Gene expression profiling of patient‐derived pancreatic cancer xenografts predicts sensitivity to the BET bromodomain inhibitor JQ1: implications for individualized medicine efforts

Abstract c‐MYC controls more than 15% of genes responsible for proliferation, differentiation, and cellular metabolism in pancreatic as well as other cancers making this transcription factor a prime target for treating patients. The transcriptome of 55 patient‐derived xenografts show that 30% of them share an exacerbated expression profile of MYC transcriptional targets (MYC‐high). This cohort is characterized by a high level of Ki67 staining, a lower differentiation state, and a shorter survival time compared to the MYC‐low subgroup. To define classifier expression signature, we selected a group of 10 MYC target transcripts which expression is increased in the MYC‐high group and six transcripts increased in the MYC‐low group. We validated the ability of these markers panel to identify MYC‐high patient‐derived xenografts from both: discovery and validation cohorts as well as primary cell cultures from the same patients. We then showed that cells from MYC‐high patients are more sensitive to JQ1 treatment compared to MYC‐low cells, in monolayer, 3D cultured spheroids and in vivo xenografted tumors, due to cell cycle arrest followed by apoptosis. Therefore, these results provide new markers and potentially novel therapeutic modalities for distinct subgroups of pancreatic tumors and may find application to the future management of these patients within the setting of individualized medicine clinics

Characterization of variantsof unknown significance in lynch syndrome

Le syndrome de Lynch est une affection héréditaire autosomique dominante due à des mutations constitutionnelles des gènes du système de réparation de l'ADN (MLH1, MSH2 et MSH6). Depuis 20 ans le réseau français des laboratoires impliqués dans le syndrome de Lynch a identifié un total de 6687 variants. Sept cent sept d'entre eux, essentiellement des variants faux sens, restent encore des variants de signification inconnue (VSI), sans utilité pour le conseil génétique. Le but de notre étude était de développer un algorithme permettant de classer les variants de signification inconnue. Les critères utilisés étaient les données des analyses in silico, phénotypiques (ségrégation, critères d'Amsterdam), l'état de la fonction MMR (MisMatch Repair) dans les cellules tumorales, les tests fonctionnels et d'épissage, ainsi que les données publiées. Cet algorithme a été appliqué à l'ensemble des VSI de la base de données française et nous a permis de caractériser 370 variants . Les données ont été intégrées dans la base de données française UMD des gènes MMR afin d'être disponibles pour la communauté scientifique. Grace aux données collectées par le réseau, nous avons également pu caractériser le phénotype du syndrome de Lynch. Nous avons ainsi confirmé que le cancer du sein ne fait pas partie du spectre du syndrome de Lynch et que les formes de ce syndrome associées à une mutation du gène EPCAM n'entrainent qu'un risque très faible de cancers de l'endomètre, permettant ainsi d'adapter les recommandations de suivi dans cette situation.de l'endomètre, permettant ainsi d'adapter les recommandations de suivi dans cette situation.Lynch syndrome is a frequent cancer predisposition with an autosomal dominant mode of inheritance and caused by heterozygous germ line mutations in one of the major DNA mismatch repair (MMR) genes (MLH1, MSH2 and MSH6). For 20 years, the French laboratories network involved in Lynch syndrome identified a total of 6687 variations. Among them, 707, mainly missense variations, remained variants of uncertain significance (VUS), thus could not be used for reliable genetic counseling. The aim of our study was to develop an algorithm able to classify VUS, according to the international consensus (IARC). This algorithm was constructed based on criteria usually required for genetic characterization such as in silico analysis, phenotypical data (segregation, Amsterdam criteria's), MMR status in tumor cells, functional assays, splicing analyses and published data. Data were registered in the French database. As a result of this work, we were able to classify 370 variants of the 707 (52,3%). As part of this work, we also analyzed phenotypical data of patients with Lynch syndrome and showed that breast cancer can definitively be excluded from the spectrum of Lynch-related cancers, and that EPCAM mutations, which may lead to Lynch syndrome, are associated with a very low incidence of endometrial cancer and have probably to be considered as an allelic disease with specific clinical recommendations

Evaluation des performances de l'échoendoscopie pancréatique dans l'indication opératoire des tumeurs intracanalaires papillaires et mucineuses du pancréas

INTRODUCTION: Les TIPMP doivent être surveillées jusqu'à l'apparition de signes de malignité en IRM ou EEP. L'OBJECTIF DE L'ETUDEétait d'évaluer les performances de l'EEP dans les critères d'indication chirurgicale à partir du compte rendu d'anatomopathologie des pancratectomies de TIPMP. MATERIEL ET METHODE: Cette étude rétrospective, incluant les patients ayant eu une pancréatectomie pour TIPMP entre 2000 et 2012 dans 4 hôpitaux. Si un examen d'imagerie (EEP, IRM ou TDM) retrouvait un critère de malignité définis par le consensus de 2012, le patient était considéré comme ayant un critère péjoratif . RESULTATS: Un cancer était retrouvé chez 36,6% des 131 patients inclus, soit 58% de ceux ayant une atteinte mixte ou du canal principal et 20% des canaux secondaires. L'EEP retrouvait des critères péjoratifs chez 71% des patients, dont 29,8% avaient un cancer contre 42,2%. Chez ceux n'ayant pas de critères péjoratifs, 22,1% des patients n'avaient pas de cancer et 6,9% en avaient. Les critères péjoratifs retrouvés en EEP avaient une bonne sensibilité (0,81) et une mauvaise spécificité (0,35). Ceux ayant la meilleure sensibilité ou composante solide (sen=0,95), un Wirsung > 10mm (spé=0,96), une cytologie suspecte (spé=0,97). Un module mural ou un Wirsung ;esur2 entre 5 et 9 mm avaient une sensibilité correcte (respectivement 0,73 et 0,67). CONCLUSION: Notre travail réalisé en centres experts confirme que l'EEP est un examen clé dans l'indication chirurgicale des TIPMIP qui doit rester pluridisciplinaire. Un compte rendu standardisé d'EEP paraît indispensableAIX-MARSEILLE2-BU Méd/Odontol. (130552103) / SudocSudocFranceF

Contribution à l'étude des lipases pancréatiques apparentées chez l'homme

AIX-MARSEILLE2-BU Méd/Odontol. (130552103) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Consideration surrounding incidental findings throughout multigene panelă testing in cancer genetics

International audienceno abstrac

Management of recto-vaginal fistulas after prosthetic reinforcement treatment for pelvic organ prolapse

AIM: To communicate our findings on successful treatment of recto-vaginal fistulas (RVFs) after prosthetic reinforcement surgery of pelvic organ prolapse (POP)

Human pancreatic lipase-related protein 2: Tissular localization along the digestive tract and quantification in pancreatic juice using a specific ELISA

International audienc

Assistance for the Prescription of Nutritional Support Must Be Required in Nonexperienced Nutritional Teams

The aim of the study was to determine the current practices of nutritional support among hospitalized patients in nonspecialized hospital departments. Materials and Methods. During an observation period of 2 months, a surgeon and a gastroenterologist designated in each of the two departments concerned, not “specialized” in nutritional assistance, have treated patients in which nutritional support seemed necessary. Assessing the degree of malnutrition of the patient, the therapeutic decision and the type of product prescribed by the doctors were secondarily compared to the proposals of a structured computer program according to the criteria and standards established by the institutions currently recognized. Results. The study included 120 patients bearing a surgical disease in 86.7% of cases and 10% of medical cases. 50% of the patients had cancer. Nutritional status was correctly evaluated in 38.3% by the initial doctors’ diagnosis—consistent with the software’s evaluation. The strategy of nutrition was concordant with the proposals of the software in 79.2% of cases. Conclusions. Despite an erroneous assessment of the nutritional status in more than two-thirds of cases the strategy of nutritional management was correct in 80% of cases. Malnutrition and its consequences can be prevented in nonexperienced nutritional teams by adequate nutritional support strategies coming from modern techniques including computerized programs

Assistance for the Prescription of Nutritional Support Must Be Required in Nonexperienced Nutritional Teams

The aim of the study was to determine the current practices of nutritional support among hospitalized patients in nonspecialized hospital departments. Materials and Methods. During an observation period of 2 months, a surgeon and a gastroenterologist designated in each of the two departments concerned, not "specialized" in nutritional assistance, have treated patients in which nutritional support seemed necessary. Assessing the degree of malnutrition of the patient, the therapeutic decision and the type of product prescribed by the doctors were secondarily compared to the proposals of a structured computer program according to the criteria and standards established by the institutions currently recognized. Results. The study included 120 patients bearing a surgical disease in 86.7% of cases and 10% of medical cases. 50% of the patients had cancer. Nutritional status was correctly evaluated in 38.3% by the initial doctors' diagnosis-consistent with the software's evaluation. The strategy of nutrition was concordant with the proposals of the software in 79.2% of cases. Conclusions. Despite an erroneous assessment of the nutritional status in more than two-thirds of cases the strategy of nutritional management was correct in 80% of cases. Malnutrition and its consequences can be prevented in nonexperienced nutritional teams by adequate nutritional support strategies coming from modern techniques including computerized programs