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Towards Precision Oncology: The Role of Smoothened and Its Variants in Cancer.

The G protein-coupled receptor Smoothened (Smo) is a central signal transducer of the Hedgehog (Hh) pathway which has been linked to diverse forms of tumours. Stimulated by advancements in structural and functional characterisation, the Smo receptor has been recognised as an important therapeutic target in Hh-driven cancers, and several Smo inhibitors have now been approved for cancer therapy. This receptor is also known to be an oncoprotein itself and its gain-of-function variants have been associated with skin, brain, and liver cancers. According to the COSMIC database, oncogenic mutations o

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… Type I tumours harbouring Smo mutants include BCC, basal cell nevus syndrome (BCN), medulloblastoma, meningioma, and HCC, and these will be described in more detail in the next chapter. … Inhibiting the Hedgehog Pathway in Patients with the Basal-Cell Nevus Syndrome N. Engl. J. Med. 2012 366 2180 2188 10.1056/NEJMoa1113538 22670904 PMC4362529 80. Robinson G.W. Orr B.A. Wu G. Gururangan S. Lin T. Qaddoumi I. Packer R.J. Goldman S. Prados M.D. Desjardins A. …

Distinct MAPK and PI3K pathway mutations in different melanoma types in Taiwanese individuals.

BACKGROUND: A number of studies investigating mutations of genes involved in MAPK and PI3K pathways in melanoma patients have been performed, most of which were based on Caucasian populations. OBJECTIVES: We sought to identify BRAF, NRAS, MEK1, PI3K, and PTEN mutations and further determine possible correlations with clinicopathological parameters in Taiwanese patients with acral, non-chronic sun damaged (NCSD), or mucosal melanoma. MATERIALS & METHODS: Forty melanocytic nevi, 24 dysplastic nevi, and 175 melanomas from Taiwanese patients were analysed for mutations in BRAF, NRAS, MEK1, PI3K,

Clinical features and prognosis of Asian patients with acral lentiginous melanoma who have nodal nevi in their sentinel lymph node biopsy specimen.

BACKGROUND: Nodal melanocytic nevi (NNs) encountered during sentinel lymph node biopsy (SLB) for malignant melanoma are usually difficult to distinguish from metastatic melanoma. However, NNs have not been well studied in acral lentiginous melanoma (ALM) in Asian populations. OBJECTIVE: To investigate the clinical characteristics and significance of NNs in SLB specimens from patients with ALM. METHODS: We retrospectively analyzed 84 patients with ALM who underwent SLB between June 2010 and July 2017. RESULTS: Of the 84 patients with ALM, 9 (10.7%) had NNs in their SLB specimens. NNs were si

Risks of Melanoma and Other Cancers in Melanoma-Prone Families over 4 Decades.

UNLABELLED: Since 1976, melanoma-prone families have been followed at the National Cancer Institute to identify etiologic factors for melanoma. We compared risks of melanoma and other cancers in 1,226 members of 56 families followed for up to 4 decades with population rates in the Surveillance, Epidemiology, and End Results program. All families were tested for mutations in CDKN2A and CDK4; 29 were mutation-positive and 27 mutation-negative. We compared rates of invasive melanomas, both first and second, by family mutation status, with Surveillance, Epidemiology, and End Results program. Compa

Immunohistochemical analysis of the biological potential of odontogenic keratocysts.

BACKGROUND: The aim of this study was to analyse the usefulness of detecting important apoptosis and proliferation markers in assessing the biological potential of odontogenic keratocysts (OKC) and thus selecting the optimal diagnostic algorithm for these lesions. METHODS: Indirect immunohistochemistry and relevant statistical methods were used for analysis of formalin-fixed and paraffin-embedded samples from 98 patients. RESULTS: Nevoid basal cell carcinoma syndrome (NBCCS) keratocysts were characterized by higher expression of Bcl-2, p27Kip1 and c-erbB-2 as well as by lower proliferative a

Carney complex.

We report an illustrated case of a 61-year-old woman with multiple atrial myxomas and cutaneous hyperpigmentation as part of the Carney complex. The case is notable for an unusually late presentation in life and a strong family history of atrial myxomas and sudden death. The importance of regular life-long echocardiographic screening and surveillance in all family members of affected cases is emphasized.

Involvement of patched (PTCH) gene in Gorlin syndrome and related disorders: three family cases.

AIM: To find genetic alterations in PTC or other genes of the Shh/PTCH pathway in tumorous and non- tumorous samples from three families and to correlate them with the varying expression of disorders in presented nevoid basal cell carcinoma syndrome (NBCCS) phenotypes. METHOD: DNA was extracted from archival paraffin-embedded tissues, tumor tissue or peripheral blood leukocytes, and the loss of heterozygosity (LOH) and single strand conformational polymorphism analysis was performed using PCR with primers for polymorphic 9q22.3 markers (D9S196, D9S287, D9S180, D9S127); PTCH exons 3, 6, 8, 13,

Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome.

The nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant disorder characterized by multiple basal cell carcinomas (BCCs), pits of the palms and soles, jaw keratocysts, a variety of other tumors, and developmental abnormalities. NBCCS maps to chromosome 9q22.3. Familial and sporadic BCCs display loss of heterozygosity in this region, consistent with the gene being a tumor suppressor. A human sequence (PTC) with strong homology to the Drosophila segment polarity gene, patched, was isolated from a YAC and cosmid contig of the NBCCS region. Mutation analysis revealed alterations o

Окулярная аднексальная плазмоцитома, представляющая собой повреждение пличного полулунариса и кранка у 21-летнего мужчины.

ЦЕЛЬ: Одиночная экстрамульгированная плазменная цитома (SEMP) составляет 2-5% плазменных клеточных дискразий и определяется как плазменная опухоль клеток в отсутствие системной множественной миеломы или другой дискразии. Редким подтипом SEMP является плазмоцитома, расположенная в окулярной аднексе, чаще всего в конъюнктуре и орбитальных мягких тканях. Мы представляем и обсуждаем случай изолированной массы сосуда и пилика полулунариса у здорового 21-летнего мужчины. ЗАМЕЧАНИЯ: 21-летний мужчина, не имеющий прошлой медицинской или окулярной истории и имеющий расширяющуюся, раздражающую массу в л

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… Benign neoplasms of the ocular adnexa include nevus (most common), sebaceous gland adenoma, squamous papilloma, pyogenic granuloma, capillary hemangioma, and reactive lymphoid hyperplasia; malignant and pre-malignant lesions include conjunctival keratoacanthoma, oncocytoma, epithelial dysplasia, follicular …

Assessment of Mammalian Target of Rapamycin Pathway Activation in Basal Cell Carcinoma as a New Therapeutic Approach.

Targeting the mammalian target of rapamycin (mTOR) pathway represents a potentially novel approach to treat basal cell carcinoma (BCC), but activation of this pathway has not been well described in human BCCs. The purpose of this study was to assess whether mTOR pathway activation occurs in BCCs (both sporadic and syndromic) and report a case of a patient with Gorlin syndrome (GS) whose clinically suspicious BCCs responded to mTOR inhibition through topical sirolimus treatment. After Stanford Institutional Review Board Approval, archived BCCs from patients with GS (n = 25), sporadic BCCs (n =

Unscheduled Visits of Patients with Familial Melanoma to a Pigmented Lesion Clinic: Evaluation of Patients' Characteristics and Suspicious Lesions.

Approximately 10% of all melanomas occur in subjects with a family history of melanoma. This retrospective follow-up study investigated the characteristics of patients with familial melanoma who made unscheduled visits to our pigmented lesions clinic, and the diagnosis of excised lesions. A total of 110 (9%) out of 1,267 patients made at least one unscheduled visit between May 2011 and February 2016. Histopathology was taken from 59 patients. Thirty-four naevi, 7 melanomas and 3 basal cell carcinomas were detected. All patients with melanoma were CDKN2A carriers and all melanomas were discover

Elevated D-dimer level in the differential diagnosis of venous malformations.

OBJECTIVE: To evaluate if elevated D-dimer level is specific for venous malformations (VMs) and thus useful for differential diagnosis, which can be problematic even in specialized interdisciplinary centers. Localized intravascular coagulopathy, characterized by elevated D-dimer levels, has been observed in approximately 40% of patients with VMs. DESIGN: Prospective convenience sample accrued from 2 interdisciplinary sites. SETTING: Two interdisciplinary centers for vascular anomalies in Brussels, Belgium, and Caen, France PARTICIPANTS: The study population comprised 280 patients with clini

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Until recently, advanced BCC were only accessible to a highly morbid surgery not necessarily proving to be carcinologic, and leaving terrible dysmorphic sequelae hard to accept by the patient. Another possibility, the only one in case of metastatic BCC, was chemotherapy which efficacy has never been proven in a clinical trial. Radiotherapy is most often not accessible because of previous radiotherapy or because of the localization or the extension of the lesion. The discovery of the importance of the sonic hedgehog pathway in the physiopathology of BCC has opened a new strategy with the develo

[Complications of head and neck skin expansion].

INTRODUCTION: Skin expansion is a good solution for the reconstruction of head and neck defects. We assessed the complications of cervico-facial skin expansion technique to draft recommendations so as to minimize risks. METHODS: We made a retrospective study from 1990 to 2005. Complications were analyzed according to age, sex, etiology, area to reconstruct, location of the expander, expander volume and number, simultaneous single or repeated technique, type of expander, duration of expansion, and type of flap used for reconstruction. RESULTS: One hundred and thirty-nine tissue expanders were

Evaluation of germline CDKN2A, ARF, CDK4, PTEN, and BRAF alterations in atypical mole syndrome.

Atypical mole syndrome is a sporadic or an inherited condition with an increased risk of melanoma. Germline mutations in the CDKN2A, ARF, CDK4 and somatic mutations in the PTEN and BRAF genes have been associated with melanoma. In this study, we evaluated genes associated with familial and sporadic melanoma for mutations in 28 probands with the atypical mole syndrome. No sequence alterations in the coding regions or in the splice junctions of CDKN2A, ARF, CDK4, PTEN or BRAF were identified. These data suggest that genes evaluated in this study are unlikely to be candidate genes for atypical mo

Is loss of heterozygosity at 9q22.3 (PTCH gene) and 19p13.3 (STK11 gene) involved in the pathogenesis of ovarian stromal tumors?

Some ovarian fibromas and rare fibrosarcomas are associated with Gorlin syndrome, which is caused by mutation in the human homologue of Drosophila patched gene (PTCH), localized on chromosome 9q22.3. The relationship between PTCH gene and sporadic ovarian tumors in the thecoma-fibroma group has not been well characterized. On the other hand, we have recently described loss of heterozygosity (LOH) at 19p13.3 in 2 sporadic fibromas with sex-cord elements. We have analyzed DNA from 8 fibromas, 6 cellular fibromas, 2 fibrothecomas, 9 luteinized thecomas, and 2 fibrosarcomas of the ovary for LOH at

Shagreen Patch in Clerous Sclerosis Institute на Ультразвуке высокого уровня Frequency

Мы представим пример 19-year-old женский пациент с туберозным комплексом склероза и шагриновым пятном на левой дорской области. Снижение эхогенности и увеличение толщины дермиса было продемонстрировано с помощью высокочастотного ультразвука. Насколько нам известно, это первое сообщение об ультразвуковом снимке шагряного пятна.

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… A shagreen patch is a type of connective tissue nevus which previous studies reported in approximately 21% to 83% of patients with tuberous sclerosis complex, and it often appears in the first decade [ 5 , 6 ]. Dark-skinned people seem to have an increased probability of a shagreen patch [ 7 ]. …

A phase 2, open-label, multicenter study of ixazomib plus lenalidomide and dexamethasone in adult Japanese patients with relapsed and/or refractory multiple myeloma.

BackgroundTOURMALINE-MM1 was a global study that demonstrated a significant improvement in progression-free survival with ixazomib plus lenalidomide and dexamethasone compared with placebo plus lenalidomide and dexamethasone, in patients with relapsed and/or refractory multiple myeloma. The current study was conducted to evaluate further the efficacy and safety of ixazomib plus lenalidomide and dexamethasone in Japanese patients.MethodsThis phase 2, open-label, single-arm, multicenter study enrolled patients aged ≥ 20 years with relapsed and/or refractory multiple myeloma at 16 sites in Japan.

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… Lipase increased 1 (3) Loss of consciousness 1 (3) Lung neoplasm malignant 1 (3) Lymphocyte count decreased 1 (3) Malignant neoplasm of unknown primary seta a 1 (3) Edema peripheral 1 (3) Osteonecrosis of jaw 1 (3) Pharyngitis 1 (3) Pneumonitis 1 (3) Rash generalized 1 (3) Macular rash 1 (3) Sebaceous nevus … Loss of consciousness | 1 (3) Lung neoplasm malignant | 1 (3) Lymphocyte count decreased | 1 (3) Malignant neoplasm of unknown primary seta a | 1 (3) Edema peripheral | 1 (3) Osteonecrosis of jaw | 1 (3) Pharyngitis | 1 (3) Pneumonitis | 1 (3) Rash generalized | 1 (3) Macular rash | 1 (3) Sebaceous nevus …