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1. Circulating Tumor DNA is Prognostic and Potentially Predictive of Eryaspase Efficacy in Second-line in Patients with Advanced Pancreatic Adenocarcinoma

Author

Pierre Laurent-Puig, Laurent Mineur, Fabienne Portales, Jean-Philippe Metges, Hélène Blons, Claire Mulot, Jason E. Cain, Jean-Baptiste Bachet, Iman El Hariry, Jérôme Cros, Camille Bourreau, Pascal Hammel, Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Service d'Hépato-Gastro-Entérologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Cooperator Multidisciplinary Oncology Group (GERCOR), Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), ERYTECH Pharma, CRLC Val d'Aurelle-Paul Lamarque, CRLCC Val d'Aurelle - Paul Lamarque, Institut Sainte Catherine [Avignon], Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Service d’Anatomie Pathologique [CHU Beaujon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Beaujon [AP-HP], Gestionnaire, HAL Sorbonne Université 5, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)

Subjects
Adult, Male, 0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, [SDV.CAN]Life Sciences [q-bio]/Cancer, Adenocarcinoma, law.invention, Proto-Oncogene Proteins p21(ras), 03 medical and health sciences, 0302 clinical medicine, Second line, [SDV.CAN] Life Sciences [q-bio]/Cancer, Randomized controlled trial, law, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, Biomarkers, Tumor, medicine, Asparaginase, Humans, In patient, predictive, Objective response, Aged, Predictive biomarker, Aged, 80 and over, circulating tumor DNA, business.industry, Middle Aged, Prognosis, medicine.disease, L-asparaginase, Progression-Free Survival, Confidence interval, Pancreatic Neoplasms, Treatment Outcome, 030104 developmental biology, phase 2, Circulating tumor DNA, 030220 oncology & carcinogenesis, Mutation, Female, Tumor Suppressor Protein p53, business, prognostic
Abstract

Purpose: Eryaspase is composed of l-asparaginase encapsulated in erythrocytes and has demonstrated significant efficacy in a randomized phase II trial. We assessed the prognostic and predictive value of circulating tumor DNA (ctDNA) in patients, plasma included in this trial. Experimental Design: Samples prospectively collected pretreatment were centrally analyzed by next-generation sequencing. Prognostic values of baseline ctDNA and ctDNA early changes between day 0 and 28 were assessed in both arms combined on objective response rate (ORR), progression-free survival (PFS), and overall survival (OS); three groups were defined: negative ctDNA (Neg), ctDNA responders (Resp), and ctDNA nonresponders (NResp). Predictive value of ctDNA for eryaspase efficacy was investigated. Results: ctDNA was positive at baseline in 77 patients of the 113 tested patients (68%). Detectable ctDNA was an independent negative prognostic factor for OS (4.6 vs. 8.8 months; P = 0.0025) and PFS (1.6 vs. 3.3 months; P = 0.00043). Early change in ctDNA levels was correlated with ORR (20%, 26%, 0%; P < 0.04), PFS (3.7, 3.4, 1.6 months; P < 0.0001), and OS (11.7, 6.5, 4.3 months; P < 0.0001) according to the three defined groups (Neg, Res, NResp, respectively). In patients with ctDNA detectable at baseline, eryaspase was associated with better PFS [HR = 0.53; 95% confidence interval (CI): 0.3–0.94)] and OS (HR = 0.52; 95% CI: 0.29–0.91). Conclusions: We confirm from a prospective randomized trial that: (i) the presence of ctDNA at baseline is a major prognostic factor, (ii) the early change of ctDNA correlates with treatment outcome, and (iii) the ctDNA could be a predictive biomarker of eryaspase efficacy.

Published
2020
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2. Nestin as a diagnostic and prognostic marker for combined hepatocellular-cholangiocarcinoma

Author

Julien Calderaro, Luca Di Tommaso, Pascale Maillé, Aurélie Beaufrère, Cong Trung Nguyen, Lara Heij, Viviane Gnemmi, Rondell P. Graham, Frédéric Charlotte, Suzanne Chartier, Dominique Wendum, Mukul Vij, Daniela Allende, Alba Diaz, Carla Fuster, Benjamin Rivière, Astrid Herrero, Jérémy Augustin, Katja Evert, Diego Francesco Calvisi, Wei Qiang Leow, Howard Ho Wai Leung, Jan Bednarsch, Emmanuel Boleslawski, Mohamed Rela, Anthony Wing-Hung Chan, Alejandro Forner, Maria Reig, Anaïs Pujals, Loetitia Favre, Manon Allaire, Olivier Scatton, Arnaud Uguen, Eric Trépo, Lukas Otero Sanchez, Denis Chatelain, Myriam Remmelink, Camille Boulagnon-Rombi, Céline Bazille, Nathalie Sturm, Benjamin Menahem, Eric Frouin, David Tougeron, Christophe Tournigand, Emmanuelle Kempf, Haeryoung Kim, Massih Ningarhari, Sophie Michalak-Provost, Jakob Nikolas Kather, Annette S.H. Gouw, Purva Gopal, Raffaele Brustia, Eric Vibert, Kornelius Schulze, Darius F. Rüther, Sören A. Weidemann, Rami Rhaiem, Jean-Charles Nault, Alexis Laurent, Giuliana Amaddeo, Hélène Regnault, Eleonora de Martin, Christine Sempoux, Pooja Navale, Jayendra Shinde, Ketan Bacchuwar, Maria Westerhoff, Regina Cheuk-Lam Lo, Mylène Sebbagh, Catherine Guettier, Marie Lequoy, Mina Komuta, Marianne Ziol, Valérie Paradis, Jeanne Shen, Stefano Caruso, Hôpital Henri Mondor, Istituto Clinico Humanitas [Milan] (IRCCS Milan), Humanitas University [Milan] (Hunimed), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service de Pathologie [Hôpital Beaujon - APHP], Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Molecular virology and immunology – Physiopathology and therapeutic of chronic viral hepatitis (Team 18) (Inserm U955), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 (CANTHER), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), CHU Lille, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), CHU Saint-Antoine [AP-HP], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Université de Montpellier (UM), Thérapies Laser Assistées par l'Image pour l'Oncologie - U 1189 (ONCO-THAI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), University of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona (UB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), CHU Henri Mondor [Créteil], Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Université libre de Bruxelles (ULB), CHirurgie, IMagerie et REgénération tissulaire de l’extrémité céphalique - Caractérisation morphologique et fonctionnelle - UR UPJV 7516 (CHIMERE), Université de Picardie Jules Verne (UPJV), Laboratoire de Signalisation et Récepteurs Matriciels (SiRMa), Matrice extracellulaire et dynamique cellulaire - UMR 7369 (MEDyC), Université de Reims Champagne-Ardenne (URCA)-SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne (URCA)-Université de Reims Champagne-Ardenne (URCA)-Centre National de la Recherche Scientifique (CNRS)-Université de Reims Champagne-Ardenne (URCA)-SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne (URCA)-Université de Reims Champagne-Ardenne (URCA)-Centre National de la Recherche Scientifique (CNRS), Imagerie et Stratégies Thérapeutiques des pathologies Cérébrales et Tumorales (ISTCT), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Département de Pathologie [CHU Caen], Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), CHU Grenoble, Unité de recherche interdisciplinaire pour la prévention et le traitement des cancers (ANTICIPE), Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN)-Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Chirurgie Viscérale et Digestive [CHU Caen], CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Centre hospitalier universitaire de Poitiers (CHU Poitiers), Laboratoire d'Informatique Médicale et Ingénierie des Connaissances en e-Santé (LIMICS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Sorbonne Paris Nord, Groupe Henri Mondor-Albert Chenevier, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Hôpital Albert Chenevier, Johns Hopkins University (JHU), Hôpital Claude Huriez [Lille], Physiopathologie et traitement des maladies du foie, Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), Centre Hospitalier Universitaire de Reims (CHU Reims), Génomique fonctionnelle des tumeurs solides = Functional Genomics of Solid Tumors [CRC] (FunGeST), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Labex OncoImmunology, Equipe labellisée Ligue Contre le Cancer, Université Paris Descartes - Paris 5 (UPD5), Service d'Hépatologie [Avicenne], Hôpital Avicenne [AP-HP], Unité de Formation et de Recherche Santé, Médecine, Biologie Humaine [Bobigny], Université Paris 13 (UP13)-Sorbonne Paris Cité, Danmarks Tekniske Universitet = Technical University of Denmark (DTU), Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Génomique Fonctionnelle des Tumeurs Solides (U1162), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Crosscope, University of Michigan [Ann Arbor], University of Michigan System, AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Hôpital Bicêtre, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d’Anatomie Pathologique [CHU Beaujon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Beaujon [AP-HP], Labex Immuno-oncology [Paris] ( Université Paris Descartes - Paris 5 - PRES Sorbonne Paris Cité), Université Paris Descartes - Paris 5 (UPD5)-PRES Sorbonne Paris Cité, Service d'Anatomie et cytologie pathologiques [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service d'Anatomie et cytologie pathologiques = Service de Pathologie [CHU Pitié-Salpêtrière] (ACP), CHU Henri Mondor, Service d'Hépato-Gastro-Entérologie [CHU Pitié-Salpêtrière], Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Centre National de la Recherche Scientifique (CNRS)-Université de Reims Champagne-Ardenne (URCA)-SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Centre National de la Recherche Scientifique (CNRS), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité)-École pratique des hautes études (EPHE), Service d'Hépato-gastro-entérologie [CHU Saint-Antoine], and Groningen Institute for Organ Transplantation (GIOT)

Subjects
Carcinoma, Hepatocellular, Hepatology, combined hepatocellular-cholangiocarcinoma, Liver Neoplasms, hepatocellular carcinoma, liver, Prognosis, Nestin, Cholangiocarcinoma, Bile Ducts, Intrahepatic, Bile Duct Neoplasms, cancer, Humans, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Background & Aims: Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is a rare primary liver cancer (PLC) associated with a poor prognosis. Given the challenges in its identification and its clinical implications, biomarkers are critically needed. We aimed to investigate the diagnostic and prognostic value of the immunohistochemical expression of Nestin, a progenitor cell marker, in a large multicentric series of PLCs.Methods: We collected 461 cHCC-CCA samples from 32 different clinical centers. Control cases included 368 hepatocellular carcinomas (HCCs) and 221 intrahepatic cholangiocarcinomas (iCCAs). Nestin immunohistochemistry was performed on whole tumor sections. Diagnostic and prognostic performances of Nestin expression were determined using receiver-operating characteristic curves and Cox regression modeling.Results: Nestin was able to distinguish cHCC-CCA from HCC with AUCs of 0.85 and 0.86 on surgical and biopsy samples, respectively. Performance was lower for the distinction of cHCC-CCA from iCCA (AUCs of 0.59 and 0.60). Nestin, however, showed a high prognostic value, allowing identification of the subset of cHCC-CCA (“Nestin High”, >30% neoplastic cells with positive staining) associated with the worst clinical outcome (shorter disease-free and overall survival) after surgical resection and liver transplantation, as well as when assessment was performed on biopsies.Conclusion: We show in different clinical settings that Nestin has diagnostic value and that it is a useful biomarker to identify the subset of cHCC-CCA associated with the worst clinical outcome. Nestin immunohistochemistry may be used to refine risk stratification and improve treatment allocation for patients with this highly aggressive malignancy. Lay summary: There are different types of primary liver cancers (i.e. cancers that originate in the liver). Accurately identifying a specific subtype of primary liver cancer (and determining its associated prognosis) is important as it can have a major impact on treatment allocation. Herein, we show that a protein called Nestin could be used to refine risk stratification and improve treatment allocation for patients with combined hepatocellular carcinoma, a rare but highly aggressive subtype of primary liver cancer.

Published
2021
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3. The triglycerides and glucose (TyG) index: A new marker associated with nonalcoholic steatohepatitis (NASH) in obese patients

Author

Benjamin Rivière, Audrey Jaussent, Valérie Macioce, Stéphanie Faure, Nicolas Builles, Patrick Lefebvre, Philippe Géraud, Marie-Christine Picot, Sandra Rebuffat, Eric Renard, Valérie Paradis, Marie-Dominique Servais, Nathalie de Preville, David Nocca, Anne-Dominique Lajoix, Georges-Philippe Pageaux, Florence Galtier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Université de Montpellier (UM), Département d'Hépato-Gastroentérologie et de Transplantation Hépatique [CHU Saint-Eloi], CHU Saint-Eloi-Université de Montpellier (UM), Institut de Génomique Fonctionnelle (IGF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Biocommunication en Cardio-Métabolique (BC2M), CIC - Montpellier, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d’Anatomie Pathologique [CHU Beaujon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Laboratoire Servier, Département de chirurgie digestive et transplantation, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-CHU Saint-Eloi, Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), CIC Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-CHU Saint-Eloi-Institut National de la Santé et de la Recherche Médicale (INSERM), and F-CRIN, Innovative clinical research network in vaccinology (I-REIVAC)

Subjects
Adult, Male, Adolescent, Endocrinology, Diabetes and Metabolism, [SDV]Life Sciences [q-bio], Biopsy, digestive system, Morbid obesity, Young Adult, Endocrinology, Non-alcoholic Fatty Liver Disease, NAFLD, Internal Medicine, Humans, Obesity, Triglycerides, Aged, NASH, nutritional and metabolic diseases, General Medicine, Middle Aged, Fibrosis, digestive system diseases, Glucose, Diabetes Mellitus, Type 2, Liver, Female, TyG, Biomarkers
Abstract

Diagnosis of nonalcoholic steatohepatitis (NASH) relies on liver biopsy. Noninvasive tools would be useful to target patients to refer for a biopsy. We aimed to determine the diagnostic value of the triglycerides and glucose (TyG) index, an insulin-resistance indicator, to predict NASH.Our study included grade II-III obese patients aged 18-65 years undergoing bariatric surgery and included in the COMET (COllection of MEtabolic Tissues) biobank (NCT02861781). Liver biopsies performed during bariatric surgery were collected from the biobank along with blood derivatives. Biopsies were analysed according to the steatosis, activity and fibrosis (SAF) scoring system to diagnose NASH, nonalcoholic fatty liver disease (NAFLD), and fibrosis. Logistic regression models were performed to identify factors predicting NASH, NAFLD, and fibrosis.Of 238 analysed subjects (mean age 43±12 years, 33.6% men), 29% had type 2 diabetes. Steatosis was present in 67.2%, while NASH and advanced fibrosis (stage F3) were diagnosed in 18.1% and 2.9% respectively. TyG index was independently associated with NASH (odds ratio (OR): 4.7 [95% confidence interval: 2.3;9.5] P0.0001), NAFLD (OR: 2.0 [1.1;3.7] P = 0.03) and stages 2-3 fibrosis (OR: 4.0 [1.5;10.8] P = 0.007). NASH was also predicted by gamma-glutamyl transferase (GGT) with an area under the ROC curve: 0.79 [0.71;0.87 P = 0.04] for GGT and TyG index combined.In our cohort of severely obese patients, TyG index, when associated with GGT level, exhibited high diagnostic performance to predict NASH. Although validation in larger populations is needed, this result may be of considerable clinical value to predict need for liver biopsy.

Published
2021
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4. CARMN-NOTCH2 fusion transcript drives high NOTCH2 expression in glomus tumors of the upper digestive tract

Author

Janick Selves, Jean-François Emile, Marie Laure Raffin-Sanson, Benoǐt Terris, Chiara Villa, Nicolas Girard, Jérôme Cros, Catherine Julie, Jean François Fléjou, Zofia Hélias-Rodzewicz, Jean Michel Coindre, Christine Lagorce-Pages, Anne Sophie de Lajarte-Thirouard, Nathalie Guedj, Florence Renaud, Dominique Cazals-Hatem, Simon Martin de Beauce, Cristi Marin, Henri Jean Garchon, Biomarqueurs et essais cliniques en Cancérologie et Onco-Hématologie (BECCOH), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay, Service de pathologie [CHU Ambroise Paré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Ambroise Paré [AP-HP], Hôpital Foch [Suresnes], CHU Pontchaillou [Rennes], Centre hospitalier [Valenciennes, Nord], Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Lille Neurosciences & Cognition - U 1172 (LilNCog (ex-JPARC)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Service d’Anatomie Pathologique [CHU Beaujon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Infection et inflammation (2I), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d’endocrinologie et nutrition [AP-HP Ambroise-Paré], Hôpital Ambroise Paré [AP-HP], Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Service de Pathologie [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil (UVSQ Santé), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Institut Bergonié [Bordeaux], UNICANCER, Validation et identification de nouvelles cibles en oncologie (VINCO), UNICANCER-UNICANCER-Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de pathologie [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Association Pour la Recherche et L'enseignement en Pathologie, AREP, The study was supported by grants from Association pour la Recherche et l'Enseignement en Pathologie (AREP). The authors would like to thank Nathalie Terrones, Dominique Pechaud, Véronique Toulza, and Tristan Robert for performing tissue arrays sections and immunohistochemistry., École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Lille Neurosciences & Cognition - U 1172 (LilNCog), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Saint-Antoine [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
Cancer Research, Pathology, medicine.medical_specialty, endocrine system, endocrine system diseases, translocation, Chromosomal translocation, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, digestive tract, Fusion gene, 03 medical and health sciences, CARMN, 0302 clinical medicine, NOTCH2, Biomarkers, Tumor, Genetics, medicine, Humans, Receptor, Notch2, Gene, Exome, Gastrointestinal Neoplasms, 030304 developmental biology, 0303 health sciences, Stomach, medicine.disease, Phenotype, Glomus tumor, MicroRNAs, medicine.anatomical_structure, Fusion transcript, glomus tumor, 030220 oncology & carcinogenesis, Gene Fusion
Abstract

International audience; Glomus tumors (GTs) are perivascular tumors mostly occurring in the distal extremities. Rare cases arise in the digestive tract and may be misdiagnosed with neuroendocrine or gastrointestinal stromal tumors. We aimed to specify the features of GT of the upper digestive tract. Clinical, histological, phenotypic, and molecular features of 16 digestive GTs were analyzed, of whom two underwent whole exome and RNA sequencing to search for gene alterations. RNA-sequencing disclosed a t(1:5)(p13;q32) translocation, which resulted in the fusion of CARMN and NOTCH2 in two GTs. The fusion gene encoded a protein sequence corresponding to the NOTCH2 intracellular domain that functions as transcription factor. These finding was supported by high expression of genes targeted by NOTCH. The CARMN-NOTCH2 translocation was detected in 14 out of 16 (88%) GTs of the upper digestive tract; but in only in two out of six cutaneous GTs (33%). Most digestive GT arose from the stomach (n = 13), and the others from duodenal (2) or oesophagous (1). Nuclear expression of NOTCH2 was detected in the 14 cases containing the fusion transcripts. The CARMN-NOTCH2 fusion transcript may contribute to activation of the NOTCH2 pathway in GT and drive tumor development. The high frequency of this translocation in GT of the upper digestive track suggest that detection of nuclear NOTCH2 expression may be useful diagnostic biomarker of these tumors.

Published
2021
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5. Radioembolization Plus Chemotherapy for First-line Treatment of Locally Advanced Intrahepatic Cholangiocarcinoma: A Phase 2 Clinical Trial

Author

Boris Guiu, Eveline Boucher, Samuel Le Sourd, Olivier Farge, David Tougeron, Astrid Lièvre, Karim Boudjema, Yann Touchefeu, Isabelle Baumgaertner, Ahmet Ayav, Etienne Garin, Luc Beuzit, Marc Pracht, Julien Edeline, Yan Rolland, Boris Campillo-Gimenez, Jonchère, Laurent, Centre Eugène Marquis (CRLCC), Nutrition, Métabolismes et Cancer (NuMeCan), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service d’Anatomie Pathologique [CHU Beaujon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre hospitalier universitaire de Poitiers (CHU Poitiers), Service d'Oncologie médicale [CHU Henri Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Henri Mondor, Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Laboratoire Traitement du Signal et de l'Image (LTSI), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pontchaillou [Rennes], Chemistry, Oncogenesis, Stress and Signaling (COSS), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), This study was partially funded by BTG Corporation and the Ligue Contre le Cancer., Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CRLCC Eugène Marquis (CRLCC)-Université de Rennes 1 (UR1), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Henri Mondor [Créteil]

Subjects
Male, Cancer Research, medicine.medical_specialty, Phases of clinical research, Gastroenterology, Cholangiocarcinoma, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, 030212 general & internal medicine, Progression-free survival, Prospective cohort study, Aged, [SDV.IB] Life Sciences [q-bio]/Bioengineering, business.industry, Combination chemotherapy, Middle Aged, Chemotherapy regimen, Gemcitabine, 3. Good health, Bile Ducts, Intrahepatic, Treatment Outcome, Bile Duct Neoplasms, Oncology, Response Evaluation Criteria in Solid Tumors, 030220 oncology & carcinogenesis, Concomitant, Female, [SDV.IB]Life Sciences [q-bio]/Bioengineering, Neoplasm Recurrence, Local, business, medicine.drug
Abstract

International audience; Importance - Patients with unresectable intrahepatic cholangiocarcinoma (ICC) have a poor prognosis. Selective internal radiotherapy (SIRT) is a promising treatment option for hepatic tumors, but no prospective studies of combination SIRT with chemotherapy have been published to our knowledge. Objective - To determine the response rate after SIRT combined with chemotherapy in patients with unresectable ICC. Design, setting, and participants - This phase 2 clinical trial, the Yttrium-90 Microspheres in Cholangiocarcinoma (MISPHEC) trial, included patients with unresectable ICC who have never received chemotherapy or intra-arterial therapy and were treated at 7 centers which had experience with SIRT between November 12, 2013, and June 21, 2016. Statistical analysis was performed from March 31, 2017, to June 17, 2019. Interventions - Concomitant first-line chemotherapy with cisplatin, 25 mg/m2, and gemcitabine, 1000 mg/m2 (gemcitabine reduced to 300 mg/m2 for the cycles just before and after SIRT), on days 1 and 8 of a 21-day cycle for 8 cycles. Selective internal radiotherapy was administered during cycle 1 (1 hemiliver disease) or cycles 1 and 3 (disease involving both hemilivers) using glass Y90 microspheres. Main outcomes and measures - Response rate at 3 months according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Secondary end points were toxic effects, progression-free survival, overall survival, disease control rate, and response rate according to Choi criteria. Results - Of 41 patients included in the study, 26 (63%) were male, with a mean (SD) age of 64.0 (10.7) years. Response rate according to RECIST was 39% (90% CI, 26%-53%) at 3 months according to local review and was confirmed at 41% as best response by central review; disease control rate was 98%. According to Choi criteria, the response rate was 93%. After a median follow-up of 36 months (95% CI, 26-52 months), median progression-free survival was 14 months (95% CI, 8-17 months), with progression-free survival rates of 55% at 12 months and 30% at 24 months. Median overall survival was 22 months (95% CI, 14-52 months), with overall survival rates of 75% at 12 months and 45% at 24 months. Of 41 patients, 29 (71%) had grades 3 to 4 toxic effects; 9 patients (22%) could be downstaged to surgical intervention, with 8 (20%) achieving R0 (microscopic-free margins) surgical resection. After a median of 46 months (95% CI, 31 months to not reached) after surgery, median relapse-free survival was not reached among patients who underwent resection. Conclusions and relevance - Combination chemotherapy and SIRT had antitumor activity as first-line treatment of unresectable ICC, and a significant proportion of patients were downstaged to surgical intervention. A phase 3 trial is ongoing.

Published
2020
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6. Inhibition of the dipeptidyl peptidase DPP4 (CD26) reveals IL-33-dependent eosinophil-mediated control of tumor growth

Author

Clémence Hollande, Wendy Sandoval, Vincent Mallet, Tamaki Nozawa, Darragh Duffy, Vincent Bondet, Stanislas Pol, Jill Schartner, Valerie Paradis, James Ziai, Rosa Barreira da Silva, Gérard Eberl, Binfeng Lu, Matthew L. Albert, Jeremy Boussier, Wilson Phung, Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Genentech, Inc. [San Francisco], University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE), Centre de Recherche Translationnelle - Center for Translational Science (CRT), Institut Pasteur [Paris], Service d’Anatomie Pathologique [CHU Beaujon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'hépatologie médicale [CHU Cochin], Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Microenvironnement et Immunité - Microenvironment and Immunity, Funding for the work was provided by Fondation ARC pour la recherche sur le cancer, Institut national de la santé et de la recherche médicale (Inserm), Fondation pour la recherche médicale (FRM, FDM 40432) and LabEx Immuno-Onco (ANR)., Thanks to H. Saklani, M. A. Ingersoll and T. Canton for their help with mouse experimental work and ethical statement., ANR-11-IDEX-0005,USPC,Université Sorbonne Paris Cité(2011), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut Pasteur [Paris] (IP)

Subjects
0301 basic medicine, Chemokine CCL11, Chemokine, Lymphocyte, Dipeptidyl Peptidase 4, Immunology, Dipeptidyl peptidase, 03 medical and health sciences, 0302 clinical medicine, Cell Movement, Cell Line, Tumor, medicine, Immunology and Allergy, CXCL10, Animals, Humans, CCL11, Mice, Knockout, Dipeptidyl-Peptidase IV Inhibitors, Mice, Inbred BALB C, biology, Chemistry, Sitagliptin Phosphate, Degranulation, Neoplasms, Experimental, Eosinophil, Interleukin-33, 3. Good health, Interleukin 33, Eosinophils, Mice, Inbred C57BL, Disease Models, Animal, 030104 developmental biology, medicine.anatomical_structure, Cancer research, biology.protein, [SDV.IMM]Life Sciences [q-bio]/Immunology, 030215 immunology
Abstract

Post-translational modification of chemokines mediated by the dipeptidyl peptidase DPP4 (CD26) has been shown to negatively regulate lymphocyte trafficking, and its inhibition enhances T cell migration and tumor immunity by preserving functional chemokine CXCL10. By extending those initial findings to pre-clinical models of hepatocellular carcinoma and breast cancer, we discovered a distinct mechanism by which inhibition of DPP4 improves anti-tumor responses. Administration of the DPP4 inhibitor sitagliptin resulted in higher concentrations of the chemokine CCL11 and increased migration of eosinophils into solid tumors. Enhanced tumor control was preserved in mice lacking lymphocytes and was ablated after depletion of eosinophils or treatment with degranulation inhibitors. We further demonstrated that tumor-cell expression of the alarmin IL-33 was necessary and sufficient for eosinophil-mediated anti-tumor responses and that this mechanism contributed to the efficacy of checkpoint-inhibitor therapy. These findings provide insight into IL-33- and eosinophil-mediated tumor control, revealed when endogenous mechanisms of DPP4 immunoregulation are inhibited. Eosinophils have been described mainly in allergy settings but are increasingly appreciated as being involved in other aspects of immunity. Albert and colleagues use a clinically approved inhibitor of the dipeptidyl peptidase DPP4 to facilitate the recruitment of eosinophils to mouse tumors, where they are essential in tumor destruction.

Published
2019
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7. REGENERATE: Design of a pivotal, randomised, phase 3 study evaluating the safety and efficacy of obeticholic acid in patients with fibrosis due to nonalcoholic steatohepatitis

Author

Amrik Shah, Vlad Ratziu, Reshma Shringarpure, Stephen A. Harrison, Mary E. Rinella, Quentin M. Anstee, Pierre Bedossa, Rohit Loomba, Leigh MacConell, Zachary Goodman, Arun J. Sanyal, Zobair M. Younossi, Sorbonne Université (SU), CHU Pitié-Salpêtrière [APHP], Virginia Commonwealth University (VCU), University of California, Northwestern University [Evanston], Newcastle University [Newcastle], Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), Service d’Anatomie Pathologique [CHU Beaujon], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Beaujon, CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Beaujon [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)

Subjects
Liver Cirrhosis, medicine.medical_specialty, Cirrhosis, Chenodeoxycholic Acid, 03 medical and health sciences, chemistry.chemical_compound, Liver disease, 0302 clinical medicine, Farnesoid X receptor, Non-alcoholic Fatty Liver Disease, Fibrosis, Internal medicine, Nonalcoholic fatty liver disease, Humans, Medicine, Pharmacology (medical), Longitudinal Studies, Nonalcoholic steatohepatitis, 030304 developmental biology, 0303 health sciences, Dose-Response Relationship, Drug, medicine.diagnostic_test, business.industry, NASH, Obeticholic acid, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, General Medicine, Health Services, medicine.disease, Interim analysis, eye diseases, Liver Transplantation, 3. Good health, Clinical trial, chemistry, Liver biopsy, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Health Resources, 030211 gastroenterology & hepatology, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business
Abstract

Background Nonalcoholic steatohepatitis (NASH) is a chronic, progressive, and severe form of nonalcoholic fatty liver disease. In FLINT, obeticholic acid (OCA) treatment improved multiple histological NASH features. The design and endpoints of REGENERATE, an ongoing phase 3 study, further evaluate OCA treatment in patients with fibrosis due to NASH. Aims The Month 18 interim analysis assesses the effect of OCA on liver histology, defined as improvement of fibrosis by ≥1 stage with no worsening of NASH or resolution of NASH with no worsening of fibrosis. The end-of-study analyses evaluate the effect of OCA on mortality, liver-related clinical outcomes, and long-term safety. Methods REGENERATE is a pivotal, long-term study of ~2400 patients with NASH, including ~2100 patients with stage 2 or 3 liver fibrosis. Additionally, ~300 patients with stage 1 fibrosis and ≥ 1 accompanying comorbidity are included to gather information on the safety of OCA and liver disease progression. Patients are randomised 1:1:1 to receive placebo or OCA (10 or 25 mg). A liver biopsy evaluation occurs at screening, Months 18 and 48, and end of study. The duration of the study is dependent upon accrual of a predetermined number of clinical outcome events. Conclusions REGENERATE is designed in conjunction with regulatory authorities to support regulatory approvals in NASH. This robust phase 3 study assesses the effect of OCA on liver histology as a surrogate for transplant-free survival and liver-related outcomes, including progression to cirrhosis and mortality, and will ultimately assess clinical benefit through specific evaluation of these outcomes ( ClinicalTrials.gov , NCT02548351 ). Clinical trial registration ClinicalTrials.gov with the identifier NCT02548351 .

Published
2019
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8. Epithelial-mesenchymal transition in cholangiocarcinoma: from clinical evidence to regulatory networks

Author

Laura Fouassier, Thanh Huong Nguyen Ho-Bouldoires, Audrey Clapéron, Valérie Paradis, Nathalie Guedj, Javier Vaquero, Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Fondation ARC pour la recherche sur le cancer, Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d’Anatomie Pathologique [CHU Beaujon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and HAL-UPMC, Gestionnaire

Subjects
0301 basic medicine, Pathology, medicine.medical_specialty, Cell type, Cell, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Cholangiocarcinoma, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Stroma, medicine, Humans, Epithelial–mesenchymal transition, Transcription factor, Tumor microenvironment, Hepatology, Mesenchymal stem cell, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Prognosis, Epithelial-mesenchymal transition, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Invasiveness, 3. Good health, 030104 developmental biology, medicine.anatomical_structure, Bile Duct Neoplasms, 030220 oncology & carcinogenesis, Cancer cell, embryonic structures, Cancer research, Chemoresistance
Abstract

International audience; Cholangiocarcinoma (CCA) is an aggressive tumor with a poor prognosis due to its late clinical presentation and the lack of effective non-surgical therapies. Unfortunately, most of the patients are not eligible for curative surgery owing to the presence of metastases at the time of diagnosis. Therefore, it is important to understand the steps leading to cell dissemination in patients with CCA. To metastasize from the primary site, cancer cells must acquire migratory and invasive properties by a cell plasticity-promoting phenomenon known as epithelial-mesenchymal transition (EMT). EMT is a reversible dynamic process by which epithelial cells gradually adopt structural and functional characteristics of mesenchymal cells, and has lately become a center of attention in the field of metastatic dissemination. In the present review, we aim to provide an extensive overview of the current clinical data and the prognostic value of different EMT markers that have been analyzed in CCA. We summarize all the regulatory networks implicated in EMT from the membrane receptors to the main EMT-inducing transcription factors (SNAIL, TWIST and ZEB). Furthermore, since a tumor is a complex structure not exclusively formed by tumor cells, we also address the prominent role of the main cell types of the desmoplastic stroma that characterizes CCA in the regulation of EMT. Finally, we discuss the therapeutic considerations and difficulties faced to develop an effective anti-EMT treatment due to the redundancies and bypasses among the pathways regulating EMT.

Published
2016
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9. Effect of TT Virus Infection on Hepatocellular Carcinoma Development: Results of a Euro‐Asian Survey

Author

Pierre Tiollais, Pascal Pineau, Mounira Meddeb, Vincenzo Mazzaferro, Roberta Raselli, Anne Dejean, Lun Xiu Qin, Zhao You Tang, Benoit Terris, Recombinaison et Expression Génétique, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Cytogénetique et Génétique Oncologiques [Villejuif], Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), IRCCS Istituto Nazionale dei Tumori [Milano], Liver Cancer Institute, Fudan University [Shanghai], Service d’Anatomie Pathologique [CHU Beaujon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Association pour la Recherche sur le Cancer (ARC), Ligue Nationale contre le Cancer, and the Italian Association for Cancer Research (AIRC), We thank Christine Fernandez for help in statistical analysis, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Pineau, Pascal

Subjects
Male, Torque teno virus, viruses, medicine.disease_cause, MESH: Liver Neoplasms / virology, 0302 clinical medicine, Parvovirus B19, Human, Immunology and Allergy, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, MESH: Aged, 0303 health sciences, MESH: Middle Aged, Liver Neoplasms, DNA virus, Dependovirus, Middle Aged, Hepatitis B, 3. Good health, Infectious Diseases, Hepatocellular carcinoma, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Female, MESH: Liver Neoplasms / etiology, 030211 gastroenterology & hepatology, MESH: DNA, Viral / analysis, Adult, Carcinoma, Hepatocellular, MESH: Carcinoma, Hepatocellular / etiology, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH: Dependovirus / isolation & purification, Biology, MESH: Carcinoma, Hepatocellular / virology, Herpesviridae, Virus, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, medicine, Humans, Aged, 030304 developmental biology, Hepatitis B virus, MESH: Humans, DNA Viruses, MESH: Adult, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, medicine.disease, Virology, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, MESH: Male, MESH: DNA Viruses / isolation & purification, DNA, Viral, MESH: Parvovirus B19, Human / isolation & purification, MESH: Female, Nested polymerase chain reaction
Abstract

International audience; A small percentage of persons with hepatocellular carcinoma (HCC) lack identifiable causes of liver pathology. The single-stranded DNA virus, TT virus (TTV), has been found in persons with acute and chronic liver injury. Nested polymerase chain reaction was used to search for both TTV and parvoviruses in 293 HCC samples from Asia and Europe. TTV was found in >30% of Chinese and Italian samples but in only 13% of French samples. No clinicopathologic differences were found between TTV-positive and -negative populations. A significant association was found between TTV infection and hepatitis B virus (P

Published
2000
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10. Close correlation between β-catenin gene alterations and nuclear accumulation of the protein in human hepatocellular carcinomas

Author

Jacques Belghiti, Pierre Tiollais, Pascal Pineau, Laurence Bregeaud, Dominique Valla, Benoit Terris, Claude Degott, Anne Dejean, Service d’Anatomie Pathologique [CHU Beaujon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Recombinaison et Expression Génétique, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d’Hépatologie [Hôpital Beaujon], Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Chirurgie Digestive [CHU Beaujon], This work was supported by a grant from the Association pour la Recherche contre le Cancer., and Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
MESH: Cell Nucleus, Cancer Research, Carcinoma, Hepatocellular, MESH: Mutation, Beta-catenin, MESH: Cytoskeletal Proteins, MESH: Trans-Activators, Adenomatous polyposis coli, [SDV]Life Sciences [q-bio], MESH: beta Catenin, medicine.disease_cause, 03 medical and health sciences, Exon, 0302 clinical medicine, MESH: Liver Neoplasms, Genetics, medicine, Humans, Missense mutation, MESH: Carcinoma, Hepatocellular, Molecular Biology, Gene, beta Catenin, 030304 developmental biology, Cell Nucleus, 0303 health sciences, Mutation, MESH: Humans, biology, Liver Neoplasms, MESH: Immunohistochemistry, hepatocellular carcinoma, β-catenin, HCCS, APC, 3. Good health, Cytoskeletal Proteins, 030220 oncology & carcinogenesis, immunohistochemistry, Trans-Activators, biology.protein, Cancer research, Carcinogenesis
Abstract

International audience; Several lines of evidence indicate that beta-catenin acquires oncogenic activity when its intracellular concentration increases as a result of either mutation in the beta-catenin gene itself or inactivation of the adenomatous polyposis coli (APC) gene. In an attempt to elucidate the molecular mechanisms underlying hepatocellular carcinogenesis, we have studied the frequency of beta-catenin gene alterations in exon 3, a region known to represent a mutation hot spot, and its inappropriate protein expression by immunohistochemistry in 73 hepatocellular carcinomas (HCCs). The results were correlated with different clinical and pathological data, particularly with the presence or not of an associated cirrhosis. Fourteen (19%) HCCs showed beta-catenin gene alterations with missense mutations in nine cases and interstitial deletions in five cases. These genetic alterations were present in both cirrhotic and non-cirrhotic groups. By contrast, we did not find any beta-catenin gene alterations in the nine fibromellar carcinomas we examined. Nuclear accumulation of the protein was observed in 18 of them (25%). Remarkably, these included ten of the 14 tumors harboring somatic mutations in the beta-catenin gene (P < 0.001). Our results indicate that accumulation of beta-catenin resulting from genetic mutations is a frequent event in non-fibrolamellar type hepatocellular carcinoma. The close association between increased beta-catenin protein stability and mutation indicates that immunohistochemistry may be a powerful method for the detection of the mutated protein in future clinical practice.

Published
1999
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11. Hepatocellular carcinoma occurring in nonfibrotic liver: Epidemiologic and histopathologic analysis of 80 French cases

Author

Gwenolé Loas, Benoit Terris, Pascal Pineau, Dominique Valla, Jacques Belghiti, Marie-Pierre Bralet, Jean-Marc Regimbeau, Sylvie Dubois, Claude Degott, Françoise Degos, Service d’Anatomie Pathologique [CHU Beaujon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Chirurgie Digestive [CHU Beaujon], Recombinaison et Expression Génétique, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Amiens-Picardie, Service d’Hépatologie [Hôpital Beaujon], Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), The authors thank Dr. M-C Bralet for assistance in statistical analysis., Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), and Pineau, Pascal

Subjects
Male, Pathology, Cirrhosis, Necrosis, Gastroenterology, 0302 clinical medicine, Medicine, MESH: Hepatitis B / complications, MESH: Aged, MESH: France / epidemiology, MESH: Middle Aged, Liver cell, Liver Neoplasms, MESH: Carcinoma, Hepatocellular / pathology, Middle Aged, Hepatitis B, Hepatitis C, 3. Good health, 030220 oncology & carcinogenesis, Hepatocellular carcinoma, Female, 030211 gastroenterology & hepatology, MESH: Liver Neoplasms / etiology, France, medicine.symptom, Adult, medicine.medical_specialty, Carcinoma, Hepatocellular, MESH: Hepatitis C / complications, MESH: Carcinoma, Hepatocellular / etiology, [SDV.CAN]Life Sciences [q-bio]/Cancer, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, Humans, MESH: Carcinoma, Hepatocellular / epidemiology, neoplasms, Hemochromatosis, Aged, Retrospective Studies, MESH: Liver Neoplasms / pathology, MESH: Humans, Hepatology, business.industry, MESH: Liver Neoplasms / epidemiology, MESH: Adult, MESH: Retrospective Studies, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, medicine.disease, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, MESH: Male, Portal fibrosis, Steatosis, business, MESH: Female
Abstract

Comment in : Occurrence of hepatocellular carcinoma in nonfibrotic livers./Bioulac-Sage P, Le Bail BL, Winnock M, Balabaud C, Bemard C, Blanc JF, Saric J. Hepatology. 2000 Dec;32(6):1411-2. doi: 10.1053/jhep.2000.20819. PMID: 11186870; International audience; Hepatocellular carcinoma (HCC) occurring in nonfibrotic liver represents a rare, ill-defined subgroup of HCC without cirrhosis in which mechanisms of hepatocarcinogenesis remain unclear. The aim of our study was to assess epidemiological factors and detailed histopathologic changes in the nontumoral liver of patients developing such tumors. Of 330 HCCs resected in our institution between 1985 and 1998, we retrospectively analyzed 80 cases (53 men, 27 women; mean age, 51 +/- 16 years) in which the nontumoral liver showed no (n = 28) or minimal (n = 52) portal fibrosis without any septal fibrosis. In the group with no portal fibrosis there was no male predominance, and patients were significantly younger (44 +/- 19 years vs. 54 +/- 14 years) than those with minimal portal fibrosis. Sixty-seven tumors were typical HCCs, 8 were of fibrolamellar type, and 5 were hepatocholangiocarcinomas. Mean tumor size was 10 +/- 5 cm. Risk factors for HCC development were found in 30 patients: hepatitis B (n = 17) or C (n = 2) virus infections, alcohol consumption (n = 11), and hemochromatosis (n = 1). In the nontumoral liver, periportal and lobular necrosis, mild portal inflammation, steatosis, and iron overload were present in 15%, 57%, 52%, and 54% of cases, respectively. Liver cell changes were noted in 6%. This study emphasizes the need for strict criteria to classify HCC without cirrhosis. HCC in nonfibrotic liver is a distinct subgroup in which nontumoral liver shows nonspecific minimal changes without regeneration or premalignant lesion. Etiologic factors are often unidentified, although presence of HBV infection in 21% suggests a direct oncogenic role of this virus.

Published
2000
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12. The acute promyelocytic leukemia PML-RARα protein induces hepatic preneoplastic and neoplastic lesions in transgenic mice

Author

Gregory David, Benoit Terris, Anne Dejean, Catherine Lavau, Agnès Marchio, Recombinaison et Expression Génétique, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d’Anatomie Pathologique [CHU Beaujon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), This work was supported by grants from the European Community (Biomed and Biotech Programs), the Association pour la Recherche sur le Cancer and la Ligue Nationale Contre le Cancer. GD is supported by a fellowship from the Institut de Formation Supérieure Biomédicale., Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Cheriet Rauline, Samia

Subjects
Male, MESH: Neoplasm Proteins, Cancer Research, Oncogene Proteins, Fusion, [SDV]Life Sciences [q-bio], Gene Expression, translocation, Mice, Tissue culture, 0302 clinical medicine, Leukemia, Promyelocytic, Acute, MESH: Liver Neoplasms, MESH: Animals, Promoter Regions, Genetic, 0303 health sciences, Liver Neoplasms, Neoplasm Proteins, 3. Good health, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, MESH: Precancerous Conditions, Liver, 030220 oncology & carcinogenesis, Hepatocyte, MESH: Zinc Sulfate, MESH: Cell Division, Female, Cell Division, Acute promyelocytic leukemia, Genetically modified mouse, MESH: Gene Expression, MESH: Mice, Transgenic, Transgene, Mice, Transgenic, Biology, transgenic mice, 03 medical and health sciences, MESH: Promoter Regions, Genetic, Genetics, medicine, Animals, Molecular Biology, MESH: Mice, 030304 developmental biology, Cell growth, MESH: Metallothionein, medicine.disease, Fusion protein, Zinc Sulfate, MESH: Male, Basophilic, APL, hepatocarcinoma, Immunology, Cancer research, Metallothionein, PML-RARa, Precancerous Conditions, MESH: Female, MESH: Leukemia, Promyelocytic, Acute, MESH: Liver, MESH: Oncogene Proteins, Fusion
Abstract

International audience; The PML-RAR alpha hybrid protein generated by the t(15;17) translocation in acute promyelocytic leukemia (APL) is thought to play a central role in the oncogenic process. However, analysis of the oncogenic activity of the fusion protein in tissue culture assays or in mice has been hampered by its apparent toxicity in multiple murine cells. To circumvent this problem, we generated an inducible line of transgenic mice, MT135, in which the expression of PML-RAR alpha is driven by the metallothionein promoter. After 5 days zinc stimulation, 27 out of 54 mice developed hepatic preneoplasia and neoplasia including foci of basophilic hepatocytes, dysplasia and carcinoma with a significantly higher incidence of lesions in females than in males. The rapid onset of liver pathologies was dependent on overexpression of the transgene since it was not detected in noninduced transgenic animals of the same age. The PML-RAR alpha protein was always present in altered tissues at much higher levels than in the surrounding normal liver tissues. In addition, overexpression of PML-RAR alpha resulted in a strong proliferative response in the hepatocytes. We conclude that overexpression of PML-RAR alpha deregulates cell proliferation and can induce tumorigenic changes in vivo.

Published
1997
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13. Recurrent attacks of acute hepatic porphyria: major role of the chronic inflammatory response in the liver

Author

Katell Peoc'h, Staffan Wahlin, Constance Delaby, Jordi To-Figueras, Philippe Lettéron, Arienne Mirmiran, Zoubida Karim, Arndt Benecke, Laurent Gouya, Hervé Puy, Caroline Schmitt, Arne K. Sandvik, Johannes R. Hov, Eliane Sardh, Laurence Chiche, Joaquim Abian, Hana Manceau, Montserrat Carrascal, Jean-Yves Scoazec, Céline Bazille, Angèle Yu, Pauline Harper, Jean-Charles Deybach, Thibaud Lefebvre, Aasne K. Aarsand, Valérie Paradis, Sverre Sandberg, Hugo Lenglet, Universitat de Barcelona, Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), Signalisation et Transports Ioniques Membranaires (STIM), Université de Poitiers-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre for Neuropsychopharmacology, Imperial College London, Laboratoire d'Excellence : Biogenèse et pathologies du globule rouge (Labex Gr-Ex), Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d’Anatomie Pathologique [CHU Beaujon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Department of Public Health and Primary Health Care, University of Bergen (UiB), Bjerknes Centre for Climate Research (BCCR), Department of Biological Sciences [Bergen] (BIO / UiB), University of Bergen (UiB)-University of Bergen (UiB), Department of Hepatobiliary Surgery, Hôpital Côte de Nacre [CHU Caen], CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Imagerie et Stratégies Thérapeutiques des pathologies Cérébrales et Tumorales (ISTCT), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Département d'anatomopathologie, biopathologie, Centre Léon Bérard [Lyon], Instituto de Investigaciones Biomedicas de Barcelona (IIBB), Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), Centre de recherche biomédicale Bichat-Beaujon (CRB3), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Lariboisière, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Poitiers-Université de Tours-Centre National de la Recherche Scientifique (CNRS), Université Paris Diderot - Paris 7 (UPD7)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université de Tours-Centre National de la Recherche Scientifique (CNRS)-Université de Poitiers, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Beaujon, University of Bergen (UIB), Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Consejo Superior de Investigaciones Científicas [Spain] (CSIC), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Lariboisière-Université Paris Diderot - Paris 7 (UPD7), Alnylam Pharmaceuticals, Schmitt, Caroline, Neuroscience Paris Seine (NPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and Schmitt, Caroline [0000-0001-5145-7260]

Subjects
0301 basic medicine, Disease, Gastroenterology, Haem oxygenase 1, Transcriptome, Cohort Studies, chemistry.chemical_compound, 0302 clinical medicine, Recurrence, Risk Factors, Iron overload, Medicine, acute intermittent porphyria, Acute intermittent porphyria, Malalties del fetge, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 3. Good health, Hydroxymethylbilane Synthase, Liver, Acute Disease, Chronic inflammatory response, Hemin, Female, medicine.symptom, 5-Aminolevulinate Synthetase, medicine.medical_specialty, Inflammation, 03 medical and health sciences, Internal medicine, Internal Medicine, Animals, Humans, hemin, iron overload, Liver diseases, Porphyria, business.industry, Membrane Proteins, medicine.disease, ALAS1, Porfíria, Mice, Inbred C57BL, Oxidative Stress, 030104 developmental biology, Cross-Sectional Studies, chemistry, inflammation, Porphyria, Acute Intermittent, haem oxygenase 1, business, 030217 neurology & neurosurgery, Heme Oxygenase-1, Follow-Up Studies
Abstract

[Background] Acute intermittent porphyria (AIP) is an inherited disorder of haem metabolism characterized by life‐threatening acute neurovisceral attacks due to the induction of hepatic δ‐aminolevulinic acid synthase 1 (ALAS1) associated with hydroxymethylbilane synthase (HMBS) deficiency. So far, the treatment of choice is hemin which represses ALAS1. The main issue in the medical care of AIP patients is the occurrence of debilitating recurrent attacks. [Objective] The aim of this study was to determine whether chronic hemin administration contributes to the recurrence of acute attacks. [Methods] A follow‐up study was conducted between 1974 and 2015 and included 602 French AIP patients, of whom 46 had recurrent AIP. Moreover, we studied the hepatic transcriptome, serum proteome, liver macrophage polarization and oxidative and inflammatory profiles of Hmbs−/− mice chronically treated by hemin and extended the investigations to five explanted livers from recurrent AIP patients. [Results] The introduction of hemin into the pharmacopeia has coincided with a 4.4‐fold increase in the prevalence of chronic patients. Moreover, we showed that both in animal model and in human liver, frequent hemin infusions generate a chronic inflammatory hepatic disease which induces HO1 remotely to hemin treatment and maintains a high ALAS1 level responsible for recurrence. [Conclusion] Altogether, this study has important impacts on AIP care underlying that hemin needs to be restricted to severe neurovisceral crisis and suggests that alternative treatment targeting the liver such as ALAS1 and HO1 inhibitors, and anti‐inflammatory therapies should be considered in patients with recurrent AIP., LG, JCD, PH, ES and AKA were funded for attending meeting related to ongoing clinical trial by Alnylam Pharmaceuticals.

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