Текст сохранён. Часть иллюстраций пока доступна только в первоисточнике; загрузка будет проверена повторно.
Introduction
Cancer patients need multimodal therapies to treat their disease increasingly. In particular, drug treatment, as chemotherapy, immunotherapy, or various associations between them are commonly used to increase efficacy. However, the use of drugs predisposes a percentage of patients to develop toxicity in multiple organs and systems [ 1 ]. They can show themselves as mild or with severe symptoms, often not recognizable by clinical examination alone. Antitumor drug therapy is nowadays based on the use of different agents with specific actions; we can distinguish several categories mainly: standard chemotherapy, molecularly targeted therapies, immunotherapy. Principle chemotherapy drugs mechanism of action is cell replication inhibition, rapidly proliferating cells especially. They usually interfere with DNA and RNA synthesis through different tools depending by the drug used: cisplatin has a DNA intercalating action, fluorouracil is an antimetabolite, vincristine a mitotic spindle inhibitor, cyclophosphamide is an alkylating agent, gemcitabine an antimetabolite [ 2 ]. Sometimes, targeted therapies induced cell apoptosis through modifying intracellular proteins or tumor growth pathways inhibition such as neoangiogenesis [ 3 ]. Immunotherapy is another tumor therapy strategy based on antitumor immunity activation trough agents as CTLA4 inhibitors (ipilimumab) or PD-1/PD-L1 inhibitors as nivolumab [ 4 ]. If, on the one hand, all these agents inhibit tumor growth, on the other, they can cause various degrees toxicity in several organs, due to their specific mechanism of action. A representative scheme was reported by Viswanathan et al. [ 3 ]. Particularly interesting are bowel toxicity, which can be clinically heterogeneous (pain, nausea, diarrhea, enterocolitis, pneumocolitis), up to severe consequences, such as ischemia, a rare occurrence. However, this event can occur both in vessels that supply intestine and in submucosa microvessels. This thesis is supported by proof that even disorders such as enteritis or perforation recognize a vascular origin [ 5 ]; as reported in two series, bevacizumab-induced perforation is caused by interference with bowel microvasculature, resulting in onset vessels ischemia and thrombosis in 0.9–4.4% of cases [ 6 , 7 ]. We report drug-related intestinal vascular damage main characteristics, showing the radiological aspect of these alterations.
Intestinal toxicity: which anticancer drugs cause it?
Common side effects during chemotherapy are observed in gastrointestinal system and consists of mucosal damage mainly, which can manifest itself with various symptoms [ 8 ]. At the cellular level, toxicity is due to apoptosis mostly induced by involved drug-specific mechanisms of small intestine crypts cells [ 9 , 10 ]. Although nausea and vomiting are the most frequent gastrointestinal symptoms for many chemotherapy regimens, their onset is not directly related to the intestinal mucosa damage, but to stimulation of serotonergic receptors of the chemoreceptor trigger zone in the fourth cerebral ventricle [ 11 , 12 ]. Diarrhea is another common chemotherapy toxic effect; the pathophysiology of chemotherapy-induced diarrhea is not well understood and is likely multifactorial [ 1 ]. Chemotherapic agents most involved in diarrhea onset are 5-fluorouracil and irinotecan [ 13 , 14 ]. SN-38, an active metabolite of irinotecan, induces direct mucosal damage as a mechanism of delayed diarrhea [ 15 ]. The mitotic phase blocking of intestinal crypt cells, as well as villous destruction and reabsorption surface reduction, can be involved in 5-FU induced diarrhea [ 16 ]. Other drugs, as vinca alkaloids, are responsible for bowel dilatation frequently; its pathophysiology can be caused by autonomic nervous system induced-neurotoxicity [ 17 ]. Likewise, docetaxel can lead to bowel damage; sporadic but severe ischemic colitis docetaxel-related cases are reported in the literature [ 18 , 19 ]. Many molecular target drugs are responsible for intestinal toxicity, some of the critical severity: first bevacizumab, related to bowel pneumatosis, bleeding, and perforation [ 20 ]. Pneumatosis can also be caused by cisplatin and irinotecan, and it referred to transmural ischemia, in the presence of portomesenteric venous gas mostly [ 21 , 22 ]. This condition is uncommon, but it is related to mortality up to 75% of cases [ 23 ]. Anti-EGFR agents, as erlotinib or cetuximab, frequently cause enteritis for direct damage to the intestinal epithelium [ 24 ]. The most common side effect of anti-EGFR and anti-VEGF agents is diarrhea, which appears in up to 40% of patients who underwent to these treatment [ 25 , 26 ]. Immune checkpoint inhibitors are related to a series of side effects termed immune-related adverse events (irAEs). Immunotherapy-related enterocolitis has features similar to graft-versus-host disease [ 27 ], presenting in different patterns (diffuse colitis, segmental colitis associated with diverticulitis and isolated recto-sigmoid colitis) related to the appearance of diarrhea (44%), colitis (18%), bowel perforation (< 1%) [ 28 , 29 ]. Although these drugs have a good tolerability profile, cases of bowel perforations caused by BRAF and MEK inhibitors/anti-CTLA-4 and anti-PD-1 antibody association are reported in the literature [ 30 ].
Indirect bowel damage: vessel toxicity drugs-related
Many anticancer drugs can induce vascular toxicity, venous, and more rarely arterial system. Great and microvessels may be affected by thrombosis and thromboembolism; if bowel vessels are involved, they can give rise to critical ischemic events, which lead to necrosis and perforation. Thrombotic and thromboembolism events pathogenesis is induced by drug-related endothelial damage, with consequent basement membrane exposure and abnormal coagulation cascade activation [ 31 , 32 ]. Platinum-based chemotherapy regimens are responsible for higher thromboembolism risk, but not other vascular events; this risk is superimposable between cisplatin and carboplatin [ 33 ]. Although gemcitabine prothrombotic mechanisms are still mostly unknown, it is responsible for increased thrombotic risk both in small peripheral vessels and in large draining veins of parenchymal organs [ 34 ]. Coagulation cascade hyperactivation as also been observed in several case series where thrombotic risk increases in patients undergoing cisplatin/gemcitabine association have been evaluated [ 35 , 36 ]. Many molecular target agents can increase thrombotic risk: thalidomide, an immunomodulatory and antiangiogenetic drug commonly used in multiple myeloma therapy, has shown thromboembolic events raise [ 36 , 37 ]; anti-VEGFR and anti-VEGF targeted agents as bevacizumab, sorafenib and sunitinib are responsible to arterial thrombotic events increase, because of their role in endothelial integrity regulation probably [ 31 ]. Their correlation with arterial thromboembolic events is shown in several case series, where mesenteric artery thromboembolism is described [ 38 – 40 ]. Thromboembolisms and vasculitis caused by immune checkpoint regulators such as anti-PDL1 seem to be rare events [ 41 ]; however, in described cases in the literature, their onset is related to very severe presentations [ 42 – 44 ].
Imaging modalities and features
Clinical features of acute ischemic bowel is very changeable: acute abdominal pain could be determined by many different causes (pancreatitis, coeliac disease, duodenal ulcers, irritable bowel syndrome) and the ‘classic triad’ of chronic mesenteric ischemia (postprandial pain, weight loss and an abdominal bruit) is rarely found in clinical practice [ 45 ].
Radiological imaging is crucial in the emergency setting. It is very difficult to make differential diagnosis only through physical examination; as explained by Terlouw et al., at least upper gastrointestinal endoscopy and abdominal imaging (computed tomography/magnetic resonance imaging) must be executed if there is a suspicious of chronic mesenteric ischemia. Colonoscopy should be performed in patients with diarrhea.
In the emergency setting the baseline of radiological examination in patient with acute abdominal pain include abdominal ultrasonography (US) and/or abdominal plain radiography. US allows to detect some differential diagnosis of acute abdominal pain such as cholecystitis, pancreatitis, hernias. Colour and Power Doppler imaging therefore could be useful to study bowel’s vascularity: an increase of vascularity of the bowel wall and adjacent mesentery is a sign of hyperemia and inflammatory bowel disease. On the contrary, a reduction of vascularity is a specific sign of ischemia [ 46 ]. Duplex ultrasound might be used for screening to evaluate an eventual significant proximal mesenteric artery stenosis: in this case, an additional CTA or MRA imaging is mandatory [ 45 ]. Plain radiography might present some warning signs of ischaemic colitis disease such as “thumbprinting”, which appears as rounded opacities near the sides of a gas-filled distended colon, loss of haustration and dilation of the colonic lumen; obviously is also possible to discover signs of advanced pathology such as intramural gas “pneumatosis linearis”, portal venous gas, megacolon and pneumoperitoneum [ 47 ].
According to Mazzei et al., MRI could play an important role not only for follow up but also for the diagnosis of acute ischemic colitis without using contrast medium through combined T2-weighted steady state free procession sequences on coronal plane and T2W fast-recovery fast-spin echo sequences both in coronal and axial plane. For example, colonic wall thickening is typical both on CT and MR in case of severe colonic: especially when this sign has segmental distribution is quite specific for ischemic colitis compared to inflammatory colitis [ 48 ]. MRI is useful especially in patients with impaired renal function or in patient with previous allergic reactions to iodine contrast agents avoiding radiation exposure. However, compared to CT, MRI shows some difficulties when performed in the emergency setting because of its long time of execution even if the spreading of newer performing scanners could overcome this problem in future.
Currently, computed tomography (CT) represents the primary imaging technique in imaging bowel injuries with numerous advantages in comparison with other diagnostic modalities [ 49 ]. In particular it may diagnose bowel injuries especially in the emergency setting, thanks to its panoramic evaluation of abdominal organs, vessels, and intestinal lumen and wall; CT can also determine the eventual presence of inflammatory collections [ 50 ].
CT findings
Mainly, multidetector CT represents the gold standard for the intestinal study because, in few minutes, it can provide a complete study of the abdomen also in non-cooperating patients and can avoid angiography through a multiphase study using contrast agents.
First, we know that oncologic patients are almost exclusively examined by CT to detect their “tumor burden” so it is possible to discover intestinal pathological features in asymptomatic patients during the planned follow-up; it is known that 70.8% of cancer patients with pneumatosis and/or bowel perforation are asymptomatic [ 49 ]. If symptomatic, it is essential to keep in mind that the principal symptom of bowel pathology and ischemia is just represented by abdominal pain, followed by diarrhoea and vomit. These symptoms are incredibly nonspecific, and they could be related to predicted effects that can appear near the administration of chemotherapy drugs and regimens. Gastrointestinal pathological processes (diverticulitis, appendicitis, enteritis, colitis, intestinal occlusions) should be recognized as soon as possible in the emergency setting because they may lead to bowel ischemia, necrosis, and perforation; dissimilar chronic mesenteric ischemia, surgery remains standard treatment of acute mesenteric ischemia. CT features of bowel ischemia and necrosis are almost similar in spite of the primary cause [ 50 ]. First is necessary to establish the correct etiology among acute arterial mesenteric ischemia (AAMI), acute venous mesenteric ischemia (AVMI), non-occlusive mesenteric ischemia (NOMI), ischemia/reperfusion injury (I/R), ischemic colitis (ischemic and reperfusive form) [ 51 – 56 ]. Mesenteric arterial occlusion or mesenteric venous thrombosis occlusion configure an arterial or venous ischemic injury, respectively. In the acute arterial mesenteric setting, the damaged small bowel loops are contracted in consequence of spastic reflex ileus, and the intestinal wall presents absence/weak enhancement. At an advanced phase, bowel wall thins, show a “paper-thin” aspect, [ 50 , 51 ]; intestinal loops appear only gas-filled and dilated (hypotonic ileus), and peritoneal free fluid may be discovered. Air–fluid levels occur when hypotonic reflex ileus evolves into paralytic ileus [ 52 ]. The most specific feature of bowel ischemia would seem to be the absence or deficient enhancement of the bowel wall, a CT finding today more easily demonstrable using the dual energy technique (DECT) [ 56 ]. Likewise, intramural gas (intestinal pneumatosis) is a particular CT feature, but it is uncommon; intramural gas is due to luminal gas penetration into the bowel wall through the damaged mucosa [ 54 , 55 ]. Another unusual CT feature of bowel ischemia is mesenteric or portal venous gas and depicts the extension of intramural gas into the mesenteric venous system. However, both of these CT signs, when present, are indicative of an advanced phase of ischemia so they should be considered as makers of severity.
Free intraperitoneal gas means perforation of an infarcted bowel segment [ 57 ]. In the venous ischemic setting (AVMI) is possible to discover focal or diffuse wall thickening bowel with or without evidence of the “target sign” and heightened enhancement of the thickened bowel wall: this event is common but nonspecific for bowel ischemia (Fig. 1 ). Venous congestion caused by blood stasis can be highlighted as mesenteric veins engorgement, and the mesenteric fat may show increased values of attenuation because of mesenteric edema [ 56 ]. On unenhanced CT scans, presence of hypo-density of bowel loops wall is evocative of intramural edema; meanwhile, hyper-density could reveal mesenteric veins engorgement, congestion and hemorrhage of bowel loops wall. NOMI includes the causes of mesenteric ischemia without a sign of occlusion of the mesenteric artery or vein in the region of bowel necrosis [ 58 – 62 ]. In the small intestine, CT and surgical findings might be similar to AAMI ones only in hyperacute settings; NOMI could be followed indeed by a reperfusion phenomena that tries to overcome the ischaemic injury caused by hypoperfusion [ 58 ]. In this case, bowel wall thickening is determined by the presence of oedema, vascular congestion and granulation tissue that are typical features of any acute inflammatory process. On unenhanced CT phase is possible to detect bowel wall thickening and its high attenuation probably due to the intramural haemorrhage and haemorrhagic infarction resulting from vascular congestion [ 63 ]. Reperfusion event determines also a regional increase of mesenteric fat density (misty mesentery) with or without the presence of mesenteric fluid [ 58 ]. DECT might help the differential diagnosis between ischemic and nonischemic intestinal segments using iodine maps and 40-keV monoenergetic images, respectively [ 56 ]; particularly, it is useful for the detection of reperfusion setting. Reduction in bowel wall attenuation on DECT is almost indicative for arterial occlusive ischemia (AAMI or NOMI) without reperfusion phenomena; on the contrary, bowel wall involved in AVMI, AAMI and NOMI followed by reperfusion shows hyper-attenuation [ 56 ]. In addition, DECT offers many advantages; its iodine sensitivity allows to reduce contrast medium dose and concentration avoiding the risk of acute kidney injury in patients with chronic kidney disease or in old patients with associated comorbidities [ 56 ]. Fig. 1 Axial and coronal CT imaging show diffuse wall thickening bowel with or without evidence of the “target sign” and heightened enhancement of the thickened bowel wall: this event is common but nonspecific for bowel ischemia ( a and b )
Иллюстрация — в первоисточнике ↗
Radiologists must take in count that bowel ischemia can also exist in malignant conditions, such as in proximity to a colonic carcinoma or a metastatic intestinal lesion [ 53 ].
Moreover, some chemotherapy agents may determine spontaneous gastrointestinal necrosis and even perforation [ 63 , 64 ]. At CT examination, chemotherapy-induced enteropathy consists mainly of focal or diffuse bowel wall thickening or as regional mesenteric vascular congestion [ 53 ]; sometimes bowel perforation appears.
Side effects from molecular target therapy include enterocolitis, pneumatosis, micro-perforations of the bowel, fistula formation, and wound dehiscence, especially in rectal carcinoma [ 57 , 65 , 66 ].
These features, however, are not specific because they can also occur after radiation that induces small-vessel occlusions and could determine ischemia anywhere in the digestive tract, especially in patients with prior abdominal surgery with adhesive changes, previous peritonitis before radiation therapy and in patients that have cardiovascular factors or risk [ 67 ]. Immunotherapy use is spreading rapidly and radiologists should consider the possibility of side effects caused by these medications. Patel et al. reported a case of a metastatic melanoma 56-year-old man undergoing immunotherapy treatment first with ipilimumab and after with nivolumab that was affected by small bowel perforation secondary to nivolumab and ipilimumab related tumor regression [ 68 ]. CT scan of the abdomen and pelvis showed a perforation of the jejunum and consequent pneumoperitoneum. The perforation site was localized near to the metastatic lesion that was reduced for dimensions thanks to the rapid response to immunotherapy. According to Patel and his group, the patient’s response to nivolumab and ipilimumab was so drastic that the tumor shrinkage caused by the medications determine perforation within the small bowel [ 68 ].
We report the case of a 35 years old male patient diagnosed in February 2017 with squamous non-small-cell lung cancer (sqNSCLC). From June 2017, he received a second-line treatment with nivolumab for advanced disease achieving a major partial response. After 23 drug administrations, he presented with symptoms of moderate left lower quadrant pain without fever. Abdominal CT with IV iodinated contrast showed sigmoid diverticulitis with colonic wall thickening and pericolic fat stranding (Fig. 2 ). The patient was managed conservatively with low dose steroids and antibiotic treatment (ceftriaxone and metronidazole) [ 69 ]. After full recovery of symptoms, the patient resumed an immune checkpoint inhibitor four weeks later. Fig. 2 CT imaging in coronal and axial plane ( a and b ). Abdominal CT with IV iodinated contrast showed sigmoid diverticulitis with colonic wall thickening and pericolic fat stranding
Иллюстрация — в первоисточнике ↗
Discussion
Cancer patients have an increased thromboembolic risk involving up to 50% of their total; many events during disease evolution remain unknown, and their diagnosis occurs at the autopsy [ 70 , 71 ]. Chemotherapy is responsible for thromboembolic risk increase, such as showed in an epidemiologic study [ 71 ]; as described above, the pathophysiology of this increased risk is multifactorial [ 72 , 73 ]. Where a thrombotic event is not diagnosed, it causes suboptimal clinical symptoms management often. This aspect is very evident when an ischemic event involves part of the intestine as it can cause not specific symptoms such as diarrhea or chronic colitis whose ischemic nature does not recognize; at the same time, major intestinal ischemic events can be fatal. Moreover, the diagnosis of ischemic origin is even more complicated if bowel microvessels are involved, which give edema or thickening as the only detectable sign. Many commonly used anticancer agents are responsible for increased ischemic risk, including cisplatin, gemcitabine, and bevacizumab, which are also used in combination with many malignancies treatment. All these medications could cause intestinal damage on unknown ischemic epithelial injury. 5-fluorouracil and irinotecan-induced diarrhea or docetaxel and anti-PD-L1-induced colitis represent two combinations of drugs that might lead to intestinal damage that are much more frequent than highlighted in the literature.
Many different pathological mechanisms can cause bowel disease or ischemia; CT is the gold standard to diagnose pathological bowel features in the emergency setting because it allows detection of vascular anatomy and secondary signs of mesenteric ischemia, with high sensitivity and specificity (82–96% and 94%, respectively) [ 74 – 80 ]. It is established that oncologic patients are almost exclusively examined by CT to detect their “tumor burden.” Hence, it is possible to discover intestinal pathological features in asymptomatic patients during the planned follow-up.
We believe that CT is the primary imaging technique with a high temporal resolution that can provide a specific diagnosis of chemotherapy-induced bowel ischemia. CT could reveal also a fearsome complication that might occur in the bowel ischemia pathological process represented by bowel perforation. A hole through the wall of the intestines can develop; this results in the contents of the intestine leaking into the abdominal cavity, causing peritonitis. An interesting study conducted by Bagdwell and his group examined the management of perforation and the associated outcomes in patients with bevacizumab-associated bowel perforation. A bevacizumab-associated perforation on CT [ 6 ]. Bowel perforation was detected on CT in 24 patients of a total of 1442 patients showing that it represents however a rare complication; 23 of 24 were also treated with chemotherapy regimens. 83% of patients had only abdominal pain and many others were asymptomatic; in these case they were able to avoid surgery especially because the rapid and focused detection of bowel perforation on CT examination [ 6 ]. Risk factors for bevacizumab-related perforation could be represented by endoscopy executed 30 days before beginning treatment, previous adjuvant radiotherapy, long-term nonsteroidal anti-inflammatory drug (NSAID) therapy, peptic ulcer disease, diverticulosis, and previous surgery. The primary limits of this study, according to the authors, is represented by the lack of registries that may help to assess the true incidence of bowel perforation in these diseases [ 81 – 84 ].
Nivolumab determined small bowel obstruction and perforation in a patient that was on long-term therapy for metastatic non-small cell lung cancer that was confirmed after surgery [ 62 ]. This particular case report shows that anti-PD-1 antibody-related bowel inflammation may induce also stricture and bowel obstruction.
Therefore, it seems to be very important for radiologists to be aware as much as possible of the various chemotherapy treatment and pathological mechanisms that can promote bowel ischemia and perforation in the oncologic setting. Radiologists should talk to oncologists in multidisciplinary teams to manage together the clinical-therapeutic pathway of these patients; according to us, the knowledge of medical history in the oncologic setting is mandatory because, for example, patients could also be subjected to radiation before our observation so in this case the intestinal illness maybe not related to the therapeutic regimen. Patients with risk factors that could develop bowel perforation (history of diverticulitis, peptic ulcer disease, prior radiation exposure, previous bowel surgery) should be detected before therapy [ 85 – 87 ]. The radiologist should diagnose drug related-bowel toxicity because imaging manifestation of the drug toxicity may often take place before a patient develops symptoms [ 88 , 89 ]. Rapid detection is essential because pneumatosis and perforation could be often treated conservatively with the interruption of therapy and supportive care. Thanks to CT reproducibility, as shown in our clinical case, radiologists can also examine patients after the suspension of the drug to evaluate if medical treatment has been definitely curative or not [ 90 , 91 ].
Conclusions
Interpretation of imaging in oncologic patients has become progressively more complicated in the context of “target therapy” and thanks to the increasing number and types of therapies provided. Radiologists should know this variety of antiangiogenic treatments and immunotherapy regimens first because they can determine atypical features of tumor response and then also because of their eventual bowel toxicity. To avoid emergency surgery and significant risk of mortality among chemotherapy-induced bowel ischemia, it is necessary to give prompt diagnoses detecting drug toxicities; the dialogue with the clinician could be helpful for radiologists for this issue. After all the recognition of risk factors for chemotherapy-associated bowel ischemia and perforation will depend on the assessment of large clinical trials and observational studies.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Funding
Open access funding provided by Università degli Studi della Campania Luigi Vanvitelli within the CRUI-CARE Agreement.
References
1. Livshits Z Rao RB Smith SW An approach to chemotherapy-associated toxicity Emerg Med Clin North Am. 2014 32 1 167 203 10.1016/j.emc.2013.09.002 24275174
2. Torrisi M J, Schwartz L H, Gollub M J, Bosl G J, Hricak H. CT Findings of Chemotherapy-induced Toxicity: What Radiologists need to know about the clinical and radiologic manifestations of chemotherapy toxicity. Radiology: Volume 258: Number 1—January 2011 doi:10.1148/radiol.10092129/-/DC1. 10.1148/radiol.10092129 21183492
3. Viswanathan C Truong MT Sagebiel TL Bronstein Y Vikram R Patnana M Silverman PM Bhosale PR Abdominal and Pelvic complications of nonoperative oncologic therapy RadioGraphics 2014 34 941 961 10.1148/rg.344140082 25019433
4. Lewis A, Chaft J, Girotra M, Fisher G W. Immune checkpoint inhibitors: a narrative review of considerations for the anaesthesiologist. British Journal of Anaesthesia, 124 (3): 251e260 (2020) 10.1016/j.bja.2019.11.034. 10.1016/j.bja.2019.11.034 PMC7890563 32007241
5. Hapani S Chu D Wu S Risk of gastrointestinal perforation in patients with cancer treated with bevacizumab: a meta-analysis Lancet Oncol 2009 10 6 559 568 10.1016/S1470-2045(09)70112-3 19482548
6. Badgwell BD Camp ER Feig B Management of bevacizumab-associated bowel perforation: a case series and review of the literature Ann Oncol 2008 19 3 577 582 10.1093/annonc/mdm508 18024857
7. Walraven M Witteveen PO Lolkema MP van Hillegersberg R Voest EE Verheul HM Antiangiogenic tyrosine kinase inhibition related gastrointestinal perforations: a case report and literature review Angiogenesis 2011 14 2 135 141 10.1007/s10456-010-9197-6 21188500 PMC3102838
8. Sonis ST Elting LS Keefe D Peterson DE Schubert M Hauer-Jensen M Perspectives on cancer therapy-induced mucosal injury: pathogenesis, measurement, epidemiology, and consequences for patients Cancer 2004 100 1995 2025 10.1002/cncr.20162 15108222
9. Keefe DM Brealey J Goland GJ Cummins AG Chemotherapy for cancer causes apoptosis that precedes hypoplasia in crypts of the small intestine in humans Gut 2000 47 632 639 10.1136/gut.47.5.632 11034578 PMC1728102
10. Keefe DM Cummins AG Dale BM Kotasek D Robb TA Sage RE Effect of high-dose chemotherapy on intestinal permeability in humans Clin Sci (Lond) 1997 4 385 389 10.1042/cs0920385 9176038
11. Mitchell EP Gastrointestinal toxicity of chemotherapeutic agents Semin Oncol 2006 33 106 120 10.1053/j.seminoncol.2005.12.001 16473649
12. Inrhaoun H Kullman T Elghissassi I Treatment of chemotherapy-induced nausea and vomiting J Gastrointest Cancer 2012 43 541 546 10.1007/s12029-012-9401-6 22733566
13. Richardson G Dobish R Chemotherapy induced diarrhea J Oncol Pharm Pract 2007 13 181 198 10.1177/1078155207077335 18045778
14. Gibson RJ Stringer AM Chemotherapy-induced diarrhea Curr Opin Support Palliat Care 2009 3 31 35 10.1097/SPC.0b013e32832531bb 19365159
15. Saliba F Hagipantelli R Misset J Pathophysiology and therapy of irinotecan-induced delayed-onset diarrhea in patients with advanced colorectal cancer: a prospective assessment J Clin Oncol. 1998 16 8 2745 2751 10.1200/JCO.1998.16.8.2745 9704727
16. Siber GR Mayer RJ Levin MJ Increased gastrointestinal absorption of large molecules in patients after 5-fluorouracil therapy for metastatic colon carcinoma Cancer Res. 1980 40 10 3430 3436 7438030
17. Rosenberg RF Caridi JG Vincristine-induced megacolon Gastrointest Radiol 1983 8 1 71 73 10.1007/BF01948092 6832541
18. Ibrahim NK Sahin AA Dubrow RA Colitis associated with docetaxel-based chemotherapy in patients with metastatic breast cancer Lancet 2000 355 281 283 10.1016/S0140-6736(99)06195-4 10675076
19. Hussein MA Bird BR O’Sullivan MJ Symptoms in cancer patients and an unusual tumor: Case 2. Docetaxel-related ischemic colitis J Clin Oncol 2005 23 9424 9425 10.1200/JCO.2004.00.9845 16361642
20. Han ES Monk BJ What is the risk of bowel perforation associated with bevacizumab therapy in ovarian cancer? Gynecologic Oncology 2007 105 3 6 10.1016/j.ygyno.2007.01.038 17383545
21. Wiesner W, Mortelé KJ, Glickman JN, Ji H, Ros PR. Pneumatosis intestinalis and portomesenteric venous gas in intestinal ischemia: correlation of CT findings with severity of ischemia and clinical outcome. AJR Am J Roentgenol 2001;177(6): 1319–1323. 10.2214/ajr.177.6.1771319 11717075
22. Kung D Ruan DT Chan RK Ericsson ML Saund MS Pneumatosis intestinalis and portal venous gas without bowel ischemia in a patient treated with irinotecan and cisplatin Dig Dis Sci 2008 53 1 217 219 10.1007/s10620-007-9846-9 17530401
23. Schulze CG Blum U Haag K Hepatic portal venous gas: imaging modalities and clinical significance Acta Radiol 1995 36 377 380 10.1177/028418519503600409 7619615
24. Harandi A Zaidi AS Stocker AM Laber DA Clinical efficacy and toxicity of anti-EGFR therapy in common cancers J Oncol 2009 2009 567486 10.1155/2009/567486 19424511 PMC2677718
25. Thoeni RF Cello JP CT imaging of colitis Radiology 2006 240 3 623 638 10.1148/radiol.2403050818 16926320
26. Asnacios A Naveau S Perlemuter G Gastrointestinal toxicities of novel agents in cancer therapy Eur J Cancer 2009 45 suppl 1 332 342 10.1016/S0959-8049(09)70047-4 19775629
27. Som A Mandaliya R Alsaadi D Immune checkpoint inhibitor-induced colitis: A comprehensive review World J Clin Cases. 2019 7 4 405 418 10.12998/wjcc.v7.i4.405 30842952 PMC6397821
28. Widakowich C de Castro Jr G de Azambuja E Dinh P Awada A Review: side effects of approved molecular targeted therapies in solid cancers Oncologist 2007 12 12 1443 1455 10.1634/theoncologist.12-12-1443 18165622
29. Gonzalez-Cao M Boada A Teixidó C Fernandez-Figueras MT Mayo C Tresserra F Bustamante J Viteri S Puertas E Santarpia MC Riso A Barron F Karachaliou N Rosell R Fatal gastrointestinal toxicity with ipilimumab after BRAF/MEK inhibitor combination in a melanoma patient achieving pathological complete response Oncotarget. 2016 7 35 56619 56627 10.18632/oncotarget.10651 27447748 PMC5302939
30. Grob JJ Amonkar MM Karaszewska B Schachter J Dummer R Mackiewicz A Stroyakovskiy D Drucis K Grange F Chiarion-Sileni V Rutkowski P Lichinitser M Levchenko E Comparison of dabrafenib and trametinib combination therapy with vemurafenib monotherapy on health-related quality of life in patients with unresectable or metastatic cutaneous BRAF Val600-mutation-positive melanoma (COMBI-v): results of a phase 3 open-label randomised trial Lancet Oncol. 2015 16 1389 1398 10.1016/S1470-2045(15)00087-X 26433819
31. Elice F Rodeghiero F Falanga A Rickles FR Thrombosis associated with angiogenesis inhibitors Best Pract Res Clin Haematol 2009 22 1 115 128 10.1016/j.beha.2009.01.001 19285278
32. Calabro’ L. Di Giacomo A.M., et al. Primary hepatic epithelioid hemangioendothelioma progressively responsive to interferon-alpha: is there room for novel anti-angiogenetic treatments? Journal of Experimental and Clinical Cancer Research March 2007 17550144
33. Gupta A Long JB Chen J Gross CP Feldman DR Steingart RM Risk of Vascular Toxicity with Platinum Based Chemotherapy in Elderly Patients with Bladder Cancer J Urol. 2016 195 1 33 40 10.1016/j.juro.2015.08.088 26341576
34. Dasanu C A. Gemcitabine: vascular toxicity and prothrombotic potential. Expert Opin. Drug Saf. (2008) 7 (6) 10.1517/14740330802374262 18983217
35. Zecchina G Ghio P Bosio S Reactive thrombocytosis might contribute to chemotherapy-related thrombophilia in patients with lung cancer Clin Lung Cancer 2007 8 264 267 10.3816/CLC.2007.n.004 17311691
36. Kuenen BC Levi M Meijers JC Potential role of platelets in endothelial damage observed during treatment with cisplatin, gemcitabine, and the angiogenesis inhibitor SU5416 J Clin Oncol 2003 21 2192 2198 10.1200/JCO.2003.08.046 12775746
37. Guerrini S, Bucalossi A, Cioffi Squitieri N, Mazzei FG, Volterrani L, Mazzei MA. Ischemic colitis diagnosed by magnetic resonance imaging during lenalidomide treatment in a patient with relapsed multiple myeloma. Tumori. 2016 Nov 11;102(Suppl. 2). doi: 10.5301/tj.5000392. 10.5301/tj.5000392 26350196
38. Bennett CL Angelotta C Yarnold PR Thalidomide and lenalidomide-associated thromboembolism among patients with cancer JAMA 2006 296 21 2558 2560 10.1001/jama.296.21.2558-c 17148721
39. Grassi R Rambaldi PF Di Grezia G Inflammatory bowel disease: Value in diagnosis and management of MDCT-enteroclysis and 99mTc-HMPAO labeled leukocyte scintigraphy Abdom Radiol 2011 36 4 372 381 10.1007/s00261-010-9652-2 20963584
40. Eskens FA Verweij J The clinical toxicity profile of vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor (VEGFR) targeting angiogenesis inhibitors; a review Eur J Cancer 2006 42 18 3127 3139 10.1016/j.ejca.2006.09.015 17098419
41. Nagai H Muto M Optimal management of immune-related adverse events resulting from treatment with immune checkpoint inhibitors: a review and update Int J Clin Oncol. 2018 23 3 410 420 10.1007/s10147-018-1259-6 29516216
42. Tsukamoto J, Monteiro M, Vale S, Lemos C, Scarpelli T, Carvalho L, Pezzutti D, Brandao R. Thromboembolic events related to treatment with checkpoint inhibitors: report of two cases. Case Rep Oncol. 2018 Sep-Dec; 11(3): 648–653. doi: 10.1159/000492463 10.1159/000492463 PMC6243904 30483092
43. Lindner AK Gruenbacher G Schachtner G Thurnher M Pichler R Rare, but Severe: Vasculitis and Checkpoint Inhibitors Eur Urol Focus. 2019 10.1016/j.euf.2019.04.014 31072806
44. Petrioli R, Mazzei MA, et al Hyperprogressive disease in advanced cancer patients treated with nivolumab: A case series study. Anti-Cancer Drugs 2020. 10.1097/CAD.0000000000000864 31850916
45. Terlouw LG Moelker A Abrahamsen J European guidelines on chronic mesenteric ischaemia-Joint United European Gastroenterology, European Association for Gastroenterology, Endoscopy and Nutrition, European Society of Gastrointestinal and Abdominal Radiology, Netherlands Association of Hepatogastroenterologists, Hellenic Society of Gastroenterology, Cardiovascular and Interventional Radiological Society of Europe, and Dutch Mesenteric Ischemia Study Group clinical guidelines on the diagnosis and treatment of patients with chronic mesenteric ischaemia United European Gastroenterol J. 2020 8 4 371 395 10.1177/2050640620916681 32297566 PMC7226699
46. Somma F Faggian A Serra N Bowel intussusceptions in adults: the role of imaging Radiol Med 2014 120 1 105 117 10.1007/s11547-014-0454-4 25115295
47. Berritto D Iacobellis F Mazzei MA Volterrani L Guglielmi G Brunese L Grassi R MDCT in ischaemic colitis: how to define the aetiology and acute, subacute and chronic phase of damage in the emergency setting Br J Radiol. 2016 89 1061 20150821 10.1259/bjr.20150821) 27007462 PMC4985456
48. Mazzei MA Guerrini S Cioffi Squitieri N Magnetic resonance imaging: is there a role in clinical management for acute ischemic colitis? World J Gastroenterol. 2013 19 8 1256 1263 10.3748/wjg.v19.i8.1256 23483002 PMC3587482
49. Krajewski KM Braschi-Amirfarzan M DiPiro PJ Jagannathan JP Shinagare AB Molecular Targeted Therapy in Modern Oncology: Imaging Assessment of Treatment Response Korean J Radiol 2017 18 1 28 41 10.3348/kjr.2017.18.1.28 28096716 PMC5240491
50. Reginelli A, Iacobellis F, Berritto D, Gagliardi G, Di Grezia G, Rossi M, Fonio P, Grassi R. Mesenteric ischemia: the importance of differential diagnosis for the surgeon BMC Surgery 2013 10.1186/1471-2482-13-S2-S51 PMC3850956 24267670
51. Mazzei MA Guerrini S Cioffi Squitieri N Genovese EA Mazzei FG Volterrani L Diagnosis of acute mesenteric ischemia/infarction in the era of multislice CT Recenti Prog Med. 2012 103 11 435 437 10.1701/1166.12884.Review.Italian 23096727
52. Berritto D Somma F Landi N Cavaliere C Corona M Russo S Fulciniti F Seven-Tesla micro-MRI in early detection of acute arterial ischaemia: evolution of findings in an in vivo rat model La Radiologia medica 2011 116 6 829 841 10.1007/s11547-011-0676-7 21509555
53. Mazzei MA Acute mesenteric ischemia: Guidelines of the World Society of Emergency Surgery: A brief radiological commentary. World Journal of Emergency Surgery 2018; 10.1186/s13017-018-0197-y PMC6064129 30069228
54. Saba L, Berritto D, et al Acute arterial mesenteric ischemia and reperfusion: macroscopic and MRI findings, preliminary report World Journal of Gastroenterology 2013 10.3748/wjg.v19.i40.6825 PMC3812481 24187457
55. Lourenco PDM Rawski R Mohammed MF Khosa F Nicolaou S McLaughlin P Dual-Energy CT Iodine Mapping and 40-keV Monoenergetic Applications in the Diagnosis of Acute Bowel Ischemia AJR Am J Roentgenol. 2018 211 3 564 570 10.2214/AJR.18.19554 29927328
56. Mazzei MA Gentili F Volterrani L Dual-Energy CT Iodine Mapping and 40-keV Monoenergetic Applications in the Diagnosis of Acute Bowel Ischemia: A Necessary Clarification AJR Am J Roentgenol. 2019 212 3 W93 W94 10.2214/AJR.18.20501) 30793946
57. Mazzei MA, Volterrani L. Non occlusive mesenteric ischemia: think about it. Radiol Med 2014.
58. Mazzei MA Guerrini S Cioffi Squitieri N Vindigni C Imbriaco G Gentili F Berritto D Mazzei FG Grassi R Volterrani L Reperfusion in non-occlusive mesenteric ischaemia (NOMI): effectiveness of CT in an emergency setting Br J Radiol. 2016 89 1061 20150956 10.1259/bjr.20150956 26846139 PMC4985474
59. Mazzei MA Guerrini S Cioffi Squitieri N Imbriaco G Mazzei FG Volterrani L Non-obstructive mesenteric ischemia after cardiovascular surgery: not so uncommon Ann Thorac Cardiovasc Surg. 2014 20 3 253 255 10.5761/atcs.le.12.02154 23445796
60. Mazzei MA, Guerrini S. Bowel obstruction and intestinal ischemia: warnings for radiologists. Abdominal Radiology 2020 10.1007/s00261-019-02252-4 31605185
61. Hou CK Mak CW Tzeng WS Chang JM CT of small bowel ischemia Abdominal Imaging 2004 29 1 18 15160748 10.1007/s00261-003-0073-3
62. Romano S Lassandro F Scaglione M Romano L Rotondo A Grassi R Ischemia and infarction of the small bowel and colon: spectrum of imaging findings Abdominal Imaging 2006 31 3 277 292 10.1007/s00261-005-0376-7 16283583
63. Furukawa A Kanasaki S Kono N Wakamiya M Tanaka T Takahashi M CT diagnosis of acute mesenteric ischemia from various causes AJR Am J Roentgenol 2009 192 408 416 10.2214/AJR.08.1138 19155403
64. Sung E. Rha, Hyun K. Ha, Soo-Hyun Lee, Ji-Hoon Kim, Jeong-Kon Kim, Jung H. Kim, Pyo N. Kim, Moon-Gyu Lee, Yong-Ho Auh. CT and MR Imaging Findings of Bowel Ischemia from Various Primary Causes. RadioGraphics 2000; 20:29–42. 10.1148/radiographics.20.1.g00ja0629 10682769
65. Bartnicke BJ Balfe DM CT appearance of intestinal ischemia and intramural hemorrhage Radiol Clin North Am 1994 32 845 860 8084999
66. Kishen Rajan Patel, Lennard YW Lee, Arvind Tripathy, David McKean: Case of small bowel perforation secondary to nivolumab and ipilimumab related tumour regression. BMJ Case Rep 2020;13:e232304. doi:10.1136/bcr-2019-232304. 10.1136/bcr-2019-232304 PMC7046463 32086324
67. Mazzei MA, Gentili F Non-occlusive mesenteric ischaemia: CT findings, clinical outcomes and assessment of the diameter of the superior mesenteric artery: Don't forget the reperfusion process! British Journal of Radiology 2019 10.1259/bjr.20180736 PMC6435074 30215531
68. Patel KR Lee LYW Case of small bowel perforation secondary to nivolumab and ipilimumab related tumour regression BMJ Case Rep 2020 13 e232304 10.1136/bcr-2019-2323041 32086324 PMC7046463
69. Lund EC Han SY Holley HC Intestinal ischemia: comparison of plain radiographic and computed tomographic findings RadioGraphics 1988 8 1083 1108 10.1148/radiographics.8.6.3205930 3205930
70. Woodhams R Nishimaki H Fujii K Kakita S Hayakawa K Usefulness of multidetector-row CT (MDCT) for the diagnosis of non-occlusive mesenteric ischemia (NOMI): assessment of morphology and diameter of the superior mesenteric artery (SMA) on multi-planar reconstructed (MPR) images European Journal of Radiology 2010 76 1 96 102 10.1016/j.ejrad.2009.05.012 19501999
71. Cappabianca S Porto A Petrillo M Greco B Reginelli A Ronza F Setola F Rossi G Di Matteo A Muto R De Rimini ML Piccolo S Catalano M Muto P De Rosa N Barra E De Rosa I Antinolfi F Antinolfi G Caputi M Brunese L Grassi R Rotondo A Preliminary study on the correlation between grading and histology of solitary pulmonary nodules and contrast enhancement and [ 18 F] fluorodeoxyglucose standardised uptake value after evaluation by dynamic multiphase CT and PET/CT Journal of Clinical Pathology 2011 64 2 114 119 10.1136/jcp.2010.076562 21169276 PMC3030774
72. Amromin GD Solomon RD Necrotizing enteropathy: a complication of treated leukemia or lymphoma patients JAMA 1962 182 133 138 10.1001/jama.1962.03050400025005 13861046
73. Allerton R Acute mesenteric ischemia associated with 5-FU, cisplatin, and vincristine chemo-therapy Clin Oncol 1996 8 116 117 10.1016/S0936-6555(96)80118-X 8859610
74. Chaudhry N S, Bi W L, Gupta S, Keraliya A, Shimizu N, Chiocca A E. Pneumatosis Intestinalis After Molecular-Targeted Therapy World Neurosurgery. 10.1016/j.wneu.2019.01.225 30763745
75. Nolan DJ Herlinger H Gore RM Levine MS Laufer I Vascular disorders Textbook of gastrointestinal radiology 1994 Philadelphia, PA Saunders 967 983
76. Haanen JBAG, Carbonnel F, Robert C, et al. Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2018 Oct 1;29(Suppl 4):iv264–iv266. 10.1093/annonc/mdy162 29917046
77. Blom JW Vanderschoot JP Oostindiër MJ Osanto S van der Meer FJ Rosendaal FR Incidence of venous thrombosis in a large cohort of 66329 cancer patients: results of a record linkage study J Thromb Haemost 2006 4 529 535 10.1111/j.1538-7836.2006.01804.x 16460435
78. White RH Chew HK Zhou H Parikh-Patel A Harris D Harvey D Wun T Incidence of venous thromboembolism in the year before the diagnosis of cancer in 528,693 adults Arch Intern Med 2005 165 1782 1787 10.1001/archinte.165.15.1782 16087828
79. Barni S Labianca R Agnelli G Bonizzoni E Verso M Mandalà M Brighenti M Petrelli F Bianchini C Perrone T and Gasparini G Chemotherapy-associated thromboembolic risk in cancer outpatients and effect of nadroparin thromboprophylaxis: results of a retrospective analysis of the PROTECHT study Journal of Translational Medicine 2011 9 179 10.1186/1479-5876-9-179 22013950 PMC3220644
80. Nadir Y Hoffman R Brenner B Drug-related thrombosis in hematologic malignancies Rev Clin Exp Hematol 2004 8 E4 16029970
81. Wiesner W Khurana B Ji H Ros PR CT of acute bowel ischemia Radiology 2003 226 635 650 10.1148/radiol.2263011540 12601205
82. Furukawa A Kanasaki S Kono N CT diagnosis of acute mesenteric ischemia from various causes AJR 2009 192 408 416 10.2214/AJR.08.1138 19155403
83. Wasnik A Kaza RK Al-Hawary MM Liu PS Platt JF Multidetector CT imaging in mesenteric ischemia—pearls and pitfalls Emergency radiology 2011 18 2 145 156 10.1007/s10140-010-0921-8 21132342
84. Blachar A Barnes S Adam SZ Levy G Weinstein I Precel R Federle MP Radiologists’ performance in the diagnosis of acute intestinal ischemia, using MDCT and specific CT findings, using a variety of CT protocols Emergency Radiology 2011 18 5 385 394 10.1007/s10140-011-0965-4 21655965
85. Reginelli A Pezzullo MG Scaglione M Scialpi M Brunese L Grassi R Gastrointestinal disorders in elderly patients Radiologic Clinics of North America 2008 46 4 755 771 10.1016/j.rcl.2008.04.013 18922291
86. Scialpi M Reginelli A D'Andrea A Pancreatic tumors imaging: An update Int J Surg 2016 28 S142 S155 10.1016/j.ijsu.2015.12.053 26777740
87. Sugrue M, Kozloff M, Hainsworth J et al. Risk factors for gastrointestinal perforations in patients with metastatic colorectal cancer receiving bevacizumab plus chemotherapy [meeting abstracts]. J Clin Oncol 2006; 24 (18 Suppl): (Abstr 3535).
88. Tso DK Avery LL Lev MH Kamalian S Nivolumab-induced small bowel obstruction and perforation: a rare but life-threatening side effect of immunotherapy Emergency Radiology 2020 27 107 110 10.1007/s10140-019-01731-x 31823117
89. Arora N Gupta A Singh PP Biological agents in gastrointestinal cancers: adverse effects and their Management J Gastrointest Oncol 2017 8 3 485 498 10.21037/jgo.2017.01.07 28736636 PMC5506281
90. Belfiore G, Belfiore MP, Reginelli A, Capasso R, Romano F, Ianniello GP, Cappabianca S, Brunese L. Concurrent chemotherapy alone versus irreversible electroporation followed by chemotherapy on survival in patients with locally advanced pancreatic cancer. Med Oncol. 2017 Mar;34(3):38. doi: 10.1007/s12032-017-0887-4. Epub 2017 Feb 4. 10.1007/s12032-017-0887-4 28161827
91. Reginelli A Vanzulli A Sgrazzutti C Vascular microinvasion from hepatocellular carcinoma: CT findings and pathologic correlation for the best therapeutic strategies Med Oncol 2017 34 93 10.1007/s12032-017-0949-7 28401484