Prolonged Survival in a Patient with Neuroendocrine Tumor of the Cecum and Diffuse Peritoneal Carcinomatosis

Peritoneal carcinomatosis is a well-known factor of poor prognosis in patients with digestive adenocarcinomas. Peritoneal dissemination may also occur in midgut well-differentiated neuroendocrine tumors, but its influence on survival is ill-defined. We report here the history of a 64-year-old woman who had a neuroendocrine tumor of the cecum with multiple synchronous metastases in the liver and diffuse peritoneal carcinomatosis. She underwent surgical resection of the primary tumor and cytoreduction of liver metastases, and received subsequently chemotherapy and somatostatin analogs. In spite of the widespread extension of the disease, she survived for 13 years and died from a carcinoid heart disease. We discuss the natural history and prognostic factors in patients with midgut well-differentiated neuroendocrine tumors, with a focus on the impact of the peritoneal carcinomatosis

Prediction of survival with second-line therapy in biliary tract cancer: Actualisation of the AGEO CT2BIL cohort and European multicentre validations

BACKGROUND: The benefit of second-line chemotherapy (L2) over standard first-line (L1) gemcitabine plus cisplatin (GEMCIS) or oxaliplatin (GEMOX) chemotherapy in advanced biliary tract cancer (aBTC) is unclear. Our aim was to identify and validate prognostic factors for overall survival (OS) with L2 in aBTC to guide clinical decisions in this setting. METHODS: We performed a retrospective analysis of four prospective patient cohorts: a development cohort (28 French centres) and three validation cohorts from Italy, UK and France. All consecutive patients with aBTC receiving L2 after GEMCIS/GEMOX L1 between 2003 and 2016 were included. The association of clinicobiological data with OS was investigated in univariate and multivariate Cox analyses. A simple score was derived from the multivariate model. RESULTS: The development cohort included 405 patients treated with L1 GEMOX (91%) or GEMCIS. Of them, 55.3% were men, and median age was 64.8 years. Prior surgical resection was observed in 26.7%, and 94.8% had metastatic disease. Performance status (PS) was 0, 1 and 2 in 17.8%, 52.4% and 29.7%, respectively. Among 22 clinical parameters, eight were associated with OS in univariate analysis. In multivariate analysis, four were independent prognostic factors (p < 0.05): PS, reason for L1 discontinuation, prior resection of primary tumour and peritoneal carcinomatosis. The model had the Harrell's concordance index of 0.655, a good calibration and was validated in the three external cohorts (N = 392). CONCLUSION: We validated previously reported predictive factors of OS with L2 and identified peritoneal carcinomatosis as a new pejorative factor in nearly 800 patients. Our model and score may be useful in daily practice and for future clinical trial design

Avancées dans le traitement médical du cancer du pancréas

International audiencePancreatic ductal adenocarcinoma (PDAC) is expected to become the second leading cause of cancer death by 2030. While overall survival rates at 5 years remains low, significant progress has been made over the last decade. For patients with operable PDAC, adjuvant chemotherapy with FOLFIRINOX has been demonstrated to be superior to gemcitabine. Preoperative treatment strategies (neoadjuvant for upfront resectable tumors, induction for borderline tumors) are currently evaluated in clinical trials. In advanced stages, maintenance treatment strategies after a period of disease control with FOLFIRINOX areemerging.While no targeted therapy had so far shownefficacy in PDAC, PARP inhibitors significantly improved progression-free survival as maintenance therapy in patients with a BRCA germline mutation (5%). Immunotherapies have been disappointing in PDAC, except for tumors with microsatellite instability (1%-2%). Supportive care is central to improving the quality of life of patients. Several national clinical trials (PRODIGE) are in progress. The chapter of the National Thesaurus of Digestive Oncology (TNCD) focusing on PDAC was recently updated (June 2018) to take account of these advances. This review provides an overview of recent practice changes in the medical treatment of PDAC

Hétérogénéité inter- et intra-tumorale et dynamique des fibroblastes associés au cancer dans l’adénocarcinome pancréatique

Les fibroblastes associés au cancer (cancer-associated fibroblasts, CAF) sont des chefs d’orchestre du microenvironnement tumoral (stroma) de l'adénocarcinome canalaire pancréatique (AP). L'hétérogénéité du stroma pourrait expliquer les rôles physiopathologiques non univoques (pro- vs. anti-tumoraux) du stroma de l’AP. Nous avons émis l'hypothèse qu'il existe plusieurs sous-types de CAFs dans l’AP qui contribuent à l'hétérogénéité du stroma notamment par leurs interactions avec les cellules tumorales et immunitaires.Ce projet s’est décomposé en trois parties :- Dans la première partie, en appliquant des analyses bioinformatiques étendues et un large éventail de tests in vitro à des cultures primaires de CAF dérivées d’AP, nous avons démontré la diversité biologique des CAFs pancréatiques humains; nous avons identifié quatre sous-types de CAFs avec des caractéristiques moléculaires et fonctionnelles spécifiques (signatures liées à la matrice et au système immunitaire, expression de vimentine et d’actine musculaire lisse, activité proliférative), et nous avons montré que l'hétérogénéité des CAFs avait un impact sur les interactions avec les cellules tumorales dans des modèles organotypiques.- Dans la deuxième partie, nous avons montré que les sous-types de CAFs et leurs combinaisons étaient associés à des caractéristiques phénotypiques distinctes des tumeurs (sous-type moléculaire et grade, abondance et activité du stroma, infiltrats immunitaires, angiogenèse) et à la survie des patients, in silico dans les données publiques de l'ICGC et par immunohistochimie dans une cohorte de patients bien caractérisés.- Dans la troisième partie, nous avons montré que plusieurs sous-types de CAFs peuvent émerger in vitro (expériences avec des milieux conditionnés) et in vivo (xénogreffes orthotopiques) à partir des cellules stellaires pancréatiques suite à leurs interactions dynamiques avec les cellules tumorales, par un processus d'«empreinte», modulé ensuite par d'autres facteurs et/ou partenaires cellulaires dans le microenvironnement tumoral; par ailleurs, nous avons confirmé dans un contexte murin nos résultats sur l'association entre l'expression des marqueurs de sous-types de CAFs et le phénotype immunitaire observé dans les tumeurs humaines. Cette classification unique des CAFs pancréatiques humains (pCAFassigner) démontre l'hétérogénéité phénotypique inter- et intra-tumorale des CAFs dans l’AP. Nos résultats ouvrent la voie à de futures études fonctionnelles et au développement de thérapies ciblant spécifiquement certaines sous-populations de CAFs dans l’AP.Cancer-associated fibroblasts (CAF) are orchestrators of the pancreatic ductal adenocarcinoma (PDAC) microenvironment. Stromal heterogeneity may explain differential pathophysiological roles of the stroma (pro- vs. anti-tumoral) in PDAC. We hypothesised that multiple CAF subtypes exist in PDAC that contribute to stromal heterogeneity through interactions with cancer and immune cells. This project comprised three parts:- In Part 1, by applying extended bioinformatics analysis and a wide range of in vitro assays to human PDAC-derived primary CAF cultures, we demonstrated the biological diversity of human pancreatic CAFs; we identified four CAF subtypes (A-D) with specific molecular and functional features (matrix- and immune-related signatures, vimentin and ?-smooth muscle actin expression, proliferation rate), and we showed that CAF heterogeneity had an impact on the interactions with cancer cells in mini-organotypic models.- In Part 2, we showed that the combination of CAF sub-populations was associated with distinct phenotypic characteristics of the tumours (tumour molecular subtype and grade, stromal abundance and activity, immune infiltrates, angiogenesis) and patient survival, in silico in the ICGC dataset and by immunohistochemistry in an extensively characterised patient cohort.- In Part 3, we showed that several CAF subtypes may emerge in vitro (conditioned media experiments) and in vivo (orthotopic xenografts) from the dynamic interactions of pancreatic stellate cells with cancer cells, through an “imprinting” process, and may be further modulated by other factors and/or cellular partners in the tumour microenvironment; in addition, we confirmed in a murine setting our findings about the association between CAF subtype marker expression and immune phenotype observed in human tumours.This unique classification for pancreatic CAFs (pCAFassigner) demonstrates the inter- and intra-tumoral phenotypic heterogeneity of CAFs in human PDAC. Our results provide a framework for future functional studies and pave the way for the development of therapies targeting specific CAF sub-populations in PDAC

Cancers des voies biliaires: nouvelles approches thérapeutiques médicales orientées par les données moléculaires

International audienc

Récidive tumorale précoce après résection d'un cancer du pancréas (la voie de HGF/c-Met et l hypoxie tumorale sont-elles des facteurs pronostiques majeurs ?)

PARIS7-Xavier Bichat (751182101) / SudocSudocFranceF

Apport de l'immunothérapie dans le traitement des cancers des voies biliaires avancés

International audienceContribution of immunotherapy in the treatment of advanced biliary tract cancer Biliary tract cancers (BTC) are rare tumors with a poor prognosis. Their treatment, at an advanced stage, relies on combinations of chemotherapies, which have a limited range and duration of benefit. Immunotherapy has emerged in recent years as a new therapeutic approach for BTC. However, the benefit with currently available treatments seems more modest than in other tumor locations and the predictive markers of response to these treatments remain to be identified. This review article summarizes the rationale, current data, and prospects and challenges for the development of immunotherapy in BTC.Les cancers des voies biliaires (CVB) sont des tumeurs rares au pronostic sombre. Leur traitement, au stade avancé, repose sur des associations de chimiothérapies, dont l'amplitude et la durée du bénéfice sont limitées. L'immunothérapie a émergé ces dernières années comme une nouvelle voie thérapeutique dans les CVB. Cependant, le bénéfice avec les traitements actuellement disponibles semble plus modeste que dans d'autres localisations tumorales et les marqueurs prédictifs de réponse à ces traitements restent à identifier. Cet article de synthèse résume le rationnel, les données actuelles et les perspectives et enjeux du développement de l'immunothérapie dans les CVB