEDUNCULATED COLONIC POLYPS: A RANDOMIZED, CONTROLLED MULTICENTER TRIAL

J. Ji 1 , K. Lee 2 , S. Lee 3 , D.B. Kim 2 , T. Gweon 1 , H. Choi 1

1 Internal Medicine, Incheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Incheon/Korea, Republic of

2 Internal Medicine, St. Vincent’s Hospital, College of Medicine, The Catholic University of Korea, Suwon/Korea, Republic of

3 Internal Medicine, Daejeon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Daejeon/Korea, Republic of

Contact E-mail Address: jjsdr@catholic.ac.kr

Introduction: Although endoscopic colonic polypectomy has been an established procedure for a long time, the risk of bleeding is still higher after resecting of pedunculated polyps, because of the presence of a large artery in the stalk. Preventive methods such as endoloop and epinephrine injection have been proposed in the management of postpolypectomy bleeding in large colonic polyps. For prophylactic clip, there was no randomized controlled study assessing the efficacy in prevention of postpolypectomy bleeding for the large pedunculated polyps.

Aims & Methods: The aim of this randomized controlled trial was to confirm the efficacy of application of prophylactic clip in the prevention of postpolypectomy bleeding in large pedunculated polyps. A total of 183 patients who had pedunculated colorectal polyps, with heads larger than 10 mm and stalks larger than 5 mm in diameter, were included. In clip group, hemoclips were applied to the base of the stalk, followed by conventional snare polypectomy. In control group, conventional snare polypectomy was done without any preventive management. Immediate and delayed bleeding complications were analyzed.

Results: A total of 200 polyps were included in the study (99 in the clip group and 101 in the control group). Clip application was possible in all the cases in the clip group. There were 5 cases of bleeding in the clip group (5.1%) and 15 cases in the control group (14.9%) (P = 0.047). Immediate bleeding episodes occurred in 4/5 polyps in the clip group and 14/15 polyps in the control group. One case of delayed bleeding was observed in both groups.

Conclusion: The application of a prophylactic clip is effective in the prevention of postpolypectomy bleeding in large pedunculated colonic polyps.

Disclosure of Interest: All authors have declared no conflicts of interest.

WEDNESDAY, NOVEMBER 01, 201708:30–10:00

LONG-TERM COMPLICATIONS IN IBD - ROOM 7.1____________________

OP324 THE RISK OF PROXIMAL DISEASE EXTENSION IN PATIENTS WITH LIMITED ULCERATIVE COLITIS IN A PROSPECTIVE EUROPEAN POPULATION-BASED INCEPTION COHORT – THE ECCO-EPICOM COHORT

J. Burisch 1 , J. Halfvarson 2 , L. Kupcinskas 3 , V. Hernández 4 , I. Kaimakliotis 5 , D. Valpiani 6 , N. Pedersen 7 , D. Duricova 8 , L. Kievit 9 , J.F. Dahlerup 10 , M. Fumery 11 , R. Salupere 12 , N. Arebi 13 , K. R. Nielsen 14 , M. Giannotta 15 , P. Oksanen 16 , K. H. Katsanos 17 , Z. Vegh 18 , P. Ellul 19 , D. Schwartz 20 , S. Čuković-Čavka 21 , R. D’Inca 22 , S. Turcan 23 , F. Magro 24 , A. Goldis 25 , E. Langholz 26 , P.L. Lakatos 18 , P. Munkholm 27

1 Department Of Gastroenterology, North Zealand University Hospital, Frederikssund/Denmark

2 Dept. Of Gastroenterology, Faculty Of Medicine And Health, Örebro University, Örebro/Sweden

3 Lithuanian University of Health Sciences Inst. for Digestive Research, Kaunas/Lithuania

4 Instituto de Investigación Biomédica, Xerencia de Gestión Integrada de Vigo, Vigo/Spain

5 American Gastroenterology Center, Nicosia/Cyprus

6 Department Of Gastroenterology And Digestive Endoscopy, Morgagni Hospital, Forli/Italy

7 Gastroenterology Department, Slagelse Hospital, Slagelse/Denmark

8 IBD Clinical And Research Center, ISCARE I.V.F. a.s., Prague/Czech Republic

9 Department Of Medicine, Herning Central Hospital, Herning/Denmark

10 Department Of Hepatology And Gastroenterology, Aarhus University Hospital, Aarhus/Denmark

11 Gastroenterology Unit, Epimad Registry, CHU Amiens Sud, Avenue Laennec-Salouel, Amiens University Hospital, Amiens/France

12 Department Of Gastroenterology, Tartu University Hospital, Tartu/Estonia

13 St. Mark's Hospital, Imperial College London, London/United Kingdom

14 Medical Department, The National Hospital of the Faroe Islands, Torshavn/Faroer Islands

15 Gastroenterology Department, OU Careggi Regional Referral Center for Inflammatory Bowel Disease, Florence/Italy

16 Department Of Gastroenterology And Alimentary Tract Surgery, Tampere University Hospital, Tampere/Finland

17 1st Division Of Internal Medicine And Hepato-gastroenterology Unit, University Hospital, Ioannina/Greece

18 1st Department Of Medicine, Semmelweis University Faculty of Medicine 1st Dept. of Medicine - 1st Department of Medicine, Semmel, Budapest/Hungary

19 Medicine, Mater Dei Hospital, Msida/Malta

20 Soroka Hospital, Beer Sheva/Israel

21 Division Of Gastroenterology And Hepatology, University Hospital Center Zagreb, University of Zagreb School of Medicine, Zagreb/Croatia

22 Department Of Surgery, Oncology And Gastroenterology, Azienda Ospedaliera di Padova, Padova/Italy

23 Gastroenterology, The State University of Medicine and Pharmacy «N. Testemitanu», Chisinau/Moldova

24 Centro Hospitalar São João, Amadora/Portugal

25 Dept. Of Gastroenterology, County Hospital Timisoara Gastroenterology, Timisoara/Romania

26 Herlev University Hospital, Herlev/Denmark

27 Gastroenterology, Hepatology, University of Copenhagen, North Zealand Hospital - Gastroenterology, Hepatology, University of Copen, Frederikssund/Denmark

Contact E-mail Address: burisch@gmail.com

Introduction: Ulcerative colitis (UC) is a progressive and dynamic disease and many patients will experience an extension of inflammation from their initial disease location. Disease extent is the most important factor determining disease prognosis over the long-term. As only few population-based studies have investigated the disease extension and subsequent risk of surgery in UC, we sought to investigate this in the European population-based EpiCom-cohort.

Aims & Methods: The EpiCom-cohort is a population-based cohort of unselected patients with inflammatory bowel disease diagnosed in 2010 in Eastern and Western European centres. Patients were followed prospectively for five years and clinical data were captured throughout the follow-up period and entered in a validated web-based database. Disease extension was defined in patients with limited UC at diagnosis (proctitis, E1 or left-sided, E2) as a progression from the initial extent defined by endoscopy or surgery. The risk of colectomy was assessed in all incident patients. Associations between progression or colectomy and multiple covariates (age, gender, initial disease extent, diagnostic delay, smoking status, increase in extent, geographic region, treatment) were analysed by Cox regression analyses using the proportional hazard assumption.

Results: Out of a total of 717 incident UC patients, 435 (61%) had E1 or E2 at diagnosis. Extent at diagnosis and during follow-up in patients with limited UC is shown in Table 1. During the follow-up period, 67 (16%) patients with E1/E2 progressed to E3, and 23 (16%) patients with E1 progressed to E2. Only the need for systemic prednisolone at diagnosis (HR: 0.4 CI95%: 0.2–0.8) and treatment with immunosupressants and/or biologics (HR: 19.8 CI95%: 7.8–50.6) were associated with the risk of extension. During follow-up, a total of 43 (6%) patients had a colectomy. Of patients with E1/E2 as initial extent a total of 19 (4%) patients had a colectomy. Progression from E1/E2 to E3 was a significant risk factor for colectomy (HR 4.4 CI95%: 1.6–12.4). No difference in the results was found between Eastern and Western European patients.

Conclusion: In this European population-based inception cohort of unselected UC patients one out of five patients with proctitis or left-sided colitis at diagnosis experienced a progression in disease extent after five years of follow-up. The risk of colectomy was increased in patients who progressed to extensive colitis. Only treatment during follow-up as an indicator for disease severity was identified as a predictor for disease extension, thus highlighting the need for new histological or serological markers in order to identify patients at risk for disease progression.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP325 EARLY FIBROSTENOSIS IN CROHN’S DISEASE IS ASSOCIATED WITH MULTIPLE SUSCEPTIBILITY LOCI ON IMMUNOCHIP ANALYSIS

T. Holvoet 1 , P. Bossuyt 2 , I. Cleynen 3 , I. De Kock 4 , P. Hindryckx 1 , S. Vermeire 5 , D. Laukens 1 , M. De Vos 1

1 Gastro-enterology, UZ Ghent, Gent/Belgium

2 Imelda General Hospital, Bonheiden/Belgium

3 Gastroenterology, University Hospitals Leuven, Leuven/Belgium

4 Radiology, University Hospital Ghent, Ghent/Belgium

5 Department of Gastroenterology, University Hospitals Leuven, Leuven/Belgium

Contact E-mail Address: t.holvoet@ugent.be

Introduction: Fibrostenosis is a common complication of Crohn’s disease (CD) occurring in about one-third of patients. Although the pathophysiology of intestinal fibrosis is incompletely understood, evidence suggests a genetic contribution. Previous genetic association studies and candidate gene studies with fibrostenotic CD were based on clinical definitions which lack both sensitivity, specificity and have a high inter-observer disagreement. Additionally, the recent genotype-phenotype analysis by the IIBDGC did not consider the time to development of fibrostenotic disease. As the genetic risk may be more important in patients with early fibrostenosis, in this study we aimed to identify novel genetic markers by focussing on early fibrostenotic disease.

Aims & Methods: In this multicenter, retrospective nested case-control study, performed at the University Hospitals of Ghent and Leuven, computed tomography (CT) and magnetic resonance imaging (MRI) from CD patients obtained between 2002 and 2016 were examined for the presence of fibrostenotic disease. Patients with early fibrostenosis, defined as a the presence of bowel thickening with luminal narrowing and prestenotic dilatation on CT/MRI occurring within 5 years following diagnosis of ileal or ileocolic disease (Montreal L1 or L3), and with available Illumina Immunochip data were included. The control cohort consisted of inflammatory CD patients, also Montreal L1 or L3, without arguments for fibrostenotic disease after min 10 years follow up. Allelic association was assessed using the PLINK v1.07 software.

Results: In total, 3024 CT or MRI scans of 2042 CD patients were screened. 112 patients were selected because of positive arguments for fibrostenosis occurring within 5 years of diagnosis. Of these, Immunochip data were available in 60 cases, and 49 (82%) had confirmed stenosis by histopathology. 343 inflammatory CD controls with genotype data were included in the analysis. Of the 156,500 SNPs analysed, only rs35223850 in the MIS18BP1 genepassed genome-wide significance level for association with early fibrostenosis ( P -value<3.3 × 10^-7, OR 3.9, 17.5% vs 5% in cases vs controls respectively). The protein encoding MIS18BP1 is known to bind to the SP1 transcription factor, and this SNP has been associated with cardiac, liver and kidney fibrosis. Five additional SNPs reached a statistically suggestive significance level of P < 5 × 10^-6, including rs116630177 in the IL23R gene, which is of particular interest as this gene has previously been associated with systemic sclerosis.

Conclusion: This carefully phenotyped study reveals an important role for genetic contribution to early development of fibrostenotic complications in CD. Our data suggest a role for MIS18BP1 and the SP1 transcription factor as well as the IL23 pathway in the pathogenesis of early intestinal fibrosis.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP326 THE ROLE OF THE IKBA GENE FAMILY MEMBER NFKBIZ IN COLITIS-ASSOCIATED CANCER

G. Ito 1 , D. Esser 2 , J. Kuiper 1 , R. Sheibani 1 , S. Schreiber 3 , P. Rosenstiel 1

1 Institute of Clinical Molecular Biology, Christian-Albrechts-University, Kiel/Germany

2 Institute for Experimental Medicine, Christian-Albrechts-University Kiel, Germany, Kiel/Germany

3 Department Of Internal Medicine, University Hospital Schleswig-Holstein, Kiel/Germany

Contact E-mail Address: g.ito@ikmb.uni-kiel.de

Introduction: Inflammatory bowel disease (IBD) is a relapsing-remitting chronic inflammatory disorder. Importantly, the risk of developing colorectal cancer is increased in IBD patients with chronically active disease. Colitis-associated cancer (CAC) has different characteristics compared to sporadic colorectal cancer, such as onset of carcinogenesis in younger patients. To investigate the genetic basis for these differences, we used the AOM/DSS murine model of CAC. Using whole exome, as well as the whole transcriptome sequencing of tumor and colonic non-tumor samples, we determined the mutational landscape to identify recurrent mutations, which may be of functional relevance for the malignant transformation. Using this approach, we identified several tumor-associated variants in the NFKBIZ gene. NFKBIZ is a member of the Ikbα gene family, and known to be induced by IL1β in hematopoietic cells. However, the precise role of NFKBIZ in the human intestinal epithelial cells (IECs) remains largely unknown.

Aims & Methods: The present study was planned to identify the role of NFKBIZ in IECs. Human and mouse intestinal epithelial cell lines, Caco2, HT29 and MODEK, were employed to analyze the NFKBIZ expression in response to IL1β by immunoblot analysis. To perform functional studies, we created cell lines that are deficient for NFKBIZ by using the CRISPR/Cas9 system. Using this cell line, functional assays were examined by immunoblots and proliferation was tested by MTS assay. To analyze the expression of NFKBIZ in human IECs, gene expression of human biopsy samples was quantified using RNA-Sequencing. We also created human organoids from IBD patients and examined the NFKBIZ expression by immunoblot.

Results: In intestinal epithelial cell lines, NFKBIZ was induced by only IL1β. To use the proteasome inhibitor MG132, degradation of NFKBIZ was clearly prevented. These results indicated NFKBIZ was degraded in proteasome. In NFKBIZ-deficient cells, immunoblots showed more LC3 lipidation by autophagy inducer rapamycin addition, and also more CHOP induction by ER stress inducer tunicamycin addition. NFKBIZ-deficient cells showed impaired autophagy and enhanced ER stress, which are associated with chronic inflammation. We could also show that NFKBIZ deficient cells exhibited impaired proliferation by MTS assay. Interestingly, hierarchical clustered heatmap of the differentially expressed genes across IBD-biopsy samples showed that expression of NFKBIZ is upregulated in IECs of IBD patients. In addition to cancer cell lines, we also use human organoids as a model. Here, by immunoblot analysis, NFKBIZ is also induced by IL1β stimulation and expression of NFKBIZ is stably upregulated in organoid derived from UC patient.

Conclusion: NFKBIZ deletion leads to a proinflammatory status and impaired proliferation. In IECs of IBD patients, NFKBIZ is overexpressed. This suggests that overexpression of NFKBIZ could induce a hyperproliferative status potentially promoting tumorigenesis. Taken together these results point to a potential role of NFKBIZ in the pathogenesis of CAC and warrants further investigation.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP327 RORGAMMA-T-EXPRESSING TREGS DRIVE GROWTH OF COLITIS-ASSOCIATED COLORECTAL CANCER BY CONTROLLING IL6 EXPRESSION OF DENDRITIC CELLS

A. Rizzo 1 , M. Di Giovangiulio 1 , E. Franzè 1 , H. Fehling 2 , R. Carsetti 3 , E. Giorda 3 , G. Monteleone 1 , M.C. Fantini 1

1 Department Of System Medicine - Gastroenterology, University of Rome “Tor Vergata”, Rome/Italy

2 University Clinics Ulm, Ulm/Germany

3 Bambino Gesù Pediatric Hospital, Rome/Italy

Contact E-mail Address: angelariz@libero.it

Introduction: Chronic inflammation drives colitis-associated colorectal cancer (CAC), a life-threatening complication of inflammatory bowel disease (IBD). FoxP3+ regulatory T cells (Tregs) co-expressing the Th17-related transcription factor RORgamma-t accumulate in the lamina propria of IBD patients where they are thought to represent an intermediate stage of development toward a Th17 proinflammatory phenotype. However, the role of these cells in CAC is unknown.

Aims & Methods: The phenotypic stability and function of RORgamma-t-expressing Tregs were investigated in Tregs fate mapping reporter and Tregs RORgamma-t conditional knockout mice undergoing the Azoxymethane/Dextran Sulphate Sodium model of CAC. Tumor development was monitored by endoscopy. Ki67, STAT3 and cytokine expression were assessed by immunohistochemistry and real-time PCR. Tumor-infiltrating Tregs were characterized by flow cytometry. The functional role of CTLA4 and FoxO3 was studied by co-culture experiments of tumor-isolated Tregs from wild type or knock-out mice with dendritic cells (DCs) and by in vivo siRNA silencing experiments.

Results: RORgamma-t expression identifies a phenotypically stable population of tumor-infiltrating Tregs. Conditional RORgamma-t knockout mice showed reduced tumor incidence and dysplastic cells exhibited low Ki67 expression and STAT3 activation. Tumor-infiltrating dendritic cells (DCs) produced less IL6, a cytokine that triggers STAT3-dependent proliferative signals in neoplastic cells. RORgamma-t-deficient Tregs isolated from tumors over-expressed CTLA4 and induced DCs to express elevated levels of the transcription factor FoxO3 thus reducing IL6 expression. Finally, in vivo silencing of FoxO3 obtained by siRNA microinjection in the tumors of RORgt-deficient mice restored IL6 expression and tumor growth.

Conclusion: These data demonstrate that RORgamma-t expressed by tumor infiltrating Tregs sustains tumor growth by leaving IL6 expression in DCs unchecked.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP328 NEW METHYLATION BIOMARKER PANEL FOR EARLY DIAGNOSTIC OF DYSPLASIA OR CANCER IN HIGH-RISK INFLAMMATORY BOWEL DISEASE PATIENTS

D. Azuara Garcia 1 , S. Aussó 2 , F. Rodriguez Moranta 3 , J. Guardiola 3 , X. Sanjuan 4 , T. Lobaton 3 , J. Boadas 5 , E. Guinó 2 , V. Moreno 2 , G. Capella 1 , J. De Oca 6

1 Translational Research Lab., Institut Catala Oncologia IDIBELL, Hospitalet de Llobregat, BCN/Spain

2 unit Of Biomarkers And Susceptibility, Institut Catala Oncologia IDIBELL, Hospitalet de Llobregat/Spain

3 Gastroenterologist, IBD Unit, Gastroenterology Department; Hospital Universitari de Bellvitge-IDIBELL, L’Hospitalet de Llobregat, Barcelona/Spain

4 Pathology, HUB-IDIBELL, Barcelona/Spain

5 Gastroenterology, Consorci Sanitari Terrassa, Terrassa/Spain

6 Surgery, HUB-IDIBELL, Hospitalet de Llobregat/Spain

Contact E-mail Address: dazuara@iconcologia.net

Introduction: Patients with inflammatory bowel disease (IBD) affecting the colon are at increased risk of developing colorectal cancer (CRC).

Aims & Methods: The aim of the study was to evaluate the effectiveness of a selected methylation gene panel for the early detection of CRC in high-risk IBD patients. Five genes ( FLI1 , EYA4 , SLIT2 , USP44 and SND1 ) were selected from genome-wide DNA methylation analysis using the Illumina HumanMethylation 450K BeadChip in a discovery phase analyzing 73 biopsies of 48 IBD patients associated or not to CRC. The panel was validated prospectively by using the Methylation-Specific Melting Curve Analysis (MS-MCA) in biopsies of 203 patients: 48 with sporadic CRC, 38 with IBD-associated neoplasia, 81 patients with IBD (25 of them with high risk) and 36 healthy controls. The biopsies were taken from diseased tissue and adjacent healthy tissue.

Results: Methylation of the panel was a common phenomenon in IBD-associated neoplasia both in diseased and adjacent healthy tissue (71% and 52% respectively) being this prevalence higher to that of healthy individuals (2/36; 6%; p = 6.72E-05). Methylation was more frequently detected in the mucosa of IBD patients at high risk of dysplasia or cancer than in patients at low risk (92% vs 57%; OR: 8.63, p = 0.001), being EYA4 and SLIT2 the markers most frequently methylated. In healthy mucosa this difference in methylation levels was more evident (82% vs 15% for high vs low risk respectively (p = 1.25E-05)) (Table).

Conclusion: The analysis of this panel of methylation markers may help in the early identification of colorectal dysplasia or cancer in high risk IBD patients.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP329 INCIDENT CANCER IN INFLAMMATORY BOWEL DISEASE IN A PROSPECTIVE MULTICENTER NESTED CASE-CONTROL IG-IBD STUDY

L. Biancone 1 , A. Armuzzi 2 , M.L. Scribano 3 , F. Castiglione 4 , R. D'Inca 5 , C. Papi 6 , M. Vecchi 7 , G. Riegler 8 , F. Mocciaro 9 , A. Ruffa 1 , B. Neri 1 , S. Festa 10 , W. Fries 11 , P. Alvisi 12 , M. Daperno 13 , G. Meucci 14 , L. Guidi 2 , L. Spina 7 , S. Renna 15 , E. Calabrese 1 , F. Rogai 16 , S. Ardizzone 17 , A. Rossi 1 , A. Orlando 18 , F. Pallone 1

1 GI Unit, Department Of Systems Medicine, University "Tor Vergata" of Rome, Italy, Rome/Italy

2 Presidio Columbus, Fondazione Policlinico Gemelli Università Cattolica, Rome/Italy

3 GI Unit, AO S. Camillo Forlanini, Rome, Rome/Italy

4 GI Unit, Università Federico II, Napoli, Naples/Italy

5 Division of Gastroenterology, Padova/Italy

6 GI Unit, AO S. Filippo Neri, Rome, Rome/Italy

7 Gastroenterology And Digestive Endoscopy Unit, IRCCS Policlinico San Donato, San Donato Milanese/Italy

8 Università della Campania L. Vanvitelli, Naples/Italy

9 Gastroenterology And Endoscopy Unit, ARNAS Civico-Di Cristina-Benfratelli Hospital, Palermo/Italy

10 GI Unit, AO S. Filippo Neri, Rome, Rome/Italy

11 GI Unit, Università di Messina, Messina, Messina/Italy

12 GI Unit, Ospedale Maggiore, Bologna, Bologna/Italy

13 GI Unit, Ospedale Mauriziano, Torino, Turin/Italy

14 GI Unit, Ospedale S. Giuseppe, Milano, Milan/Italy

15 GI Unit, Ospedale Cervello, Palermo/Italy

16 GI Unit, AOU Careggi, Firenze, Florence/Italy

17 Department Of Biomedical And Clinical Sciences, Università degli Studi di Milano, Milano/Italy

18 GI Unit, Ospedale Cervello, Palermo/Italy

Contact E-mail Address: biancone@med.uniroma2.it

Introduction: Cancer risk using immunomodulators in Inflammatory Bowel Disease (IBD) is under investigation. The possible role of clinical characteristics of IBD in determining this risk is undefined (1).

Aims & Methods: The primary end point was to characterize, in an ongoing prospective, multicenter, nested case-control study at 4 years (yrs), incident cases of any cancer in IBD (2). Secondary end point was to assess risk factors for any cancer in IBD, including the role of clinical characteristics of the disease versus the use of thiopurines (IS) and/or anti-TNFs. From January 2012 to March 2017, all incident cases of cancer in IBD patients (pts) referring to 16 Units (≥2 visits/yr) were recorded. Each IBD pt with cancer (IBD-K) was matched with 2 IBD pts with no cancer (IBD-C) for: IBD type (Crohn’s Disase, CD vs Ulcerative Colitis, UC), gender, age (±5 yrs). Statistical analysis: data expressed as median (range). The Wilcoxon, Chi-squared or Fisher’s exact tests and multivariate logistic regression analysis were used as appropriate.

Results: Incident cancer occurred in 270 IBD pts (IBD-K): 147 CD (CD-K), 123 UC (UC-K). In the tested population, the frequency of incident cancer was higher in pts with CD than with UC (54.4% vs 45.6%; p = 0.04). In IBD, the observed cases of incident cancer (n = 270) involved or included: the digestive system (n = 92;34%), skin (n = 43;16%:20 NMSC, 21 melanoma, 2 others), urinary tract (n = 27;10%), lung (n = 19;7%), breast (10%;n = 27), genital tract (6%;n = 16), thyroid (n = 8;3%), lymphoma (n = 6; 2%; all in CD:3 NHL [IS 1;IS + anti-TNFs 1]), others (n = 32;12%). Lymphoma (n = 6) and small bowel cancers (n = 8) were observed only in CD. The frequency of incident cancers were comparable between CD and UC groups when considering: cancers of the digestive system (n = [%]: 44 [48%] vs 48 [52%];p = 0.48), skin. cancers (25 [58%] vs 18 [42%];p = 0.19), urinary tract cancers (11 [41%] vs 16 [59%]; p = 0.27), In multivariate analysis, the following risk factors for any cancer were considered: age (<40 vs ≥40 yrs), IBD duration (<10 vs ≥10 yrs), smoking (Yes/No;Y/N), ISS-anti-TNFs (Y/N), IBD-related surgery, UC extent (extensive vs distal; subtotal vs distal), CD pattern (B3 vs B1, B2 vs B1), perianal CD. In our UC group, UC-related surgery (not related to CRC) was the only significant risk factor for any cancer OR [95% CI]: 4.79 [2.20–12.07I]). The other risk factors considered were not statistically significant: OR 1.41 [0.70–3.01]; OR 1.14 [0.68–1.81]; OR 0.98 [0.48–1.91]; OR 0.60 [0.30–1.20]; OR 1.62 [0.96–2.73]; OR 1.58 [0.83–2.96], respectively). In CD, perforating pattern was the only significant risk factor for any cancer (OR 1.72 [0.92–3.25I, as no other significant risk factors were identified (OR 0.91 [0.53–1.57]; OR 0.96 [0.62–1, 52]; OR 0.80 [0.51–1.23]; OR 1.35 [0.87–2.12], OR 1.46 [0.88–2.44], OR 0.96 [0.56–1.66], OR 1.11 [0.66–1.84], respectively). When comparing in a chi-squared analysis CD pts with or withour cancer (CD-K vs CD-C) within the subgroups of pts with different CD patterns, only the percentage of pts with penetrating CD was higher in CD-K vs CD-C (27% [40/147] vs 16% [48/294]; p = 0.02), when including in the chi-squared analysis also CD-K vs CD-C with an inflammatory pattern (34% [50/147] vs 42% ([125/294]) and CD-K vs CD-C with a non-penetrating non-fibrostricturing pattern (39% [57/147] vs 41% [121/294]). When comparing UC-K and UC-C according to UC extent, only the percentage of pts with extensive UC was higher in UC-K vs UC-C (49% [60/123] vs 36% [88/245]; p = 0.01), when considering in this analysis also pts with distal UC (UC-K vs UC-C: 20% [24/123] vs 18% [43/245]) and with subtotal UC (UC-K vs UC-C: 32% [39/123] vs 47% [114/245]). Second (n = 11) or third incident cancers (n = 2) occurred in 11 IBD pts.

Conclusion: In a prospective, multicenter, nested-case control study, CD phenotype, penetrating CD and UC-related surgery were identified as significant risk factors for incident cancer. Small bowel cancers and lymphoma occurred only in CD. In our IBD population, a high frequency of second and third incident cancer was observed, thus supporting a higher cancer risk in subgroups of patients.

Disclosure of Interest: L. Biancone: The study was not supported by any grant nor funded and any of the below reported disclosures are related to the study. LB. Lecture fees or Advisory Board: Zambon, MS&D, Takeda, Abbvie, Sofar, Ferring, Wassermann;

A. Armuzzi: The study was not supported by any grant nor funded. No disclosures are related to the study. Consulting/lecture/Research Grant:Abbvie, Astra, Biogen, Celltrion, Ferring, Hospira, Janssen, Lilly, MSD, Mundipharma, Pfizer, Samsung, Sofar, Takeda, Zambon. Research grant

M.L. Scribano: The study was not supported by any grant nor funded and any of the below reported disclosures are related to the study. Lecture fees: Zambon; Advisory Board: Abbvie, Biogen Idec, Mundipharma, Pfizer, Takeda

F. Castiglione: The study was not supported by any grant nor funded No disclosures are related to the study. Consultant/Lecture fee or urestricted Reasearch grant: Mundipharma, Abbvie, MS&D Takeda, Janssen, Roche, Celgene;, Ferring, Allergy Therapeutics; Giuliani, Sofar

R. D'inca: The study was not supported by any grant nor funded and any of the below reported disclosures are related to the study. Speaker and advisory board member: Abbvie, MSD, Zambon, Mundipharma, Hospira, Biogen, Takeda, Holstone

C. Papi: The study was not supported by any grant nor funded and any of the below reported disclosures are related to the study. Consultant or educational grants: Takeda, Abbvie, MSD Chiesi. Sofar, alfa Wassermann

M. Vecchi: The study was not supported by any grant nor funded. None of the disclosures are related to the study. Advisory Board/Lecture fees or Research grants: Abbvie, Takeda, Hospira, Mundipharma, Pfizer, Biogen, Jannsen; Sofar, Chiesi, MS&D, alfa-Wassermann; Pfizer

G. Riegler: The study was not supported by any grant nor funded and any of the below reported disclosures are related to the study. Lecture fees: Zambon, Abbvie.

W. Fries: The study was not supported by any grant nor funded and any of the below reported disclosures are related to the study. Advisory boards: Abbvie, Mundipharma, speaker fees: Takeda, Zambon, educational grant: MSD

M. Daperno: The study was not supported by any grant nor funded and any of the below reported disclosures are related to the study. Lectures, board and/or congress fees: Abbvie, Pfizer, Takeda, Mundipharma, Janssen, MS&D, SOFAR, Ferring, Chiesi;

L. guidi: The study was not supported by any grant nor funded. None of the reported disclosures are related to the study Lecture fees/consultant: Abbvie, MSD, Takeda, Zambon, ;Mundipharma financial support for research not related to the study: AbbVie, MSD;

E. calabrese: The study was not supported by any grant nor funded and any of the below reported disclosures are related to the study. Lecture fees from Abbvie, Takeda, MSD

S. Ardizzone: The study was not supported by any grant nor funded. None of the reported disclosures are related to the study. Consultant to/Unconditionated grants: Abbvie, Mundipharma, MS&D, Takeda, Recordati, Zambon; Ferring, Sofar

A. Orlando: The study was not supported by any grant nor funded. None of the disclosures are related to the study. Lecture fees: Abbvie, Chiesi, MSD, Otsuka, Takeda, Sofar, Mundipharma: Consultant: Abbvie, MSD, Sofar, Takeda

F. Pallone: The study was not supported by any grant nor funded and any of the below reported disclosures are related to the study. Lecture fees: Zambon, Takeda.

All other authors have declared no conflicts of interest.

References

1. Beaugerie L. N Engl J Med 2015;372:1441

2. Biancone L. JCC 2016;10(8):913

WEDNESDAY, NOVEMBER 01, 201708:30-10:00

PATHOGENESIS OF IBD - ROOM E2____________________

OP330 THE UBIQUITIN-LIKE PROTEIN UBIQUITIN D IS UP-REGULATED BY SYNERGY OF NOTCH AND PRO-INFLAMMATORY CYTOKINES IN THE INFLAMED INTESTINAL EPITHELIA OF IBD PATIENTS

A. Kawamoto 1 , G. Ito 2 , T. Nakata 2 , S. Fujii 2 , K. Suzuki 2 , F. Ishibashi 2 , H. Shimizu 2 , S. Nagata 2 , S. Anzai 2 , R. Kuno 2 , K. Kuwabara 2 , M. Kawai 2 , J. Takahashi 2 , M. Hama 2 , K. Tsuchiya 3 , T. Nakamura 2 , R. Okamoto 1 , M. Watanabe 1

1 Gastroenterology And Hepatology, Tokyo Medical and Dental University, Tokyo/Japan

2 Department Of Gastroenterology And Hepatology, Tokyo Medical and Dental University, Tokyo/Japan

3 Tokyo Medical And Dental University, Tokyo/Japan

Contact E-mail Address: akawgast@tmd.ac.jp

Introduction: It is well acknowledged that the intestinal epithelium of inflammatory bowel disease (IBD) patients is exposed to pro-inflammatory cytokines such as TNF-α and IFN-γ. We have previously shown that the Notch signalling pathway is also up-regulated in the intestinal epithelial cells (IECs) of such epithelia, and contributes to IEC proliferation and epithelial regeneration. The mechanisms and consequences of how these signals interact are little known.

Aims & Methods: We aimed to reproduce such an inflamed epithelial environment in vitro and explore the gene regulation involved. Microarray analysis was performed on a human colonic epithelial cell line LS174T where the Notch intracellular domain (NICD) was inducibly over-expressed by Doxycycline, while simultaneously adding TNF-α and IFN-γ. The expression of UBD was analysed by quantitative RT-PCR and western blot. The transcriptional activity of UBD was measured by a gene-specific promoter-driven luciferase assay. Human intestinal organoid lines were established from biopsies taken from the small intestine and colon of ulcerative colitis (UC) and Crohn’s disease (CD) patients undergoing screening endoscopy. Surgical tissues from the small intestine and colon of UC and CD patients were immunostained to compare the distribution of UBD expression in inflamed and uninflamed states.

Results: Microarray analysis revealed that out of the genes that were up-regulated by the simultaneous addition TNF-α and IFN-γ while NICD was over-expressed, the ubiquitin-like protein Ubiquitin D (UBD) which was observed to undergo a 597-fold increase was found to be the most up-regulated of them all. Quantitative RT-PCR and western blot confirmed a synergistically increased expression of UBD on simultaneous NICD over-expression with TNF-α and IFN-γ co-addition. UBD promoter-driven luciferase assay showed significantly increased promoter activity on simultaneous NICD over-expression and co-addition of TNF-α and IFN-γ in LS174T cells, revealing the expression of UBD to be regulated at the transcriptional level under this condition. Western blot of several human intestinal organoid lines derived from both the small intestine and colon of UC and CD patients showed increased expression of UBD on co-addition of TNF-α and IFN-γ, which was suppressed on addition of dibenzazipine, a Notch-signal inhibitor. Immunostaining of uninflamed small intestinal and colonic tissues from IBD patients showed UBD expression to be limited to crypt base columnar cells, whereas an increased number of UBD expressing IECs were seen in the inflamed small intestine and colon.

Conclusion: The Notch signalling pathway and the pro-inflammatory cytokines TNF-α and IFN-γ synergistically up-regulate the expression of UBD, possibly bearing crucial roles in protection and survival of IECs through the anti-apoptotic property of UBD.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP331 WNT5B UP-REGULATION IN THE MUCOSA OF PATIENTS WITH INFLAMMATORY BOWEL DISEASE COULD CONTRIBUTE TO THE REGENERATION OF INTESTINAL EPITHELIUM

I. Dotti 1 , E. Ferrer-Picón 1 , N. Planell 2 , E.H. Van Herk 3 , M. Cuatrecasas 4 , J. Panés 5 , A. Salas 1

1 Experimental Gastroenterology Laboratory, IDIBAPS, Barcelona/Spain

2 Bioinformatics Platform, CIBERehd, Barcelona/Spain

3 Academic Medical Center, Tytgat Institute for Liver and Intestinal Research, Amsterdam/Netherlands

4 Department Of Pathology, Hospital Clínic, Barcelona/Spain

5 Department Of Gastroenterology, Hospital Clínic, Barcelona/Spain

Contact E-mail Address: idotti@clinic.ub.es

Introduction: Epithelial to mesenchymal transition (EMT) has been postulated to contribute to wound healing 1 . Emerging evidence indicates that Wnt5b could play a role in EMT 2 . We hypothesize that Wnt5b is expressed in the intestinal mucosa of patients with inflammatory bowel disease (IBD) and contributes to regeneration through EMT.

Aims & Methods: To test our hypothesis, we: 1) evaluated Wnt5b expression in the intestine of patients with IBD and 2) investigated the effect of Wnt5b on human epithelial organoid cultures (EpOCs) 3 . Human intestinal samples were used for in situ hybridization and RNAseq to characterize Wnt5b expression in controls and IBD patients. Intestinal crypts were used to generate EpOCs for subsequent incubation with Wnt5b, TGF-β or LY2157299 (TGF-βR1 inhibitor). Total RNA was isolated for transcriptional analysis. Migration assays were performed to check Wnt5b-induced mesenchymal changes in EpOCs.

Results: WNT5B mRNA was expressed in both the lamina propria and the epithelium of healthy human gut. Its transcription was greater in inflamed, versus non-inflamed, IBD samples. In EpOCs, Wnt5b promoted changes resembling the TGF-β-induced phenotype. These included a significant up-regulation of EMT markers, TGF-β targets and TGF-β itself. Indeed, LY2157299 fully suppressed the Wnt5b-mediated changes. Finally, Wnt5b-treated EpOCs showed higher migratory potential compared to un-stimulated cultures.

Conclusion: In conclusion, we show that Wnt5b acts on intestinal epithelium by potentiating a TGF-β -dependent EMT response. Its up-regulation in IBD mucosa could promote epithelial cell migration, thus contributing to a regenerative response in the context of tissue injury.

Disclosure of Interest: All authors have declared no conflicts of interest.

References

1. Nieto MA, Huang RY, Jackson RA, Thiery JP. EMT: 2016. Cell 2016; 166: 21–45.

2. Harada T, Yamamoto H, Kishida S et al. Wnt5b-associated exosomes promote cancer cell migration and proliferation. Cancer Sci 2017; 108: 42–52.

3. Dotti I, Mora-Buch R, Ferrer-Picon E et al. Alterations in the epithelial stem cell compartment could contribute to permanent changes in the mucosa of patients with ulcerative colitis. Gut 2016.

OP332 NOVEL HUMAN GUT XENOGRAFT MOUSE MODEL FOR INTESTINAL FISTULAS

R.S. Bruckner 1 , N. Marsiano 2 , E. Nissim-Eliraz 2 , E. Nir 2 , M. Leutenegger 1 , C. Gottier 1 , S. Lang 1 , M. R. Spalinger 1 , G. Rogler 1 , S. Yagel 3 , M. Scharl 1 , N. Y. Shpigel 2

1 Gastroenterology And Hepatology, University Hospital Zurich, Zurich/Switzerland

2 Koret School Of Veterinary Medicine, Hebrew University of Jerusalem, Rehovot/Israel

3 Department Of Obstetrics & Gynecology, Hadassah University Hospital, Jerusalem/Israel

Contact E-mail Address: ramona.bruckner@usz.ch

Introduction: Fistulas represent a frequent complication in Crohn’s disease (CD) patients and surgical resection is often required. Despite some progress in understanding the pathogenesis and improving the treatment of inflammatory bowel disease (IBD), more effective medical treatments are required, especially for CD patients with fistula formation. Previously, we demonstrated that epithelial-to-mesenchymal transition (EMT) plays a critical role for fistula development in CD patients. Preceding upregulation of TGF-beta, IL-13, TNF and their receptors along fistula tracts in CD patients seems to orchestrate a number of events contributing to fistula development by inducing EMT. Due to a lack of a reliable in vivo model, new drug developments are complicated. Here, we describe a new xenograft (XGR) mouse model of intestinal fistula resembling the human condition.

Aims & Methods: 12–18 weeks (w) old human fetal small intestine was transplanted subcutaneously onto the backs of SCID mice. After 12–16w, ∼15% of the mature xenografts spontaneously developed enterocutaneous fistulas. Using systemic LPS treatment followed by mild skin irritation adjacent to the transplant, we established a reproducible model system, resulting in enterocutaneous fistulas 2–4w later. Samples were analysed by immunohistochemistry staining (IHC) for EMT-, immune cell- and necroptosis markers, as well as RNA sequencing.

Results: Histopathological analysis of the fistulating XGR samples revealed a characteristic loss of villous structures and flattening of the intestinal epithelial cells lining the fistula tract, resembling transitional cells described in human CD fistula samples. IHC stainings for various EMT markers (e.g. SLUG, β6-integrin) showed similar expression pattern as in samples from fistulas of CD patients. The expression of the mesenchymal marker alpha-smooth muscle actin confirmed the hypothesis that EMT plays a critical role for the fistula development in the XGR samples, as well. Inflammation in the XGR was apparent up- and downstream to the fistulous tracts. Most of this inflammatory response consisted of human CD45+ cells, but only very few murine CD45+ cells. Further characterization revealed large numbers of human CD3+ cells. Collagen staining showed that those inflammatory regions were associated with extensive fibrosis suggesting extracellular matrix remodeling. We also detected strong staining for necroptotic markers (RIP kinases and MLKL) in the fistulated XGRs compared to unfistulated control samples. RNA sequencing of inflamed LPS-treated XGRs revealed a significant upregulation of genes related to IBD, necroptosis, ripoptosome and NF-κB signaling.

Conclusion: Our data demonstrate that the in vivo model recapitulates, both morphologically and mechanistically, the human disease. Necroptosis might be the underlying molecular mechanism driving inflammation, EMT and finally fistula formation in vivo.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP333 REPROGRAMMED ATOH1 + INTESTINAL EPITHELIAL CELLS CONTRIBUTE TO REGENERATE DAMAGED COLONIC MUCOSA IN DSS-INDUCED COLITIS

F. Ishibashi 1 , H. Shimizu 1 , A. Kawamoto 1 , G. Ito 1 , T. Nakata 1 , S. Fujii 1 , K. Suzuki 1 , R. Kuno 1 , S. Anzai 1 , K. Kuwabara 1 , M. Kawai 1 , J. Takahashi 1 , M. Hama 1 , S. Nagata 1 , K. Tsuchiya 2 , T. Nakamura 1 , R. Okamoto 1 , M. Watanabe 1

1 Department Of Gastroenterology And Hepatology, Tokyo Medical and Dental University, Tokyo/Japan

2 Tokyo Medical And Dental University, Tokyo/Japan

Contact E-mail Address: f.jazzmaster@gmail.com

Introduction: Atoh1 is a master transcription factor for secretory lineage cell fate commitment of intestinal epithelial cells (IECs). We have previously identified that Atoh1 expression is maintained throughout the differentiation process of secretory IECs, starting from early immature secretory progenitor IECs to terminally differentiated secretory-lineage IECs. Recent series of studies have demonstrated the plasticity of lineage-committed IECs, and their ability to be reprogrammed back to intestinal stem cells (ISCs) upon severe tissue injury. However, the comprehensive contribution of reprogrammed secretory lineage IECs in maintenance and regeneration of the intestinal mucosa remains unknown.

Aims & Methods: To identify the contribution of Atoh1 + secretory lineage IECs in homeostatic as well as colitic environment, we established an in vivo lineage tracing system. Mice carrying CrePGR knock-in allele at the Atoh1 gene locus was crossed with those carrying Cre-inducible reporter allele to generate Atoh1-reporter mice. Lineage tracing of Atoh1 + IECs was performed under homeostatic condition, and also under induction of dextran sodium sulphate (DSS) colitis. Immunohistochemical analysis was used to identify reprogramming of Atoh1 + IECs, as determined by the formation of Atoh1 + IEC-derived clonal ribbons (Atoh1 + ICRs). Comprehensive gene expression of reprogrammed Atoh1 + IECs was examined by microarray. Reprogramming of Atoh1 + IECs was further analysed by In vitro assays using the 3D organoid culture technique.

Results: Under homeostatic condition, a certain number of Atoh1 + IECs were reprogrammed backwards to the IEC pool, as shown by the formation of Atoh1 + ICRs. Interestingly, reprogramming events of Atoh1 + IECs appeared to happen more frequently in the colon, compared to the small intestine. Those reprogrammed Atoh1 + IECs acquired gene expression profile comparable to genuine ISCs, as confirmed by microarray and GSEA analysis. Also, Atoh1 + IEC-derived organoids, as well as de novo formation of Atoh1 + ICRs, could be established and confirmed in vitro. Such a formation of Atoh1 + ICRs was significantly enhanced by DSS colitis-induced mucosal damage. Atoh1 + IEC-intrinsic gene expression analysis identified and featured substantial induction of NF-kB signalling by the colitic environment. Consistently, exposure to inflammatory cytokines and bacterial components appeared to enhance formation of Atoh1 + ICRs in vitro, through activation of NF-kB.

Conclusion: Reprogrammed Atoh1 + IECs acquire ISC properties, and contribute to maintenance and regeneration of the colonic mucosa. Robust activation of the NF-kB pathway may play a key role in Atoh1 + IEC reprogramming under the colitic environment.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP334 THE ROLE OF PH-SENSING RECEPTOR TDAG8 (GPR65) IN INTESTINAL INFLAMMATION

I. Tcymbarevich 1 , J. Cosin Roger 1 , S.M. Richards 2 , K. Baebler 1 , M. R. Spalinger 1 , G. Russo 3 , K. Atrott 1 , I. Frey-Wagner 1 , C.A. Wagner 4 , B. Misselwitz 1 , K. Seuwen 2 , G. Rogler 1 , C. De Vallière 1

1 Gastroenterology And Hepatology, University Hospital Zurich, University of Zurich, Zurich/Switzerland

2 Novartis Institutes for Biomedical Research, Basel, Switzerland, Basel/Switzerland

3 Functional Genomics Center Zurich, ETH Zurich/University of Zurich, Zürich/Switzerland

4 Institute of Physiology, University of Zürich, Zürich/Switzerland

Contact E-mail Address: Jesus.Cosin@uv.es

Introduction: The two major forms of inflammatory bowel diseases (IBD), Crohn’s disease (CD) and ulcerative colitis (UC), typically result in decrease of extracellular pH of the affected mucosa. Genome-wide association studies (GWAS) identified over 240 non-overlapping single-nucleotide polymorphisms (SNP) associated with IBD. G-protein-coupled receptor 65 (GPR65) or T-cell death associated gene 8 (TDAG8) has been reported to be a genetic risk factor for IBD in recent GWAS. TDAG8 belongs to a family of proton-sensing GPCRs, including TDAG8, ovarian cancer G-protein coupled receptor 1 (OGR1) and GPR4. However, the role of TDAG8 is not fully understood.

Aims & Methods: In this study we investigate the role of TDAG8 in a murine IBD model. Chronic colitis was induced in WT and Tdag8 −/− (KO) mice with 4 cycles of 2% DSS in drinking water for 7 days followed by 10 days of regular drinking water. Colon specimens were obtained and RT-qPCR and immunohistochemistry (IHC) were perfomed. Quinescent peritoneal macrophages (MΦs) from WT and Tdag8 −/− mice were isolated, cells were treated for 24 h with pH 6.8 serum free medium to activate TDAG8, using pH 7.6 as negative controls. RNA was isolated for RNA sequencing.

Results: In the chronic colitis model, no significant differences in the typical inflammatory markers were observed between WT and KO groups. However, mRNA expression of IFNγ, TNF, IL6, iNOS was increased in the KO group, but no significant differences of IL17a, Gata3, Foxp3 and RORc were detected. IHC staining revealed that DSS-treated Tdag8 −/− mice showed increased immunoreactivity of MΦ marker F4/80 compared to WT and water controls. Protein staining of T cell marker CD3 showed no difference between WT and Tdag8 −/− mice. Interestingly, mRNA and protein expression of OGR1 were downregulated in Tdag8 −/− colon tissue. To further examine the role of TDAG8 in MΦs, we performed RNA-sequencing upon a 24 h pH shift from pH 7.6 to pH 6.8. Pathways in mouse MΦs, mediated by TDAG8, were positively enriched for regulation of lymphocyte and leukocyte activation, apoptosis and M1 regulation. Conversely, pathways in TDAG8-deficient MΦs were upregulated for cytokine production involved in inflammatory response and M2 regulation. Moreover, expression of OGR1 was significantly downregulated in TDAG8 −/− MΦs.

Conclusion: No significant differences for colitis activity were observed in chronic DSS colitis in WT and Tdag8 − / − mice, suggesting that TDAG8-dependent anti-inflammatory responses are not able to down-regulate inflammation in this IBD model. Although lack of TDAG8 did not affect outcomes in the murine chronic colitis model, TDAG8 was able to reduce the inflammatory response of macrophages. TDAG8 also upregulates expression of the pro-inflammatory pH receptor OGR1, potentially providing a feedback loop for pH dependent immune activation.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP335 PRO-INFLAMMATORY HUMAN CD11C + MACROPHAGES, BUT NOT THEIR TOLEROGENIC CD11C DIM OR CD11C − COUNTERPARTS, ARE EXPANDED IN THE INFLAMED MUCOSA FROM PATIENTS WITH INFLAMMATORY BOWEL DISEASE

D. Bernardo 1 , I. Mora-Gutierrez 1 , A. C. Marín 1 , A. Montalban-Arques 1 , S. Fernandez-Tome 1 , A. Diaz-Guerra 1 , R. Caminero-Fernandez 2 , S. Casabona 2 , P. Miranda 2 , F. Casals 2 , M. Caldas Álvarez 2 , M. Jimenez 2 , F. De La Morena 2 , C. Santander 1 , M. Chaparro 1 , J. P. Gisbert 1

1 Instituto Investigación Sanitaria Princesa (IIS-IP) & CIBEREHD, Madrid/Spain

2 Department Of Gastroenterology, Hospital Universitario de La Princesa, Madrid/Spain

Contact E-mail Address: d.bernardo.ordiz@gmail.com

Introduction: Inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), is a chronic inflammation of the human gastrointestinal (GI) tract. Macrophages (MΦ), the most abundant GI-mononuclear phagocytes, are critical at shaping immune responses since they typically maintain the mechanisms of immune tolerance in health, although they can also exacerbate immune responses during inflammation. However, despite their relevance modulating GI-immune responses, there is not much information about their properties in the human GI-tract.

Aims & Methods: Our aim was to characterize human GI-MΦ subsets, phenotype and function both in health and in IBD patients. To that end, human intestinal biopsies were obtained from healthy controls and IBD patients (including UC and CD; both active and quiescent). Tissue was disaggregated and the lamina propria mononuclear cells characterized by flow cytometry. In other cases, intestinal biopsies were cultured overnight to obtain GI-secretomes which were used to assess the mucosa capacity to recruit circulating CD14 + monocytes (enriched from the blood from healthy controls) on transwell culture assays.

Results: Human intestinal MΦ (identified within singlet viable cells as CD45 + HLA-DR + CD14 + CD64 + ) were further divided into CD11c high , CD11c dim and CD11c − subsets. While the CD11c high subset resembled the phenotype of circulating phagocytic (Dextran high ) pro-inflammatory CD14 + monocytes (CX3CR1 + , SIRPα high , CCR2 + , CD40 + ), the CD11c dim subset displayed an intermediate phenotype towards the CD11c − MΦ subset, which was not phagocytic (Dextran low ), had higher expression of HLA-DR and CD64 and lower expression of CX3CR1, SIRPα, CCR2 and CD40. CD11c + MΦ displayed a higher production of IL-1β both in resting conditions and after LPS stimulation, compared with the CD11c − subset, which produced larger amounts of IL-10 and was hyporesponsive to LPS stimulation. In health, CD11c high MΦ were the predominant subset in the distal GI-compartments (distal and proximal colon) while CD11c − MΦ were in a higher proportion in the terminal ileum and became predominant in the duodenum. Total MΦ numbers were increased in the inflamed colon from IBD patients (both UC and CD), although not on the non-inflamed tissue from the same patients or from quiescent patients, due to specifically higher numbers of the CD11c high subset. Finally, colonic secretomes from healthy controls recruited circulating CD14 + monocytes, while such capacity was further increased on those from inflamed IBD patients (both UC and CD) but not on quiescent patients.

Conclusion: MΦ subsets are likely to represent transition stages from newly arrived pro-inflammatory monocytes (CD11c high ) into transient (CD11c dim ) and resident (CD11c − ) MΦ as reflected by the mucosal capacity to recruit circulating CD14 + monocytes, which was indeed further increased on active IBD patients where the CD11c high macrophages are expanded.

Disclosure of Interest: All authors have declared no conflicts of interest.

WEDNESDAY, NOVEMBER 01, 201708:30-10:00

CAN COLONIC POLYPS BE DIAGNOSED IN REAL TIME? - ROOM E3____________________

OP336 DOES CHROMOENDOSCOPY REDUCE COLORECTAL NEOPLASIA DURING SURVEILLANCE IN LYNCH SYNDROME? A RANDOMIZED TRIAL

J. Haanstra 1 , E. Dekker 2 , A. Cats 3 , F.M. Nagengast 4 , J. Hardwick 5 , S. Vanhoutvin 3 , W. De Vos Tot Nederveen Cappel 6 , H. Vasen 7 , J. Kleibeuker 1 , J.J. Koornstra 1

1 Gastroenterology And Hepatology, University Medical Center Groningen, University of Groningen, Groningen/Netherlands

2 Gastroenterology And Hepatology, Academic Medical Center, Amsterdam/Netherlands

3 Gastroenterology And Hepatology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital (NKI-AVL), Amsterdam/Netherlands

4 Gastroenteroly And Hepatology, Radboud University Medical Centre, Nijmegen/Netherlands

5 Gastroenterology And Hepatology, Leiden University Medical Center, Leiden/Netherlands

6 Isala Clinics, Zwolle/Netherlands

7 Gastroenterology And Hepatology, The Netherlands Foundation for the Detection of Hereditary Tumours, Leiden/Netherlands

Contact E-mail Address: j.f.haanstra@isala.nl

Introduction: Lynch syndrome (LS) is associated with an increased risk of colorectal carcinoma (CRC). Regular surveillance at 1–2 yearly intervals has shown to reduce this risk. Still, LS patients develop CRC, frequently in the proximal colon. Chromoendoscopy is reported to be superior to white-light endoscopy in LS with respect to the detection of flat adenomas. The aim of this study was to determine whether chromoendoscopy reduces colorectal neoplasia at follow-up endoscopy.

Aims & Methods: In a prospective randomized controlled multicenter trial 246 proven mismatch repair gene mutation carriers (mean age: 46 years, range 21–70 years) were randomized between conventional white-light colonoscopy and colonoscopy using chromoendoscopy in the colon proximal from the splenic flexure. After 2 years, both groups underwent colonoscopy using chromoendoscopy. The number of neoplastic lesions at baseline and at follow-up colonoscopy was recorded.

Results: The number of patients with neoplasia in the entire colon was not significantly different between chromoendoscopy and white-light colonoscopy (36/118 (0 CRC) versus 33/123 (2 CRC), p = 0.28). Using chromoendoscopy, significantly more proximal adenomas were detected compared with conventional white-light colonoscopy during the first procedure (44 versus 26 adenomas, p = 0.04). Chromoendoscopy took significantly more procedure time than conventional colonoscopy (p < 0.01), due to a significant difference in median withdrawal time (18 versus 12 minutes, p < 0.01). At follow-up colonoscopy after 2 years, no difference was found with respect to the number of patients with neoplastic lesions in the entire colon between the groups (35/118 (4 CRC) versus 29/118 (1 CRC), p = 0.56). The number of proximal adenomas found was also not significantly different (36 versus 47, p = 0.22).

Conclusion: Chromoendoscopy increases the detection of adenomas in LS, but does not significantly reduce the adenoma detection rate at follow-up endoscopy.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP337 LEAVING COLORECTAL POLYPS IN PLACE CAN BE ACHIEVED WITH HIGH ACCURACY USING BLUE LIGHT IMAGING (BLI)

H. Neumann 1 , H. Neumann Sen 2 , F. Thieringer 1 , F. Rahman 1 , G.E. Tontini 3 , P. R. Galle 1

1 Interdisciplinary Endoscopy, University Medical Center Mainz, Mainz/Germany

2 Gastroenterologische Schwerpunktpraxis, Bad Salzuflen/Germany

3 Gastroenterology And Digestive Endoscopy Unit, IRCCS Policlinico San Domato, San Donato Milanese/Italy

Contact E-mail Address: helmut.neumann@unimedizin-mainz.de

Introduction: The ASGE PIVI statement is proposing a negative predictive value (NPV) >90% for a new technology to leave distal diminutive colorectal polyps in place without resection. To our knowledge no prior prospective study has yet evaluated the feasibility of the most recently introduced Blue Light Imaging (BLI) system for real-time endoscopic prediction of polyp histology for the specific endpoint of leaving hyperplastic polyps in place.

Aims & Methods: Main study objective was the prospective assessment of real-time prediction of colorectal polyps by using BLI. Therefore, 177 consecutive patients undergoing screening or surveillance colonoscopy were included. Colorectal polyps were evaluated in real-time by using high-definition endoscopy and the BLI technology without optical magnification. The endoscopist described each polyp according to size, shape and surface characteristics (pit and vascular pattern, color, depression) and histology was predicted with a level of confidence (high or low).

Results: High-confidence prediction of histology was performed in 92% of polyps. Sensitivity of BLI for prediction of adenomatous histology was 98.7% with a specificity and accuracy of 97.4% and 98.2%, respectively. The positive and negative predictive values were calculated with 97.9% and 98.4%, respectively.

Conclusion: The most recently introduced BLI technology is accurate enough to leave distal colorectal polyps in place without resection. This approach has therefore the potential to reduce costs and risks associated with the redundant removal of diminutive colorectal polyps.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP338 A STUDY ON DIAGNOSTIC ABILITY TO DISTINGUISH BETWEEN ADENOMAS AND INVASIVE COLORECTAL CANCERS USING COMPUTER-AIDED ENDOCYTOSCOPY

K. Takeda 1 , S. Kudo 1 , Y. Mori 1 , M. Misawa 1 , S. Kataoka 1 , Y. Maeda 1 , Y. Ogawa 1 , K. Ichimasa 1 , T. Kudo 1 , K. Wakamura 1 , T. Baba 1 , E. Hidaka 1 , F. Ishida 1 , H. Inoue 2 , M. Oda 3 , K. Mori 3

1 Digestive Disease Center, Showa University Yokohama Northern Hospital, Yokohama/Japan

2 Digestive Disease Center, Showa University Koto-Toyosu Hospital, Tokyo/Japan

3 Graduate School Of Informatics, Nagoya University, Nagoya/Japan

Contact E-mail Address: ktluck1208@yahoo.co.jp

Introduction: Endocytoscopy (EC) enables in vivo observation of nuclei at about 500-fold magnification during gastrointestinal endoscopy[1]. We have reported the usefulness of EC for colorectal lesions, but in clinical practice it seemed that there is a need for an easy-to-use diagnostic aid system for trainees with little experience. To address this task, we have developed a computer-aided diagnosis system for EC imaging (EC-CAD) that provides fully-automated classification of colorectal lesions (2, 3). And we have recently reported its diagnosing ability for invasive colorectal cancer[4]. Whether it is a lesion at risk of lymph node metastasis is important in considering the indication of surgical operation. Therefore, it is very important to distinguish lesions that may have lymph node metastasis such as invasive cancers from other lesions. In this task, it is thought that the EC-CAD can be a very useful diagnostic tool.

Aims & Methods: The aim of the present study was to evaluate diagnostic ability to distinguish between adenoma and invasive colorectal cancer. EC-CAD analyzes EC images based on the information from nuclei and texture analysis. All 296 features (eight features from nuclei, 288 from texture analysis) are used as the data for evaluating EC images and EC-CAD automatically present the pathological diagnosis. We used a support vector machine (SVM) to help classify these many features. EC-CAD requires machine learning for construction of diagnostic algorithm. We used 8761 EC images for machine learning in the process of construction of the model. And we selected randomly 200 EC images, which were different from images used for machine learning, from data base of EC images for test data. We evaluated the diagnostic ability of EC-CAD for distinguishing invasive cancers from adenomas.

Results: The time taken for EC-CAD to diagnose the test image was only 0.3 seconds per image. The diagnostic ability of EC-CAD to distinguish invasive cancers from adenomas, the sensitivity, specificity, accuracy, positive predictive value (PPV), negative predictive value (NPV) were 80.0%, 98.8%, 90.1%, 98.2% and 85.3%, respectively. In addition to the predicted pathological diagnosis, EC-CAD simultaneously present the probability of diagnosis calculated by SVM. When the diagnosis probability was 90% or more, the sensitivity, specificity, accuracy, PPV, NPV were 90.9%, 100%, 95.9%, 100% and 93.1%, respectively.

Conclusion: This study indicates the usefulness of EC-CAD system for to distinguish invasive colorectal cancer from adenoma. In considering surgical indication for colorectal lesions, it was suggested that the high diagnostic ability for invasive colorectal cancer of the EC-CAD may be useful for determining treatment strategies.

Disclosure of Interest: All authors have declared no conflicts of interest.

References

1. Kudo SE, Mori Y, Wakamura K, et al. Endocytoscopy can provide additional diagnostic ability to magnifying chromoendoscopy for colorectal neoplasms. J Gastroenterol Hepatol . 2014 Jan; 29(1): 83–90.

2. Mori Y, Kudo SE, Wakamura K, et al. Novel computer-aided diagnostic system for colorectal lesions by using endocytoscopy (with videos). Gastrointest Endosc . 2015 Mar; 81(3): 621–629.

3. Misawa M, Kudo SE, Mori Y, et al. Characterization of colorectal lesions using a computer-aided diagnostic system for narrow-band imaging endocytoscopy. Gastroenterology . 2016 Jun; 150(7): 1531–1532.e3.

4. Takeda K, Kudo SE, Mori Y, et al. Accuracy of diagnosing invasive colorectal cancer using computer-aided endocytoscopy. Endoscopy in press.

OP339 ENDOSCOPIC AND MOLECULAR CHARACTERISTICS IN COLORECTAL SERRATED LESIONS REPRESENT SUBCLASSES OF THE SERRATED NEOPLASIA PATHWAY

H. Aoki 1 , E. Yamamoto 2 , H. Yamano 2 , H. Matsushita 3 , K. Yoshikawa 3 , R. Takagi 3 , E. Harada 3 , Y. Tanaka 3 , T. Harada 4 , T. Sugai 5 , H. Suzuki 1

1 Dept. Of Molecular Biology, Sapporo Medical University, Sapporo/Japan

2 Department Of Gastroenterology And Hepatology, Sapporo Medical University, Sapporo/Japan

3 Department of Gastroenterology, Akita Red Cross Hospital, Akita/Japan

4 Center for Gastroenterology, Teine-Keijinkai Hospital, Sapporo/Japan

5 Department of Molecular Diagnostic Pathology, Iwate Medical University, Morioka/Japan

Contact E-mail Address: hironori_a1123@yahoo.co.jp

Introduction: Colorectal serrated lesions (SLs) include hyperplastic polyp (HP), traditional serrated adenoma (TSA) and sessile serrated adenoma/polyp (SSA/P). SLs are important premalignant lesions, but its clinical and biological features are not fully understood.

Aims & Methods: To establish accurate colonoscopic diagnosis and treatment of SLs, we aimed to clarify the associations between morphological, pathological and molecular characteristics in SLs. A total of 401 premalignant and malignant colorectal lesions were enrolled in this study. Microsurface structures were assessed by magnifying colonoscopy according to Kudo’s pit pattern classification system. Type II pit pattern was subcategorized into classical Type-II, Type II-Open (Type II-O) and Type II-Long (Type II-L). Biopsy specimens were obtained from all lesions for genomic DNA extraction, after which lesions were treated by endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD). BRAF/KRAS mutations and methylation of CpG islands were analyzed by pyrosequencing. CpG island methylator phenotype (CIMP) status (CIMP-high, -low and -negative) was determined by using the five markers (MINT1, −2, −12, −31 and p16).

Results: Pit patterns of the 401 colorectal lesions were as follows: Type II (n = 48), Type II-L (n = 15), Type II-O (n = 91), Type II plus III/IV (n = 23), Type II-L plus III/IV (n = 28), Type II-O plus III/IV (n = 36), Type II-L plus V (n = 4), Type II-O plus V (n = 9) and Type III/IV (n = 147). Type II-O was tightly associated with sessile serrated adenoma/polyps (SSA/Ps) with BRAF mutation and CIMP-high. Majority of lesions with simple Type II or Type II-L were hyperplastic polyps (HPs), while mixtures of Type II or Type II-L plus III/IV were characteristic to traditional serrated adenomas (TSAs) (sensitivity, 69%; specificity, 95%). Type II-positive TSAs frequently exhibited BRAF mutation and CIMP-low, while Type II-L-positive TSAs were tightly associated with KRAS mutation and CIMP-low. Analysis in lesions containing both premalignant and cancer components suggested that Type II-L-positive TSAs may develop to KRAS mutated/CIMP-low cancers, while Type II-O-positive SSA/Ps develop to BRAF mutated/CIMP-high cancers.

Conclusion: Our results suggest that Type II subtypes may reflect distinct molecular subclasses in the serrated neoplasia pathway, and that they could be useful hallmarks to identify SLs at a high risk to develop CRC.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP340 CLASSIFICATION OF CELL NUCLEI MORPHOLOGY OF EC FINDINGS IN COLORECTAL ENDOCYTOSCOPY

K. Suzuki , S. Kudo, T. Kudo, Y. Mori, K. Wakamura, M. Misawa, Y. Ogawa, Y. Maeda, K. Takeda, H. Nakamura, T. Hayashi, T. Baba, F. Ishida

Digestive Disease Center, Showa University Northern Yokohama Hospital, Yokohama/Japan

Contact E-mail Address: kenichi.suzuki.19860617@gmail.com

Introduction: Endocytoscopy (EC) is a next-generation endoscopy that enables diagnostic imaging at 450× magnification. To date, excellent results have been achieved using EC classifications for qualitative diagnosis and assessment of depth of invasion of colorectal lesions (neoplasia/non-neoplasia accuracy: 96.5%; accuracy for carcinomas with massive submucosal invasion (SM-m): 96.3%). (1, 2)

Aims & Methods: In the EC classifications, lesions diagnosed as EC3a vary extensively from adenoma to SM-m, including some lesions that are unsuitable for endoscopic treatment. Therefore, to improve the accuracy of assessing the depth of invasion based on the EC classification, we investigated the presence or absence of certain endoscopic factors in EC3a findings that could be indicators of SM-m. Among lesions that were observed by EC between May 2005 and January 2015, we retrospectively examined 668 lesions diagnosed as EC2 or EC3, according to the EC classification. The presence or absence of 8 factors (1. branch-like glandular lumens, 2. wide and irregular glandular lumens, 3. unclear glandular lumens (ULs), 4. high degree of nuclear enlargement (HNE), 5. multilayered nuclei (MNs), 6. marked dilation of vessels, 7. marked wriggling vessels, and 8. fine granular structures) that are indicators of SM-m were examined by EC. In addition, we compared the diagnostic ability of EC for SM-m with that of other modalities (narrow-band imaging (JNET classification) and pit pattern(Kudo pit pattern classification)).

Results: The multivariate analysis indicated that unclear glandular lumens (ULs), high degree of nuclear enlargement (HNE), and multilayered nuclei (MNs) were the most useful factors for the diagnosis of SM-m or worse. The sensitivity, specificity, positive predictive value, negative predictive value, accuracy, and positive likelihood ratio for the diagnostic accuracy of the EC3a subclassification were 88.9%, 91.3%, 75.0%, 96.6%, 90.8%, and 10.2, respectively (P < .001). The sensitivity, negative predictive value, and accuracy of EC were significantly higher than those of narrow-band imaging and pit pattern.

Conclusion: From the EC findings, the presence of ULs, HNE, and MNs are important risk factors for SM-m or worse outcomes. Furthermore, the EC3a subclassification taking these findings into consideration could be effective for the diagnosis of SM-m or worse.

Disclosure of Interest: All authors have declared no conflicts of interest.

References

1. Kudo SE, et al. Diagnosis of colorectal lesions with a novel endocytoscopic classification - a pilot study. Endoscopy . 2011 Oct;43(10):869–75.

2. Kudo SE, et al. Endocytoscopy can provide additional diagnostic ability to magnifying chromoendoscopy for colorectal neoplasms. J Gastroenterol Hepatol . 2014 Jan;29(1):83–90.

OP341 COMPUTER-AIDED DIAGNOSTIC SYSTEM USING ARTIFICIAL INTELLIGENCE FOR PREDICTING THE NBI INTERNATIONAL COLORECTAL ENDOSCOPIC CLASSIFICATION OF COLORECTAL TUMORS

J. Byeon 1 , E.M. Song 1 , S.H. Lee 2 , K.J. Change 2 , S.W. Hwang 1 , S.H. Park 1 , D. Yang 1 , B.D. Ye 2 , S. Myung 1 , S. Yang 1 , B.H. Park 2 , N.K. Kim 2 , J.B. Seo 2

1 Dept. Of Gastroenterology, Asan Medical Center, Seoul/Korea, Republic of

2 Asan Medical Center, Seoul/Korea, Republic of

Contact E-mail Address: jsbyeon@amc.seoul.kr

Introduction: Image enhanced endoscopy such as narrow-band imaging (NBI) can help endoscopists predict the histopathology of colon polyps through various NBI finding classification systems such as the NBI international colorectal endoscopic (NICE) classification. However, the accurate diagnosis by the NBI system requires a significant learning curve. We developed a computer-aided diagnostic system using artificial intelligence and investigated its usefulness to predict the NICE classification of colorectal tumors.

Aims & Methods: An experienced, board-certified gastrointestinal endoscopist classified the NICE classification of NBI near-focus images of 133 endoscopically resected colorectal tumors from 98 patients (25 tumors classified as NICE type I; 89 as NICE type II; 19 as NICE type III). Of these, 106 images were used as a training image set with which the computer-aided automated diagnostic system was developed and trained. Deep learning method based on the convolutional neural network and weakly supervised learning method with visualization of class activation map were used to develop the diagnostic system. The other 27 NBI images were used as a test image set.

Results: The computer-aided automated diagnostic system yielded an overall diagnostic accuracy of 84.4% for the test image set. In the analysis using the test set, the specific diagnostic accuracy was 88.7% for the NICE type I lesions (sensitivity, 64.0%; specificity, 94.3%), 84.4% for the NICE type II lesions (sensitivity, 91.1%; specificity 71.1%) and 95.7% for the NICE type III lesions (sensitivity, 80.0%; specificity, 98.5%). As for the NICE type I polyps suggesting hyperplastic polyps, the negative predictive value was 98.1%. The class activation map suggested that the computer-aided diagnostic system might see the representative portion of tumor surface which is typical for each NICE type.

Conclusion: The computer-aided diagnostic system using artificial intelligence was useful to predict the NICE classification of colorectal tumors. Further investigations will be needed to improve the accuracy and to apply the system in real-time colonoscopy.

Disclosure of Interest: All authors have declared no conflicts of interest.

WEDNESDAY, NOVEMBER 01, 201710:30-12:00

MICROBIOTA IN LIVER DISEASE - ROOM B3____________________

OP342 LONG-TERM PROTON PUMP INHIBITOR USE INCREASES INTESTINAL DYSBIOSIS, GUT PERMEABILITY, INFLAMMATION AND MORTALITY IN PATIENTS WITH LIVER CIRRHOSIS

A. Horvath 1 , F. Rainer 2 , M. Bashir 3 , B. Leber 1 , B. Schmerboeck 1 , H. Grønbæk 4 , H.J. Møller 5 , T. Madl 6 , A. Groselj-Strele 7 , P. Fickert 2 , P. Stiegler 1 , V. Stadlbauer 2

1 Department Of Transplantation Surgery, Medical University of Graz, Graz/Austria

2 Department Of Gastroenterology And Hepatology, Medical University of Graz, Graz/Austria

3 Department For Endocrinology And Diabetology, Medical University of Graz, Graz/Austria

4 Department Of Hepatology And Gastroenterology, Aarhus University Hospital, Aarhus/Denmark

5 Department Of Clinical Biochemistry, Aarhus University Hospital, Aarhus/Denmark

6 Institute Of Molecular Biology And Biochemistry, Medical University of Graz, Graz/Austria

7 Core Facility Computational Bioanalytics, Medical University of Graz, Graz/Austria

Contact E-mail Address: angela.horvath@medunigraz.at

Introduction: Proton pump inhibitor (PPI) use is highly common in patients with liver cirrhosis, often without proven indication, although recent studies demonstrated an association between their use and the mortality risk in this cohort. The underlying mechanisms however are not fully understood.

Aims & Methods: In this study, we suggest a link between long-term PPI use, intestinal dysbiosis, increased gut permeability, and inflammation leading to increased mortality. We analysed the intestinal microbiome composition of 87 cirrhotic patients with and without ongoing PPI therapy based on sequencing data of the hypervariable region 1–2 of the 16S rRNA gene in order to identify biomarkers for PPI-associated intestinal dysbiosis. Gut permeability as assessed by lactulose-mannitol ratio, sucrose recovery, diamine oxidase and zonulin levels in stool, intestinal (calprotectin in stool) as well as hepatic inflammation (sCD163 and sMR) were analysed at inclusion. Outcome data regarding complications of cirrhosis and mortality were collected for an average of 37 months.

Results: The use of PPI was associated with significant oralisation of the gut microbiome composition. The most pronounced difference between PPI users and non-users was the high Veillonella parvula abundance which was closely associated with an increased abundance of Streptococcus salivarius and Streptococcus parasanguinis . Dysbiosis was accompanied by an increased gut permeability (increased lactulose-mannitol ratio, sucrose recovery and zonulin in stool), intestinal (elevated calprotectin levels in stool) and hepatic inflammation (increased levels of macrophage activation markers, sCD163 and sMR). Higher V. parvula abundance was also associated with a higher risk to develop complications of liver cirrhosis, including severe infections, as well as with higher mortality.

Conclusion: Our data show that in cirrhotic patients with long-term PPI therapy, the intestine is increasingly colonized by bacteria coming from the oral cavity. This is associated with increased gut permeability, intestinal inflammation, risk for portal decompensation and mortality. The indication for PPI therapy in cirrhotic patients should therefore be carefully evaluated.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP343 CO-ADMINISTRATION OF PROBIOTIC WITH OMEGA-3 FATTY ACIDS IN NAFLD MANAGEMENT: EVIDENCE FROM ANIMALS TO RANDOMIZED CLINICAL STUDIES

N. Kobyliak 1 , T. Falalyeyeva 2 , G. Mykhalchyshyn 1 , O. Dynnyk 3 , D. Kyriienko 4 , I. Komisarenko 1

1 Endocrinology, Bogomolets National Medical University, Kyiv/Ukraine

2 Taras Shevchenko National University of Kyiv, Kyiv/Ukraine

3 Bogomolets Institute of physiology of the Ukrainian National Academy of Sciences, Kyiv/Ukraine

4 Kyiv City Clinical Endocrinology Center, Kyiv/Ukraine

Contact E-mail Address: nazariikobyliak@gmail.com

Introduction: We have previously shown that in rats with momosodiume glutamate induced obesity supplementation of alive probiotics mixture with omega-3 leads to more pronounced reduction for steatosis degree (0.73 ± 0.11 vs 0.93 ± 0.22, p = 0.199) which accompanied with significant decreasing of triglyceride (5.1 ± 0.25 vs 6.26 ± 0.23, p < 0.05) accumulation in liver as compared to probiotic alone. Despite of animal data, randomized placebo-controlled trials (RCT) in NAFLD are still lacking in humans.

Aims & Methods: In respect to our experimental data we studied, in double-blind single center RCT, the efficacy of co-administration of probiotic with omega-3 vs. placebo in type 2 diabetes patient with NAFLD detected on ultrasonography (US). A total of 48 patients met the criteria for inclusion. They were randomly assigned to receive “Symbiter Omega” combination of probiotic biomass supplemented with flax and wheat germ oil (250 mg of each, concentration of omega-3 fatty acids 1–5%) or placebo for 8-weeks administered as a sachet formulation in double-blind treatment. The primary main outcomes were the change in fatty liver index (FLI) and liver stiffness (LS) measured by Shear Wave Elastography (SWE). FLI a validated prediction score for hepatic steatosis severity designed Bedogni et al. Secondary outcomes were the changes in transaminases activity, serum lipids and cytokines (TNF-α, IL-1β, IL-6, IL-8, INF-γ) levels. ANCOVA was used to assess the difference between groups.

Results: All subjects completed the study and received more than 90% of prescribed sachets. Both probiotic and placebo were well tolerated and during study period the participants reported only several minor adverse events. In probiotic group FLI significantly decreased from 83.53 ± 2.60 to 76.26 ± 2.96 (p < 0.001) and but remained static in the placebo group (82.86 ± 2.45 to 81.09 ± 2.84; p = 0.156). In respect to our other primary endpoint the changes of LS measured by SWE in both interventional groups were insignificant, but more pronounced decrease was observed for interventional group as compared to placebo. Analysis of secondary outcomes showed that co-administration of probiotic with omega-3 lead to significant slight body weight loss, reduction of waist circumference, level of serum gamma-glutamyl transpeptidase (GGT), triglycerides (TG) and total cholesterol (TC). Markers of chronic systemic inflammatory state after intervention changes significantly only in Symbiter Omega group: IL-1β – 39.28 ± 3.59 vs 35.66 ± 3.13 (p = 0.029) as compared to week 8; TNF-α – 49.66 ± 3.51 vs 42.31 ± 3.05 (p < 0.001); IL-8 – 29.21 ± 1.83 vs 26.11 ± 1.58 (p = 0.029); IL-6 – 16.7 ± 3.06 vs 10.51 ± 2.03 (p = 0.003) and INF-γ – 178.45 ± 13.4 vs 153.32 ± 12.45 (p = 0.016) respectively.

Conclusion: In this RCT, we confirmed animal data previously reported by us, that co-administration of probiotic with omega-3 can reduce liver fat, improve serum lipids, metabolic profile and reduce chronic systemic inflammatory state. Therefore, modulation of the gut microbiota with probiotic and different nutraceuticals represents a new branch in NAFLD management, but further studies in larger cohorts are required to determine this beneficial effect.

Disclosure of Interest: All authors have declared no conflicts of interest.

WEDNESDAY, NOVEMBER 01, 201710:30-12:00

HOT TOPICS IN GORD AND EOE - ROOM E4____________________

OP344 ORAL ALGINATE SOLUTION REDUCES SENSITIVITY TO ESOPHAGEAL ACID PERFUSION IN PATIENTS WITH HEARTBURN. INTERIM REPORT OF A DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY

J.L.S. Ooi 1 , P. Woodland 1 , D. Sifrim 2

1 Wingate Institute For Neurogastroenterology, Barts and the London School of Medicine, Queen Mary University, London/United Kingdom

2 Wingate Institute, Queen Mary University London Wingate Institute Centre for Digestive Diseases, London/United Kingdom

Contact E-mail Address: joanne.ooi@gmail.com

Introduction: Oral alginates are well known to reduce symptoms from gastro-oesophageal reflux disease (GORD) by reducing/modifying reflux episodes forming a raft capping gastric contents and the postprandial acid pocket. In vitro studies in our lab demonstrated a protectant effect of alginates on human oesophageal mucosa lasting at least 60 min. We hypothesised that a second mechanism of action of alginates, i.e. topical mucosal protection, may contribute to reduction of symptoms in GORD patients.

Aims & Methods: To evaluate the effect of oral alginate on heartburn perception induced by intra-oesophageal acid perfusion. 21 adults with endoscopy-negative heartburn underwent 2 study visits, 2 weeks apart in a double-blind crossover study. 10 ml alginate (Gaviscon Advance, Reckitt Benckiser, Hull, UK) or placebo was given 15 minutes prior to oesophageal acid perfusion. Acid perfusion (10 minutes HCL pH 1, at 10 ml/min) was performed 10 cm above the manometrically identified lower oesophageal sphincter with subjects sat upright. Subjects reported time to first perception of heartburn (latency), and symptom intensity at the end of acid challenge on a scale of 0 (no heartburn) to 10 (maximum heartburn). Patients underwent impedance-pH reflux monitoring “off PPI” for accurate phenotyping.

Results: Compared to placebo, alginate pre-treatment produced increase in latency and decrease in intensity of acid-induced heartburn. When all 21 subjects were analysed, latency to heartburn increased from 60 (34–107) seconds with placebo to 90 (47–190) seconds with alginate, (p = 0.0524). When only the 12 patients with pathological acid exposure were analysed (AET 8.3% (5.6–12.9) (true NERD) the effect on latency was more pronounced (from 54 (34–80) second with placebo to 199 (58–190) seconds with alginates (p = 0.04). The intensity of heartburn perception was significantly reduced by alginate pre-treatment compared to placebo. The intensity score went from 0.69 (0.52–0.87) with placebo to 0.54 (0.30–0.80) with alginate (p = 0.029).

Conclusion: Oral alginate appears to reduce sensitivity to acid perfusion in patients with heartburn, particularly more so in those patients with increased acid exposure (true NERD). This effect might add to the reduction in reflux events. Studies are ongoing to confirm this preliminary results in a larger group of patients, and to uncover the mechanisms underlying the mucosal protectant effect of alginates in vivo.

Disclosure of Interest: P. Woodland: research grant Reckkit Benkiser

D. Sifrim: research grant Reckkit Benkiser (Hull UK) research grant Sandhill Scientific (Denver USA)

All other authors have declared no conflicts of interest.

OP345 SYMPTOM ASSOCIATION PROBABILITY DETERMINES THE OUTCOME OF BACLOFEN THERAPY IN REFRACTORY GASTRO-OESOPHAGEAL REFLUX DISEASE

A. Pauwels , E. Deloose, V. Boecxstaens, C. Broers, T. Vanuytsel, J. Tack

Targid, Katholieke Universiteit Leuven, Leuven/Belgium

Contact E-mail Address: ans.pauwels@med.kuleuven.be

Introduction: A significant proportion of patients with gastro-oesophageal reflux disease (GORD) remains symptomatic while on proton pump inhibitor (PPI) therapy. PPIs significantly reduce the proportion of acid reflux, however they have no effect on non-acid reflux which can provoke symptoms in GORD patients. Baclofen, a γ-aminobutyric acid agonist, is able to decrease both acid and non-acid reflux. To date, studies with baclofen focused on mechanistic aspects in patients with proven ongoing weakly acidic reflux, but the symptomatic outcome of patients with refractory GORD symptoms has not received much attention.

Aims & Methods: The aim of this study was to assess the efficacy of baclofen 10 mg t.i.d. vs placebo as add-on therapy in GORD patients with insufficient response to PPI therapy, in a randomized, parallel, double-blind, placebo-controlled study. Patients with an incomplete control of typical GORD symptoms (heartburn/regurgitation) in spite of PPI therapy were randomized into add-on baclofen 10 mg or placebo t.i.d. for 4 weeks to b.i.d. PPIs. Prior to the study and at the end of the treatment, patients underwent a 24 h impedance-pH monitoring. All patients were asked to fill out the ReQuest diaries starting 2 weeks prior to inclusion and continued during the entire course of the study. Data of the diaries were averaged per week. Reflux parameters post-treatment were compared to baseline using Wilcoxon signed rank test and were compared between baclofen and placebo using Mann-Whitney test. The differences in different ReQuest domains were compared using mixed models.

Results: 60 patients were included (age 47.5y (range 19–73), 41f/19 m), with 31 patients into the baclofen arm and 29 into the placebo arm. One patient decided not to start with the medication and 5 patients did not complete the study due to side effects (headache, nausea, drowsiness); all 5 of them were taking baclofen at that time. Final analyses was performed on 26 patients in the baclofen arm and 28 patients in the placebo arm. There was a decrease in total nr. of reflux episodes (p = 0.0019), the nr. of non-acid reflux episodes (p = 0.048) and the nr. of reflux episodes with a high proximal extent (p = 0.0057) in the baclofen condition compared to baseline, while no differences were observed in the placebo condition. When dividing patients into symptom association probability (SAP)- (n = 29) and SAP+ (n = 25) at baseline, we found a significant time by condition by SAP interaction for general wellbeing (p = 0.0091), with a significant difference in SAP+ patients between placebo and baclofen (p = 0.0434, after correction). There was no difference between placebo and baclofen condition at the end of the treatment period in SAP-patients. At baseline, women had a lower general wellbeing compared to men (p = 0.0044). Men tended to feel worse after placebo, while women improved both under baclofen as well as placebo (time by condition by gender interaction p = 0.0881). The presence of increased reflux parameters at baseline did not predict the outcome of baclofen add-on treatment.

Conclusion: This study confirms that baclofen decreases different reflux parameters in PPI refractory patients. We showed that only the SAP+ patients show general wellbeing benefit from treatment with baclofen. Women appear to be more sensitive to a placebo effect.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP346 GASTRO-ESOPHAGEAL REFLUX AFTER PERORAL ENDOSCOPIC MYOTOMY AS COMPARED WITH HELLER’S MYOTOMY: A SYSTEMATIC REVIEW WITH META-ANALYSIS

A. Repici 1 , L. Fuccio 2 , R. Maselli 3 , F. Mazza 3 , L. Correale 3 , D. Mandolesi 2 , C. Bellisario 3 , A. Sethi 4 , M. Kashab 5 , T. Rösch 6 , C. Hassan 7

1 Dept. Of Gastroenterology, Ist. Clinico Humanitas Rozzano Dept. of Gastroenterology, Milano/Italy

2 Deprtment Of Medical And Surgical Sciences, S.Orsola-Malpighi University Hospital, Bologna/Italy

3 Digestive Endoscopy Unit, Division Of Gastroenterology, Humanitas Research Hospital, Rozzano, Milan, Italy, Rozzano/Italy

4 Gastroenterology, Columbia University, New York/United States of America/MD

5 Johns Hopkins Medicine, Baltimore/United States of America

6 Klinik Für Interdisziplinäre Endoskopie, Clinic for Interdisciplinary Endoscopy, Hamburg/Germany

7 Gastroenterology, Nuovo Regina Margherita Hospital, italy/Italy

Contact E-mail Address: alessandro.repici@humanitas.it

Introduction: Per-Oral Endoscopic Myotomy (POEM) represents a less invasive alternative, as compared with conventional laparoscopic Heller’s myotomy (LHM), for achalasia patients. It cannot be excluded, however, that the lack of fundoplication in the POEM procedure may result in a higher incidence of reflux disease, as compared with LHM.

Aims & Methods: Aim of our meta-analysis was to systematically assess the incidence of reflux disease after POEM and LHM, when taking into consideration symptoms, endoscopic and pH-monitoring findings. This systematic review was carried out in according with the guidelines of the preferred reported items for systematic review and meta-analyses. Literature search with PubMed, EMBASE, SCOPUS, Google Scholar and the Cochrane Central Register of Clinical Trials was performed to identify full articles on the incidence of gastro-esophageal reflux symptoms, endoscopic- and pH-monitoring-findings following POEM and LHM (with fundoplication). Heterogeneity among studies was assessed by using the I 2 statistic, and explored by means of sensitivity, subgroup and meta-regression analyses.

Results: From a total of 296 and 1379 records, 19 and 28 prospective studies, including 1542 and 2581 subjects who underwent POEM and LHM, respectively, were included. Pooled rate of post-procedure symptoms was 19.5% (95% CIs: 16.3–23.1; I 2 :43.3%) after POEM, and 8.8% (95% CIs: 5.3%−14.1, I 2 :80%) after LHM, respectively. Pooled rate estimate of abnormal acid exposure at pH-monitoring was 39.0% (95% CI, 24.5%–55.8%; I 2 :85%) after POEM, and 16.8% (95% CI, 10.2%–26.4%, I 2 :86%) after LHM, respectively. Rate of post-POEM esophagitis (grade A to D, Los Angel Classification) was 29.4% (95% CI: 18.5–43.3%, I 2 : 93%) after POEM, and 7.6% (95% CI: 4.1; 13.7%, I 2 : 62.5%) after LHM. At meta-regression, heterogeneity was partly explained by POEM approach and study population.

Conclusion: Incidence of reflux-disease appears to be significantly more frequent after POEM than after LHM with fundoplication. pH-monitoring and appropriate treatment after POEM should be considered in order to prevent long-term reflux-related complications.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP347 ESSENTIAL ROLE OF INTERLEUIKIN-33-INDUCED INNATE LYMPHOID CELLS IN DEVELOPMENT OF EOSINOPHILIC ESOPHAGITIS IN MICE

N. Oshima , S. Ishihara, H. Sonoyama, N. Yamashita, N. Fukuba, Y. Mishima, I. Moriyama, K. Kawashima, N. Ishimura, Y. Kinoshita

Gastroenterology And Hepatology, Shimane University School of Medicine, Izumo/Japan

Contact E-mail Address: n-oshima@med.shimane-u.ac.jp

Introduction: Eosinophilic esophagitis (EoE) is a chronic inflammatory disorder of the esophagus characterized by mucosal infiltration of eosinophils. Although enhanced mucosal T helper type 2 (Th2) cell cytokine response is associated with the pathogenesis of EoE, the details are not fully understood. Interleukin (IL)-33 is a member of the IL-1 cytokine family that is constitutively expressed in epithelial cells. Epithelial-derived IL-33 induces innate lymphoid cell group 2 (ILC2) activities in various organs, which subsequently activates Th2 cytokines and leads to development of eosinophil-related allergic diseases. However, little is known regarding the roles of IL-33 and ILC2 activity induced by it in the pathogenesis of EoE. In the present study, several experimental protocols were designed to clarify these issues.

Aims & Methods: Using intraperitoneal sensitization with ovalbumin (OVA) followed by intranasal challenge with OVA in 8-week-old BALC/c mice, an EoE model was established. The presence of eosinophil infiltration-related esophagitis was confirmed by histological findings, while esophageal expressions of IL-33, IL-5, and IL-13 were examined by real-time PCR. Furthermore, production of IL-33 by cultured epithelial cells (Het1A) was examined by flow cytometry (FACS). To further investigate the effect of IL-33 on the pathogenesis of EoE, we established another model using 8-week-old BALB/c mice with intraperitoneal injection of recombinant IL-33 (control, PBS injection). IL-33-induced esophageal infiltration of eosinophils (Siglec F + and CD11b + ) and ILC2 cells (Lineage − , CD25 + and CD127 + ) was detected by FACS. In addition, the expression profiles of Th2- and allergy-related genes in esophageal tissues were investigated in this model using a PCR array system.

Results: In the OVA-induced EoE model, expressions of the IL-33, IL-5, and IL-13 genes in esophageal tissues were increased. In association with those cytokine levels, esophageal mucosa showed marked infiltration by eosinophils. Production of IL-33 by esophageal epithelial cells (Het1A) was clearly confirmed by FACS. In the IL-33-injected model, we found esophageal mucosa thickening following infiltration of eosinophils as well as the presence of other various inflammatory cells. Also, PCR array analysis demonstrated that injection of IL-33 significantly induced expressions of a variety of Th2- and allergy-related cytokines in the esophagus as compared to control mice. Moreover, FACS results clearly showed esophageal infiltration by CD25 + and CD127 + ILC2 cells, which was closely associated with the expression profiles of Th2- and allergy-related cytokines.

Conclusion: IL-33-induced ILC2 cell activity leads to infiltration of esophageal mucosa by eosinophils via production of Th2- and allergy-related cytokines, which may play an important role in EoE development.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP348 EFFICACY AND SAFETY OF BUDESONIDE ORODISPERSIBLE TABLETS IN ACTIVE EOSINOPHILIC OESOPHAGITIS: RESULTS FROM A RANDOMISED, DOUBLE-BLIND, PLACEBO-CONTROLLED, PIVOTAL, EUROPEAN MULTICENRE TRIAL (EOS-1)

A. Straumann 1 , A. J. Lucendo Villarin 2 , S. Miehlke 3 , M. Vieth 4 , C. Schlag 5 , U. Von Arnim 6 , J. Molina-Infante 7 , D. Hartmann 8 , A.J. Bredenoord 9 , C. Ciriza De Los Rios 10 , S. Schubert 11 , S. Brueckner 12 , A. Madisch 13 , J. Hayat 14 , J. Tack 15 , A. Schoepfer 16 , R. Greinwald 17 , R. Mueller 17 , S. Attwood 18

1 Gastroenterology FMH, Swiss EoE Research Network, Olten/Switzerland

2 Dept. Of Gastroenterology, Hospital General de Tomelloso, Tomelloso/Spain

3 Center for Digestive Diseases, Internal Medicine Center Eppendorf, Hamburg/Germany

4 Abt. Pathologie, Klinikum Bayreuth, Bayreuth/Germany

5 II. Medizinische Klinik, Klinikum rechts der Isar - TU München, München/Germany

6 Dept. Of Gastroenterology, Hepatology And Infectious Diseases, University Hospital Magdeburg, Magdeburg/Germany

7 Gastroenterology, Hospital San Pedro de Alcántara, Cáceres/Spain

8 Klinik Für Innere Med I - Gastroenterologie, Sana Klinikum Lichtenberg, Berlin/Germany

9 Dept. Of Gastroenterology, Academisch Med. Centrum Amsterdam, Amsterdam/Netherlands

10 Gastroenterology, Hospital 12 de Octubre Dept. de Gastroenterologia, Madrid/Spain

11 Praxis, Berlin/Germany

12 Med Klinik Und Poliklinik I, Universitätsklinikum Carl Gustav Carus TU Dresden, Dresden/Germany

13 Medical Department I, Klinikum Siloah, Hannover/Germany

14 Gastroenterology, St. George`s University Hospitals, London/United Kingdom

15 Gastroenterology, University of Leuven, University Hospital Gasthuisberg, Leuven/Belgium

16 Dept. Of Gastroenterology & Hepatology, University Hospital Lausanne (CHUV), Lausanne/Switzerland

17 Dept Clinical Research & Development, Dr. Falk Pharma GmbH, Freiburg/Germany

18 Health Services Research, Durham University, North Tyneside/United Kingdom

Contact E-mail Address: alex.straumann@hin.ch

Introduction: Eosinophilic Oesophagitis (EoE) is a rapidly emerging, chronic-inflammatory disease of the oesophagus. Until now, no approved drug therapy is available, although swallowed topical corticosteroids have indicated efficacy in the treatment of EoE.

Aims & Methods: To evaluate in a pivotal Phase 3 trial efficacy and safety of a novel budesonide orodispersible tablet formulation specifically designed for EoE for the induction of clinico-histological remission in adult patients with active EoE. Eighty-eight patients were randomised to receive 6-weeks double-blind (DB) treatment with either 1 mg budesonide orodispersible tablets (BUL 1mg) twice daily (BID) (n = 59) or placebo BID (n = 29). Non-responder could receive further 6-week open-label induction (OLI) treatment with BUL 1 mg BID. Primary endpoint: Rate of clinico-histological remission. Secondary endpoints: Rate of histological remission, change in peak eos/mm 2 hpf, rate of clinical remission (resolution of dysphagia and odynophagia), rate of clinical remission defined by EEsAI-PRO ≤20, rate of endoscopic normalisation. Secondary endpoint (OLI): Rate of clinico-histological remission after 12 weeks of treatment with BUL 1 mg BID.

Conclusion: A 6-week course of BUL 1 mg BID was highly effective and safe in bringing active EoE rapidly in clinical and histological remission, as well as in normalising endoscopic alterations. A prolongation up to 12 weeks brought additional 27% of patients into clinico-pathological remission.

Results: BUL 1 mg BID was highly statistically superior to placebo in achieving remission/improvement in clinical, endoscopic and histological endpoints (see table). A prolonged treatment of up to 12-weeks increased the overall cumulative clinico-pathological remission rate up to 84.7%. In 3 patients (5.1%) under BUL 1 mg BID vs none under placebo, suspected local fungal infections with endoscopic and clinical signs (all mild) were histologically confirmed by sensitive Grocott staining. Bolus impaction requiring an emergency endoscopy for retraction was observed in 1 patient of the placebo group. Neither serious adverse events nor clinically relevant changes in the morning serum cortisol levels were observed in any treatment group.

Disclosure of Interest: A. Straumann: Consultancy for Dr. Falk Pharma GmbH

S. Miehlke: Lecture fee from Dr. Falk Pharma GmbH

M. Vieth: Lecture fee from Falk Foundation, Olympus, Shire

S. Schubert: Lecture fees from Abbvie, Falk Foundation, MSD

A. Madisch: Lecture fee from Falk Foundation

A. Schoepfer: Consultany for Dr Falk Pharma

R. Greinwald: Employed by Dr. Falk Pharma GmbH

R. Mueller: Employed by Dr. Falk Pharma GmbH

All other authors have declared no conflicts of interest.

OP349 LONG-TERM TREATMENT OF EOSINOPHILIC OESOPHAGITIS WITH SWALLOWED TOPICAL CORTICOSTEROIDS: DEVELOPMENT AND EVALUATION OF A THERAPEUTIC CONCEPT

T. Greuter 1 , C. Bussmann 2 , E. Safroneeva 3 , A. Schoepfer 4 , L. Biedermann 1 , S. Vavricka 1 , A. Straumann 5

1 Gastroenterologie Und Hepatologie, University Hospital Zurich, Zürich/Switzerland

2 Division Of Pathology, Histopathology Viollier, Basel/Switzerland

3 Inst. Für Sozial- Und, Universität Bern ISPM, Bern/Switzerland

4 Dept. Of Gastroenterology & Hepatology, University Hospital Lausanne (CHUV), Lausanne/Switzerland

5 Gastroenterology Fmh, Swiss EoE Research Network, Olten/Switzerland

Contact E-mail Address: th_greuter@bluewin.ch

Introduction: Swallowed topical corticosteroids are highly efficacious in inducing clinical and histological remission in patients with active eosinophilic oesophagitis (EoE) and also in maintaining such remission. However, it has not yet been evaluated if a long-lasting remission can be achieved, and whether maintenance treatment can be stopped once patients have achieved such a remission.

Aims & Methods: Since 2007, adult and adolescent EoE patients included into a large cohort at the Swiss EoE Clinics were treated long-term with swallowed topical corticosteroids. Clinical, endoscopic and histological disease activity was assessed at annual visits. In patients that achieved clinical (no EoE-related symptoms), endoscopic (absence of white exudates, furrows, and edema) and histological remission (peak eosinophilic count <5/hpf) for at least 6 months (defined as deep remission), treatment was stopped. All patients treated at the Swiss EoE Clinics according to this concept were analyzed retrospectively.

Results: Thirty-three of the 370 patients (8.9%) who were treated with swallowed topical corticosteroids achieved deep remission. Mean age of remitters at disease onset was 35.7 years (±17.4) and median diagnostic delay was 5.4 years (IQR 1.2–11.4). Median time to clinical, endoscopic and histological remission was 26.0 weeks (IQR 4.3–77.0), 72.5 weeks (IQR 58.6–104.1) and 61.4 weeks (IQR 14.3–101.3), respectively. Deep remission was achieved after a median of 82.9 weeks (IQR 64.4–172.3). The proportion of female patients was higher in the group of patients that achieved remission when compared to those that did not (19/33, 57.6% vs. 79/337, 23.4%, p = 0.016). No differences with regards to the age at disease onset, diagnostic delay, family history of EoE, concomitant atopic diseases and serum IgE levels between remitters and non-remitters were observed. Female sex was an independent prognostic factor for achieving deep remission (OR 2.45, 95% CI 1.17–5.13, p = 0.017). Overall, swallowed topical corticosteroids were stopped after 104.7 weeks (IQR 65.5–176.6). A cumulative dose of 297.5 mg (IQR 216.0–529.9) was required. Only two patients were concomitantly treated with PPI. No mucosal damage, such as epithelial atrophy or dysplasia, was observed upon histologic examination. In 27 of the 33 remitters (81.8%) a clinical relapse occurred after a median of 26.0 weeks (95% CI 6.7–45.3) after treatment cessation. Six remitters (18.2%) did not experience a clinical relapse during a median follow-up of 35.5 weeks (IQR 18.4–45.4) after cessation of swallowed topical corticosteroids.

Conclusion: Only a minority of EoE patients achieved deep remission despite adequate long-term treatment with topical corticosteroids. Female sex is the only prognostic factor for achievement of deep remission. After cessation of the medication the majority of patients experienced a relapse.

Disclosure of Interest: All authors have declared no conflicts of interest.

WEDNESDAY, NOVEMBER 01, 201710:30-12:00

SAFETY AND LONG-TERM OUTCOMES WITH BIOLOGICS IN IBD - ROOM 7.1____________________

OP350 PYRAMID REGISTRY: LONG-TERM SAFETY OF ADALIMUMAB BY AGE IN PATIENTS WITH CROHN’S DISEASE

J. Colombel 1 , G. D'Haens 2 , W. Reinisch 3 , E.V. Loftus Jr 4 , R. Panaccione 5 , J. Satsangi 6 , G. Alperovich 7 , S. Berg 8 , J. Kalabic 9 , M. Bereswill 10 , J. Petersson 11 , A.M. Robinson 12

1 Department Of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York/United States of America/NY

2 Academic Medical Center, Amsterdam/Netherlands

3 Medical University of Vienna, Vienna/Austria

4 Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester/United States of America/MN

5 Department Of Medicine, University of Calgary, Calgary/Canada

6 University Of Edinburgh, Gastrointestinal Unit, Edinburgh/United Kingdom

7 Medical, Abbvie, Madrid/Spain

8 AbbVie, Solna/Sweden

9 AbbVie Deutschland GmbH & Co, Ludwigshafen/Germany

10 AbbVie Deutschland GmbH & Co. KG, Ludwigshafen/Germany

11 Global Medical Affairs, AbbVie Inc, North Chicago/United States of America

12 AbbVie Inc., North Chicago/United States of America

Contact E-mail Address: jean-frederic.colombel@mssm.edu

Introduction: The global post-marketing observational registry PYRAMID assessed the long-term safety and effectiveness of adalimumab (ADA) as used in routine clinical practice in patients with moderately to severely active Crohn’s disease (CD).

Aims & Methods: Patients were enrolled in the registry if they were newly prescribed ADA or currently receiving ADA according to the local product label; patients were followed for up to 6 years. This analysis assessed the long-term safety of ADA by age subgroups (<40, 40–59, and ≥60 years) at registry enrolment (baseline). Registry treatment-emergent (TE) adverse events (AEs), defined as any event with onset on/after first dose of ADA in the registry up to 70 days after last ADA injection are reported as events per 100 patient-years (PY).

Results: A total of 5025 patients in the registry received at least one dose of ADA and were included in the analysis; at baseline, 2981 patients (59.3%) were aged <40 years (female, 57.1%; median age, 29.0 years; median CD duration, 7.0 years), 1717 patients (34.2%) were aged 40–59 years (female, 57.8%; median age, 47.0 years; median CD duration, 13.0 years) and 327 patients (6.5%) were aged ≥60 years (female, 52.9%; median age, 64.0 years; median CD duration, 13.5 years). Of those aged ≥60 years at baseline, 23/327 (7.0%) were ≥75 years old. Cumulative registry ADA exposure by baseline age groups was 9681.1 PY (<40 years), 6009.3 PY (40– 59 years) and 990.0 PY (≥60 years). Approximately 46–52% of patients were receiving ADA monotherapy (without immunomodulators or corticosteroids) at baseline across the age subgroups. Rates of any registry TEAEs, including serious AEs and AEs of special interest, by age subgroups at baseline are shown in Table 1. Similar rates of registry TE serious infections and opportunistic infections were observed across the younger age subgroups, but numerically higher in the ≥60 years subgroup. Rates of any registry TE malignancies and non-melanoma skin cancer were significantly higher in older patients (aged ≥60 years at baseline). There was no event of lymphoma reported in the subgroup of patients aged ≥60 years at baseline; however, during the follow-up in the registry, 3 patients classified in the 40–59 years at baseline age group were diagnosed with lymphoma when they were ≥60 years of age. No patients in the ≥60 years group reported active/latent tuberculosis.

Conclusion: Long-term treatment with ADA was well tolerated in patients with moderately to severely active CD, irrespective of patient age. The rate of exposure-adjusted registry TEAEs (per 100 PY) was generally higher in older (≥60 years) compared to younger patients (<60 years); however, no new safety signals were identified in this age group.

Disclosure of Interest: J. Colombel: Consultant/Ad board/Speaker/Research for AbbVie, Amgen, BI, Celgene, Celltrion, Enterome, Ferring, Genentech, Janssen, Medimmune, Merck, Pfizer, Protagonist, Second Genome, Seres, Shire, Takeda, Theradiag. Stock: IB Development, Genefit.

G. D'Haens: Consulting/research/speaking/lecture AbbVie, ActoGeniX, AIM, BI, Centocor, ChemoCentryx, Cosmo, Elan, enGene, Falk, Ferring, Galapagos, GiulianiSpA, Given, GSK, Janssen, MSD, Neovacs, NovoNordisk, Norgine. Additional disclosures available on request.

W. Reinisch: Speaker/consultant/ad board/research Abbott, AbbVie, AESCA, Amgen, AM-Pharma, Aptalis, Astellas, AZ, Avaxia, BioClinica, Biogen, BMS, Cellerix, ChemoCentryx, Celgene, Centocor, Celltrion, Covance, Danone, Elan, Falk, Ferring. Additional disclosures available on request.

E.V. Loftus Jr: Consultant/research support for AbbVie, UCB, Janssen, Takeda, Celgene, Genentech, Bristol-Myers Squibb, Eli Lilly, Mesoblast, Amgen, Salix, Pfizer, Robarts Clinical Trials, Gilead, Receptos, Seres Pharmaceuticals, Medimmune.

R. Panaccione: Consultant/speaker AbbVie, Amgen, AZ, Aptalis, Biogen, BMS, Centocor, ChemoCentryx, Eisai, Elan, Ferring, Genentech, GSK, Janssen, MSD, Takeda, Ocera, Otsuka America, Pfizer, Shire, Prometheus, Schering-Plough, Synta, Teva, UCB, Warner Chilcott

J. Satsangi: Speaker, consultancy, or travel support from AbbVie, MSD, Takeda, Shire, Ferring

G. Alperovich: AbbVie employee; may own AbbVie stock and/or options

S. Berg: AbbVie employee; may own AbbVie stock and/or options

J. Kalabic: AbbVie employee; may own AbbVie stock and/or options

M. Bereswill: AbbVie employee; may own AbbVie stock and/or options

J. Petersson: AbbVie employee; may own AbbVie stock and/or options

A.M. Robinson: AbbVie employee; may own AbbVie stock and/or options

OP351 EXPOSURE TO COMBINATION THERAPY WITH THIOPURINES AND ANTI-TNF AGENTS IS ASSOCIATED WITH REDUCED INCIDENCE OF ACUTE ARTERIAL EVENTS IN PATIENTS WITH INFLAMMATORY BOWEL DISEASE (IBD): A NATIONWIDE FRENCH COHORT STUDY

J. Kirchgesner 1 , N.N. Andersen 2 , F. Carrat 3 , M. Schwarzinger 4 , T. Jess 5 , L. Beaugerie 6

1 UMRS 1136, INSERM, UPMC Univ Paris 0 6 Sorbonne Universités, Paris/France

2 Department Of Epidemiology Research, Statens Serum Institute, Copenhagen/Denmark

3 Department Of Public Health, AP-HP, Hôpital Saint-Antoine, Paris/France

4 Then, Translational Health Economics Network, Paris/France

5 Department Of Clinical Epidemiology, Bispebjerg Hospital, Copenhagen/Denmark

6 Department Of Gastroenterology, AP-HP, Hôpital Saint-Antoine, Paris/France

Contact E-mail Address: julien.kirchgesner@gmx.com

Introduction: Patients with inflammatory bowel disease (IBD) are at increased risk of acute arterial events, probably due to a systemic inflammation leading to atherosclerosis. Anti-TNFs and thiopurines are effective in the treatment of patients with IBD and may, due to their anti-inflammatory properties, lower the risk of acute arterial events, however this remains unknown.

Aims & Methods: The aim of this study was to assess the impact of thiopurines and anti-TNFs on risk of acute arterial events in patients with IBD. Patients affiliated to the French national health insurance with a diagnosis of IBD based on listed long-term diseases (30 chronic diseases, including IBD, that allow for a 100% reimbursement of health expenses) and/or hospital discharge diagnosis were included from 2010 to 2012, and followed up until 31 December 2014. Occurrence of acute arterial events, cardiovascular risk factors (hypertension, dyslipidemia, diabetes, obesity, smoking, and alcohol use disorder), surgical procedures, and hospitalisations related to IBD was assessed. Acute arterial events included ischemic heart disease, cerebrovascular disease, and peripheral artery disease excluding acute mesenteric ischemia. Risks of acute arterial events were compared between thiopurines and anti-TNFs exposed and unexposed patients with marginal structural Cox proportional hazard models adjusting for baseline and time-varying demographics, medications, and comorbidities, including IBD disease activity.

Results: A total of 178,360 IBD patients were included (54% females, mean age at cohort entry 46.3 years, 50.7% Crohn’s disease). Among them, 22.8%, 13.5% and 5.7% were exposed to thiopurine monotherapy, anti-TNF monotherapy and combination therapy during follow-up, respectively. Overall, 4376 incident acute arterial events occurred (incidence rates: 5.6 per 1000 PY, person-years), including 2204 (50.4%) ischemic heart diseases, 1476 (33.7%) cerebrovascular diseases, and 696 (15.9%) peripheral artery diseases. Exposure to thiopurine monotherapy, anti-TNF monotherapy and combination therapy were all numerically associated with a decreased risk of acute arterial events compared to unexposed patients, but the difference was only statistically significant for patients exposed to combination therapy (hazard ratio [HR] 0.91; confidence interval 95% [0.82–1.02], HR95%: 0.90 [0.77–1.04], HR95%: 0.82 [0.68–0.99], respectively). Similar findings were found for ischemic heart disease, cerebrovascular disease and peripheral artery disease. The magnitude in risk reduction was highest in men with Crohn’s disease exposed to combination therapy (HR 95%: 0.61 [0.44–0.85]).

Conclusion: Exposure to combination therapy with thiopurines and anti-TNFs is associated with decreased risk of acute arterial events in patients with IBD, particularly in men with Crohn’s disease. Prevention of acute arterial events should be considered in the benefit-risk balance assessment of thiopurines and anti-TNFs treatment in patients with IBD.

Disclosure of Interest: N.N. Andersen: Lecture fees from MSD and Ferring.

M. Schwarzinger: Michaël Schwarzinger is an employee of Translational Health Economics Network (THEN), Paris, France that received research grants of Abbvie, Gilead, Merck and co, Novartis, outside and unrelated to the submitted work.

L. Beaugerie: Lecture fees from Abbott, Abbvie, MSD, Ferring Pharmaceuticals, Janssen, and research support from Abbott, Biocodex and Ferring Pharmaceuticals.

All other authors have declared no conflicts of interest.

OP352 PYRAMID REGISTRY: LONG-TERM SAFETY AND EFFECTIVENESS OF ADALIMUMAB BY BASELINE IMMUNOMODULATOR USE IN PATIENTS WITH CROHN’S DISEASE

W. Reinisch 1 , R. Panaccione 2 , G. R. D'Haens 3 , E.V. Loftus Jr 4 , J. Satsangi 5 , J. Colombel 6 , G. Alperovich 7 , S. Berg 8 , J. Kalabic 9 , M. Bereswill 10 , J. Petersson 11 , A.M. Robinson 12

1 Medical University of Vienna, Vienna/Austria

2 Department Of Medicine, University of Calgary, Calgary/Canada

3 Academic Medical Center, AMC Amsterdam Inflammatory Bowel Disease Centre - Academic Medical Center, AMC Amsterdam Inflammator, Amsterdam/Netherlands

4 Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester/United States of America/AL

5 University Of Edinburgh, Gastrointestinal Unit, Edinburgh/United Kingdom

6 Icahn School of Medicine at Mount Sinai, New York/United States of America

7 Medical, Abbvie, Madrid/Spain

8 AbbVie, Solna/Sweden

9 AbbVie Deutschland GmbH & Co, Ludwigshafen/Germany

10 AbbVie Deutschland GmbH & Co. KG, Ludwigshafen/Germany

11 Global Medical Affairs, AbbVie Inc, North Chicago/United States of America

12 AbbVie Inc., North Chicago/United States of America

Contact E-mail Address: walter.reinisch@meduniwien.ac.at

Introduction: A recent post hoc analysis of four adalimumab (ADA) clinical trials in patients (pts) with Crohn’s disease (CD) demonstrated no higher benefit in clinical efficacy up to Week 52 of ADA monotherapy (mono) compared to ADA combination (combo) therapy with immunomodulators (IMM) 1 . The long-term safety and effectiveness of ADA mono vs ADA combo therapy is reported using data from the global post-marketing observational registry, PYRAMID, which assessed the safety and effectiveness of ADA in pts with moderately to severely active CD treated in routine clinical practice.

Aims & Methods: Registry enrolled pts who were newly prescribed ADA or receiving ADA according to the local product label were followed for up to 6 years. In this subgroup analysis, pts were stratified by IMM use (azathioprine, mercaptopurine, or methotrexate) at registry enrolment (baseline [BL]). Effectiveness was measured using the Harvey Bradshaw index (HBI) and was calculated for all pts who received ≥1 dose of ADA in the registry and summarised for pts with available data at the respective registry visits (as observed analysis). Remission (HBI < 5) was assessed at each visit in ADA mono and combo groups. Rates of registry treatment-emergent (TE) adverse events (AEs), defined as any event with onset on/after first dose of ADA in the registry up to 70 days after last ADA injection, are reported as events (E)/100 patient-years (PY).

Results: At BL, 3227/5025 pts (64.2%) were receiving ADA mono (58.1% female; median age, 36.0 years; median CD duration, 8.4 years) and 1798/5025 pts (35.8%) were receiving ADA + IMM (55.3% female; median age, 35.0 years; median CD duration, 8.8 years). The mean ± SD duration of ADA exposure during the registry was similar for pts receiving ADA mono (1179.6 ± 837.8 days) and combo therapy (1271.4 ± 828.0 days). Mean ± SD HBI at BL was similar for pts receiving ADA mono or combo therapy (5.6 ± 5.0 vs 5.8 ± 5.0, respectively). The proportion of pts achieving remission during PYRAMID is shown in Table 1 by BL IMM use. One year after enrolment, a similarly high proportion of pts (approximately 70%) in the ADA mono and combo groups achieved remission. Rates of remission were sustained over time during PYRAMID and were similar between the subgroups. Similar rates of registry TEAEs (37.4 E/100 PY vs 35.6E/100 PY), serious AEs (25.1 E/100 PY vs 24.1 E/100 PY), serious infections (4.7 E/100 PY vs 4.8 E/100 PY), and AEs leading to treatment discontinuation (4.7E/100 PY vs 4.4 E/100 PY) were reported for pts receiving ADA mono and combo therapy, respectively. Numerically higher proportion of pts with ≥1 event of any AE, serious infections, AEs leading to discontinuation, and significantly more pts with ≥1 serious AEs (39.5% [95%CI 37.3–41.8] vs 35.4%, [95%CI 33.7–37.1]) were seen for combo vs mono therapy. Malignancy rates were 0.7 E/100 PY (n[%] = 62[1.9]) in the ADA mono group and 1.0 E/100 PY (n[%] = 54[3.0]) in the combo group, with a significant difference in non-melanoma skin cancer incidence rates (0.2 [95%CI, 0.10–0.27] E/100 PY (n[%] = 12[0.4]) vs (0.5 [95%CI, 0.34–0.70] E/100 PY (n[%] = 24[1.3])), but similar rates for lymphoma (<0.1 E/100 PY (n[%] = 5[0.2]) vs (<0.1 E/100 PY (n[%] = 5[0.2]).

Conclusion: The long-term effectiveness of ADA in pts with moderately to severely active CD enrolled in the PYRAMID registry was similar for those treated with ADA mono or combo therapy at registry entry. Exposure-adjusted malignancy rates tended to be higher in pts treated with ADA combo therapy.

Disclosure of Interest: W. Reinisch: Speaker/consultant/ad board/research Abbott, AbbVie, AESCA, Amgen, AM-Pharma, Aptalis, Astellas, AZ, Avaxia, BioClinica, Biogen, BMS, Cellerix, ChemoCentryx, Celgene, Centocor, Celltrion, Covance, Danone, Elan, Falk, Ferring. Additional disclosures available on request.

R. Panaccione: Consultant/speaker AbbVie, Amgen, AZ, Aptalis, Biogen, BMS, Centocor, ChemoCentryx, Eisai, Elan, Ferring, Genentech, GSK, Janssen, MSD, Takeda, Ocera, Otsuka America, Pfizer, Shire, Prometheus, Schering-Plough, Synta, Teva, UCB, Warner Chilcott.

G.R. D'Haens: Consulting/research/speaking/lecture AbbVie, ActoGeniX, AIM, BI, Centocor, ChemoCentryx, Cosmo, Elan, enGene, Falk, Ferring, Galapagos, GiulianiSpA, Given, GSK, Janssen, MSD, Neovacs, NovoNordisk, Norgine. Additional disclosures available on request.

E.V. Loftus Jr: Consultant/research support for AbbVie, UCB, Janssen, Takeda, Celgene, Genentech, Bristol-Myers Squibb, Eli Lilly, Mesoblast, Amgen, Salix, Pfizer, Robarts Clinical Trials, Gilead, Receptos, Seres Pharmaceuticals, Medimmune.

J. Satsangi: Speaker, consultancy, or travel support from AbbVie, MSD, Takeda, Shire, Ferring.

J. Colombel: Consultant/Ad board/Speaker/Research for AbbVie, Amgen, BI, Celgene, Celltrion, Enterome, Ferring, Genentech, Janssen, Medimmune, Merck, Pfizer, Protagonist, Second Genome, Seres, Shire, Takeda, Theradiag. Stock: IB Development, Genefit.

G. Alperovich: AbbVie employee; may own AbbVie stock and/or options.

S. Berg: AbbVie employee; may own AbbVie stock and/or options.

J. Kalabic: AbbVie employee; may own AbbVie stock and/or options.

M. Bereswill: AbbVie employee; may own AbbVie stock and/or options.

J. Petersson: AbbVie employee; may own AbbVie stock and/or options.

A.M. Robinson: AbbVie employee; may own AbbVie stock and/or options.

Reference

1. Colombel J-F, et al. Aliment Pharmacol Ther 2017; 45:50–62.

OP353 INTEGRATED SAFETY ANALYSES OF TOFACITINIB IN ULCERATIVE COLITIS CLINICAL TRIALS

W. J. Sandborn 1 , J. Panés 2 , G. D’Haens 3 , B. E. Sands 4 , C. Su 5 , M. Moscariello 5 , T.V. Jones 5 , R. Pedersen 5 , G. Friedman 5 , N. Lawendy 5 , G. Chan 5

1 Division Of Gastroenterology, University of California, La Jolla, San Diego/United States of America/CA

2 Hospital Clinic de Barcelona, IDIBAPS, CIBERehd, Barcelona/Spain

3 Department Of Gastroenterology, Academic Medical Centre, Amsterdam/Netherlands

4 Dr. Henry D. Janowitz Division Of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York/United States of America/NY

5 Pfizer Inc, Collegeville/United States of America/PA

Contact E-mail Address: wsandborn@ucsd.edu

Introduction: Tofacitinib is an oral, small molecule Janus kinase inhibitor that is being investigated for ulcerative colitis (UC). The efficacy and safety of tofacitinib for treatment of moderate to severe UC was evaluated in induction and maintenance Phase (P) 3, randomised, placebo (PBO)-controlled studies. 1, 2

Aims & Methods: We describe safety data for tofacitinib in patients (pts) with moderate to severe UC, based on integrated analyses of one P2 (8 weeks) and two P3 induction (8 weeks each) studies, one P3 maintenance (52 weeks) study and one long-term extension (LTE) study (ongoing). Analyses were performed for three cohorts (C): C1, P2P3 induction studies; C2, P3 maintenance study; and C3, tofacitinib-treated pts in P2P3 LTE studies. Pts received tofacitinib 10 mg twice daily (BID) in P3 induction studies and 5 and 10 mg BID in P3 maintenance and open-label LTE studies. Adverse events (AEs) of special interest (opportunistic infections [OIs], malignancies, major adverse cardiovascular events [MACEs], hepatic injury and gastrointestinal perforation [GIP]) were reviewed by independent adjudication committees.

Results: Of 1240 pts, 1156 received ≥1 dose of tofacitinib 5 or 10 mg BID with 1366 patient-years (PY) of tofacitinib exposure and up to 3.9 years of treatment. 85% of pts primarily received tofacitinib 10 mg BID. Demographics and baseline characteristics were similar across treatment arms within each cohort. There were a total of 4 deaths in C3. The proportion of pts with AEs, serious AEs (SAEs) and severe AEs was similar between treatment arms within C1 and C2. In C3, the most common AEs were nasopharyngitis and worsening of UC. Serious infections occurred in ≤1% of pts in any treatment arm in C1 and C2, with similar incidence rates (IRs) between arms in C2. Herpes zoster (HZ) IRs for tofacitinib 5 (2.05/100 PY), or 10 mg BID (6.64/100 PY) in C2 were numerically higher than PBO (0.97/100 PY). In C3, most HZ were limited to cutaneous involvement and non-SAEs. OIs were infrequent, and mainly HZ (14/18 events). Tofacitinib arms in C2 had no malignancies (excl. non-melanoma skin cancer [NMSC]), or GIP, and both NMSC and MACE IRs were similar to PBO. IRs of serious infection, OI, HZ, NMSC and MACE in C3 were generally similar to those in C2. In C3, there were no Hy’s law cases; GIP occurred in 3 pts and malignancies (excl. NMSC) occurred in 7 pts without specific cancer type clustering.

Conclusion: The tofacitinib UC programme provided a robust safety database, and integrated analyses revealed no unexpected safety signals. These results showed an overall acceptable safety profile for tofacitinib 10 mg BID induction therapy and for tofacitinib 5 and 10 mg BID maintenance therapy in pts with moderate to severe UC.

Disclosure of Interest: W.J. Sandborn: Grant support, personal fees and non-financial support: Pfizer Inc

J. Panés: Consulting fees from Pfizer Inc

G. D’Haens: Advisor for Pfizer Inc

B.E. Sands: Grant support/personal fees: Amgen, AZ, Celgene, Millennium, Pfizer Prometheus, AbbVie, Takeda, Janssen, BMS, Boehringer, Salix, Luitpold, Shire, Lilly, TiGenix, Immune, Arena, Akros, Forward, Theravance, Receptos, Vedanta, Synergy, Topivert

C. Su: Employee and shareholder of Pfizer Inc

M. Moscariello: Employee and shareholder of Pfizer Inc

T.V. Jones: Employee and shareholder of Pfizer Inc

R. Pedersen: Employee and shareholder of Pfizer Inc

G. Friedman: Employee and shareholder of Pfizer Inc

N. Lawendy: Employee and shareholder of Pfizer Inc

G. Chan: Employee and shareholder of Pfizer Inc

References

1. Sandborn WJ et al. J Crohns Colitis 2016;10(S1):S15, Abstract OP019

2. Sandborn WJ et al. J Crohns Colitis 2017:11(S1):S19–20, Abstract OP03

OP354 LONG-TERM HEALTH OUTCOMES OF 1000 CHILDREN BORN TO MOTHERS WITH INFLAMMATORY BOWEL DISEASE IN THE ANTI-TNF ERA

S. Kanis 1 , S. Modderman 2 , J.C. Escher 3 , R. Beukers 4 , K.h.n. De Boer 5 , A. Bodelier 6 , A. Depla 7 , G. Dijkstra 8 , A. Van Dijk 1 , L. P. l. Gilissen 9 , F. Hoentjen 10 , J.M. Jansen 11 , J. Kuijvenhoven 12 , N. Mahmmod 13 , R. Mallant 14 , A. E. Van Der Meulen - De Jong 15 , A. Noruzi 2 , B. Oldenburg 16 , L.E. Oostenbrug 17 , R.J. Ouwendijk 18 , M.J. Pierik 19 , M. Romberg Camps 20 , W.J. Thijs 21 , R. West 22 , A. Lima 1 , C.J. Van Der Woude 1

1 Department Of Gastroenterology And Hepatology, Erasmus University Medical Center, Rotterdam/Netherlands

2 Erasmus University Medical Center, Rotterdam/Netherlands

3 Pediatric Gastroenterology, Erasmus Medical Center-Sophia Children's Hospital, Rotterdam/Netherlands

4 Albert Schweitzer Hospital Dept. of Gastroenterology, Dordrecht/Netherlands

5 Gastroenterology And Hepatology, VU University Medical Center, Amsterdam/Netherlands

6 Amphia Ziekenhuis, Breda/Netherlands

7 Slotervaarthospital, Amsterdam/Netherlands

8 UMC Groningen Gastroenterology and Hepatology, Groningen/Netherlands

9 Gastroenterology And Hepatology, Catharina Ziekenhuis, Eindhoven/Netherlands

10 Dept Of Gastroenterology And Hepatology, Universitair Medisch Centrum St. Radboud, Nijmegen/Netherlands

11 Departement Of Gastroenterology And Hepatology, Onze Lieve Vrouwe Gasthuis, Amsterdam/Netherlands

12 Gastroenterology And Hepatology, Spaarne Gasthuis, Haarlem/Netherlands

13 Gastroenterology, St. Antonius Ziekenhuis, Nieuwegein/Netherlands

14 Gastroenterology andHepatology, Flevoziekenhuis, Almere, Netherlands, Almere/Netherlands

15 Leiden University Medical Center Dept. of Gastroenterology, Leiden/Netherlands

16 University Medical Center Utrecht, Utrecht/Netherlands

17 Atrium MC Parkstad Dept. of Gastroenterology, Heerlen/Netherlands

18 Ikazia Ziekenhuis, Rotterdam/Netherlands

19 Dept Of Gastroenterology And Hepatology, Maastrich University Medical Center Dept. of Gastroenterology, Maastricht/Netherlands

20 Department Of Internal Medicine And Gastroenterology, Zuyderland Medical Center, Amstenrade/Netherlands

21 Martiniziekenhuis Dept. of Gastroenterology, Groningen/Netherlands

22 Dept. Of Gastroenterology, SFG, Rotterdam/Netherlands

Contact E-mail Address: s.kanis@erasmusmc.nl

Introduction: Long-term health outcomes of children born to mothers with Inflammatory Bowel Disease (IBD) are relatively unexplored. The aim of this study was to describe the long-term health of children born to mothers with IBD and to assess whether medication use affects outcome.

Aims & Methods: We performed a multicenter retrospective study in The Netherlands. Women diagnosed with IBD prior to their pregnancy giving birth from January 1999 through April 2015 were identified in 20 participating hospitals and were invited per letter to participate. After consent, information regarding disease characteristics, medication use, life style factors during pregnancy (smoking, folic acid intake), birth outcomes (gestational age, birth weight, major congenital abnormalities) and long-term health outcomes of children (growth, severe infections necessitating hospitalization, chronic diseases and adverse reactions to vaccinations) were retrieved during a telephone interview with the mother. Information regarding antibiotic-treated infections was retrieved from the general practitioners (GPs). Adverse long-term health outcomes were defined as growth failure for which children were referred to a pediatrician, hospital admission because of a severe infection and/or chronic disease.

Results: From 20 Dutch hospitals, 1000 children born to 605 mothers (369 (61%) Crohn’s Disease (CD), 217 (36%) ulcerative colitis (UC), 19 (3%) IBDU) were included. Median follow up was 60 (IQR 36–60) months. In utero, 198 (20%) children had been exposed to anti-TNF, 241 (24%) to thiopurine monotherapy, 80 (1%) to systemic steroids and 481 (48%) to 5-ASA or no IBD medication. During pregnancy, mothers diagnosed with UC/IBDU more often relapsed (n = 138, 36%) than mothers with CD (n = 92, 15%) (p = 0.0001) and an endoscopy during pregnancy was more often performed in women with UC/IBDU (n = 49, 13%) than women with CD (n = 30, 5%) (p = 0.0001). Anti-TNF treatment was more often stopped before the third trimester (n = 87, 55%) in CD women than UC/IBDU women (n = 11, 28%) (p = 0.002). However, birth outcomes were similar for both groups. Exposure to anti-TNF and/or thiopurine was not associated with adverse birth outcomes, however, after adjusting for disease activity, systemic steroids use was associated with preterm birth (aOR 2.67, 95%CI 1.59–4.47). A total of 143 adverse health outcomes were reported in 132 children; 111 (11%) children were admitted to hospital for a severe infection of which, 74 (69%) occurred in the first year of life; 16 (2%) had growth failure and 16 (2%) children were diagnosed with a chronic disease before the age of 5 years. Seven children (1%) were treated for an adverse reaction to vaccination. Information from the GPs was retrieved for 668 (67%) children showing a median number of antibiotic-treated infections per year of 0.3 (IQR 0.00- 0.68). The number of children treated for one or more infections were the highest in year 1 (n = 240, 38%) and year 2 (n = 218, 38%). This infection rate decreased significantly over time to 104 (26%) children in year 5 (p = 0.0001). IBD type and IBD treatment did not influence long-term adverse health outcomes, adverse reaction to vaccination or infection rates.

Conclusion: In our long-term follow-up study, we found no evidence that IBD type or medical treatment for IBD during pregnancy affects long-term health outcomes of children. On behalf of the Initiative on Crohn and Colitis (ICC).

Disclosure of Interest: K.H.N. de Boer: Nanne de Boer has received a research and travel grant from TAKEDA outside the submitted work and served as principal investigator and consultant for TEVA.

B. Oldenburg: Abbvie, MSD, Takeda, Pfizer, Ferring en Falk (unrestricted grants)

C.J. van der Woude: C. Janneke van der Woude has served as a speaker and a consultant for Abbot, Abbvie, MSD and as a consultant for Shire and received funding from Janssen Biologics BV.

All other authors have declared no conflicts of interest.

OP355 SAFETY OF HERPES ZOSTER VACCINATION AMONG INFLAMMATORY BOWEL DISEASE PATIENTS BEING TREATED WITH ANTI-TNF MEDICATIONS

C. Trivedi 1 , Y. Shah 2 , N. Khan 2

1 Gastroenterology, Corporal Michael J. Crescenz VAMC, Philadelphia/United States of America/PA

2 Gastroenterology, University of Pennsylvania, Philadelphia/United States of America/PA

Contact E-mail Address: nabeel.khan@va.gov

Introduction: The risk of herpes zoster (HZ) is elevated in patients with Inflammatory Bowel Disease (IBD) who are treated with anti-TNF medications. However, since herpes zoster vaccine (HZV) is a live vaccine, it is not recommended to be administered in patients who are currently taking anti-TNF medications. ECCO suggests administering HZV 3 weeks prior to starting the immunosuppressive therapy or 3–6 months after stopping it. Although it is optimal to give the HZV prior to starting anti-TNF medications, in many clinical scenarios there is an urgent need to start the medication.

Aims & Methods: Our aim was to determine the safety of giving HZV while patients are on anti-TNF therapy. We conducted a retrospective cohort study involving IBD patients who were followed in the Veterans Affairs (VA) healthcare system between 2001 and 2016. We obtained inpatient and outpatient pharmacy data on our patients from the VA’s Pharmacy Benefits Management database and exposure periods to infliximab, adalimumab, certolizumab and golimumab were determined. Patients who received HZV while on anti-TNF medication were identified through vaccination codes and confirmed through individual chart review. Our outcome of interest was development of herpes zoster (HZ) between 0–42 days post HZV administration. This was determined by individual review of the patients’ charts.

Results: 56,417 patients with IBD were followed in the VA healthcare system from 2001 to 2016. A total of 59 patients were on an anti-TNF medication when they were given the HZV, and amongst them, 13 (22%) were also taking a thiopurine. Majority of the population was male and caucasian i.e. 51 (86.4%) and 53 (89.8%) respectively. Almost all patients 56 (94.9%) had charlson comorbidity index (CCI) of ≥2 (Table 1). The median interval between the start of anti-TNF therapy and HZV was 88 days (IQR 29–481.5). Median duration between the last administration of infliximab and administration of HZV was 23 days (IQR 13.5–32.25) while for adalimumab, median was 8 days (IQR 4.75–10.25). Median age of at the time of HZV was 64.9 years (IQR 60–69). Median number of encounters within 42 days after receiving HZV was 2 (IQR 2–3). No case of HZ related to live zoster vaccine type virus was found within 0–42 days of HZV administration.

Conclusion: In this nationwide cohort of patients, our data suggest that administering the HZV to IBD patients who are concomitantly taking anti-TNF medications is relatively safe. This study significantly expands the evidence supporting the use of HZV in this population, having included an elderly group of patients with a high CCI who are likely at a much higher risk of developing HZ.

Disclosure of Interest: N. Khan: Research grant from Pfizer Pharmaceuticals.

All other authors have declared no conflicts of interest.

WEDNESDAY, NOVEMBER 01, 201710:30–12:00

THERAPEUTIC APPROACHES TARGETING THE TUMOUR ENVIRONMENT IN PANCREATIC CANCER: HOPE OR HYPE? - ROOM E1____________________

OP356 THE CONTRIBUTION OF LYMPHOTOXIN TO PANCREATIC CARCINOGENESIS - FROM PANINS TO TUMOR DEVELOPMENT

G.M. Seleznik 1 , T. Reding 1 , C. Waschkies 1 , D. Lenggenhager 2 , A. Gupta 1 , E. Diamantis 3 , A. Perren 3 , M. Heikenwälder 4 , R. Graf 1

1 Visceral & Transplantation Surgery, University Hospital Zurich, Swiss HPB Centre, Zurich/Switzerland

2 Institute Of Pathology, University Hospital Zurich, Zurich/Switzerland

3 Institut Of Pathology, University Bern, Bern/Switzerland

4 Institute Of Virology, Technische Universität München, Helmholtz Center Munich, Munich/Germany

Contact E-mail Address: gitta.wanner-seleznik@usz.ch

Introduction: Pancreatic inflammation is a well-known risk factor for the development of pancreatic ductal adenocarcinoma (PDAC). Still, little is known about the cellular and molecular mechanisms how inflammation promotes pre-malignant lesions and subsequent PDAC. Chronic inflammatory processes affect all stages of tumor development as well as therapeutic interventions. We therefore set out to analyze the role of chronic inflammation in the initiation and pre-malignant phase. Furthermore, we investigate how malignant transformation and tumor microenvironment are influenced by inflammation. We have previously shown that patients suffering from chronic pancreatitis or pancreatic cancer show increased expression of lymphotoxin (LT) in the pancreas. Furthermore, in mice LT overexpression in the exocrine pancreas leads to pancreatitis (chronic, autoimmune). Therefore, we aimed to assess the role of LT-mediated inflammation in pancreatic carcinogenesis.

Aims & Methods: We established a mouse model by intercrossing p48 +/Cre ;Kras +/G12D ( KC ) mice to transgenic mice overexpressing LT ( Tg(Ela1-Lta, b) ; p48 +/CreTg+ ; Kras G12Dflox/+ ) ( LTKC ). To evaluate tumor development, we introduced a deletion in the TP53 tumor suppressor gene ( KPC; LTKPC ). Immunohistochemistry and RT-PCR were used to describe the inflammatory signature. In KPC and LTKPC animals tumor growth was assessed by MRI, furthermore tumors were compared histologically and biochemically focusing mostly on the distribution of immune cells and formation of tertiary lymphoid organs (TLOs).

Results: In line with earlier experiments, LT overexpression dramatically accelerated the development of pre-malignant lesions in KC animals. 8 week-old LTKC mice already showed extensive PanIN lesions, which are normally observed in 16-week-old KC animals. When focusing on tumor formation and survival, we have observed that LTKPC animals succumbed to tumors earlier than the KPC group. MRI measurements confirmed the accelerated PanIN and tumor development in LTKPC mice. Characterization of the tumor environment revealed that LT overexpression contributed to the formation of TLOs in the pancreatic tumors. Furthermore, ex vivo experiments with primary cultures from pancreata with LT demonstrated EGFR-independent formation of acinar-to-duct metaplasia, while wild-type cells required activation through external addition of TGFa. Similarly, acinar cells from KC animals did not require further activation.

Conclusion: We conclude that LT not only accelerated PanIN lesions, but also tumor growth. Moreover, LT overexpression led to changes in tumor microenvironment, which suggests that TLO formation may have a role in pancreatic cancer.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP357 RELA/NF-ΚB CONTROLLED ONCO-IMMUNO CROSSTALK IN PANCREATIC CANCER – ROLE OF CCL20 AND CX3CL1 IN APOPTOSIS RESISTANCE

C. Geismann , F. Grohmann, S. Schreiber, A. Arlt

Department Of Medicine, University Hospital of Schleswig-Holstein, Campus Kiel, Kiel/Germany

Contact E-mail Address: cgeismann@email.uni-kiel.de

Introduction: Pancreatic ductal adenocarcinoma (PDAC) exhibits one of the worst survival rates of all cancers. While in the majority of cancer, death rates show declining trends, PDAC register rising rates. For the majority of patients a “curative” intended resection is not feasible and the response rates to present chemo- and radiotherapeutic approaches remain highly unsatisfactory. One hallmark of PDAC is a profound desmoplastic stroma reaction. One component of this tumor microenvironment is a dysregulated immune response essentially contributing to therapy resistance of PDAC. We and others have shown that inflammation and tumorigenesis are functionally connected and controlled by the NF-kB/RelA signaling pathway, mediating apoptosis resistance in PDAC.

Aims & Methods: In the present study, a panel of human pancreatic carcinoma cell lines and cell lines isolated from PDAC mouse models were analysed for the role of RelA target genes in the resistance against chemotherapeutic drug or TRAIL induced apoptosis and the composition of the tumormicroenvironment.

Results: PDAC cell lines were treated with gemcitabine, etoposide or TRAIL and in dependency of the apoptosis response designated as apoptosis resistant or sensitive. Resistant cells already exhibited a high basal RelA/NF-κB activity that was further strongly induced by TRAIL and in a lower extend but prolonged extent by the chemotherapeutic drugs. Inhibition of NF-κB by pharmacological, siRNA or Crispr/CAS9 approaches sensitized the resistant PDAC cells. Gel shift analysis revealed that the p65/RelA subunit is critical component of the NF-κB complex in PDAC. By using a genome-wide unbiased approach we were able to establish the chemokines CCL20 and CX3CL1 as central (Top 5 upregulated) RelA/NF-kB target genes in resistant PDAC. Using Chip, luciferase and gel shift assays we were able to describe the RelA responsive element in the promoters of the genes. Realtime PCR, Western Blot and ELISA confirmed RelA dependent upregulation of CCL20 and CX3CL1 after TRAIL treatment. Surprisingly targeting CCL20 and/or CX3CL1 by siRNA, blocking antibodies or by downregulation of the CCL20 receptor CCR6 or the CX3CL1 receptor CX3CR1 had no effect on PDAC cell death or cancer cell migration. However, by using various complementary in vitro , ex vivo and in vivo models we were able to show that these chemokines secreted by resistant PDAC cells act in a paracrine fashion, leading to an increased recruitment of inflammatory cells. Furthermore these PBMC showed a chemokine dependent differentiation in immune cell subtypes which confer apoptotic protection of PDAC cells against TRAIL induced apoptosis.

Conclusion: In conclusion we were able to establish a RelA controlled chemokine pathway in apoptosis resistant PDAC cells which does not confer direct apoptotic protection or migration of the tumor cells but instead leads to the recruitment and immune cell differentation which in turn mediate apoptosis resistance of PDAC cells.

Disclosure of Interest: All authors have declared no conflicts of interest.

WEDNESDAY, NOVEMBER 01, 201710:30–12:00

ENDOLUMINAL AND TRANSLUMINAL INTERVENTIONS IN THE UPPER GI TRACT - ROOM E2____________________

OP358 ENDOLUMINAL AND INTRACAVITAL VACUUM COMBINED WITH STENT-OVER-SPONGE (SOS) TREATMENT FOR FOREGUT PERFORATIONS AND LEAKS

P.V. Valli 1 , J. Mertens 1 , A. Kroeger 1 , P.M. Schneider 2 , C. Gutschow 2 , C. Gubler 1 , P. Bauerfeind 1

1 Division Of Gastroenterology And Hepatology, University Hospital Zurich, Zurich/Switzerland

2 Division Of Visceral Surgery And Transplantation, University Hospital Zurich, Zurich/Switzerland

Contact E-mail Address: piero.valli@usz.ch

Introduction: Iatrogenic and emetogenic perforations or anastomotic leakage of the upper gastrointestinal (GI) tract can result in life-threatening mediastinitis or abdominal infections. Abscess drainage and defect repair, commonly achieved by surgical procedures in the past, are the crucial steps to control infection and life threatening sepsis. Endoluminal vacuum therapy for foregut wall defects has evolved as a promising endoscopic treatment option in addition to classic closure techniques using clips or stents. To improve suction and to maintain swallow function, we combined endosponge (ES) treatment with fully covered self-expandable metallic stent (SEMS).

Aims & Methods: ES therapy using the Endo-SPONGE or Eso-SPONGE (B. Braun Medical, Melsungen, Germany) was used in 18 consecutive patients suffering from foregut wall defects between 2012 and 2016 at our institution. Upon diagnosis, post-surgical leakage, iatrogenic or emetogenic perforation or chronic fistula dimensions were evaluated by oral and intravenous contrast-enhanced computed tomography (CT) and endoscopy. Depending on the defect type, ES was placed intraluminal or intracavital and if feasible, combined with SEMS placement (SOS, stent-over-sponge).

Results: Indications for ES were anastomotic leakage after surgery (n = 12, 66.7%), esophageal perforation (n = 4, 22.2%) and chronic foregut fistula (n = 2, 11.1%). The overall success rate with achievement of lesion closure was 83% (15/18). Ten patients were primarily treated with luminal ES placement (55.6%), whereas in 8 (44.4%) patients, ES were preferably inserted into the abscess cavity. In 12 (66.6%) patients, ES treatment was combined with SEMS overstenting (Stent-Over-Sponge, SOS). The median number of utilized ES per case was 3.5 (range 1–17). ES remained in situ for a median time of 5 days (range 2–18). No adverse events directly connected to the ES/SEMS placement and their removal were recorded. Two patients developed esophageal stricture after leak closure and were successfully treated by endoscopic dilatation.

Conclusion: ES treatment is a successful method to treat infected foregut wall defects of any kind. ES plus SEMS overstenting seems even more powerful than ES alone in cases of large infected cavities. ES or SOS treatment should always be evaluated in patients with upper GI leakage before performing a surgical repair.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP359 INTRADUCTAL BILIARY OR PANCREATIC ABLATION DURING ENDOSCOPIC AMPULLECTOMY MAY REDUCE THE LONG-TERM RECURRENCE RATE

E. Perez-Cuadrado-Robles 1 , H. Piessevaux 1 , T. Moreels 1 , R. Yeung 1 , T. Aouattah 1 , A. Jouret-Mourin 2 , M. Komuta 2 , P.H. Deprez 1

1 Gastroenterology Department, Cliniques Universitaires Saint-Luc, Brussels/Belgium

2 Pathology, Cliniques Universitaires Saint-Luc, Brussels/Belgium

Contact E-mail Address: kikemurcia@gmail.com

Introduction: The feasibility and outcome of endoscopic resection in ampullary tumors with intraductal growth remains unclear.

Aims & Methods: All consecutive patients from 2000 to 2016 who underwent an endoscopic snare ampullectomy with a 6-month minimum follow-up were included. Factors related to recurrence were collected and analyzed. Intraductal ablation by wire guided radiofrequency or wire-guided 6, 8 or 10 Fr cystostome in cases of intraductal growth was evaluated in terms of safety and effectiveness.

Results: Seventy-three patients (58 ± 14 y, 49.3% men, 34.2% FAP) presented with an indication for endoscopic ampullectomy. Median tumor size was 20 mm (range: 8–80 mm) and 79.5% of patients were symptomatic at diagnosis. EUS detected intraductal infra- (n = 13) or supra-centimetric (n = 3) ingrowth in 21.9% of cases (8 biliary and pancreatic, 3 pancreatic, 5 biliary). Ablation was performed by RFA in 2 patients and 6–10French cystostome in 14, followed by pancreatic and biliary stenting. There were no recurrences observed in these patients. In the full group, en-bloc resection was achieved in 34 lesions (46.6%, 28 R0-status) in a median of 1 (1–5) session. High-grade dysplasia was observed in 27 cases (37%) and adenocarcinoma in 6 (8.2%). Twelve patients experienced recurrence (16.4%) and 3 required surgery (median follow-up: 23 months). Familial adenomatous polyposis was not associated with recurrence (20% vs. 14.6%, p = 0.553). By multivariate logistic regression analysis, ≥2 endoscopic sessions was the only factor associated with recurrence (OR:7.60 [95%CI:1.869–30.896], p = 0.005). Complications (19.2%) were bleeding (n = 6), pancreatitis (n = 3), perforation (n = 3) and biliopancreatic stenosis (n = 2). There were no differences in the complication rate in patients with/without intraductal ablation (18.8% vs. 19.3%, p = 0.961)

Conclusion: Intraductal biliary and pancreatic ablation is feasible, safe and may reduce the recurrence rate in ampullary tumors with intraductal ingrowth.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP360 EFFECT OF SUBMUCOSAL INJECTION IN ENDOSCOPIC PAPILLECTOMY OF AMPULLARY TUMOR: A PROPENSITY ANALYSIS

K.H. Chung 1 , S.H. Lee 2 , J.H. Choi 2 , J.W. Kang 2 , J.K. Ryu 2 , Y. Kim 2

1 Depertment Of Internal Medicine, Armed Forces Capital Hospital, Gyeonggi-do/Korea, Republic of

2 Department Of Internal Medicine And Liver Research Institute, Seoul National University College of Medicine, Seoul/Korea, Republic of

Contact E-mail Address: kwasay@gmail.com

Introduction: The role of submucosal injection before the endoscopic papillectomy (EP) is controversial. This study was aimed to investigate the effect of submucosal injection before the EP of ampullary tumors.

Aims & Methods: Between March 2006 and March 2014, all patients who received initial curative EP at Seoul National University Hospital were retrospectively recruited. The early recurrence rate (within 3 months which presumed due to incomplete resection), recurrence-free survival and post-procedural adverse events were compared between the submucosal injection (SI) group and non-injection (NI) group. Outcomes were also assessed after matching according to propensity score to reduce the effects of selection bias and potential confounders.

Results: In total 122 patients were included; 26 in the SI group and 96 in the NI group. Early recurrence was more frequent in SI group than NI group (26.9% vs. 8.3%, P = 0.010). The recurrence-free survival was not significantly different between the two groups (P = 0.145). After propensity score matching, total 26 pair patients were selected in both group. In this cohort, early recurrence was not occurred in NI group. Meanwhile, 7 (26.9%) patients in SI group had tumor recurrence (P = 0.010). The recurrent free survival of NI group was significantly longer than SI group (P = 0.024). In multivariate analysis, factors significantly related with recurrence-free survival was pathologic grade (P = 0.004) and submucosal injection (P = 0.012). Before the propensity score matching, post-procedural adverse events were significantly more common in SI group than NI group (pancreatitis, 26.9% vs. 10.4%, P = 0.031; bleeding, 19.2% vs. 5.2%, P = 0.021; perforation, 7.7% vs. 0%, P = 0.044) however, the difference was decreased and not statistically significant in propensity score matched cohort.

Conclusion: Submucosal injection before the EP of ampullary tumor was related with more frequent early recurrence and shorter recurrence-free survival. Moreover, it was not reduced the rate of post-procedural adverse events. Submucosal injection would not be suggested before the EP.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP361 EUS-GUIDED GASTROENTEROSTOMY: A LARGE MULTICENTER STUDY COMPARING THE DIRECT AND BALLOON-ASSISTED TECHNIQUES

Y. Chen 1 , R. Kunda 2 , A. C. Storm 3 , C. C. Thompson 3 , J. Nieto 4 , A. A. Siddiqui 5 , T. James 6 , M. A. Bukhari 1 , O.I Brewer Gutierrez 1 , M.I. Canto 1 , V. K. Singh 1 , T.H. Baron 6 , M.A. Khashab 1

1 Gastroenterology And Hepatology, Johns Hopkins Hospital, Baltimore/United States of America

2 Aarhus University Hospital, Aahrus/Denmark

3 Division Of Gastroenterology, Hepatology, And Endoscopy, Brigham and Women's Hospital, Boston/United States of America

4 Borland Groover Clinic, Jacksonville/United States of America

5 Division Of Gastroenterology And Hepatology, Thomas Jefferson University, Philadelphia/United States of America

6 Division Of Gastroenterology And Hepatology, University of North Carolina, Chape Hill/United States of America/NC

Contact E-mail Address: mkhasha1@jhmi.edu

Introduction: Several techniques have been developed for EUS-guided gastroenterostomy (EUS-GE) for the management of gastric outlet obstruction (GOO), including the direct (DGE) and balloon-assisted (BAGE) methods. A standardized approach to EUS-GE, however, is lacking and there are currently no data ascertaining the optimal technique.

Aims & Methods: We aimed to compare DGE with BAGE in terms of technical success and clinical outcomes. This is a multicenter, retrospective study involving 5 US and 1 European tertiary institutions. Consecutive patients who underwent EUS-GE with either the DGE or BAGE technique for malignant or benign GOO were included between 1/2014 and 10/2016. The primary outcome was technical success. Secondary outcomes included clinical success (ability to tolerate a full fluid diet), procedure time, and rate of adverse events with severity graded per the ASGE lexicon.

Results: A total of 72 patients (43.1% female; mean age 63.0 ± 11.8yrs) underwent EUS-GE for GOO (n = 55 DGE and n = 17 BAGE). GOO was of malignant and benign etiology in 65.3% and 34.7% of the patients, respectively. Benign etiologies included strictures from acute/or chronic pancreatitis (40%), surgical anastomotic (24%), peptic ulcer (16%), superior mesentery artery syndrome (4%), caustic injury (4%), NSAID-induced (4%), hematoma (4%), other (4%). Malignant etiologies included metastatic cancer (53.2%), pancreatic cancer (19.1%), duodenal/ampullary cancer (19.1%), gastric cancer (4.3%), cholangiocarcinoma (2.1%), and gallbladder cancer (2.1%). Sites of GOO were 16.7% prepyloric/pyloric, 11.1% first part of the duodenum, 68.1% descending duodenum, and 4.2% jejunum. There was no significant difference between DGE and BAGE groups in terms of demographics, etiology of GOO, location of obstruction, and history of enteral stenting or dilation. Technical success was achieved in 94.5% of DGE and 94.1% of BAGE patients (p = 1.00). Mean stent diameter was comparable between the two groups. Mean procedure time was significantly shorter in the DGE group as compared to the BAGE group (35.1 ± 31.2 min vs. 89.9 ± 33.3 min, p < 0.001). Clinical success rate was similar between both groups (92.7% vs 93.7%, p = 1.00) with a median follow-up of 116 days (IQR 33–310) (Table 1). Mean time to oral intake was 1.37 ± 2.81 days. A total of 4 AEs were noted (AE rate of 5.6%), all of which were stent misdeployments (AE severity: moderate n = 3 and severe n = 1). AE rates were comparable between the two cohorts (DGE 5.5% vs. BAGE 5.9% p = 1.00). Post-procedure length of stay, need for re-intervention, and survival were also comparable between the two cohorts.

Conclusion: This is the largest study on EUS-GE to date and suggests DGE as the more efficient technique. Nonetheless, both DGE and BAGE are effective and safe procedures when performed by experienced operators.

Disclosure of Interest: R. Kunda: Consultant for Boston Scientific

C.C. Thompson: Consultant for Boston Scientific

T.H. Baron: Consultant for Boston Scientific

M.A. Khashab: Consultant for Boston Scientific

All other authors have declared no conflicts of interest.

OP362 MINIMALLY INVASIVE SURGERY VERSUS ENDOSCOPY RANDOMIZED (MISER) TRIAL FOR NECROTIZING PANCREATITIS

J.Y. Bang 1 , J.P. Arnoletti 2 , B.A. Holt 3 , U. Navaneethan 1 , M. Hasan 1 , C.M. Wilcox 4 , R. Hawes 1 , S. Varadarajulu 1

1 Center For Interventional Endoscopy, Florida Hospital, Orlando/United States of America/FL

2 Surgery, Florida Hospital, Orlando/United States of America/FL

3 Gastroenterology, St. Vincent's Hospital, Melbourne/Australia

4 Gastroenterology, University of Alabama at Birmingham, Birmingham/United States of America/AL

Contact E-mail Address: jybang213@gmail.com

Introduction: Necrotizing pancreatitis is a highly morbid disease with poor clinical outcomes. The treatment strategy has evolved over time from open necrosectomy to other minimally invasive techniques.

Aims & Methods: We aimed to compare the clinical outcomes between minimally invasive surgery (MIS) and endoscopic approaches for treatment of necrotizing pancreatitis. Consecutive patients with necrotizing pancreatitis were randomized to MIS or endoscopic interventions. MIS involved laparoscopic cystogastrostomy with internal debridement or video-assisted retroperitoneal debridement. Endoscopic interventions were tailored to the size and extent of the necrotic collection: Initial session involved drainage by single-gate, multi-gate or dual (endoscopic and percutaneous drainage) modality techniques followed by necrosectomy if required. Patients who underwent only percutaneous drainage and did not require surgical or endoscopic interventions were excluded. The primary end point was to compare the composite of major complications (new onset multi-organ failure, new onset multiple systemic complications, perforation of visceral organ, entero/pancreaticocutaneous fistula, bleeding) or death until 3 months. Secondary outcome measures were to compare early (≥25% decrease in size of necrotic collection with systemic inflammatory response syndrome [SIRS] resolution at 72 hours), mid (≥50% decrease in necrotic collection with symptom relief at discharge) and late-term (complete resolution of necrotic collection with symptom relief at 6 months) treatment success (intention-to-treat), treatment failure (open necrosectomy or cross-over to the alternate treatment arm), adverse events, re-interventions and post-procedure length of stay (LOS).

Results: 66 patients were randomized to endoscopic (n = 34) or MIS (n = 32). The primary outcome occurred in 5.9% of endoscopic and 34.4% of MIS cohorts (risk ratio 0.17; 95% CI, 0.04–0.71, p = 0.004). While there was no significant difference in late-term treatment success (96.2 vs. 84.0%, p = 0.19), endoscopy was associated with higher early (97.1 vs. 53.1%, p < 0.001) and mid-term (100 vs. 81.3%, p = 0.01) treatment success. Treatment failure was significantly higher for MIS (18.8% vs. 0, p = 0.01). There was no significant difference in mortality (2.9 vs. 6.3%, p = 0.61), adverse events (41.2 vs. 53.1%, p = 0.33), re-interventions (44.1 vs. 28.1%, p = 0.18) and LOS (median 14 days [IQR 6–22] vs. 18.5 days [IQR 11.5–29.5], p = 0.057) between endoscopy and MIS cohorts, respectively.

Conclusion: Endoscopy-based interventions, as compared to minimally invasive surgery, was associated with a lower rate of composite end point of major complications or death among patients with necrotizing pancreatitis.

Disclosure of Interest: R. Hawes: Consultant for Boston Scientific Corporation and Olympus America Inc.

S. Varadarajulu: Consultant for Boston Scientific Corporation and Olympus America Inc.

All other authors have declared no conflicts of interest.

OP363 LUMEN APPOSING METAL STENTS ARE COST-EFFECTIVE WHEN COMPARED WITH PLASTIC STENTS IN THE MANAGEMENT OF PANCREATIC WALLED-OFF NECROSIS

O.I. Brewer Gutierrez 1 , Y.I. Chen 1 , A. Barkun 2 , V. Adam 2 , L. Fayad 1 , G. Bai 3 , V. K. Singh 1 , M. A. Bukhari 1 , O. Sanaei 1 , B. J. Elmunzer 4 , T.H. Baron 5 , S. Ngamruengphong 1 , M.I. Canto 1 , A. Repici 6 , M. A. Khashab 1

1 Gastroenterology And Hepatology, Johns Hopkins Hospital, Baltimore/United States of America

2 Division Of Gastroenterology, McGill University and the McGill University Health Centre, Montreal/Canada

3 Johns Hopkins Carey Business School, Baltimore/United States of America

4 Medical University of South Carolina, Charleston/United States of America

5 Gastroenterology & Hepatology, University of North Carolina, North Carolina/United States of America

6 Dept. Of Gastroenterology, Ist. Clinico Humanitas Rozzano Dept. of Gastroenterology, Milano/Italy

Contact E-mail Address: leafayad@gmail.com

Introduction: Background: Pancreatic walled-off necrosis (WON) is a common and potentially fatal complication of acute pancreatitis. EUS-guided drainage is an effective and accepted primary modality for the management of WON. A lumen apposing metal stent (LAMS) has recently been developed specifically for the drainage of pancreatic fluid collections, offering a large stent diameter, anti-migration properties and single-step deployment. However, LAMS have higher cost than plastic stents (PS). Data on the cost-effectiveness of LAMS when compared to drainage with PS is lacking.

Aims & Methods: We aimed to compare the cost-effectiveness of LAMS with PS for EUS-guided drainage of symptomatic WON. A decision tree was developed to assess two different endoscopic drainage strategies: LAMS and PS. For each strategy, in-patients receive a stent and are followed for subsequent need for direct endoscopic necrosectomy, adverse events leading to unplanned endoscopy, percutaneous drainage (PD), surgery, and successful endoscopic drainage using probabilities obtained from a systematic review of the literature. The unit of effectiveness is defined as successful endoscopic drainage without need for PD or surgery. The total cost of successful and unsuccessful endoscopic drainage are computed. Time horizon is set at 6 months. Costs in 2016 US$ are based on inpatient institutional costs from patients who underwent WON drainage with LAMS or PS from 2014 to 2016. Physician fees are obtained from the American Medical Association. A third party payer perspective is adopted. Univariate sensitivity analyses are performed.

Results: For all in-patients, LAMS was more efficacious than PS with 92.3% and 84.0% of the patients achieving successful endoscopic drainage of WON, respectively (incremental effectiveness: 8.25%, table 1). LAMS, however, was more costly with an average cost per patient of US$ 20,029 compared to US$ 15,941 with PS (incremental cost US$ 4089, table 1). The incremental cost effectiveness ratio favored LAMS at a cost US$ 49,214 per additional patient successfully treated. The cost of procedure for LAMS insertion was fixed at US$5237 in the model (based on the institutional cost). The sensitivity analysis showed that if the cost of procedure for LAMS insertion decreased below US$2647, then the cost per successful drainage associated to LAMS choice becomes better than PS. Additional sensitivity analysis performed by varying the main probabilities by ±20% and main costs by ±50% showed that these results are robust.

Conclusion: LAMS improves the effectiveness of endoscopic management of in-patients with WON when compared to PS at an incremental increase in cost of US$ 49, 214 per additional patient successfully treated. The assessment of additional variations in health state probabilities and costs are needed to confirm the generalizability of these findings.

Disclosure of Interest: A. Barkun: Consultant for Cook medical

V.K. Singh: Consultant for Abbvie, Kowa, Novo Nordisk and Ariel Advisory borad participant for Akcea and Nordmark

T.H. Baron: Boston Scientific

M.A. Khashab: Consultant for Boston Scientific

All other authors have declared no conflicts of interest.

WEDNESDAY, NOVEMBER 01, 201710:30-12:00

BUGS IN LOWER GI DISEASES - ROOM E3____________________

OP364 EVALUATION OF MULTIPLEX PCR FOR DIAGNOSIS OF GASTROINTESTINAL TUBERCULOSIS

N. Berry , S. Malik, K. Sharma, S. K. Sinha, N. Dhaka, R. Kochhar, K. Vaiphei

Gastroenterology, Postgraduate Institute of Medical Education and Research, Chandigarh/India

Contact E-mail Address: sarthakmalik87@gmail.com

Introduction: Prompt and accurate diagnosis of gastrointestinal tuberculosis (GITB) is highly challenging due to pauci-bacillary nature of disease. Current conventional techniques like smear, histopathology and culture lack sensitivity and are time consuming and have limited sensitivity. New rapid diagnostic methods like multiplex PCR seem to have a promising role.

Aims & Methods: Aim of current study was to evaluate the role of multiplex PCR using specific primers against IS6110, MPB64 and Protein b for the diagnosis of GITB and compare it with histopathology. In this prospective study conducted from July 2015 to November 2016, adult cases of clinically suspected GITB were recruited. All patients underwent mantoux test, contrast enhanced computed tomography of abdomen, esophagogastroduodenoscopy or colonoscopy as indicated. Multiple biopsies for tissue diagnosis were taken from lesions by a single observer. All specimens were subjected to Ziehl Neelsen staining for detection of acid fast bacilli. Tissue obtained were analysed by H&E by two independent pathologists. Multiplex PCR on tissue specimens using specific primers against IS6110, MPB64 and Protein b was also performed. The performance of the assay was assessed using a composite gold standard for diagnosis of tuberculosis, which comprised a combination of clinical characteristics, microbiology smear showing acid fast bacilli, histopathology showing caseous necrosis with granulomatous inflammation and response to antitubercular therapy.

Results: A total of 55 cases of clinically suspected GITB were recruited. A final diagnosis of tuberculosis was made in 32 cases (duodenal n = 4, ileocolic n = 28) and rest 23 acted as control group. The mean age, haemoglobin and erythrocyte sedimentation rate of patients with tuberculosis were 36.41 + 14.6 years, 10.2 + 2.4 g/dl, 37.8 + 15.3 mm/hr respectively. The most common endoscopic findings were ulcerations (75%), nodularity (46.8), distorted ileocecal valve (28%) and strictures (21.8%). The most common radiological findings were mural wall thickening (65.6%), mesenteric lymphadenopathy (56%) and strictures (40%). The sensitivity, specificity, positive predictive value and negative predictive value of histopathology (H&E) for diagnosis of GITB was 28.12%, 100%, 100% and 48.89% respectively (Table 1). The sensitivity, specificity, positive predictive value and negative predictive value of multiplex PCR for diagnosis of GITB was 86.33%, 100%, 100% and 86.2% respectively (Table 1). Four patients underwent surgery for subacute intestinal obstruction while on treatment; rest twenty eight patients completed nine months of antitubercular therapy and improved.

Conclusion: Multiplex PCR using specific primers against IS6110, MPB64 and Protein b has a higher sensitivity compared to conventional techniques for diagnosis of GITB

Disclosure of Interest: All authors have declared no conflicts of interest.

OP365 1-DAY OR 5-DAY FECAL SAMPLES: WHICH ONE IS MORE BENEFICIAL TO BE USED FOR DNA-BASED GUT MICROBIOTA STUDY

T. Su , S. Chen

Department Of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University, Institute of Gastroenterology, Zhejiang University, Hangzhou/China

Contact E-mail Address: 4094108@qq.com

Introduction: Fecal sample collection is an important influential factor for DNA-based gut microbiota study. In a majority of studies, fecal samples of participants were collected at one random day. However, many factors have been illuminated to have potential effect on gut microbial composition. 1–4 Therefore, It is controversial whether the microbiome detected in fecal sample collected at one random day could fully represent the gut microbial community. Some researchers mixed up fecal samples collected at five consecutive days in gut microbiota study considering that the use of 5-day fecal samples may be more accurate than 1-day fecal samples. 5 But no study has been published to assess the representation and repeatability of 1-day fecal samples and compare it with 5-day fecal samples.

Aims & Methods: To figure out whether the use of fecal sample mixture collected at consecutive five days could more accurately represent gut microbial community, 1-day and 5-day fecal samples were collected from 8 healthy adults and analyzed by 16S rRNA sequence.

Results: Our results indicated that both 1-day fecal samples and 5-day samples exhibited relatively high repeatability. The relative abundance of majority of bacterial taxa did not changed between 1-day fecal samples and 5-day fecal samples. However, the alpha diversity of 5-day fecal samples was higher than that of 1-day fecal samples.

Conclusion: When the aims of studies are to analyze the relative abundance of specific OTUs among subjects, fecal samples collected at one day could be used. When microbial diversity is one of essential factors to be analyzed, the use of 5-day fecal samples may be more recommended.

Disclosure of Interest: All authors have declared no conflicts of interest.

References

1. Vandeputte D, Falony G, Vieira-Silva S, Tito RY, Joossens M, Raes J: Stool consistency is strongly associated with gut microbiota richness and composition, enterotypes and bacterial growth rates. Gut 2016, 65(1):57–62.

2. Falony G, Joossens M, Vieira-Silva S, Wang J, Darzi Y, Faust K, Kurilshikov A, Bonder MJ, Valles-Colomer M, Vandeputte D et al: Population-level analysis of gut microbiome variation. Science ( New York, NY ) 2016, 352(6285):560–564.

3. Flores R, Shi J, Fuhrman B, Xu X, Veenstra TD, Gail MH, Gajer P, Ravel J, Goedert JJ: Fecal microbial determinants of fecal and systemic estrogens and estrogen metabolites: a cross-sectional study. Journal of translational medicine 2012, 10:253.

4. Clarke SF, Murphy EF, O'Sullivan O, Lucey AJ, Humphreys M, Hogan A, Hayes P, O'Reilly M, Jeffery IB, Wood-Martin R et al: Exercise and associated dietary extremes impact on gut microbial diversity. Gut 2014, 63(12):1913–1920.

5. Halmos EP, Christophersen CT, Bird AR, Shepherd SJ, Gibson PR, Muir JG: Diets that differ in their FODMAP content alter the colonic luminal microenvironment. Gut 2015, 64(1):93–100.

OP366 THE IN-HOSPITAL MORTALITY RATE FOR CLOSTRIDIUM DIFFICILE INFECTION HAS DECREASED OVER THE PAST DECADE IN THE UNITED STATES: A NATIONWIDE ANALYSIS

P.T. Kroener 1 , P. Jirapinyo 2 , M. S. Abougergi 3 , C. C. Thompson 2

1 Mt. Sinai St. Luke's/West, New York/United States of America

2 Division Of Gastroenterology, Hepatology And Endoscopy, Brigham and Women's Hospital, Boston/United States of America/MA

3 Catalyst Medical Consulting, Simpsonville/United States of America/SC

Contact E-mail Address: thomaskroner@gmail.com

Introduction: Over the past decade, the rates of Clostridium difficile infection (CDI) and associated mortality were reported to have increased. This period saw significant epidemiological changes in terms of emergence of more virulent strains, development of improved diagnostic methods and new therapies. Though some studies have evaluated the burden of CDI at a national level, these are now relatively old and display limited number of outcomes. Therefore, the aim of this study was to explore the recent incidence, morbidity, mortality, and resource utilization of patients with CDI throughout the past decade using a national database.

Aims & Methods: Retrospective cohort study using the National Inpatient Sample from 2004 to 2013, which is the largest publically available inpatient database in the US. All patients with an ICD-9CM code for a principal diagnosis code of C. difficile infection were included in the study. There were no exclusion criteria. The primary outcome was inpatient mortality. Secondary outcomes were inpatient morbidity, measured by colectomy rates; resource utilization, measured by colonoscopy rates and length of hospital stay (LOS), and total hospitalization charges (adjusted for inflation). Odds ratios and means were adjusted for age, sex, race, median income in the patient’s zip code, Charlson Comorbidity Index, hospital region, rural location, size and teaching status using multivariate logistic regression.

Results: A total of 3,325,872 patients with CDI were identified, of which 1,021,454 met the inclusion criteria and were included. Mean age was 68 years and 65% of patients were female. Total cases increased from 60,137 in 2004 to 111,285 in 2013. Figure 1 shows the mortality trend in the U.S. throughout the past decade. Although the mortality rate peaked at 4.1% in 2005, the overall mortality in the cohort decreased 44% during the past decade, from 3.6% to 2%. Of the patients with CDI, 16,313 (1.6%) underwent colonoscopy throughout the study period, while 4440 patients (0.4%) underwent colectomy. The use of colonoscopy, colectomy rates, and LOS decreased, while total hospitalization charges increased in throughout the study period. Table 1 shows all adjusted odds ratios, means and change magnitude for the variables.

Conclusion: Despite having peaked in the latter half of the past decade, Clostridium difficile infection mortality rates saw a significant decrease within the past 5 years in the United States. This may reflect the impact of improved detection methods, novel therapies and increased situational awareness. Similarly, colectomy procedures in patients with CDI declined during the study period. Regarding resource utilization, colonoscopy and hospital length of stay also decreased in the past decade. However, total hospitalization charges have increased significantly, in part reflecting the increasing costs of the new measures.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP367 SINGLE-INFUSION FECAL MICROBIOTA TRANSPLANTATION IS NOT EFFECTIVE IN TREATING SEVERE CLOSTRIDIUM DIFFICILE INFECTION

G. Ianiro 1 , L. Masucci 2 , C. Simonelli 1 , M. Sanguinetti 2 , A. Gasbarrini 1 , G. Cammarota 1

1 Internal Medicine, Gastroenterology And Liver Unit - Gastroenterology Area, Fondazione Policlinico Universitario "A. Gemelli" - Catholic University of Rome, Rome/Italy

2 Institute Of Microbiology, Fondazione Policlinico Universitario "A. Gemelli" - Catholic University of Rome, Rome/Italy

Contact E-mail Address: gianluca.ianiro@hotmail.it

Introduction: Fecal microbiota transplantation (FMT) is an effective therapeutic option against recurrent Clostridium difficile infection (rCDI).1 A growing body of evidence shows that a single fecal infusion achieves lower CDI cure rates than multiple fecal infusions.2–3 This finding is particularly remarkable when dealing with severe CDI, which has been identified as a predictor of failure after single fecal infusion.4–5 However, the efficacy outcomes of single and multiple fecal infusions for the treatment of severe CDI have been compared only in few studies to date.2

Aims & Methods: We evaluated a prospective cohort of patients who received FMT by colonoscopy for severe rCDI from June 2013 to January 2017. All subjects provided their written informed consent. This study was approved by our local ethics committee. rCDI and severe CDI were defined according to the ESCMID guidelines. 6 In particular, severe CDI was defined as an episode of CDI with one or more specific signs and symptoms of severe colitis, or a complicated course of disease, with significant systemic toxin effects and shock, and consequent need for Intensive Care Unit admission or colectomy. 6 We defined treatment failure as post-procedural persistence of diarrhea, or diarrhea recurrence after early improvement within 8 weeks after fecal infusion. Clinical cure was defined as disappearance of diarrhea. Multiple fecal infusions were administered when a single fecal infusion failed to treat CDI. Selection of donors, preparation of fresh and frozen feces, and FMT procedure, were carried out as previously reported. 2, 7 All patients were carefully followed up until 8 weeks after FMT, by weekly clinical examinations.

Results: In the study period, 33 subjects with severe rCDI received FMT. They were mostly females (N = 20) and 74 year-old on average (range = 60–93). The mean number of previous recurrences was 3 (range = 1–5). Thirty subjects (91%) were inpatients. Pseudomembranous colitis was identified at endoscopic evaluation in 22 subjects (67%). A single fecal infusion was able to cure 9 of 33 patients (27%). Among nonresponders to single fecal infusions, 3 critically ill subjects were not able to repeat the procedure; 2 of them died for overwhelming CDI, and the other one died for other reasons not related to CDI. All remaining 21 subjects received repeated fecal infusions (mean = 3; range = 2–5), and 19 of them (90%) were successfully treated. In this series of patients, we performed a total of 68 infusions of feces, using feces from unrelated donors in 47 cases (69%), and frozen feces in 27 procedures (40%). Overall, FMT (including single and multiple infusions) was able to cure 28 of 33 patients with severe CDI (85%).

Conclusion: Our findings remark that single fecal infusion is not effective in patients with severe CDI, and should be no longer considered as a reliable treatment options for this clinical picture. As severe CDI is a life-threatening disease, dedicated protocols, including multiple-infusion FMT, are necessary to offer patients an effective therapeutic option to cure this condition.

Disclosure of Interest: All authors have declared no conflicts of interest.

References

1. Cammarota G, Ianiro G, Tilg H, et al; European FMT Working Group. European consensus conference on faecal microbiota transplantation in clinical practice. Gut 2017.

2. Fischer M, Sipe BW, Rogers NA, et al. Faecal microbiota transplantation plus selected use of vancomycin for severe complicated Clostridium difficile infection: description of a protocol with high success rate. Aliment Pharmacol Ther 2015

3. Hota SS, Sales V, Tomlinson G, et al. Oral Vancomycin Followed by Fecal Transplantation Versus Tapering Oral Vancomycin Treatment for Recurrent Clostridium difficile Infection: An Open-Label, Randomized Controlled Trial. Clin Infect Dis 2017

4. Ianiro G, Valerio L, Masucci L, et al. Predictors of failure after single faecal microbiota transplantation in patients with recurrent Clostridium difficile infection: results from a three-year, single-centre cohort study. Clin Microbiol Infect 2017

5. Fischer M, Kao D, Mehta SR, Martin T, Dimitry J, Keshteli AH, et al. Predictors of Early Failure After Faecal Microbiota Transplantation for the Therapy of Clostridium Difficile Infection: A Multicentre Study. Am J Gastroenterol 2016

6. Debast SB, Bauer MP, Kuijper EJ; European Society of Clinical Microbiology and Infectious Diseases. European Society of Clinical Microbiology and Infectious Diseases: update of the treatment guidance document for Clostridium difficile infection. Clin Microbiol Infect 2014.

7. Satokari R, Mattila E, Kainulainen V, Arkkila PE. Simple faecal preparation and efficacy of frozen inoculum in faecal microbiota transplantation for recurrent Clostridium difficile infection–an observational cohort study. Aliment Pharmacol Ther 2015

OP368 FAECAL MICROBIOTA TRANSFER IN IRRITABLE BOWEL SYNDROME – CLINICAL OUTCOMES OF A RANDOMISED PLACEBO-CONTROLLED TRIAL

S. Holster , D. Repsilber, R. J. Brummer, J. König

Nutrition-Gut-Brain Interactions Research Centre, School Of Medical Sciences, Örebro University, Örebro/Sweden

Contact E-mail Address: savanne.holster@oru.se

Introduction: Irritable Bowel Syndrome (IBS) is a gastrointestinal disorder characterised by chronic abdominal pain and altered bowel movements. Due to the potential involvement of the gut-brain-axis in the pathogenesis of IBS and the reported altered gut microbiota composition in IBS patients, Faecal Microbiota Transfer (FMT) is suggested as a potential effective treatment in IBS patients (1). So far, no placebo-controlled randomised clinical trials have been reported.

Aims & Methods: The aim of this study was to investigate the effect of FMT on the symptoms of IBS patients in a randomised, double-blinded placebo-controlled trial (clinicaltrials.gov NCT02092402 ). 16 IBS patients were included; 8 patients received donor faeces material (treatment) and 8 received their own faeces material (placebo) via colonoscopy into the caecum. Symptom scores were assessed by the IBS - Symptom Severity Score (IBS-SSS) and Gastrointestinal Symptom Rating Scale - IBS (GSRS-IBS) before and at several time points after intervention. Quality of life (QoL) was assessed by IBS-QoL and SF-36 before and after intervention. Anxiety and depression symptoms were assessed by the Hospital Anxiety and Depression scale (HADS). Differences in questionnaire scores from baseline as well as between treatment and placebo were assessed with one- and two-sample t-tests, respectively.

Results: The IBS-SSS scores of patients receiving donor faecal material significantly decreased 4 weeks and 8 weeks after FMT compared to baseline (mean difference: −61.6 ± 50.8, p < 0.01, and −63.3 ± 43.1, p < 0.01, respectively). No significant differences in the placebo group compared to baseline were observed, and neither between treatment and placebo. The GSRS-IBS total score significantly decreased for both the treatment and the placebo group 2 weeks after FMT (−0.46 ± 0.32 p < 0.01, and −0.71 ± 0.73 p < 0.05, respectively) and 4 weeks after FMT compared to baseline (−0.79 ± 0.57, p < 0.01, and −0.57 ± 0.63, p < 0.05, respectively). Again, no differences between the two intervention groups were observed. The IBS-QoL total score was significantly increased in the treatment but not in the placebo group at 8 weeks (10.0 ± 6.3, p < 0.01). Similar results were observed in three out of eight SF-36 subscores, especially in the general health subscore. This score was significantly increased in the treatment compared to the placebo group 8 weeks after FMT (11.8 ± 8.3 compared to −8.1 ± 11.3, p < 0.01). No significant differences were observed in the HADS scores, however, in the treatment group, the depression subscores showed a trend towards reduction 8 weeks after FMT compared to baseline (−1.4 ± 0.9, p = 0.08). This trend did not occur in the placebo group.

Conclusion: These data showed that there is a beneficial effect of FMT on symptom scores and quality of life in IBS patients. This effect is also observed in the placebo group, although to a lesser extent, indicating that placebo-controlled studies are essential in IBS patients. The bowel cleansing and the processing of the autologous faecal material might have contributed to the placebo effect. Further analysis on individual basis, separation into non-responders and responders as well as correlation with additional outcomes such as microbiota composition will provide more insight.

Disclosure of Interest: All authors have declared no conflicts of interest.

Reference

König J, Siebenhaar A, Hoegenauer C, Arkkila P, Nieuwdorp M, Norén T, Ponsioen C, Rosien U, Rossen N, Satokari R, Stallmach A, de Vos W, Keller J, Brummer RJ. Consensus report: Faecal microbiota transfer – clinical applications and procedures. Aliment Pharmacol Ther . 2017; 45(2): 222–239.

OP369 INTRODUCTION OF MOLECULAR STOOL TESTING FOR PATIENTS WITH GASTROENTERITIS IS ASSOCIATED WITH INCREASED INCIDENCE AND ANTIBIOTIC TREATMENT OF BLASTOCYSTIS AND DIENTAMOEBA

A. Schierenberg 1 , P. C.j. Bruijning-Verhagen 1 , M. D. Nipshagen 2 , J. Kusters 2 , S. Van Delft 3 , M.J.m. Bonten 2 , N.J. De Wit 1

1 Julius Center For Health Sciences And Primary Care, University Medical Center Utrecht, Utrecht/Netherlands

2 Department Of Medical Microbiology, University Medical Center Utrecht, Utrecht/Netherlands

3 Saltro Diagnostic Center, Utrecht/Netherlands

Contact E-mail Address: a.schierenberg@umcutrecht.nl

Introduction: Availability of molecular diagnostics demonstrated Blastocystis hominis and Dientamoeba fragilis to be highly prevalent in stool samples of patients with gastroenteritis (GE). However, their pathogenicity remains uncertain (1, 2) and treatment fails to shows significant clinical improvement (3–6).

Aims & Methods: Here we evaluate the effect of replacing conventional Triple Feces Test (TFT) with molecular Polymerase Chain Reaction (PCR) for the detection and subsequent antibiotic treatment of Blastocystis and Dientamoeba in primary care patients with GE. In the Utrecht General Practitioner (GP) Network primary care database (approx. 225 GPs), we identified patients diagnosed between 2010–2014 with GE (ICPC codes D11, D70 or D73) and collected the parasite stool testing results. We compared the incidence rates of Blastocystis and Dientamoeba in 2010/11 (identified through TFT testing) with 2013/14 (identified through PCR testing). Patient characteristics, comorbidities and new prescriptions for clioquinol and metronidazole were collected. Incidence rates were calculated per 1.000 person-years and before-after Rate Ratio’s (RR) including 95% confidence intervals (CI) estimated using the Exact Poisson test.

Results: The primary care cohort contained a total of 959.840 person-years in the four included study years. In total 24.218 GE cases (25 per 1000 person-years) were identified. Parasite stool testing in patients with GE was requested in 14.7% of the GE cases (n = 3115), 9.5% (n = 1042/10947) under TFT and 15.6% (n = 2073/13271) under PCR testing. Between groups tested for parasites with TFT and PCR, no significant differences were observed in age distribution and prevalence of comorbidities. After PCR introduction, parasite stool testing in the primary care cohort significantly increased from 2.5 to 4 per 1000 person-years (RR = 1.7, 95%CI 1.6–1.8), detection rate of Blastocystis increased from 0.01 to (0.9 RR = 78, 95%CI: 33–240) and of Dientamoeba from 0.05 to 0.9 per 1000 patient-years (RR = 20.5, 95%CI: 13–34). Similarly, the prescription rate for antibiotic treatment of single infections with either Blastocystis or Dientamoeba (without parasitic co-infection) increased from 0.02 to 0.6 per 1000 person-years for metronidazole (RR = 24, 95%CI: 13–48) and from 0 to 0.05 for clioquinol after introduction of PCR parasite testing.

Conclusion: The introduction of PCR parasite stool testing in primary care patients with GE is associated with a twofold increase in testing rate, a 20–78-fold increase in incidence rate of Blastocystis and Dientamoeba and a 24-fold increase in antibiotic prescription rate for Blastocystis and Dientamoeba infections. In the Netherlands, this translates to additional 10.356 antibiotic prescriptions yearly. Given the low pathogenic profile of these parasites, this increase in testing and treatment seems disproportional.

Disclosure of Interest: All authors have declared no conflicts of interest.

References

1. Stark D, Barratt J, Chan D, Ellis JT. Dientamoeba fragilis, the Neglected Trichomonad of the Human Bowel. Clin Microbiol Rev. American Society for Microbiology ; 2016 Jul; 29(3): 553–80.

2. Roberts T, Stark D, Harkness J, Ellis J. Update on the pathogenic potential and treatment options for Blastocystis sp. Gut Pathog . 2014 Jan; 6: 17.

3. Heyland K, Friedt M, Buehr P, Braegger CP. No advantage for antibiotic treatment over placebo in Blastocystis hominis-positive children with recurrent abdominal pain. J Pediatr Gastroenterol Nutr . 2012 May; 54(5): 677–9.

4. Nigro L, Larocca L, Massarelli L, Patamia I, Minniti S, Palermo F, et al. A placebo-controlled treatment trial of Blastocystis hominis infection with metronidazole. J Travel Med . 2003 Apr; 10(2): 128–30.

5. Roser D, Simonsen J, Stensvold CR, Olsen KE, Bytzer P, Nielsen H V., et al. Metronidazole therapy for treating dientamoebiasis in children is not associated with better clinical outcomes: a randomized, double-blinded and placebo-controlled clinical trial. Clin Infect Dis . 2014 Jun; 58(12): 1692–9.

6. Dinleyici EC, Eren M, Dogan N, Reyhanioglu S, Yargic ZA, Vandenplas Y. Clinical efficacy of Saccharomyces boulardii or metronidazole in symptomatic children with Blastocystis hominis infection. Parasitol Res . 2011 Mar; 108(3): 541–5.

WEDNESDAY, NOVEMBER 01, 201710:30-12:00

ABSTRACTS ON FIRE: DIAGNOSIS AND TREATMENT OF UPPER GI DISEASES IN CHILDREN AND ADULTS - HOTSPOT____________________

OP370 THE RESULTS OF ENDOSCOPIC AND SURGICAL TREATMENT FOR ACHALASIA IN ENGLAND BETWEEN 2005 AND 2016

P. Harvey 1 , B. Coupland 2 , J. Mytton 2 , F. Evison 2 , P. Patel 2 , N. Trudgill 1

1 Gastroenterology, Sandwell and West Birmingham NHS Trust, Birmingham/United Kingdom

2 Health Informatics, University Hospital Birmingham, Birmingham/United Kingdom

Contact E-mail Address: Philipharvey@nhs.net

Introduction: Achalasia is an uncommon condition characterised by failed relaxation of the lower oesophageal sphincter. Achalasia can be treated by botulinum toxin injection, pneumatic dilatation, Heller’s myotomy or per-oral endoscopic myotomy. The aim of this study is to examine long term outcomes of the major treatment modalities.

Aims & Methods: The Hospital Episode Statistics (HES) database includes diagnostic and procedural data for all hospital attendances in England. All subjects with an ICD10 code for achalasia and initial treatment between January 2006- September 2016 were grouped by coded initial treatment; injection, endoscopic dilatation or surgery. Procedural success was defined by time to further treatment, in the case of dilatations up to 3 procedures over 10 years were considered to not be a failure (Boeckxstaens GE, 2011). Adverse events were recorded per procedure and predictors sought by logistic regression.

Results: 7373 subjects were included of whom 3828 (51.9%) were male, mean age at diagnosis 59.6 years (SD 19.75). 435 initially received (5.90%) endoscopic injection, 4748 (64.4%) dilatation and 2190 (29.7%) underwent surgery. Perforation rate following dilatation was 1.62%. Charlson score was 1–4 in 8.74%, 10.00%, 10.87% and >4 in 13.33%, 12.64%, 3.01% of the injection, dilatation and surgical groups respectively. Mortality at 30 days was; 2.99%, 1.87%, 0%, for the injection, dilatation and surgical groups, respectively. Factors predicting mortality after dilation included; age quintiles 66–77 (OR 3.94, 95% CI 1.83–8.46, p < 0.001), >77 (7.93, 3.74–16.81, p < 0.001), Charlson co-morbidity score >4 (2.99, 2.21–4.04 p < 0.001), and previous surgical treatment (2.03, 1.09–3.78, p = 0.025). Only Charlson score >4 (2.55 (1.11–5.85 p < 0.028) predicted mortality in those receiving endoscopic injection. Durability for each group of single initial treatment at 9 years follow-up was 19.23%, 43.97%, 85.78% for injection, dilatation and surgical treatment respectively. The durability of up to 3 dilatations compared to single surgical treatment is reported in table 1.

Conclusion: The durability of surgical and pnuematic dilatation therapy for achalasia appears to be similar over up to 9 years. There was no mortality associated with surgery but 1.87% of subjects died within 30 days of dilatation. Older age and increased co-morbidity predicted mortality in subjects.

Disclosure of Interest: All authors have declared no conflicts of interest.

Reference

Boeckxstaens GE, Annese V, et al. (2011). Pneumatic Dilation versus Laparoscopic Heller’s Myotomy for Idiopathic Achalasia. NEJM , 1807–1816.

OP371 SPECTRUM OF HISTOPATHOLOGIC PATTERNS AMONG ACHALASIA SUBTYPES

N. Nakajima 1 , H. Sato 1 , K. Takahashi 1 , G. Hasegawa 2 , K. Mizuno 1 , S. Hashimoto 1 , Y. Sato 1 , S. Terai 1

1 Division Of Gastroenterology And Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata/Japan

2 Division Of Cellular And Molecular Pathology, Department Of Cellular Function, Graduate School of Medical and Dental Sciences, Niigata University, Niigata/Japan

Contact E-mail Address: naon_funky1@yahoo.co.jp

Introduction: High-resolution manometry (HRM) allowed us to plot all the pressure changes consecutively from the pharynx through esophago-gastric junction. Chicago classification criteria classifies achalasia into three types as follows, type I (classic achalasia), mean integrated relaxation pressure (IRP) >upper limit of normal (a common finding in all achalasia subtypes), 100% failed peristalsis; type II, no normal peristalsis, pan-esophageal pressurization with ≥20% of swallows; and type III, no normal peristalsis, preserved fragments of distal peristalsis or premature (spastic) contractions with ≥20% of swallows. Histopathology of muscularis externa in classic achalasia has been characterized previously, however, correlation between findings of HRM and histopathology is still unknown among achalasia subtypes. We aimed to correlate the results of HRM and histology of musclaris externa in achalasia subtypes.

Aims & Methods: Peroral esophageal muscle biopsy (POEM-b) was performed during peroral endoscopic myotomy, and the specimens of muscularis externa obtained in the lower esophagus were used for histopathological analysis. Immunohistochemical staining for c-kit and nNOS was performed to assess the number of interstitial cells of Cajal (ICCs) and oxidoreductase that synthesize nitric oxide (NO; one of non-adrenergic, non-cholinergic neurotransmitters). Hematoxylin Eosin and Azan-Mallory staining were used to assess fibrosis and atrophy. Full-layer normal slices from esophagectomies of patients with esophageal carcinoma were used as controls.

Results: Slides from 31 achalasia patients (Male: Female 14: 17, mean age 53.3 ± 16.2 years, type I: 19, type II: 8, type III: 4) were compared with 5 controls (Male 5, mean age 73.0 ± 5.4 years). The number of ICCs in type I and II was significantly lower than that of control, types I: 3.9 ± 1.5 cells/high power field [HPF] (p = 0.002), type II: 4.0 ± 2.1 cells/HPF (p = 0.01), control: 9.4 ± 2.8 cells/HPF. In type III achalasia, the number of ICCs were preserved: 8.2 ± 2.7 cells/HPF (p = 0.62). The number of nNOS-positive cells in type I achalasia: 3.3 ± 2.1 cells/HPF (p = 0.01) was significantly lower than that of control: 6.1 ± 1.3 cells/HPF. The number of nNOS-positive cells in type II: 3.3 ± 2.3 cells/HPF, and type III: 3.9 ± 2.6 cells/HPF was also lower without statistical significance (p = 0.09, 0.22). Severe fibrosis was observed in 28.4% cases of type I achalasia, although, no cases showed severe fibrosis in type II and III achalasia. Atrophy of muscularis externa was seen in 58.2% and 60.0% cases of type I and II achalasia, respectively, however, type III did not show such atrophy.

Conclusion: The present study showed type III achalasia had preserved number of ICCs, behind a loss of ICCs in type I and II. Histopathological patterns of fibrosis and atrophy were also different. Achalasia subtypes may have different pathophysiology. Key Points Significant reduction of nNOS immunoreactivity was observed in all achalasia subtypes, although type III achalasia showed preserved number of ICCs. Histopathological examination of the muscularis externa in achalasia subtypes may elucidate the pathological difference.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP372 THE TAUROLIDINE-CITRATE-HEPARIN CATHETER LOCK REDUCES CATHETER-RELATED BLOODSTREAM INFECTIONS IN INTESTINAL FAILURE PATIENTS RECEIVING HOME PARENTERAL SUPPORT: A RANDOMISED AND PLACEBO-CONTROLLED TRIAL

S. Tribler 1 , C. F. Brandt 1 , A. H. Petersen 2 , J. H. Petersen 2 , K. A. Fuglsang 1 , M. Staun 1 , P. Brøbech 1 , C. E. Moser 3 , P.B. Jeppesen 1

1 Department Of Medical Gastroenterology, University Hospital of Copenhagen, Rigshospitalet, Copenhagen/Denmark

2 Department Of Biostatistics, University of Copenhagen, Copenhagen/Denmark

3 Department Of Clinical Microbiology, University Hospital of Copenhagen, Rigshospitalet, Copenhagen/Denmark

Contact E-mail Address: stribler@gmail.com

Introduction: Patients with chronic intestinal failure (IF) are life-dependent on the provision of home parenteral support (HPS). The continuous presence of a central venous catheter (CVC) inflict a constant risk-of developing catheter-related bloodstream infections (CRBSIs) leading to health-impairment and high cost[1]. Antimicrobial lock-solutions containing taurolidine are promising in the prevention of CRBSI[2].

Aims & Methods: This study investigates efficacy and safety of the antimicrobial catheter lock solution, taurolidine-citrate-heparin, compared to heparin 100 IE/mL on the CRBSI occurrence. Forty-one adult high-risk HPS patients with a previous CRBSI rate of 2.4 episodes/1000 days (95% Poisson CL; 2.12–2.71) were randomised, in a double-blinded, placebo-controlled trial. An external stratified randomisation was performed according to age, gender and prior CRBSI rate. The primary endpoint was difference in mean CRBSI rate. Secondary endpoints were occurrence of other catheter-related complications, patient satisfaction, side-effects and a cost-benefit analysis. The maximum treatment period was two years or until the occurrence of a CRBSI or right-censoring because of central venous catheter (CVC) removal. Exact permutation tests were used to calculate p-values for the log-rank tests, thereby eliminating small-sample issues.

Results: Twenty patients received the taurolidine lock and 21 heparin 100 IE/mL, with 9622 and 6956 treatment days, respectively. Zero CRBSIs occurred in the taurolidine arm versus 7 in the heparin arm with a rate of 1.0/1000 days (0.4–2.07) ( P = 0.005). The CVC removal rates were 0.52 (0.17–1.21) and 1.72 (0.89- 3.0) in the taurolidine and heparin arm, respectively, tending to prolong CVC survival in the taurolidine arm ( P = 0.06). Local infection rates were 0.49 (0.13–1.25) and 1.58 (0.72–3.0) in the taurolidine and heparin arm, respectively ( P = 0.07). No difference in mechanical CVC complications was observed ( P = 0.4). Study lock treatment was associated with mild and tolerable side-effects (n = 13), as changed taste sensation or short-lasting oropharyngeal tingling sensation at lock instillation. High patient satisfaction was reported with no difference between the two groups ( P = 0.48). The costs per treatment year were lower in the taurolidine arm (2348 €) versus the heparin arm (6744 €) due to fewer admission days related to treatment of CVC-related complications ( P = 0.02).

Conclusion: In IF patients receiving HPS and with known high-risk of developing CRBSIs the antimicrobial catheter lock, taurolidine-citrate-heparin, demonstrates a clinically significant and cost-beneficial reduction of CRBSI occurrence compared to heparin. Taurolidine-containing lock solutions should be considered in high-risk patients on long-term parenteral support. www.ClinicalTrials.gov ( NCT01948245 ).

Disclosure of Interest: S. Tribler: TauroPharm GmbH, Jägerstr. 5a, D-97297 Waldbüttelbrunn, Germany, manufacturing blinded ampoules and study lock solutions. S. Tribler received a research grant. S. Tribler received honoraria from a multicentre study from Geistlich Pharma AG.

All other authors have declared no conflicts of interest.

References

1. Pironi L, Arends J, Bozzetti F, et al. ESPEN guidelines on chronic intestinal failure in adults. Clin Nutr 2016; 35: 247–307. doi:10.1016/j.clnu.2016.01.020

2. Bisseling TM, Willems MC, Versleijen MW, et al. Taurolidine lock is highly effective in preventing catheter-related bloodstream infections in patients on home parenteral nutrition: a heparin-controlled prospective trial. Clin Nutr 2010; 29: 464–8. doi:10.1016/j.clnu.2009.12.005

OP373 REDUCING FODMAP CONTENT IN THE BREASTFEEDING MOTHER’S DIET ALLEVIATES THE SYMPTOMS OF INFANTILE COLIC: A RANDOMISED CONTROLLED DOUBLE-BLIND CROSSOVER STUDY

M. Iacovou , P.R. Gibson, J. G. Muir

Department Of Gastroenterology, Monash University, Melbourne/Australia

Contact E-mail Address: marina.iacovou@monash.edu

Introduction: Infantile colic is the most common cause for presentation of mother/infant to emergency departments, but there are few evidence-based therapies. ‘Windy foods’ such as cabbage, onion and garlic are commonly reduced.

Aims & Methods: This study aimed to (1) compare via a randomised, double-blinded crossover study the effects of a low FODMAP diet with that of a typical Australian diet on infant crying-fussing durations of exclusively breastfed infants with colic; and (2) address potential mechanisms. Exclusively breastfeeding mothers and their typically-developing infant aged <9 weeks meeting the Wessel Criteria for infantile colic were recruited. After a 7-day qualifying baseline period, exclusively breastfeeding mothers were randomly assigned to either a 10-day low FODMAP or typical Australian (control) diet and then crossed over to the alternate diet. All meals were provided. Mothers completed a daily Baby Day Diary to measure the primary outcome infant crying-fussing durations and a daily dietary diary for each of the study diets. At baseline and on day 10 of each study diet, mothers completed a depression, anxiety and stress scale (DASS) questionnaire, and collected samples of breast milk for FODMAP analysis and infant faeces for calprotectin concentrations and pH.

Results: 14 mother-infant dyads were recruited and 13 dyads completed both arms. Compliance with diets was high (≥98%) except in one in the low FODMAP arm (70%). Compared to baseline mean (95% CI) crying fussing durations of 269 (224–314) min, there were greater reductions with the low FODMAP diet of 152 (102–210) min when compared to those with the control diet of 185 (135–234) min ( p = 0.05; two-way ANOVA; intention-to-treat). There was a mean (95% CI) reduction of 39 (75–3) min (8% change) following the control diet and 74 (107–40) min (35% change) following the low FODMAP diet p = 0.003; paired t test). There were no confounding effects of order of the diets or of infant age. Lactose concentration in breast milk was stable and other known dietary FODMAPs were not detected. Changes in infant faecal calprotectin were similar with each diet and faecal pH did not change. Although mean DASS scores were within normal range throughout the study, significant reduction in anxiety (0.9) and stress (9.4) compared to baseline (3.5, p = 0.009; 13.4, p = 0.004, respectively; 2-way ANOVA]), were seen with the control diet, but not with the low FODMAP diet.

Conclusion: Maternal low FODMAP diet was associated with a significant and clinically-relevant reduction in crying-fussing durations of infants with colic. This was not related to changes in maternal stress or anxiety or to gross changes in breast milk or infant faeces. Mechanisms by which changes in maternal diet affect infant behaviour require elucidation.

Disclosure of Interest: P.R. Gibson: The Department of Gastroenterology financially benefits from the sales of a digital application and booklets on the low FODMAP diet. P Gibson has published an educational/recipe book on the low FODMAP diet.

J.G. Muir: The Department of Gastroenterology financially benefits from the sales of a digital application and booklets on the low FODMAP diet.

All other authors have declared no conflicts of interest.

OP374 COMPARISON OF TWO STRATEGIES FOR PREVENTION OF REBLEEDING AMONG CHILDREN WITH PEPTIC ULCER

O. Belei 1 , L. Olariu 2 , C. Jinca 3 , T. Marcovici 2 , O. Marginean 2

1 Pharmacy Victor Babes, University Of Medicine And Pharmacy Victor Babes, Timisoara/Romania

2 First Pediatric Clinic, University of Medicine and Pharmacy Victor Babes, Timisoara/Romania

3 Third Pediatric Clinic, University of Medicine and Pharmacy Victor Babes, Timisoara/Romania

Contact E-mail Address: belei.oana@gmail.com

Introduction: For children with acute gastrointestinal bleeding the majority of studies are retrospective, focusing on therapeutic endoscopy. Previous studies performed on adult patients have demonstrated that both scheduled second-look endoscopy and high-dose continuous proton pomp inhibitors infusion are effective in preventing peptic ulcer rebleeding.

Aims & Methods: The aim of this study was to compare the two strategies of scheduled second-look endoscopy plus bolus esomeprazole with high-dose continuous esomeprazole infusion for the prevention of ulcer rebleeding after endoscopic haemostasis in children. Consecutive children who underwent endoscopic treatment for bleeding peptic ulcers were randomized to two treatment groups following haemostasis. They were randomized either to undergo a scheduled second-look endoscopy with appropriate therapy in case of bleeding stigmata within 12–24 hours of the initial endoscopy plus intravenous esomeprazole bolus 0.5 mg/kg (maximum 40 mg) every 12 hours for 72 hours (first group) or to receive high-dose continuous esomeprazole infusion (1 mg/kg intravenous bolus followed by 0.1 mg/kg/hour continuous infusion for 72 hours) without endoscopic reassessment unless for rebleeding (the second group).

Results: 63 children were randomized to second-look endoscopy group and 64 to esomeprazole continuous infusion group. Rebleeding occurred within 14 days in 4 patients (6.3%) in the first group and in 3 patients (4.6%) in the second group (p = 0.7).

Conclusion: Pharmaceutical approach by high-dose continuous esomeprazole infusion in children after initial endoscopic haemostasis has similar efficacy compared to second-look endoscopy and bolus esomeprazole administration in preventing peptic ulcer rebleeding. Thus, the discomfort of a second endoscopy in children can be avoided, keeping this recommendation only for high-risk selected cases.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP375 EXPLOITING THE MECHANISM OF GASTROPROTECTION BY ADIPONECTIN IN MICE FED A HIGH FAT DIET AND CHALLENGED BY ETHANOL. RELEVANCE TO ETHANOL CONSUMPTION IN HUMAN OBESITY

A. Szlachcic , J. Majka, M. Magierowski, D. Wojcik, M. Surmiak, K. Magierowska, S. Kwiecien, G. Ginter, T. Brzozowski

Physiology, Jagiellonian University Medical College, Cracow/Poland

Contact E-mail Address: mpbrzozo@cyf-kr.edu.pl

Introduction: Hormones involved in the regulation of brain-gut axis and the adipokines released from adipose tissue interact to control metabolic pathways and the integrity of the gastric mucosa. The impairment in the brain-gut-adipose axis can lead to metabolic disorders including obesity which may weaken the gastric mucosal integrity and mucosal defense. The possiblity that visceral obesity can enhance the gastric mucosal susceptibility to necrotizing substances such as ethanol has not been explored. Adiponectin, an adipokine predominantly secreted from adipocytes has been reported to play general protective role against chronic alcohol consumption in humans. Adiponectin exerts anti-inflammatory properties in addition to various biological functions, and its plasma concentrations are reduced in obese subjects. Although lipid peroxidation and oxidative stress are considered as critical events for ethanol-induced gastric damage, the effect of adiponectin on ethanol-induced gastric damage, an increase in lipid peroxidation and the parameters of oxidative stress is not clearly understood.

Aims & Methods: This study was designed to determine the effect of single administration of ethanol in mice that were fed a standard diet (SD) and a high fat diet (HFD) for a period of 90 days and then the SD- and HFD-fed mice were pretreated with vehicle (saline) or adiponectin (0.1–25 μg/kg i.p.) 30 min prior to exposure with 75% ethanol (0.5 ml i.g.). Thirty min after the ethanol instillation, the macroscopic and microscopic gastric lesions was determined by lesion index and histology, respectively, the gastric blood flow (GBF) was assessed by H 2 -gas clearance method, the blood was withdrawn for the measurement of plasma adiponectin- and leptin levels. Gastric mucosal biopsy specimens were collected for MPO activity, the malondialdehyde (MDA) concentration as an index of oxygen-radical lipid peroxidation, the activity of superoxide dismutase (SOD), glutathione peroxidase (GPx) and reduced glutathione (GSH) were analyzed in the gastric mucosa. The expression of mRNA for cNOS and proinflammatory factors HIF-1α, iNOS, IL-1β, TNF-α and IL-6 mRNAs in the gastric mucosa and the plasma levels of IL-1β, TNF-α and IL-6 were analyzed by RT-PCR and Luminex, respectively.

Results: Ethanol caused mucosal damage and significantly decreased GBF and raised MDA content in mice fed SD but the lesion index, the fall in GBF and an increase in MDA were exacerbated in those fed HFD. Plasma adiponectin was significantly reduced in HFD mice vs. SD fed animals and this effect was potentiated by application of ethanol in mice fed HFD. Pretreatment with adiponectin (ED 50 = 5 μg/kg i.p.) dose-dependently inhibited macroscopic and histological gastric lesions induced by ethanol and significantly increased GBF as compared to vehicle-controls. Adiponectin (5 μg/kg i.p.) significantly reduced MPO activity, MDA content and significantly raised SOD, GPx activity and GSH content as compared with the respective values in vehicle-pretreated mice fed HFD. Pretreatment with adiponectin significantly diminished the increased expression of HIF-1α, iNOS, IL-1β, TNF-α and IL-6 in vehicle pretreated HFD mice exposed to ethanol.

Conclusion: 1) The gastric mucosa of obese animals is more susceptible to ethanol damage as compared with those fed a standard diet, 2) the pretreatment with adiponectin protects the gastric mucosa against ethanol-induced gastric lesions suggesting that the underlying mechanism of this protection might be linked to the adiponectin-induced increase in the gastric blood flow, the inhibition of lipid peroxidation, the attenuation of oxidative stress and antiinflammatory properties of this peptide, and 3) our data imply that adiponectin may be useful in preventing gastric adverse effects associated with alcohol consumption in obesity.

Disclosure of Interest: All authors have declared no conflicts of interest.

OP376 PAN-EUROPEAN REGISTRY ON H. PYLORI MANAGEMENT (HP-EUREG): INTERIM ANALYSIS OF 4417 SECOND-LINE TREATMENTS

A.G. Mcnicholl 1 , O.P. Nyssen 1 , D. S. Bordin 2 , B. Tepeš 3 , M.Á. Perez Aisa 4 , B. Vaira 5 , M. Caldas Álvarez 6 , L. Bujanda Fernández De Piérola 7 , M. Castro Fernández 8 , F. Lerang 9 , M. Leja 10 , L. Rodrigo 11 , T. Rokkas 12 , L. Kupcinskas 13 , J. Perez-Lasala 14 , L. Jonaitis 13 , O. Shvets 15 , A. Gasbarrini 16 , H. Şimşek 17 , A. Axon 18 , G.M. Buzás 19 , J.C.L. Machado 20 , Y. Niv 21 , L. Boyanova 22 , A. Goldis 23 , V. Lamy 24 , M. Katicic 25 , K. Przytulski 26 , C. Beglinger 27 , M. Venerito 28 , P. Bytzer 29 , L. Capelle 30 , T. Milosavljevic 31 , L. Veijola 32 , J. Molina Infante 33 , L. Vologzhanina 34 , G. Fadeenko 35 , I. Ariño 36 , G. Fiorini 5 , M. Ramas 1 , M. Garcia Donday 1 , F. Megraud 37 , C. O'Morain 38 , J. P. Gisbert 1

1 Gastroenterology, H La Princesa, IIS-IP and Ciberehd, Madrid/Spain

2 Department Of Pancreatic, Biliary And Upper Gi Diseases, Moscow Clinical Scientific Center, Moscow/Russian Federation

3 Gastroenterology, AM DC Rogaska, Rogaska Slatina/Slovenia

4 Digestive, Agencia Sanitaria Costa del Sol, Marbella/Spain

5 Gastroenterology, S. Orsola Malpighi Hospital, Bologna/Italy

6 Gastroenterology, H La Princesa, Madrid/Spain

7 Gastroenterology, Hospital Donostia/Instituto Biodonostia, CIBERehd. Universidad del País Vasco (UPV/EHU), San Sebastian/Spain

8 Digestive Unit, Hospital de Valme, Sevilla/Spain

9 Medical, Central Hospital of Ostfold, Frdedrikstad/Norway

10 Institute For Clinical And Preventive Medicine, University of Latvia, Riga/Latvia

11 Gastroenterology, Hospital Universitario Central de Asturias, Oviedo/Spain

12 Gastroenterology, Henry Dunant Hospital, Athens/Greece

13 Gastroenterology, Lithuanian University of Health Sciences, Kaunas/Lithuania

14 Digestive, HM Sanchinarro, Madrid/Spain

15 Internal Medicine, Internal Diseases Department No. 1 National Medical University named after O.O. Bogomolets, Kyiv/Ukraine

16 Fondazione Policlinico A. Gemelli, Rome/Italy

17 Internal Medicine/gastroenterology, Hacettepe University Faculty of Medicine, Ankara/Turkey

18 Gastroenterology, University of Leeds, Leeds/United Kingdom

19 Gastroenterology, Ferencváros Policlinic, Budapest/Hungary

20 Gastroenterology, Instituto de Investigação e Inovação em Saúde, Universidade do Porto, and Ipatimup - Institute of Molecular Pathology and Immunology of the University of Porto, Porto/Portugal

21 Gastroenterology, Rabin Medical Center, Tel Aviv University, Petach Tikva/Israel

22 Medical Microbiology, Medical University of Sofia, Sophia/Bulgaria

23 Gastroenterology, Timisoara Hospital, Timisoara/Romania

24 Gastroenterology, Hepatology & Nutrition, CHU Charleroi, Charleroi/Belgium

25 Gastroenterology, University Hospital Merkur Polyclinic Nola, Zagreb/Croatia

26 Gastroenterology, Medical Centre for Postgraduate Education, Warszawa/Poland

27 Gastroenterology, Hospital de Basel, Basel/Switzerland

28 Gastroenterology Hepatology And Infectious Diseases, Otto-von-Guericke University Hospital, Magdeburg/Germany

29 Medicine, Zealand University Hospital, Køge/Denmark

30 Gastroenterology And Hepatology, Erasmus MC University, Rotterdam/Netherlands

31 Medical, Clinical Center of Serbia Clinic for Gastroenterology and hepatology, University of Belgrade, Belgrade/Serbia

32 Internal Medicine, Herttoniemi Hospital, Helsinki/Finland

33 Gastroenterology, Hospital San Pedro de Alcantara and CIBERehd, Caceres/Spain

34 Gastroenterology, Gastrocentr, Perm, Perm/Russian Federation

35 Gastroenterology, Digestive Ukrainian Academy of Medical Sciences, Kyiv/Ukraine

36 Gastroenterology, Hospital ClÍnico Universitario Lozano Blesa, Zaragoza/Spain

37 Gastroenterology, Laboratoire de Bactériologie, Hôpital Pellegrin, Bordeaux/France

38 Clinical Medicine, Trinity College Dublin, Dublin/Ireland

Contact E-mail Address: opnyssen@gmail.com

Introduction: After a failed eradication attempt, H. pylori treatment’s efficacy is compromised due to the selection or acquisition of resistant strains.

Aims & Methods: We aimed to evaluate the efficacy of second-line treatments in Europe. A systematic prospective registry of the clinical practice of European gastroenterologists regarding H. pylori infection and treatment (30 countries and 250 recruiting investigators). A local coordinator was selected from each country with more than 10 H. pylori references on PubMed. Each coordinator selected a representative group of recruiting investigators from its country (250 so far). An e-CRF was created on AEG-REDCap to systematically register all adult patients infected with H. pylori . Variables included : Patient’s demographics, previous eradication attempts, prescribed eradication treatment, adverse events, and outcomes (cure rates, compliance, follow up, etc.). Data extraction: All cases with treatment failure after just one eradication attempt.

Results: Up to now, 4417 second-line treatments have been recorded. Second-line patients had a mean age of 52 years. 3.5% had penicillin allergy. 57% of indications were dyspepsia and 16% gastroduodenal ulcer. Second-line use and efficacy per antibiotic combination is shown in the table.

Conclusion: Second-line triple therapies generally provide low eradication rates except when prescribing moxifloxacin for 14 days. Bismuth-containing quadruple therapies seem to provide higher efficacy, especially the combination of bismuth with a PPI, levofloxacin and amoxicillin.

Disclosure of Interest: A.G. McNicholl: Dr. McNicholl has received retribution from Allergan for formative actions.

D.S. Bordin: Dr. Bordin has served as lecturer for Astellas, AstraZeneca, KRKA and Abbott.

Perez Aisa: Dr. Perez-Aísa has received retribution from Allergan and Mylan for formative actions.

M. Castro Fernández: Dr. Castro-Fernandez has received retribution from Allergan for formative actions.

P. Bytzer: Dr. Bytzer has served as speaker, consultant and advisory member for or has received research funding from Almirall, Allergan and Reckitt Benckiser.

J. Molina Infante: Dr. Molina-Infante has served as a consultant for Casen Recordati and has received retribution from Allergan for formative actions.

J.P. Gisbert: Dr. Gisbert has served as speaker, consultant and advisory member for or has received research funding from Almirall, Nycomed, AstraZeneca, Casen Recordati, and Allergan.

All other authors have declared no conflicts of interest.

OP377 CAPSULE ENDOSCOPY IN INTESTINAL LYMPHAGIECTASIA: A NOVEL ENDOSCOPIC CLASSIFICATION AND ITS CLINICAL CORRELATION

K. Liu , W. Shen, J. Wu

Beijing Shijitan Hospital, Capital Medical University, Beijing/China

Contact E-mail Address: kuikuimd@126.com

Introduction: Intestinal lymphagiectasia (IL) is a rare protein-losing enteropathy caused by disorder of the intestinal lymphatics, presenting as hypoproteinemia, bilateral lower limb edema, and ascites. Accoding to the etiology, this disease can be classified into primary or secondary IL. Endoscopy is the main modality for diagnosing IL, however, conventional esophagogastroduodenoscopy and colonoscopy, even ballon-assisted enteroscopy could not visualize the whole intestine. Capsule endoscopy, being a novel device introduced in recent decades, could be used to explore the whole segment of small bowel, is a suitable option for evaluation of intestinal lymphagiectasia.

Aims & Methods: Although Capsule Endoscopy (CE) is useful in diagnosis of intestinal lymphagiectasia (IL) systemic analysis of endoscopic and clinical characteristics remains unavailable. Between March 2011 and July 2015, patients clinically suspected IL underwent capsule endoscopy in our center were included in our study. Clinical data retrieved included age, sex, past medical history, presenting symptoms, laboratory examination, radiological findings, and medical management. The diagnosis of IL was confirmed by the presence of typical endoscopic manifestations or pathological findings in biopsy or surgical specimens. All patients followed a clear liquid diet for 24 h plus 12 h fasting prior to CE (PillCam® SB2, Given® Imaging Ltd. Yoqneam, Israel). PEG or oral electrolyte solution (for patients younger than 10 years old) was used for bowel preparation.

Results: A total of 54 patients with median age of 24 (4–56) years were included. 42 cases were diagnosed as primary IL. Typical endoscopic characteristics included scattering, grouping or diffuse white-yellow spotty, patchy or scaly lymphagiectasia. Untypical characteristics included enlarged, swollen or extremely dilated villi, possibly “white-veil-like” or “pavement-like” appearance, and “blue bleb”(dilated vein) can be noted sometimes. The endoscopic classification was established as follows: type I, alteration mostly restricted to untypical abnormal villi; type II, scattering typical lymphagiectasia, usually involving one or two of all three third bowel segment; type III, diffuse typical patchy or scaly lymphagiectasia, mostly involving whole bowel. According to this criteria, 17(31.5%), 24(44.4%) and 13 (24.1%) cases were classified into type I, II and III respectively. The patients falling into type III are all diagnosed as primary IL and the average age was significantly younger than type I and type II. As for complications, a total of 16 cases of lymph leakage, 2 cases of stenosis (both type I) and 5 cases of bleeding were noted. Lymphatic leakage was detected both by capsule endoscopy and bowel albumin scintigraphy in 10 cases and the judging of leaking location were all consistent using these two modalities, but CE provided more precise information than scintigraphy.

Conclusion: Providing comprehensive evaluation of whole small bowel, CE may play a great role in diagnosis, management and surveillance of IL. Endoscopic classification of IL may correlate with specific clinical outcome.

Disclosure of Interest: All authors have declared no conflicts of interest.

References

1. Vignes S, Bellanger J. Primary intestinal lymphangiectasia (Waldmann’s disease). Orphanet J Rare Dis 2008, 3: 5.

2. Lai Y, Yu T, Qiao XY, Zhao LN, Chen QK. Primary intestinal lymphangiectasia diagnosed by double-balloon enteroscopy and treated by medium-chain triglycerides: a casereport. J Med Case Rep 2013, 7:19.

3. Laharie D, Degenne V, Laharie H, et al. Remission of protein-losing enteropathy after nodal lymphoma treatment in a patient with primary intestinal lymphangiectasis. Eur J Gastroenterol Hepatol , 2005, 17:1417–1419.

OP378 LONG-TERM OUTCOMES OF PATIENTS WITH EARLY GASTRIC CANCER DIAGNOSED AS PATHOLOGICAL EXTRA-INDICATED LESION AFTER ENDOSCOPIC SUBMUCOSAL DISSECTION

K. Ishido 1 , T. Yano 1 , S. Tanabe 2 , T. Wada 1 , M. Azuma 1 , C. Katada 1 , W. Koizumi 1

1 Gastroenterology, Kitasato University School of Medicine, Sagamihara/Japan

2 Research And Development Center For New Frontier, Kitasato University School of Medicine, Sagamihara/Japan

Contact E-mail Address: k.ishido@kitasato-u.ac.jp

Introduction: Gastric cancer treatment guidelines recommend additional surgery as the standard treatment of the extra-indicated lesions for endoscopic submucosal dissection (ESD). However, the incidence of lymph-node metastasis is low in most patients.

Aims & Methods: The study group comprised 231 patients (231 lesions) who underwent ESD for early gastric cancer in our hospital from September 2002 through March 2015 and were histopathologically confirmed the extra-indicated lesions for ESD. Patients with a gastric tube or remnant stomach were excluded. The patients were divided into an additional operation group and a follow-up group, and long-term outcomes were studied retrospectively. Risk factors for metastasis and recurrence were also studied (capture rate, 98.7%).

Results: The median follow-up was 48 months. There were 174 men and 57 women with a median age of 72 years. The additional operation group comprised 118 patients, and the follow-up group comprised 113 patients. The rates of 5-year cause-specific survival and 5-year overall survival were significantly higher in the additional operation group (100% and 96.0%, respectively) than in the follow-up group (92.6% and 73.3%, respectively; both p = 0.010). In the follow-up group, 5 patients (4.4%) died of gastric cancer (p = 0.021). Among elderly patients 75 years or older, long-term outcomes did not differ significantly between the groups. Surgery was avoided because of underlying disease in 88 patients (77.9%) in the follow-up group (p < 0.001). Sixteen patients (12 in the additional operation group and 4 in the follow-up group) had metastasis or recurrence, and the presence of lymphatic involvement was an independent risk factor for metastasis, recurrence, or both (p = 0.003; odds ratio, 10.594; 95% confidence interval, 2.294 to 48.927).

Conclusion: In patients with early gastric cancer who were confirmed the extra-indicated lesions for ESD, additional surgery should be aggressively performed if the patient can tolerate such treatment. In elderly patients aged 75 years or older and patients with serious underlying diseases, follow-up observation was suggested to be one option in patients who give informed consent after receiving an explanation of the risk of recurrence.

Disclosure of Interest: All authors have declared no conflicts of interest.

Supplementary Material

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Associated Data

Supplementary Materials

Supplementary material