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32 results on '"[SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology"'

1. Conventional and artificial intelligence-based imaging for biomarker discovery in chronic liver disease

Author

Jérémy Dana, Aïna Venkatasamy, Antonio Saviano, Joachim Lupberger, Yujin Hoshida, Valérie Vilgrain, Pierre Nahon, Caroline Reinhold, Benoit Gallix, Thomas F. Baumert, Institut de Recherche sur les Maladies Virales et Hépatiques (IVH), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), L'Institut hospitalo-universitaire de Strasbourg (IHU Strasbourg), Institut National de Recherche en Informatique et en Automatique (Inria)-l'Institut de Recherche contre les Cancers de l'Appareil Digestif (IRCAD)-Les Hôpitaux Universitaires de Strasbourg (HUS)-La Fédération des Crédits Mutuels Centre Est (FCMCE)-L'Association pour la Recherche contre le Cancer (ARC)-La société Karl STORZ, McGill University = Université McGill [Montréal, Canada], Pôle Hépato-digestif [Strasbourg], Nouvel Hôpital Civil [Strasbourg], CHU Strasbourg-CHU Strasbourg, Harold C. Simmons Comprehensive Cancer Center [Dallas, TX, États-Unis], University of Texas Southwestern Medical Center [Dallas], Laboratory of Imaging Biomarkers, UMR1149, INSERM-University Paris-Diderot, Paris, AP-HP - Hôpitaux Universitaires Paris Seine-Saint-Denis (GHU 93), Augmented Intelligence and Precision Health Laboratory (AIPHL), Department of Radiology, McGill University, Montreal, QC H3G 1A4, Canada, ANR-10-LABX-0028,HepSys,Functional genomics of viral hepatitis and liver disease(2010), ANR-10-IAHU-0002,MIX-Surg,Institut de Chirurgie Mini-Invasive guidée par l'Image(2010), European Project: 671231,H2020,ERC-2014-ADG,HEPCIR(2016), and European Project: 667273,H2020,H2020-PHC-2015-two-stage,HEP-CAR(2016)

Subjects
Liver Cirrhosis, Chronic liver disease Histo-pathological features Pejorative evolution Quantitative biomarkers Elastography Machine learning Radiomics Deep learning, Sciences du Vivant [q-bio]/Médecine humaine et pathologie, Article, methods, Artificial Intelligence, Hypertension, Portal, Machine learning, Humans, Quantitative biomarkers, Histo-pathological features, diagnostic imaging, pathology, Radiomics, Hepatology, Liver Neoplasms, Chronic liver disease, Deep learning, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Magnetic Resonance Imaging, Fatty Liver, Liver, Pejorative evolution, Disease Progression, Elasticity Imaging Techniques, Elastography, Biomarkers
Abstract

Chronic liver diseases, resulting from chronic injuries of various causes, lead to cirrhosis with life-threatening complications including liver failure, portal hypertension, hepatocellular carcinoma. A key unmet medical need is robust non-invasive biomarkers to predict patient outcome, stratify patients for risk of disease progression and monitor response to emerging therapies. Quantitative imaging biomarkers have already been developed, for instance, liver elastography for staging fibrosis or proton density fat fraction on magnetic resonance imaging for liver steatosis. Yet, major improvements, in the field of image acquisition and analysis, are still required to be able to accurately characterize the liver parenchyma, monitor its changes and predict any pejorative evolution across disease progression. Artificial intelligence has the potential to augment the exploitation of massive multi-parametric data to extract valuable information and achieve precision medicine. Machine learning algorithms have been developed to assess non-invasively certain histological characteristics of chronic liver diseases, including fibrosis and steatosis. Although still at an early stage of development, artificial intelligence-based imaging biomarkers provide novel opportunities to predict the risk of progression from early-stage chronic liver diseases toward cirrhosis-related complications, with the ultimate perspective of precision medicine. This review provides an overview of emerging quantitative imaging techniques and the application of artificial intelligence for biomarker discovery in chronic liver disease. journal article review 2022 Jun 2022 02 09 imported

Published
2022

2. A phase 2a randomized clinical trial of intravenous vedolizumab for the treatment of steroid-refractory intestinal acute graft-versus-host disease

Author

Mark A. Schroeder, Steven M. Devine, Yi-Bin Chen, Andrejus Parfionovas, Yngvar Fløisand, Syed Quadri, Dominik Selleslag, Chunlin Chen, Ibrahim Yakoub-Agha, Patrice Chevallier, Mona Akbari, Mohamad Mohty, Johan Jansson, Anne S. Renteria, Oslo University Hospital [Oslo], Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), Centre hospitalier universitaire de Nantes (CHU Nantes), Center for International Blood and Marrow Transplant Research, Pathologies biliaires, fibrose et cancer du foie [CRSA], 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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Institute for Translational Research in Inflammation - U 1286 (INFINITE (Ex-Liric)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Millennium Pharmaceuticals, Massachusetts General Hospital [Boston], Pathologies biliaires, fibrose et cancer du foie [CHU Saint-Antoine], Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [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)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [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), and HAL-SU, Gestionnaire

Subjects
[SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, medicine.medical_specialty, Ruxolitinib, Population, Graft vs Host Disease, Drug development, Antibodies, Monoclonal, Humanized, Graft-versus-host disease, Gastroenterology, Article, Vedolizumab, law.invention, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, immune system diseases, law, hemic and lymphatic diseases, Internal medicine, medicine, Humans, education, Adverse effect, Transplantation, education.field_of_study, integumentary system, business.industry, Hematopoietic Stem Cell Transplantation, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, Hematology, medicine.disease, Ulcerative colitis, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, 3. Good health, surgical procedures, operative, Tolerability, Molecularly targeted therapy, 030220 oncology & carcinogenesis, Acute Disease, Steroids, [SDV.IMM.IMM] Life Sciences [q-bio]/Immunology/Immunotherapy, business, 030215 immunology, medicine.drug
Abstract

Steroid-refractory (SR) acute graft-versus-host disease (aGvHD) remains a significant complication after allogeneic hematopoietic cell transplantation. Systemic corticosteroids are first-line therapy for aGvHD, but apart from ruxolitinib, there are no approved treatments for SR aGvHD. Vedolizumab is approved for treatment of ulcerative colitis and Crohn’s disease, and may be effective for treatment of SR intestinal aGvHD. We conducted a phase 2a trial (NCT02993783) to evaluate the clinical efficacy, tolerability, and safety of vedolizumab 300 and 600 mg for SR intestinal aGvHD. This study was terminated before full enrollment was completed because early results failed to demonstrate positive proof-of-concept in efficacy. Before termination, 17 participants had enrolled and an early response in intestinal aGvHD was observed in 11 and eight participants at days 15 and 28, respectively. All adverse events observed were consistent with those expected in a population with SR intestinal aGvHD. Overall, vedolizumab did not meet the primary efficacy endpoint (overall response at day 28), likely owing to premature study drug discontinuation, lack of efficacy, and the competing risks inherent with a population with advanced SR intestinal aGvHD. Nevertheless, this study provides valuable insights into the considerations needed when conducting studies in patients with SR intestinal aGvHD.

Published
2021

3. Population pharmacokinetic model of irinotecan and its four main metabolites in patients treated with FOLFIRI or FOLFIRINOX regimen

Author

Florence Gattacceca, Alexandre Evrard, Marc Ychou, Laure Deyme, Dominique Barbolosi, Nicole Tubiana-Mathieu, Litaty Mbatchi, Méthodes computationnelles pour la prise en charge thérapeutique en oncologie : Optimisation des stratégies par modélisation mécaniste et statistique (COMPO), Inria Sophia Antipolis - Méditerranée (CRISAM), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), CHU Limoges, Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), and GATTACCECA, Florence

Subjects
Male, 0301 basic medicine, Oncology, Cancer Research, FOLFIRINOX, Leucovorin, Toxicology, 0302 clinical medicine, CPT-11, Antineoplastic Combined Chemotherapy Protocols, Pharmacology (medical), Population pharmacokinetics, ComputingMilieux_MISCELLANEOUS, education.field_of_study, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, [SDV.SP] Life Sciences [q-bio]/Pharmaceutical sciences, Oxaliplatin, 030220 oncology & carcinogenesis, FOLFIRI, Female, Fluorouracil, Folfirinox Regimen, Colorectal Neoplasms, medicine.drug, medicine.medical_specialty, Population, [SDV.CAN]Life Sciences [q-bio]/Cancer, Context (language use), Irinotecan, Nonlinear mixed effect modelling, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Pharmacokinetics, Internal medicine, medicine, Humans, education, Pharmacology, business.industry, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, stomatognathic diseases, 030104 developmental biology, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Camptothecin, Topoisomerase I Inhibitors, business
Abstract

International audience; PurposeThe aim of the present study was to characterize the pharmacokinetics of irinotecan and its four main metabolites (SN-38, SN-38G, APC and NPC) in metastatic colorectal cancer patients treated with FOLFIRI and FOLFIRINOX regimens and to quantify and explain the inter-individual pharmacokinetic variability in this context.MethodsA multicenter study including 109 metastatic colorectal cancer patients treated with FOLFIRI or FOLFIRINOX regimen, associated or not with a monoclonal antibody, was conducted. Concentrations of irinotecan and its four main metabolites were measured in 506 blood samples during the first cycle of treatment. Collected data were analyzed using the population approach. First, fixed and random effects models were selected using statistical and graphical methods; second, the impact of covariates on pharmacokinetic parameters was evaluated to explain the inter-individual variability in pharmacokinetic parameters.ResultsA seven-compartment model best described the pharmacokinetics of irinotecan and its four main metabolites. First-order rates were assigned to distribution, elimination, and metabolism processes, except for the transformation of irinotecan to NPC which was nonlinear. Addition of a direct conversion of NPC into SN-38 significantly improved the model. Co-administration of oxaliplatin significantly modified the distribution of SN-38.ConclusionTo our knowledge, the present model is the first to allow a simultaneous description of irinotecan pharmacokinetics and of its four main metabolites. Moreover, a direct conversion of NPC into SN-38 had never been described before in a population pharmacokinetic model of irinotecan. The model will be useful to develop pharmacokinetic-pharmacodynamic models relating SN-38 concentrations to efficacy and digestive toxicities.

Published
2021

4. French survey on a cohort of emergency general surgery modifications induced by lockdown of the SARS-CoV-2 pandemic

Author

Clement, Julien, Pauline, Duconseil, Diane, Mege, Damien, Massalou, Todor, Ivanov, Raffaele, Brustia, Ghislain, Pauleau, Stéphane V, Berdah, Thierry, Bège, Charles, Vanbrugghe, CHU Pitié-Salpêtrière [AP-HP], and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)

Subjects
medicine.medical_specialty, Multivariate analysis, Coronavirus disease 2019 (COVID-19), Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Acute abdominal surgery, [SDV.MHEP.CHI]Life Sciences [q-bio]/Human health and pathology/Surgery, 030204 cardiovascular system & hematology, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Pandemic, Humans, Medicine, In patient, 030212 general & internal medicine, Pandemics, Medical treatment, SARS-CoV-2, business.industry, General surgery, COVID-19, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, General Medicine, 3. Good health, Communicable Disease Control, Cohort, Original Article, Loss of chance, Digestive surgery, business, Healthcare system
Abstract

International audience; Purpose: The brutal COVID-19 pandemic has majorly impacted populations and health systems, and surgeons have observed dramatic changes in their daily clinical activities. A survey of French digestive surgeons was conducted to assess these changes.Methods: An electronic survey was sent to French digestive and general surgeons in the Societe Francaise de Chirurgie Digestive (SFCD) to assess the surgeons' daily activity during the pandemic and investigate changes in patients' management. The care deviations were classified as delay of management, modification of strategy, or modification of organization, and the impact of these changes on patients was evaluated by the surgeon's estimation of loss of chance.Results: A major reduction in surgical elective activity was observed in 50 (75%) of the 67 hospitals that responded. Of these, 48 hospitals (71.6%) reported receiving SARS-CoV-2 patients. A deviation from usual care was observed in 10% of patients admitted for emergency general surgery. Among 140 patients presenting a deviation from usual care, 74 (52.9%) had delayed management, 53 (37.9%) had a modification of strategy, and 64 (45.7%) had a modification of organization. Medical treatment instead of surgical treatment was decided for 37 (26.4%) patients, resulting in a high loss of chance for 6 patients. Delays (p < 0.001) and a switch from surgical to medical treatment (p = 0.002) were independently correlated with overall loss of chance based on multivariate analysis.Conclusion: This study highlighted the deviations in general emergency surgery patients and provided implications for the solutions that should be implemented during a new health crisis.

Published
2021

5. Sustained-hepatic arterial infusion of oxaliplatin: pharmacokinetic advantages over hepatic arterial infusion using a preclinical animal tumour model

Author

Laurence Moine, Lambros Tselikas, Shinji Motoyama, Thomas Isoardo, Frederic Deschamps, Michel Ducreux, Thierry de Baere, Masako Tasaki, Dragica Paunovic, Institut Gustave Roussy (IGR), Imagerie thérapeutique (radiologie interventionnelle), Département d'imagerie médicale [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Immunologie anti-tumorale et immunothérapie des cancers (ITIC), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Université Paris-Saclay, Oncologie digestive, Département de médecine oncologique [Gustave Roussy], Institut Galien Paris-Sud (IGPS), and Université Paris-Sud - Paris 11 (UP11)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)

Subjects
medicine.medical_specialty, Cmax, Pharmaceutical Science, [SDV.CAN]Life Sciences [q-bio]/Cancer, 02 engineering and technology, 030226 pharmacology & pharmacy, Gastroenterology, 03 medical and health sciences, 0302 clinical medicine, Therapeutic index, Hepatic arterial infusion, Pharmacokinetics, Internal medicine, medicine, Lung, business.industry, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, 021001 nanoscience & nanotechnology, medicine.disease, 3. Good health, Oxaliplatin, medicine.anatomical_structure, Hepatocellular carcinoma, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Lipiodol, 0210 nano-technology, business, medicine.drug
Abstract

International audience; Hepatic arterial infusion (HAI) of oxaliplatin allows greater liver tumour drug exposure compared to systemic infusion. However, the therapeutic index of HAI oxaliplatin remains poor. Using Pickering emulsion technology, we developed a platform able to provide sustained releases of oxaliplatin. The goal of this study was to evaluate the pharmacokinetic advantages of sustained-HAI oxaliplatin over HAI using a preclinical animal tumour model. Injections of 0.6 mg oxaliplatin in 20 min were selectively done in left hepatic arteries of 20 rabbits bearing a VX2 liver tumour in the middle left-lobe, using HAI (n = 10) or sustained-HAI (n = 10). In each group, half of the rabbits were sacrificed at 24 h and half at 72 h. Mass spectrometry was used to quantify drug pharmacokinetics in blood and oxaliplatin concentrations in tumour tissues, right- and middle left-liver lobes, spleen and lung. Compared to HAI, sustained-HAI of oxaliplatin resulted in lower plasmatic peak (Cmax: 275 ± 41 vs. 416 ± 133 ng/mL, p = 0.02) and higher concentration in the tumour at 24 h (2118 ± 2107 vs. 210 ± 93 ng/g, p = 0.008). After HAI, oxaliplatin concentration in tumours was significantly higher than in lung at 24 h (p = 0.03) but no other difference was found between oxaliplatin concentrations in tumours and in liver lobes, spleen or lung, neither at 24 h nor at 72 h. On the opposite, sustained-HAI resulted in higher concentrations of oxaliplatin in tumour compared to oxaliplatin concentrations in the middle left lobe (163 ± 86 ng/g at 24 h, p = 0.01, and 90 ± 15 ng/g at 72 h, p = 0.04), right lobe (174 ± 112 ng/g at 24 h, p = 0.01, and 112 ± 35 ng/g, p = 0.04 at 72 h), spleen (142 ± 21 ng/g at 24 h, p = 0.01, and 98 ± 12 ng/g at 72 h, p = 0.04), and lung (85 ± 11 ng/g at 24 h, p = 0.01, and 52 ± 4 ng/g at 72 h, p = 0.03). Sustained-HAI improves the therapeutic index of HAI oxaliplatin and offers a great potential for patients suffering from unresectable colorectal liver metastases or hepatocellular carcinoma.

Published
2021

6. Weight Loss After Sleeve Gastrectomy: Does Type 2 Diabetes Status Impact Weight and Body Composition Trajectories?

Author

Christine Poitou, Jean-Michel Oppert, Marc Diedisheim, Jean-Luc Bouillot, Judith Aron-Wisnewsky, C. Ciangura, Karine Clément, Laurent Genser, Chloé Amouyal, Service de Nutrition [CHU Pitié-Salpétrière], Institut E3M [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)-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), Nutrition et obésités: approches systémiques (UMR-S 1269) (Nutriomics), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Centre hospitalier Saint-Joseph [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), 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), Service de nutrition [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Nutrition et obésités: approches systémiques (nutriomics) (UMR-S 1269 INSERM - Sorbonne Université), 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), and Gestionnaire, HAL Sorbonne Université 5

Subjects
Sleeve gastrectomy, medicine.medical_specialty, endocrine system diseases, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Gastric bypass, Gastric Bypass, 030209 endocrinology & metabolism, [SDV.MHEP.CHI]Life Sciences [q-bio]/Human health and pathology/Surgery, Type 2 diabetes, Body composition, Gastroenterology, Fat mass, 03 medical and health sciences, 0302 clinical medicine, Gastrectomy, Weight loss, Internal medicine, Weight Loss, medicine, Humans, Obesity, Retrospective Studies, Glycemic, Bariatric surgery, Nutrition and Dietetics, business.industry, nutritional and metabolic diseases, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, medicine.disease, Obesity, Morbid, [SDV.AEN] Life Sciences [q-bio]/Food and Nutrition, Diabetes Mellitus, Type 2, Weight-loss, 030211 gastroenterology & hepatology, Surgery, medicine.symptom, business, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition
Abstract

International audience; Introduction/ purpose: Sleeve gastrectomy (SG), the most frequently performed bariatric procedure, induces marked weight-loss, but with high inter-individual variability. Since type 2 diabetes (T2D) negatively impacts weight-loss outcomes after Roux-en-Y gastric bypass (RYGB), we herein aimed to evaluate whether and how T2D status may influence weight-loss and body composition changes in individuals with or without T2D after SG.Material and Methods: We retrospectively included individuals with obesity operated from SG and prospectively followed at our center: 373 patients including 152 with T2D (40%). All subjects’ clinical characteristics were collected before and during 4 years of follow-up post-SG. Linear mixed models were applied to analyze weight-loss trajectories post-surgery.Results: Compared to individuals with obesity but no T2D, those with T2D before SG displayed lower weight-loss at 1 year (21 vs. 27% from baseline, p 7%) at baseline. Furthermore, patients with T2D underwent less favorable body composition changes at 1-year post-SG compared to individuals without T2D (% fat mass reduction: 28 vs. 37%, p

Published
2020

7. A New, Non-Invasive Scale for Steatosis Developed Using Real-World Data From Russian Outpatients to Aid in the Diagnosis of Non-Alcoholic Fatty Liver Disease

Author

Vlad Ratziu, Igor V. Maev, Elena I Vovk, Elena V Golovanova, Kirill M Starostin, Alexey A. Samsonov, Leonid Lazebnik, Chavdar S Pavlov, A.I. Yevdokimov Moscow State University of Medicine and Dentistry [Moscow, Russia], Sechenov First Moscow State Medical University, CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université - Faculté de Médecine (SU FM), and Sorbonne Université (SU)

Subjects
Adult, Male, medicine.medical_specialty, Adolescent, Population, Russia, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Non-alcoholic Fatty Liver Disease, NAFLD, Internal medicine, Outpatients, Diagnosis, Epidemiology, medicine, Humans, Pharmacology (medical), Child, education, Original Research, Retrospective Studies, 2. Zero hunger, education.field_of_study, business.industry, Fatty liver, NASH, nutritional and metabolic diseases, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, General Medicine, medicine.disease, Metabolic syndrome, digestive system diseases, Scale, 3. Good health, Cross-Sectional Studies, Diabetes Mellitus, Type 2, 030220 oncology & carcinogenesis, Cohort, Female, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, 030211 gastroenterology & hepatology, Steatosis, Steatohepatitis, business, Body mass index
Abstract

International audience; Introduction: The current non-invasive tools for the diagnosis of non-alcoholic fatty liver disease (NAFLD) have methodological limitations. We aimed to develop a non-invasive scale to assist in the diagnosis of NAFLD. To achieve our aim, we conducted a secondary analysis of data from a large observational study conducted in Russia.Methods: This retrospective analysis assessed the frequency of NAFLD in the population of patients in the DIREG_L_06725 study, an epidemiological, observational, cross-sectional, multicenter study performed in 50,145 outpatients from 16 Russian cities. Among the cohort of patients diagnosed with NAFLD, we identified factors associated with the risk of NAFLD. To develop a non-invasive tool for diagnosing NAFLD, we also determined the frequency of steatohepatitis.Results: Our analysis included 48,297 patients; NAFLD was present in 20,281 patients (42.0%). The majority (64.1%) were women (80.3% post-menopause), and 87% had a body mass index (BMI) > 27.0 kg/m2. We developed a fully non-invasive scale (St-index) that showed a specificity of 91.4% for ruling in steatosis, and a sensitivity of 93.8% for ruling out steatosis. Multivariate regression analyses conducted in the subgroups of patients aged ≥ 12 and < 18 years and those with BMI < 25.0 kg/m2 produced area under the receiver operating characteristic (AUROC) curve values of 0.8243 and 0.7054, respectively. The factors most strongly associated with the development of NAFLD were age > 35 years, presence of type 2 diabetes mellitus, and a waist circumference/height ratio > 0.54.Conclusion: Our non-invasive steatosis scale, St-index, can help physicians diagnose NAFLD in high-risk patients in the absence of ultrasound data.

Published
2020

8. Managing the challenge of drug-induced liver injury: a roadmap for the development and deployment of preclinical predictive models

Author

Raymond Pieters, Klaus Gjervig Jensen, Philip G. Hewitt, Jan Snoeys, Bob van de Water, B. Kevin Park, Ursula Klingmüller, André Guillouzo, Ian M. Copple, Dominic P. Williams, Michael J. Liguori, Cerys A. Lovatt, Paul Morgan, Satu Juhila, Eric A.G. Blomme, Magnus Ingelman-Sundberg, Dean J. Naisbitt, Gilles Labbe, Amy E. Chadwick, Christopher E. Goldring, Helga H.J. Gerets, Richard J. Weaver, Jonchère, Laurent, Mechanism-Based Integrated Systems for the Prediction of Drug-Induced Liver Injury - MIP-DILI - - EC:FP7:SP1-JTI2012-02-01 - 2017-01-31 - 115336 - VALID, University of Liverpool, 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), Merck Research Laboratories, Karolinska Institutet [Stockholm], Division Systems Biology of Signal Transduction, German Cancer Research Center (DKFZ), German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), SANOFI Recherche, Abbvie Inc. [North Chicago], GlaxoSmithKline, Glaxo Smith Kline, AstraZeneca, University Medical Center [Utrecht], Janssen Research & Development, Leiden University, Institut de Recherches Internationales Servier [Suresnes] (IRIS), UCB BioPharma [Braine l’Alleud, Belgium], This work was supported by the European Community (Contract MIP-DILI-115336) under the Innovative Medicines Initiative Joint Undertaking, a contribution from the European Union's Seventh Framework Programme (FP7/20072013) and European Federation of Pharmaceutical Industries and Associations (EFPIA) companies (http://www.imi.europa.eu/) and by the German Ministry of Education and Research (BMBF) within ‘Multi-Scale Modeling of Drug-Induced Liver Injury’ (MS_DILI, 031L0074A)., European Project: 115336,EC:FP7:SP1-JTI,IMI-JU-03-2010,MIP-DILI(2012), 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), and Universiteit Leiden

Subjects
0301 basic medicine, Drug, Drug-Related Side Effects and Adverse Reactions, [SDV]Life Sciences [q-bio], media_common.quotation_subject, In vitro model, 03 medical and health sciences, Preclinical research, 0302 clinical medicine, Predictive Value of Tests, Drug Discovery, Animals, Humans, Medicine, media_common, Pharmacology, Adverse effects, business.industry, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, General Medicine, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, 3. Good health, [SDV] Life Sciences [q-bio], Disease Models, Animal, 030104 developmental biology, Risk analysis (engineering), Software deployment, Preclinical testing, 030220 oncology & carcinogenesis, Chemical and Drug Induced Liver Injury, business
Abstract

International audience; Drug-induced liver injury (DILI) is a patient-specific, temporal, multifactorial pathophysiological process that cannot yet be recapitulated in a single in vitro model. Current preclinical testing regimes for the detection of human DILI thus remain inadequate. A systematic and concerted research effort is required to address the deficiencies in current models and to present a defined approach towards the development of new or adapted model systems for DILI prediction. This Perspective defines the current status of available models and the mechanistic understanding of DILI, and proposes our vision of a roadmap for the development of predictive preclinical models of human DILI.

Published
2019

9. Accuracy of citrulline, I-FABP and d-lactate in the diagnosis of acute mesenteric ischemia

Author

Katell Peoc'h, Alexy Tran-Dinh, Nathalie Gault, Yoram Bouhnik, Kevin Guedj, Antonino Nicoletti, Yves Castier, Claude Hercend, Alexandre Nuzzo, Olivier Corcos, Maxime Ronot, Claude Bendavid, Sonja Curac, Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Laboratoire de Recherche Vasculaire Translationnelle (LVTS (UMR_S_1148 / U1148)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Université Sorbonne Paris Nord, Nutrition, Métabolismes et Cancer (NuMeCan), 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 Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), CHU Pontchaillou [Rennes], AP-HP - Hôpital Bichat - Claude Bernard [Paris], Centre d'investigation Clinique [CHU Bichat] - Épidémiologie clinique (CIC 1425), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), SURVI (Structure d’URgences Vasculaires Intestinales) Research Group (French Intestinal Stroke Center): Audrey Huguet, Carmen Stefanescu, Xavier Treton, Francisca Joly, Lore Billiauws, Annick Hamon, Aureline Boitet, Céline Lekhal, David Deutsch, Elsa Oiknin, Laura Cohen, Gabriel Marcellier, Jean Senemaud, Felix Corre, Damien Soudan, Cosmin Voican, Jean-Baptiste Leclère, Jules Iquilles, Lucas Raynaud, Luisa Paulatto, Manon Haas, Mathieu Uzzan, Mathilde Cohen, Sara Tadbiri, Servane Prevot, Yves Panis, Alice Frontali, Simon Msika, Lara Ribeiro, Lionel Rebibo, Konstantinos Arapis, Marion Orville, Annie Sibert, Pauline Copin, Magaly Zappa, Marco Dioguardi Burgio, Valérie Vilgrain, Caroline Bertin, Anne Kerbaol, Wassim Allaham, Quentin Pellenc, Arnaud Roussel, Pierre Cerceau, Iannis Ben Abdallah, Antoine Girault, Pierre Mordant, Romain De Blic, Catherine Paugam, Emmanuel Weiss, Paer-Selim Abback, Isabelle Enriquez, Sylvie Janny, Helene Bout, Mikhael Giabicani, Marina Achouf, Bénédicte Grigoresco, Linda Koy Ear, Sonja Curac, Agnès Cachier, Aurelie Plessier, Pierre-Emmanuel Rautou, Dominique Valla, Audrey Payancé, Alain Sauvanet, Safi Dokmak, Federica Dondero, Ailton Sepulveda, Olivier Farges, Beatrice Aussilhou, Bénédicte Jais, Dominique Cazals-Hatem, Emmanuelle De Raucourt, Larbi Boudaoud, Catherine Trichet, Herve Puy, Nathalie Pons-Kerjean, Jeanick Stocco, Julie Bataille, Valérie Bouton, Philippe Montravers, Pascal Augustin, Brice Lortat Jacob, Jean-Baptiste Michel, Dominique Gauguier, Marc-Emmanuel Dumas, François Brial, Antonis Myridakis, Laura Martinez-Gili, Michael Olanipekun, Estelle Marcault, Cindie Nilusmas, Anne Barnier, Aminata Souare, Grants from MSD-Avenir and APHP funded the SURVIBIO study, Alexandre Nuzzo received Ph.D. Grants from 'Fondation de l'Avenir' and the French Gastroenterology Society (SNFGE)., Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, 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), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), and Jonchère, Laurent

Subjects
Male, [SDV]Life Sciences [q-bio], Statistical difference, Acute abdominal pain, Diseases, Gastroenterology, chemistry.chemical_compound, 0302 clinical medicine, Acute mesenteric ischemia, Citrulline, Stroke, Abdomen, Acute, Multidisciplinary, PLASMA CITRULLINE, CELIAC-DISEASE, Middle Aged, ACID-BINDING-PROTEIN, 3. Good health, Multidisciplinary Sciences, [SDV] Life Sciences [q-bio], 030220 oncology & carcinogenesis, Science & Technology - Other Topics, Medicine, Biomarker (medicine), Female, 030211 gastroenterology & hepatology, Adult, medicine.medical_specialty, VILLOUS ATROPHY, Science, Cardiology, Fatty Acid-Binding Proteins, Article, INTESTINAL ISCHEMIA, 03 medical and health sciences, [CHIM.ANAL]Chemical Sciences/Analytical chemistry, Internal medicine, MANAGEMENT, medicine, Humans, Lactic Acid, cardiovascular diseases, Aged, Science & Technology, business.industry, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, medicine.disease, SERUM D(-)-LACTATE LEVELS, SURVI (Structure d’URgences Vasculaires Intestinales) Research Group (French Intestinal Stroke Center), Circulating biomarkers, SEROLOGICAL MARKERS, Cross-Sectional Studies, Early Diagnosis, chemistry, Mesenteric Ischemia, ENTEROCYTE MASS, Tomography, X-Ray Computed, D lactate, business, Biomarkers
Abstract

Early diagnosis of acute mesenteric ischemia (AMI) remains a clinical challenge, and no biomarker has been consistently validated. We aimed to assess the accuracy of three promising circulating biomarkers for diagnosing AMI—citrulline, intestinal fatty acid-binding protein (I-FABP), and d-lactate. A cross-sectional diagnostic study enrolled AMI patients admitted to the intestinal stroke center and controls with acute abdominal pain of another origin. We included 129 patients—50 AMI and 79 controls. Plasma citrulline concentrations were significantly lower in AMI patients compared to the controls [15.3 μmol/L (12.0–26.0) vs. 23.3 μmol/L (18.3–29.8), p = 0.001]. However, the area under the receiver operating curves (AUROC) for the diagnosis of AMI by Citrulline was low: 0.68 (95% confidence interval = 0.58–0.78). No statistical difference was found in plasma I-FABP and plasma d-lactate concentrations between the AMI and control groups, with an AUROC of 0.44, and 0.40, respectively. In this large cross-sectional study, citrulline, I-FABP, and d-lactate failed to differentiate patients with AMI from patients with acute abdominal pain of another origin. Further research should focus on the discovery of new biomarkers.

Published
2021

10. Revisiting immune escape in colorectal cancer in the era of immunotherapy

Author

Hans Morreau, Marieke E. Ijsselsteijn, Catherine Sautès-Fridman, Florent Petitprez, Noel Filipe da Cunha Carvalho de Miranda, Ruud van der Breggen, Laetitia Lacroix, Catherine Julie, Wolf H. Fridman, Dina Ruano, Leiden University Medical Center (LUMC), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Université Sorbonne Paris Cité (USPC), Ligue Nationale Contre le Cancer - Paris, Ligue Nationnale Contre le Cancer, Service de pathologie [CHU Ambroise Paré], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Ambroise Paré, École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Ambroise Paré [AP-HP]

Subjects
Male, Cancer Research, Carcinogenesis, Colorectal cancer, T-Lymphocytes, medicine.medical_treatment, Antigen presentation, Genes, MHC Class I, [SDV.CAN]Life Sciences [q-bio]/Cancer, Human leukocyte antigen, Brief Communication, medicine.disease_cause, Metastasis, 03 medical and health sciences, 0302 clinical medicine, Immunoediting, Neoplastic Syndromes, Hereditary, medicine, Humans, Neoplasm Metastasis, Oncogenesis, Regulation of gene expression, Antigen Presentation, Brain Neoplasms, Immune evasion, business.industry, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, Immunotherapy, Middle Aged, medicine.disease, Phenotype, digestive system diseases, 3. Good health, Blockade, Gene Expression Regulation, Neoplastic, Genes, cdc, Liver, Oncology, 030220 oncology & carcinogenesis, Cancer research, Female, Colorectal Neoplasms, business
Abstract

International audience; In colorectal cancer (CRC), T-cell checkpoint blockade is only effective in patients diagnosed with mismatch repair-deficient (MMR-d) cancers. However, defects in Human Leukocyte Antigen (HLA) class I expression were reported to occur in most MMR-d CRCs, which would preclude antigen presentation in these tumours, considered essential for the clinical activity of this immunotherapeutic modality. We revisited this paradox by characterising HLA class I expression in two independent cohorts of CRC. We determined that loss of HLA class I expression occurred in the majority (73-78%) of MMR-d cases. This phenotype was rare in CRC liver metastases, irrespective of MMR status, whereas weak, inducible expression of HLA class I molecules was frequent in liver lesions. We propose that HLA class I is an important determinant of metastatic homing in CRCs. This observation is paramount to understand CRC carcinogenesis and for the application of immunotherapies in the metastatic setting.

Published
2019

11. Yttrium-90 glass microspheres radioembolization (RE) for biliary tract cancer: a large single-center experience

Author

Vincent Manceau, Luc Beuzit, Yan Rolland, Marc Pracht, Julien Edeline, Xavier Palard, Astrid Lièvre, Fanny Le Du, Thomas Uguen, Héloïse Bourien, Karim Boudjema, Samuel Le Sourd, Etienne Garin, CRLCC Eugène Marquis (CRLCC), Département de Radiologie [CHU de Rennes], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), CHU Pontchaillou [Rennes], Nutrition, Métabolismes et Cancer (NuMeCan), 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), ANR-11-LABX-0018-01, Agence Nationale de la Recherche (FR), ANR-11-LABX-0018,IRON,Radiopharmaceutiques Innovants en Oncologie et Neurologie(2011), Université de Rennes (UR), and Institut National de la Recherche Agronomique (INRA)-Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Male, medicine.medical_specialty, [SDV]Life Sciences [q-bio], medicine.medical_treatment, [SDV.CAN]Life Sciences [q-bio]/Cancer, Single Center, Gastroenterology, 030218 nuclear medicine & medical imaging, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Dosimetry, Internal medicine, medicine, Humans, Yttrium Radioisotopes, Radiology, Nuclear Medicine and imaging, Radioembolization, 90Y, Retrospective Studies, Intrahepatic cholangiocarcinoma, Chemotherapy, business.industry, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, General Medicine, Embolization, Therapeutic, Survival Analysis, Microspheres, Confidence interval, 3. Good health, Clinical trial, Biliary Tract Neoplasms, Biliary tract, 030220 oncology & carcinogenesis, Concomitant, Cohort, Orthopedic surgery, Biliary tract cancer, Female, Glass, business
Abstract

International audience; Purpose - Radioembolization (RE) is a promising treatment option for biliary tract cancers (BTC). We report here the largest series to date using this treatment modality. Methods - We retrospectively studied data from 64 patients treated outside prospective clinical trial at our institution. We studied baseline characteristics as potential prognostic factors. We studied dose delivered to the tumor as predictive factors of outcomes in patients not receiving concomitant chemotherapy. Results - The Progression-Free Survival and Overall Survival (OS) were 7.6 months [95% Confidence Interval (CI): 4.6-10.6] and 16.4 months [95% CI: 7.8-25.0] in the whole cohort. The factors independently associated with OS in multivariable analysis were the primary localization of ICC (HR = 0.27, 95% CI: 0.11-0.68, p = 0.005) and a PS > 0 (HR = 2.21, 95% CI: 1.11-4.38, p = 0.024). During follow-up, 12 patients (19%) underwent surgery following downstaging, with a median OS of 51.9 months. In patients not treated with concomitant chemotherapy (n = 31), OS was significantly higher in patients with a dose delivered to the tumor 260Gy or higher than in patients with a dose delivered to the tumor lower than 260Gy (median 28.2 vs 11.4 months, log-rank p = 0.019). Conclusion - Our results confirm that RE is a promising treatment modality in BTC. A high proportion of patients could be downstaged to surgery, with promising long-term survival. Dose delivered to the tumor correlated with clinical outcomes when chemotherapy was not used concomitantly.

Published
2018

12. Revealing links between gut microbiome and its fungal community in Type 2 Diabetes Mellitus among Emirati subjects: A pilot study

Author

Karine Clément, Mohammad Tahseen Al Bataineh, Nihar Ranjan Dash, Pierre Bel Lassen, Bayan Hassan Banimfreg, Aml Mohamed Nada, Eugeni Belda, University of Sharjah (UoS), Nutrition et obésités: approches systémiques (nutriomics) (UMR-S 1269 INSERM - Sorbonne Université), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Service de nutrition [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), American University of Sharjah, Integromics [Paris], Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], This work was supported by Research Institute of Medical and Health Sciences at University of Sharjah grant P1701090226 (M.A.B), Boehringer Ingelheim grant 2016-17 (N.R.D), EU litmus grant (K.C), Le Ducq foundation (K.C. and P.B.L), and JPI-HDHL MICRODIET consortium grant (K.C and P.B.L)., Service de Nutrition [CHU Pitié-Salpétrière], Institut E3M [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Bodescot, Myriam, Nutrition et obésités: approches systémiques (UMR-S 1269) (Nutriomics), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-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), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
Male, 0301 basic medicine, endocrine system diseases, Prevotella, Pilot Projects, Overweight, Polymerase Chain Reaction, 0302 clinical medicine, RNA, Ribosomal, 16S, Bacteroides, 2. Zero hunger, Genetics, education.field_of_study, Multidisciplinary, biology, Fungal genetics, Endocrine system and metabolic diseases, Middle Aged, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Medicine, Female, Enterotype, medicine.symptom, Microbial genetics, Adult, Science, Population, United Arab Emirates, Microbial communities, 030209 endocrinology & metabolism, Article, Young Adult, 03 medical and health sciences, medicine, Humans, Microbiome, Author Correction, education, [SDV.MP] Life Sciences [q-bio]/Microbiology and Parasitology, Aged, nutritional and metabolic diseases, Type 2 Diabetes Mellitus, RNA, Fungal, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, biology.organism_classification, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Gastrointestinal Microbiome, 030104 developmental biology, Diabetes Mellitus, Type 2, Mycobiome
Abstract

Type 2 diabetes mellitus (T2DM) drastically affects the population of Middle East countries with an ever-increasing number of overweight and obese individuals. The precise links between T2DM and gut microbiome composition remain elusive in these populations. Here, we performed 16 S rRNA and ITS2- gene based microbial profiling of 50 stool samples from Emirati adults with or without T2DM. The four major enterotypes initially described in westernized cohorts were retrieved in this Emirati population. T2DM and non-T2DM healthy controls had different microbiome compositions, with an enrichment in Prevotella enterotype in non-T2DM controls whereas T2DM individuals had a higher proportion of the dysbiotic Bacteroides 2 enterotype. No significant differences in microbial diversity were observed in T2DM individuals after controlling for cofounding factors, contrasting with reports from westernized cohorts. Interestingly, fungal diversity was significantly decreased in Bacteroides 2 enterotype. Functional profiling from 16 S rRNA gene data showed marked differences between T2DM and non-T2DM controls, with an enrichment in amino acid degradation and LPS-related modules in T2DM individuals, whereas non-T2DM controls had increased abundance of carbohydrate degradation modules in concordance with enterotype composition. These differences provide an insight into gut microbiome composition in Emirati population and its potential role in the development of diabetes mellitus.

Published
2020

13. A retrospective study of patient-tailored FOLFIRINOX as a first-line chemotherapy for patients with advanced biliary tract cancer

Author

Gabriella Pittau, Pamela Biondani, Wathek Almohamad, Ayhan Ulusakarya, Abdoulaye Karaboué, Oriana Ciacio, Mazen Haydar, Yusuf Gumus, Amale Chebib, Pasquale F. Innominato, Department of Medical Oncology [Villejuif], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse, Modèles de Cellules Souches Malignes et Thérapeutiques, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Sud - Paris 11 (UP11), Medical oncology unit [Montfermeil], Groupe Hospitalier Intercommunal Le Raincy-Montfermeil, Department of Surgery [Villejuif], Betsi Cadwaladr University Health Board [Bangor, Royaume-Uni], Warwick Medical School, University of Warwick [Coventry], Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Bodescot, Myriam

Subjects
Male, Cancer Research, FOLFIRINOX, Advanced biliary tract cancer, Leucovorin, Real life practice, Gastroenterology, Cholangiocarcinoma, 0302 clinical medicine, Antineoplastic Combined Chemotherapy Protocols, Aged, 80 and over, 0303 health sciences, Middle Aged, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, 3. Good health, [SDV.SP] Life Sciences [q-bio]/Pharmaceutical sciences, Oxaliplatin, Biliary Tract Neoplasms, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, Female, Fluorouracil, France, Research Article, medicine.drug, Adult, medicine.medical_specialty, [SDV.CAN]Life Sciences [q-bio]/Cancer, Irinotecan, lcsh:RC254-282, Disease-Free Survival, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, Pancreatic cancer, Genetics, medicine, Carcinoma, Humans, Response Evaluation Criteria in Solid Tumors, Aged, Neoplasm Staging, Retrospective Studies, 030304 developmental biology, business.industry, Gallbladder, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Retrospective cohort study, medicine.disease, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Gemcitabine, Regimen, business, Febrile neutropenia
Abstract

Background FOLFIRINOX is a pillar first-line regimen in the treatment of pancreatic cancer. Historically, biliary tract cancer (BTC) and pancreatic cancer have been treated similarly with gemcitabine alone or combined with a platinum compound. With growing evidence supporting the role of fluoropyrimidines in the treatment of BTC, we aimed at assessing the outcomes of patients (pts) with BTC on frontline FOLFIRINOX. Methods We retrospectively analyzed data of all our consecutive patients with locally advanced (LA) or metastatic (M) BTC who were registered to receive FOLFIRINOX as a first-line therapy between 12/2013 and 11/2017 at Paul Brousse university hospital. The main endpoints were Overall Survival (OS), Time-to-Progression (TTP), best Objective Response Rate (ORR), Disease Control rate (DCR), secondary macroscopically-complete resection (res) and incidence of severe (grade 3–4) toxicity (tox). Results There were 17 male (40%) and 25 female (60%) pts. aged 36 to 84 years (median: 67). They had PS of 0 (55%) or 1 (45%), and intrahepatic cholangiocarcinoma (CCA) (21 pts., 50%), gallbladder carcinoma (8 pts., 19%), perihilar CCA (7 pts., 17%), distal CCA (4 pts., 10%) and ampulloma (2 pts., 5%). BTC was LA or M in 10 (24%) and 32 pts. (76%) respectively. Biliary stent was placed in 14 pts. (33%). A median of 10 courses was given with median treatment duration of 6 months. There were no untoward toxicity issues, with no febrile neutropenia, emergency admission for toxicity or toxic death. We observed 12 partial responses (29%) and 19 disease stabilisations (45%). Six patients (14%) underwent secondary R0-R1 resection. Median TTP was 8 months [95%CL, 6–10] and median OS was 15 months [13–17]. Patients undergoing secondary resection displayed a 3-y disease-free rate of 83%. Conclusions First-line FOLFIRINOX offers promising results in patients with LA and M-BTC. It deserves prospective evaluation to further improve outcomes for advanced BTC.

Published
2020

14. Study of a classification algorithm for AIEC identification in geographically distinct E. coli strains

Author

Margarita Martinez-Medina, Paula Bustamante, Claire L. O'Brien, Roberto Vidal, Carla Camprubí-Font, Nicolas Barnich, Universitat de Girona (UdG), Universidad de Chile = University of Chile [Santiago] (UCHILE), University of Wollongong [Australia], Australian National University (ANU), Canberra Hospital, Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte (M2iSH), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre de Recherche en Nutrition Humaine d'Auvergne (CRNH d'Auvergne)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), and Bodescot, Myriam

Subjects
0301 basic medicine, lcsh:Medicine, Single-nucleotide polymorphism, Disease pathogenesis, Biology, medicine.disease_cause, Polymorphism, Single Nucleotide, Microbiology, Bacterial Adhesion, Article, Inflammatory bowel disease, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Molecular marker, Escherichia coli, medicine, Humans, INVASIVE ESCHERICHIA COLI, lcsh:Science, 10. No inequality, Escherichia coli Infections, Phylogeny, Multidisciplinary, Geography, lcsh:R, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, 030104 developmental biology, chemistry, Geographic origin, lcsh:Q, 030211 gastroenterology & hepatology, Identification (biology), [SDV.MP.BAC] Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Algorithm, Algorithms
Abstract

Adherent-invasive Escherichia coli (AIEC) have been extensively implicated in Crohn’s disease pathogenesis. Currently, AIEC is identified phenotypically, since no molecular marker specific for AIEC exists. An algorithm based on single nucleotide polymorphisms was previously presented as a potential molecular tool to classify AIEC/non-AIEC, with 84% accuracy on a collection of 50 strains isolated in Girona (Spain). Herein, our aim was to determine the accuracy of the tool using AIEC/non-AIEC isolates from different geographical origins and extraintestinal pathogenic E. coli (ExPEC) strains. The accuracy of the tool was significantly reduced (61%) when external AIEC/non-AIEC strains from France, Chile, Mallorca (Spain) and Australia (82 AIEC, 57 non-AIEC and 45 ExPEC strains in total) were included. However, the inclusion of only the ExPEC strains showed that the tool was fairly accurate at differentiating these two close pathotypes (84.6% sensitivity; 79% accuracy). Moreover, the accuracy was still high (81%) for those AIEC/non-AIEC strains isolated from Girona and Mallorca (N = 63); two collections obtained from independent studies but geographically close. Our findings indicate that the presented tool is not universal since it would be only applicable for strains from similar geographic origin and demonstrates the need to include strains from different origins to validate such tools.

Published
2020

15. Characterization of immortalized human islet stromal cells reveals a MSC-like profile with pancreatic features

Author

Danièle Noël, Claire Bony, Guilhem Couderc, Orianne Villard, Jérôme Moreaux, Anne Wojtusciszyn, Bernard Klein, Jean-Luc Veyrune, Mathieu Armanet, John DeVos, 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 Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Département d'hématologie biologique[Montpellier], Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-CHU Saint-Eloi, Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Saint Eloi (CHRU Montpellier), and Herrada, Anthony

Subjects
Stromal cell, Pancreatic islets, Mesenchymal stromal cells, Medicine (miscellaneous), Biology, Biochemistry, Genetics and Molecular Biology (miscellaneous), Cell therapy, lcsh:Biochemistry, Extracellular matrix, 03 medical and health sciences, 0302 clinical medicine, medicine, lcsh:QD415-436, CD90, Conditioned medium, 030304 developmental biology, lcsh:R5-920, 0303 health sciences, Mesenchymal stem cell, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Cell Biology, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Cell biology, Transplantation, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Molecular Medicine, Pancreatic islet transplantation, Stem cell, lcsh:Medicine (General)
Abstract

BackgroundMesenchymal stromal cells (MSCs) represent an interesting tool to improve pancreatic islet transplantation. They have immunomodulatory properties and secrete supportive proteins. However, the functional properties of MSCs vary according to many factors such as donor characteristics, tissue origin, or isolation methods. To counteract this heterogeneity, we aimed to immortalize and characterize adherent cells derived from human pancreatic islets (hISCs), using phenotypic, transcriptomic, and functional analysis.MethodsAdherent cells derived from human islets in culture were infected with a hTERT retrovirus vector and then characterized by microarray hybridization, flow cytometry analysis, and immunofluorescence assays. Osteogenic, adipogenic, and chondrogenic differentiation as well as PBMC proliferation suppression assays were used to compare the functional abilities of hISCs and MSCs. Extracellular matrix (ECM) gene expression profile analysis was performed using the SAM (Significance Analysis of Microarrays) software, and protein expression was confirmed by western blotting.ResultshISCs kept an unlimited proliferative potential. They exhibited several properties of MSCs such as CD73, CD90, and CD105 expression and differentiation capacity. From a functional point of view, hISCs inhibited the proliferation of activated peripheral blood mononuclear cells. The transcriptomic profile of hISCs highly clusterized with bone marrow (BM)-MSCs and revealed a differential enrichment of genes involved in the organization of the ECM. Indeed, the expression and secretion profiles of ECM proteins including collagens I, IV, and VI, fibronectin, and laminins, known to be expressed in abundance around and within the islets, were different between hISCs and BM-MSCs.ConclusionWe generated a new human cell line from pancreatic islets, with MSCs properties and retaining some pancreatic specificities related to the production of ECM proteins. hISCs appear as a very promising tool in islet transplantation by their availability (as a source of inexhaustible source of cells) and ability to secrete a supportive “pancreatic” microenvironment.

Published
2020

16. Treatment intensification with hepatic arterial infusion chemotherapy in patients with liver-only colorectal metastases still unresectable after systemic induction chemotherapy – a randomized phase II study -- SULTAN UCGI 30/PRODIGE 53 (NCT03164655)- study protocol

Author

Veronica Pezzella, Maximiliano Gelli, Julien Taieb, Christophe Laurent, Veronique Guerin-Meyer, Diane Goéré, Mathilde Wagner, Valérie Boige, Eric Dupont Bierre, Aline Maillard, Ayhan Ulusakarya, Samuel Le Sourd, Denis Smisth, Alice Boilève, Thierry de Baere, Clarisse Dromain, Franck Audemar, Gestionnaire, Hal Sorbonne Université, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Radiologie [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], Centre Eugène Marquis (CRLCC), Le CHCB, Centre Hospitalier de la Côte Basque, Hôpital Paul Brousse, Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse, Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), 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), Université Sorbonne Paris Cité (USPC), Université Paris Cité - UFR Médecine [Santé] (UPCité UFR Médecine), Université Paris Cité (UPCité), This study is financially supported by a governmental grant from the National Institute of Cancer (INCa)., This study is sponsored by UNICANCER and supported by PRODIGE group which regroup FFCD (Féderation Francophone de Cancérologie Digestive), GERCOR (Groupe Coopérateur Multidisciplinaire en Oncologie) and UNICANCER gastrointestinal group. The manuscript was peer reviewed by the funding body and the sponsor (UNICANCER)., Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université de Paris - UFR Médecine Paris Centre [Santé] (UP Médecine Paris Centre), Université de Paris (UP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), and Hôpital Paul Brousse-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)

Subjects
Male, Cancer Research, medicine.medical_specialty, Bevacizumab, medicine.medical_treatment, Salvage therapy, Phases of clinical research, [SDV.CAN]Life Sciences [q-bio]/Cancer, lcsh:RC254-282, Gastroenterology, Targeted therapy, Study Protocol, Liver metastases, 03 medical and health sciences, Hepatic Artery, 0302 clinical medicine, Hepatic arterial infusion, Clinical Protocols, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, Genetics, Humans, Infusions, Intra-Arterial, Medicine, Liver resection, business.industry, Liver Neoplasms, Induction chemotherapy, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Induction Chemotherapy, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Colorectal cancer, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, 3. Good health, Oxaliplatin, Oncology, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, 030220 oncology & carcinogenesis, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, FOLFIRI, Female, 030211 gastroenterology & hepatology, Randomized trial, Colorectal Neoplasms, business, medicine.drug
Abstract

Background Approximately 40% of colorectal cancer patients will develop colorectal liver metastases (CRLM). The most effective approach to increase long-term survival is CRLM complete resection. Unfortunately, only 10–15% of CRLM are initially considered resectable. The objective response rates (ORR) after current first-line systemic chemotherapy (sys-CT) regimens range from 40 to 80% and complete resection rates (CRR) range from 25 to 50% in patients with initially unresectable CRLM. When CRLM patients are not amenable to complete resection after induction of sys-CT, ORRs obtained with second-line sys-CT are much lower (between 10 and 30%) and consequently CRRs are also low ( Objectives and endpoints of the phase II study Our main objective is to investigate the efficacy, in term of CRR (R0-R1), of treatment intensification in patients with liver-only CRLM not amenable to curative-intent resection (and/or ablation) after at least 2 months of induction sys-CT. Patients will receive either HAI oxaliplatin plus systemic FOLFIRI plus targeted therapy (i.e. anti-EGFR antibody or bevacizumab) or conventional sys-CT plus targeted therapy (i.e. anti-EGFR or antiangiogenic antibody). Secondary objectives are to compare: progression-free survival, overall survival, objective response rate, depth of response, feasibility of delivering HAI oxaliplatin including HAI catheter-related complications, and toxicity (NCI-CTCAE v4.0). Methods This study is a multicenter, randomized, comparative phase II trial (power, 80%; two-sided alpha-risk, 5%). Patients will be randomly assigned in a 1:1 ratio to receive HAI oxaliplatin combined with systemic FOLFIRI plus targeted therapy (experimental arm) or the best sys-CT plus targeted therapy on the basis of their first-line prior sys-CT history and current guidelines (control arm). One hundred forty patients are required to account for non-evaluable patients. Trial registration ClinicalTrials.gov, (NCT03164655). Trial registration date: 11th May 2017.

Published
2020

17. RECIST and CHOI criteria in the evaluation of tumor response in patients with metastatic colorectal cancer treated with regorafenib, a prospective multicenter study

Author

Olivier Lucidarme, Benoist Chibaudel, Stefano Kim, Benoit Rousseau, Julie Henriques, Mathilde Wagner, Thierry André, Aurélien Gobert, Jean-Baptiste Bachet, Romain Cohen, Marie-Line Garcia-Larnicol, Paul Gillard, Christophe Louvet, Thibault Mazard, Laboratoire d'Imagerie Biomédicale (LIB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), CIC Pitié BT, Institut National de la Santé et de la Recherche Médicale (INSERM)-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), Cooperator Multidisciplinary Oncology Group (GERCOR), CHU Henri Mondor, Institut du Cancer de Montpellier (ICM), Service d'Oncologie Médicale [Montsouris], Institut Mutualiste de Montsouris (IMM), Service d'Oncologie Médicale [Institut Hospitalier Franco-Britannique], Division of Medical Oncology - Institut Hospitalier Franco-Britannique, CHU Saint-Antoine [AP-HP], Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (RIGHT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC), and Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)

Subjects
Male, Oncology, Pyridines, Colorectal cancer, Tumor response, 030218 nuclear medicine & medical imaging, chemistry.chemical_compound, 0302 clinical medicine, Choi Criteria, Clinical endpoint, Prospective Studies, Neoplasm Metastasis, Computed tomography, education.field_of_study, Radiological and Ultrasound Technology, General Medicine, Middle Aged, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, 3. Good health, 030220 oncology & carcinogenesis, Female, Colorectal Neoplasms, Research Article, Adult, lcsh:Medical physics. Medical radiology. Nuclear medicine, medicine.medical_specialty, lcsh:R895-920, Population, [SDV.CAN]Life Sciences [q-bio]/Cancer, lcsh:RC254-282, 03 medical and health sciences, Internal medicine, Regorafenib, medicine, Humans, Radiology, Nuclear Medicine and imaging, In patient, education, Response Evaluation Criteria in Solid Tumors, Aged, business.industry, Phenylurea Compounds, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, medicine.disease, Multicenter study, chemistry, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Tomography, X-Ray Computed, business
Abstract

Background To evaluate the objective response rate (ORR) at 2 months of treatment with regorafenib according to RECIST 1.1, Choi, and modified Choi (mChoi) criteria in patients with metastatic colorectal cancer (mCRC). Methods Baseline and 2-month contrast-enhanced computed-tomography (CECT) scans of 55 patients with mCRC, prospectively enrolled in phase II TEXCAN trial, were centrally assessed. The primary endpoint was 2-month ORR by RECIST 1.1, Choi, and mChoi criteria. Final outcome was overall survival (OS). Results Of 55 patients included in this study (Intention-to-treat [ITT1] population), 35 had CECT at 2 months (ITT2 population). According to RECIST 1.1 criteria, 20 (57%) patients were SD and 15 were PD (43%) in the ITT2 population. According to Choi criteria, 18 (51%) patients were responders and 17 (48%) were non-responders. Median OS was 5.3 months (95% CI 3.7–8.6) in the ITT1 population and 8.9 months (95% CI 5.1–12.6) in the ITT2 population. In the ITT2 population, median OS was 16 months (95% CI 6.6–17.5) in SD patients (n = 20) and 4.6 months (95% CI 3.3–5.8) in PD patients (n = 15), according to RECIST 1.1 criteria (HR = 6.48). Median OS was 7.9 months (95% CI 4.2–17.5) in responders (n = 18) and 9.9 months (95% CI 3.7-NA) in non-responders (n = 17) according to Choi criteria (HR = 1.06). All patients except one were classified as non-responders with mChoi criteria. Conclusion At 2 months, unlike RECIST 1.1, Choi and mChoi criteria could not identify mCRC patients with regorafenib survival benefit. Trial registration ClinicalTrials.gov Identifier: NCT02699073.Registered March 4, 2016, Retrospectively registered.

Published
2019

18. Circulating tumor DNA as a prognostic indicator in resectable pancreatic ductal adenocarcinoma: A systematic review and meta-analysis

Author

Jee Soo Lee, Hee Jung Kang, Shinichi Yachida, Daniel Pietrasz, Young Kyung Lee, Jung Woo Lee, Erina Takai, Hyoung chul Park, Kibum Jeon, Dae Young Zang, Miyoung Kim, Sun Young Kong, Jean-Baptiste Bachet, Jiwon Lee, Tae Min Rhee, Tatsuhiro Shibata, Han Sung Kim, Pierre Laurent-Puig, Hallym University, Seoul National University [Seoul] (SNU), Université Sorbonne Paris Cité (USPC), Sorbonne Université (SU), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Descartes - Paris 5 (UPD5), National Cancer Center Research Institute [Tokyo], and CHU Pitié-Salpêtrière [APHP]

Subjects
Oncology, medicine.medical_specialty, Pancreatic ductal adenocarcinoma, lcsh:Medicine, [SDV.CAN]Life Sciences [q-bio]/Cancer, Disease, Cochrane Library, Disease-Free Survival, Article, Circulating Tumor DNA, Prognostic markers, 03 medical and health sciences, 0302 clinical medicine, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Internal medicine, Cancer genomics, Carcinoma, Humans, Medicine, Postoperative Period, lcsh:Science, Cancer genetics, 030304 developmental biology, 0303 health sciences, Multidisciplinary, business.industry, lcsh:R, Hazard ratio, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Pancreatic cancer, Prognosis, medicine.disease, Confidence interval, 3. Good health, Pancreatic Neoplasms, Circulating tumor DNA, 030220 oncology & carcinogenesis, Meta-analysis, lcsh:Q, Neoplasm Recurrence, Local, business, Carcinoma, Pancreatic Ductal
Abstract

Circulating tumor DNA (ctDNA) is a promising prognostic biomarker in various cancers. Due to the high recurrence rate of resectable pancreatic ductal adenocarcinoma (PDAC), effective strategies for prognostic stratification are necessary. Yet, for resectable PDAC, prognostic impact of ctDNA lacks systemic evidence. We sought to investigate the prognostic significance of baseline ctDNA and postoperative ctDNA in patients with resectable PDAC. PubMed, EMBASE, and the Cochrane library were searched up to March 2019. Five studies met the inclusion criteria, and 375 patients were pooled for the meta-analysis. Positive ctDNA significantly indicated poor overall survival (at baseline, hazard ratio [HR] 2.27, 95% confidence interval [CI] 1.13–4.56; postoperative, HR 3.66, 95% CI 1.45–9.28). Patients with detectable ctDNA showed the trend to have higher risk for disease recurrence than those without detectable ctDNA (at baseline, HR 1.96, 95% CI 0.65–5.87; postoperative, HR 2.20, 95% CI 0.99–4.87). The results were consistent regardless of pre- or post-operative ctDNA. There was no significant heterogeneity among the included studies. In conclusion, our meta-analysis revealed that ctDNA, either at baseline or postoperative, might be a useful prognostic biomarker for stratifying risk of death and recurrence in resectable PDAC.

Published
2019

19. Hepatospecific ablation of p38α MAPK governs liver regeneration through modulation of inflammatory response to CCl4-induced acute injury

Author

Nadia Boussetta, Sandrine Pham, Jean-Pierre Couty, Chantal Desdouets, Séverine Celton-Morizur, Manon Fortier, Mathilde Cadoux, Romain Donne, Gestionnaire, Hal Sorbonne Université, 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)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Sorbonne Université (SU), Université Sorbonne Paris Cité (USPC), Institut Cochin (IC UM3 (UMR 8104 / U1016)), and Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Chemokine, lcsh:Medicine, Inflammation, CCL4, CCL2, 03 medical and health sciences, 0302 clinical medicine, Immune system, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, medicine, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, lcsh:Science, Multidisciplinary, biology, Chemistry, lcsh:R, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Liver regeneration, Cell biology, 030104 developmental biology, medicine.anatomical_structure, Hepatoprotection, Hepatocyte, biology.protein, lcsh:Q, 030211 gastroenterology & hepatology, medicine.symptom
Abstract

Mammalian p38α MAPK (Mitogen-Activated Protein Kinase) transduces a variety of extracellular signals that regulate cellular processes, such as inflammation, differentiation, proliferation or apoptosis. In the liver, depending of the physiopathological context, p38α acts as a negative regulator of hepatocyte proliferation as well as a promotor of inflammatory processes. However, its function during an acute injury, in adult liver, remains uncharacterized. In this study, using mice that are deficient in p38α specifically in mature hepatocytes, we unexpectedly found that lack of p38α protected against acute injury induced by CCl4 compound. We demonstrated that the hepatoprotective effect alleviated ROS accumulation and shaped the inflammatory response to promote efficient tissue repair. Mechanistically, we provided strong evidence that Ccl2/Ccl5 chemokines were crucial for a proper hepatoprotective response observed secondary to p38α ablation. Indeed, antibody blockade of Ccl2/Ccl5 was sufficient to abrogate hepatoprotection through a concomitant decrease of both inflammatory cells recruitment and antioxidative response that result ultimately in higher liver damages. Our findings suggest that targeting p38α expression and consequently orientating immune response may represent an attractive approach to favor tissue recovery after acute liver injury.

Published
2019

20. Discrepancy Between Clinical and Pathologic Nodal Status of Esophageal Cancer and Impact on Prognosis and Therapeutic Strategy

Author

Alain Duhamel, Christophe Mariette, Bernard Meunier, Gil Lebreton, Denis Collet, Arnaud Pasquer, Cécile Brigand, Hélène Behal, Sheraz R. Markar, Jérémie Thereaux, Caroline Gronnier, Florence Renaud, Johan Gagnière, Guillaume Piessen, Imperial College London, Hôpital Claude Huriez [Lille], CHU Lille, Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL), Site de Recherche Intégrée en Cancérologie (SIRIC-ONCOLille), Université de Lille, Sciences et Technologies-Université de Lille, Sciences Humaines et Sociales-Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université de Lille-UNICANCER-Université de Lille-UNICANCER-Cancéropole Nord-Ouest-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Hôpital de la Cavale Blanche - CHRU Brest (CHU - BREST ), CHU Clermont-Ferrand, CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Hôpital de Hautepierre [Strasbourg], Service de pathologie [CHU Lille], CHU Pontchaillou [Rennes], Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], Herrada, Anthony, Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, Université Lille Nord de France (COMUE)-UNICANCER-Université Lille Nord de France (COMUE)-UNICANCER-Cancéropole Nord-Ouest-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Inserm, Université de Lille, Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer (JPArc) - U1172, Centre Hospitalier Régional Universitaire [Lille] [CHRU Lille], Evaluation des technologies de santé et des pratiques médicales - ULR 2694 [METRICS], Centre Hospitalier Régional Universitaire de Brest [CHRU Brest], and Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 [JPArc]

Subjects
Male, Pathology, Esophageal Neoplasms, [SDV.MHEP.CHI] Life Sciences [q-bio]/Human health and pathology/Surgery, medicine.medical_treatment, Aucun, Gastroenterology, 0302 clinical medicine, Risk Factors, Surgical oncology, Medicine, 10. No inequality, Neoadjuvant therapy, Hazard ratio, Middle Aged, Esophageal cancer, 3. Good health, Survival Rate, Oncology, 030220 oncology & carcinogenesis, Resection margin, Adenocarcinoma, Female, 030211 gastroenterology & hepatology, medicine.medical_specialty, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.MHEP.CHI]Life Sciences [q-bio]/Human health and pathology/Surgery, Sciences du Vivant [q-bio]/Médecine humaine et pathologie, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, Humans, Survival rate, Neoplasm Staging, Retrospective Studies, Gastrointestinal Oncology, business.industry, [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, T-stage, Surgery, Lymph Nodes, business, Follow-Up Studies
Abstract

International audience; BACKGROUND: The impact of discrepancies between clinical (c) and pathologic (p) stages of esophageal cancer remains a poorly understood issue. This study aimed to compare the prognosis of patient groups treated by primary surgery including clinical N0/pathologic N0 (cN0pN0), clinical N0/pathologic N+ (cN0pN+), clinical N+/pathologic N0 (cN+pN0), and clinical N+/pathologic N+ (cN+pN+).METHODS: Data were collected from 30 European centers during the years 2000 to 2010. Among 2944 recruited patients, 1554 patients receiving primary surgery met the inclusion criteria including 613 cN0pN0, 403 cN0pN+, 220 cN+pN0, and 318 cN+pN+ patients. Analyses with adjustment of the propensity score were used to compensate for differences in baseline characteristics.RESULTS: Clinical T stages 3 and 4 were increased in cN+pN+ (73.0%), cN0pN+ (49.6%), and cN+pN0 (51.8%) compared with cN0pN0 (32.8%). Compared with cN0pN0, cN+pN+ and cN0pN+ showed an increase in the proportion of adenocarcinoma histologic subtype, poor tumor differentiation, pathologic T3 and T4 stages, and R1/2 resection margin. Adjusted 5-year overall survival (hazard ratio [HR] 3.12; 95% confidence interval [CI] 2.57-3.78; P

Published
2017

21. The performance of PI-RADSv2 and quantitative apparent diffusion coefficient for predicting confirmatory prostate biopsy findings in patients considered for active surveillance of prostate cancer

Author

Andreas M. Hötker, Behfar Ehdaie, Evis Sala, Nicola L Robertson, Nicolas Molinari, Stephanie Nougaret, Jennifer S. Golia Pernicka, Hedvig Hricak, Hebert Alberto Vargas, Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), UNICANCER - Institut régional du Cancer Montpellier Val d'Aurelle (ICM), CRLCC Val d'Aurelle - Paul Lamarque, Institut Montpelliérain Alexander Grothendieck (IMAG), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), and Memorial Sloane Kettering Cancer Center [New York]

Subjects
Male, PI-RADSv2, Oncology, Prostate biopsy, [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, [SDV]Life Sciences [q-bio], Biopsy, 030232 urology & nephrology, Contrast Media, 0302 clinical medicine, Prostate, Stage (cooking), ComputingMilieux_MISCELLANEOUS, Cancer, Aged, 80 and over, Radiological and Ultrasound Technology, medicine.diagnostic_test, Gastroenterology, Middle Aged, 3. Good health, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Radiology, Adult, medicine.medical_specialty, Urology, Active surveillance of prostate cancer, [SDV.IB.MN]Life Sciences [q-bio]/Bioengineering/Nuclear medicine, Sensitivity and Specificity, Article, 03 medical and health sciences, Predictive Value of Tests, Internal medicine, medicine, Humans, Effective diffusion coefficient, Radiology, Nuclear Medicine and imaging, Aged, Retrospective Studies, business.industry, Prostatic Neoplasms, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Retrospective cohort study, medicine.disease, Confirmatory, body regions, Diffusion Magnetic Resonance Imaging, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Neoplasm Grading, business
Abstract

To assess the performance of the updated Prostate Imaging Reporting and Data System (PI-RADSv2) and the apparent diffusion coefficient (ADC) for predicting confirmatory biopsy results in patients considered for active surveillance of prostate cancer (PCA). IRB-approved, retrospective study of 371 consecutive men with clinically low-risk PCA (initial biopsy Gleason score ≤6, prostate-specific antigen

Published
2017

22. Claudins in viral infection: from entry to spread

Author

Thomas F. Baumert, Che C. Colpitts, Institut de Recherche sur les Maladies Virales et Hépatiques (IVH), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Interaction virus-hôte et maladies du foie, and daulny, anne

Subjects
0301 basic medicine, Physiology, viruses, Viral pathogenesis, Clinical Biochemistry, Sciences du Vivant [q-bio]/Médecine humaine et pathologie, Dengue virus, Biology, medicine.disease_cause, Antiviral Agents, Article, Tight Junctions, 03 medical and health sciences, 0302 clinical medicine, Physiology (medical), Cell polarity, medicine, Animals, Humans, Claudin, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Tight Junction Proteins, Innate immune system, Tight junction, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Virology, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, 3. Good health, Cell biology, 030104 developmental biology, Virus Diseases, Paracellular transport, Claudins, Signal transduction, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030217 neurology & neurosurgery
Abstract

Tight junctions are critically important for many physiological functions, including the maintenance of cell polarity, regulation of paracellular permeability, and involvement in signal transduction pathways to regulate integral cellular processes. Furthermore, tight junctions enable epithelial cells to form physical barriers, which act as an innate immune mechanism that can impede viral infection. Viruses, in turn, have evolved mechanisms to exploit tight junction proteins to gain access to cells or spread through tissues in an infected host. Claudin family proteins are integral components of tight junctions and are thought to play crucial roles in regulating their permeability. Claudins have been implicated in the infection process of several medically important human pathogens, including hepatitis C virus, dengue virus, West Nile virus, and human immunodeficiency virus, among others. In this review, we summarize the role of claudins in viral infections and discuss their potential as novel antiviral targets. A better understanding of claudins during viral infection may provide insight into physiological roles of claudins and uncover novel therapeutic antiviral strategies.

Published
2016

23. Impact of Non-alcoholic Fatty Liver Disease on long-term cardiovascular events and death in Chronic Obstructive Pulmonary Disease

Author

Ingrid Jullian-Desayes, Renaud Tamisier, Jean-Pierre Zarski, Sébastien Bailly, Marie Joyeux-Faure, Vincent Leroy, Maxime Maignan, Jean-Louis Pépin, Meriem Benmerad, Damien Viglino, Anais Plazanet, SALAS, Danielle, Hypoxie : Physiopathologie Respiratoire et Cardiovasculaire (HP2 ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), and Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Male, medicine.medical_specialty, lcsh:Medicine, Comorbidity, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Gastroenterology, Article, Pulmonary Disease, Chronic Obstructive, 03 medical and health sciences, 0302 clinical medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Non-alcoholic Fatty Liver Disease, Risk Factors, Internal medicine, medicine, Humans, Prospective Studies, lcsh:Science, Prospective cohort study, Aged, Proportional Hazards Models, COPD, Univariate analysis, Multidisciplinary, Proportional hazards model, business.industry, Incidence, lcsh:R, Hazard ratio, Fatty liver, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Middle Aged, medicine.disease, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, 030228 respiratory system, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Cardiovascular Diseases, [SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, lcsh:Q, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Female, 030211 gastroenterology & hepatology, France, Steatosis, Steatohepatitis, business, Algorithms
Abstract

Chronic Obstructive Pulmonary Disease (COPD) and Non-Alcoholic Fatty Liver Disease (NAFLD) both independently increase cardiovascular risk. We hypothesized that NAFLD might increase the incidence of cardiovascular disease and death in COPD patients. The relationship between NAFLD, incident cardiovascular events, and death was assessed in a prospective cohort of COPD patients with 5-year follow-up. Noninvasive algorithms combining biological parameters (FibroMax®) were used to evaluate steatosis, non-alcoholic steatohepatitis (NASH) and liver fibrosis. Univariate and multivariate Cox regression models were used to assess the hazard for composite outcome at the endpoint (death or cardiovascular event) for each liver pathology. In 111 COPD patients, 75% exhibited liver damage with a prevalence of steatosis, NASH and fibrosis of 41%, 37% and 61%, respectively. During 5-year follow-up, 31 experienced at least one cardiovascular event and 7 died. In univariate analysis, patients with liver fibrosis had more cardiovascular events and higher mortality (Hazard ratio [95% CI]: 2.75 [1.26; 6.03]) than those with no fibrosis; this remained significant in multivariate analysis (Hazard ratio [95% CI]: 2.94 [1.18; 7.33]). We also found that steatosis and NASH were not associated with increased cardiovascular events or mortality. To conclude, early assessment of liver damage might participate to improve cardiovascular outcomes in COPD patients.

Published
2018

24. A prospective clinical and biological database for pancreatic adenocarcinoma: the BACAP cohort

Author

Cindy Canivet, Sophie Gourgou-Bourgade, Bertrand Napoléon, Laurent Palazzo, Nicolas Flori, Pierre Guibert, Guillaume Piessen, Dominique Farges-Bancel, Jean-François Seitz, Eric Assenat, Véronique Vendrely, Stéphanie Truant, Geoffroy Vanbiervliet, Philippe Berthelémy, Stéphane Garcia, Anne Gomez-Brouchet, Louis Buscail, Barbara Bournet, The BACAP Consortium, Hôpital de Rangueil, CHU Toulouse [Toulouse], CRLCC Val d'Aurelle - Paul Lamarque, Hôpital privé Jean Mermoz, Centre Léon Bérard [Lyon], Hôpital Claude Huriez, Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service de Médecine Interne [Saint-Louis], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Service d'oncologie digestive et hépato-gastro-entérologie [Hôpital de la Timone - APHM], Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), 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), Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre Hospitalier Universitaire de Nice (CHU Nice), Centre hospitalier de Pau, Hôpital Nord [CHU - APHM], 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 de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Hôpital Claude Huriez [Lille], CHU Lille, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), and Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris]

Subjects
Male, Endoscopic ultrasound, Oncology, Cancer Research, Cohort Studies, Study Protocol, 0302 clinical medicine, medicine.diagnostic_test, Five-year survival rate, Middle Aged, Prognosis, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Primary tumor, 3. Good health, Fine-needle aspiration, Databases as Topic, 030220 oncology & carcinogenesis, Cohort, Adenocarcinoma, Female, 030211 gastroenterology & hepatology, France, Cohort study, Carcinoma, Pancreatic Ductal, medicine.medical_specialty, [SDV.CAN]Life Sciences [q-bio]/Cancer, Outcomes, lcsh:RC254-282, 03 medical and health sciences, Internal medicine, Pancreatic cancer, Biomarkers, Tumor, Genetics, medicine, Humans, Aged, Biobank, business.industry, Quality control, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, DNA, medicine.disease, Pancreatic Neoplasms, RNA, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, Pancreatic adenocarcinoma, Biomarkers
Abstract

International audience; BACKGROUND: The prognosis for pancreatic cancer remains poor despite diagnostic advances and treatments with new chemotherapeutic regimens. The five year survival rate remains below 3%. Consequently, there is an urgent need for new treatments to significantly improve the prognosis. In addition, there is a big gap in terms of the screening, early diagnosis and prevention of pancreatic cancer the incidence of which is increasing dramatically.METHODS: Design: the BACAP cohort is a prospective multicenter pancreatic cancer cohort (pancreatic ductal carcinoma) with clinical and multiple biological samples; Participating centers: 15 French academic and private hospitals; Study Population: any cytologically and/or histologically proven pancreatic carcinoma regardless of the stage (resectable, borderline, locally advanced or metastatic) or treatment (surgery, palliative chemotherapy, best supportive care). At least 1500 patients will be included. Clinical data collected include: disease presentation, epidemiological and social factors, baseline biology, radiology, endoscopic ultrasound, staging, pathology, treatments, follow-up (including biological and radiological), and survival. All these data are collected and stored through an e-observation system at a centralized data center. Biological samples and derived products (i.e. before any treatment): blood, saliva, endoscopic ultrasound-guided fine needle aspiration materials from the primary tumor, fine needle biopsy of metastases and surgically resected tissue. DNA and RNA are extracted from fine needle aspiration materials and are quantified and characterized for quality. Whole blood, plasma and serum are isolated from blood samples. Frozen tissues were specifically allocated to the cohort. All derived products and saliva are stored at - 80 °C. Main end-points: i) to centralize clinical data together with multiple biological samples that are harmonized in terms of sampling, the post sampling process and storage; ii) to identify new molecular markers for the diagnosis, prognosis and possibly the predictive response to pancreatic cancer surgery and or chemotherapy.DISCUSSION: The BACAP cohort is a unique prospective biological clinical database that provides the opportunity to identify correlations between the presence/expression of a broad panel of biomarkers (DNA, RNA, miRNA, proteins, etc.), epidemiological and social data, various clinical situations, various stages and the differentiation of the tumor, treatments and survival.TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02818829 . Registration date: June 30, 2016.

Published
2018

25. Characterisation of Agomelatine-Induced Increase in Liver Enzymes: Frequency and Risk Factors Determined from a Pooled Analysis of 7605 Treated Patients

Author

Cécile Batailler, Dominique Valla, Barbara Saba, Gabriel Perlemuter, Patrice Cacoub, Dominique Guyader, Kevin Moore, Cytokines, chimiokines et immunopathologie, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Immunologie - Immunopathologie - Immunothérapie (I3), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), 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 des maladies du foie, Centre Hospitalier Universitaire [Rennes]-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou, Foie, métabolismes et cancer, 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)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service des maladies du foie [CHU Rennes], Centre Hospitalier Universitaire [Rennes], Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)

Subjects
Adult, Male, medicine.medical_specialty, Placebo-controlled study, [SDV.CAN]Life Sciences [q-bio]/Cancer, Pharmacology, Placebo, Gastroenterology, Transaminase, 03 medical and health sciences, Clinical Trials, Phase II as Topic, 0302 clinical medicine, Liver Function Tests, Risk Factors, Internal medicine, Acetamides, medicine, Humans, Agomelatine, Pharmacology (medical), Transaminases, Retrospective Studies, Liver injury, medicine.diagnostic_test, business.industry, Fatty liver, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Middle Aged, medicine.disease, Antidepressive Agents, 030227 psychiatry, 3. Good health, Psychiatry and Mental health, Clinical Trials, Phase III as Topic, Elevated transaminases, Female, Neurology (clinical), Chemical and Drug Induced Liver Injury, Liver function tests, business, 030217 neurology & neurosurgery, medicine.drug
Abstract

International audience; Background: Antidepressant-induced liver injury is a major concern and a liver monitoring scheme has been recommended by the European Medicines Agency for agomelatine. Objective: The objective of this study was to assess the liver safety and identify the characteristics of patients who developed a significant increase in transaminases whilst taking agomelatine. Method: A retrospective pooled analysis of changes in transaminase levels in 9234 patients treated with agomelatine (25 or 50 mg/day; n = 7605) or placebo (n = 1629) from 49 phase II and III studies was undertaken. A significant increase in transaminase levels was defined as an increase to >3 times the upper limit of normal (ULN) (>3 × ULN). Final causality was determined in a case-by-case review by five academic experts. Results: Serum transaminases increased to >3 × ULN in 1.3 and 2.5 % of patients treated with 25 and 50 mg of agomelatine, respectively, compared with 0.5 % for placebo. The onset of increased transaminases occurred before 12 weeks in 64 % of patients. The median time to recovery (to ≤2 × ULN) was 14 days following treatment withdrawal. Liver function tests recovered in 36.1 % of patients despite continuation of agomelatine, suggesting the presence of a liver adaptive mechanism. No cases of acute liver failure or fatal outcome occurred. Patients with elevated transaminases at baseline, secondary to obesity/fatty liver disease, had an equally increased risk of developing further elevations of transaminases with agomelatine and placebo. Conclusion: Incidence of abnormal transaminases was low and dose dependent. No specific population was identified regarding potential risk factors. Withdrawal of agomelatine led to rapid recovery, and some patients exhibited an adaptive phenomenon. Overall, in clinical trials, the liver profile of agomelatine seems safe when serum transaminases are monitored. © 2016, Springer International Publishing Switzerland.

Published
2016

26. De novo MEIS2 mutation causes syndromic developmental delay with persistent gastro-esophageal reflux

Author

Hirotomo Saitsu, Pierre Corre, Yoshinori Tsurusaki, Mitsuko Nakashima, Atsushi Fujita, Noriko Miyake, Nobuhiko Okamoto, Bertrand Isidor, Naomichi Matsumoto, Hugues Piloquet, Gifu University Graduate School of Medicine, Centre hospitalier universitaire de Nantes (CHU Nantes), Physiologie des Adaptations Nutritionnelles (PhAN), and Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN)

Subjects
0301 basic medicine, Pediatrics, medicine.medical_specialty, Constipation, Genotype, Developmental Disabilities, DNA Mutational Analysis, Nonsense mutation, 030105 genetics & heredity, Biology, 03 medical and health sciences, Intellectual disability, Genetics, medicine, Humans, Exome, Genetics (clinical), Homeodomain Proteins, Point mutation, Reflux, Facies, High-Throughput Nucleotide Sequencing, Infant, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Syndrome, medicine.disease, Phenotype, 030104 developmental biology, Statistical genetics, Mutation, Gastroesophageal Reflux, Medical genetics, Female, medicine.symptom, Haploinsufficiency, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, Transcription Factors
Abstract

International audience; MEIS2 aberrations are considered to be the cause of intellectual disability, cleft palate and cardiac septal defect, as MEIS2 copy number variation is often observed with these phenotypes. To our knowledge, only one nucleotide-level change-specifically, an in-frame MEIS2 deletion-has so far been reported. Here, we report a female patient with a de novo nonsense mutation (c.611C>G, p.Ser204*) in MEIS2. She showed severe intellectual disability, moderate motor/verbal developmental delay, cleft palate, cardiac septal defect, hypermetropia, severe feeding difficulties with gastro-esophageal reflux and constipation. By reviewing this patient and previous patients with MEIS2 point mutations, we found that feeding difficulty with gastro-esophageal reflux appears to be one of the core clinical features of MEIS2 haploinsufficiency, in addition to intellectual disability, cleft palate and cardiac septal defect.

Published
2016

27. The loss-of-function PCSK9 p.R46L genetic variant does not alter glucose homeostasis

Author

Cédric Le May, Michel Marre, Loic Yengo, Beverley Balkau, Guillaume Charpentier, Frédéric Fumeron, Bertrand Cariou, Sylvia Franc, Philippe Froguel, Amélie Bonnefond, Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (GI3M), 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 National de la Recherche Scientifique (CNRS), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Immunologie et Cancérologie Intégratives (CRC - Inserm U1138), Centre de Recherche des Cordeliers (CRC), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Sorbonne Paris Cite, Université Paris Diderot - Paris 7 (UPD7), Service d'endocrinologie, diabétologie et nutrition [CHU Bichat], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'études et de recherches pour l'intensification du traitement du diabète (CERITD), Centre Hospitalier Sud Francilien, CH Evry-Corbeil, Imperial College London, Génomique Intégrative et Modélisation des Maladies Métaboliques (EGID), 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), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris]-Université Paris Diderot - Paris 7 (UPD7), Hôpital Paul Brousse-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (EGENODIA (GI3M)), Unité de recherche de l'institut du thorax (ITX-lab), Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Male, Blood Glucose, [SDV]Life Sciences [q-bio], Endocrinology, Diabetes and Metabolism, Type 2 diabetes, 030204 cardiovascular system & hematology, Body Mass Index, 0302 clinical medicine, Risk Factors, Homeostasis, Glucose homeostasis, Longitudinal Studies, humans, ComputingMilieux_MISCELLANEOUS, 0303 health sciences, adult, Serine Endopeptidases, Age Factors, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Middle Aged, 3. Good health, Cholesterol, Regression Analysis, Kexin, Female, Proprotein Convertases, France, Proprotein Convertase 9, Type 2, medicine.medical_specialty, Genotype, Biology, 03 medical and health sciences, Sex Factors, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Internal medicine, Diabetes mellitus, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Diabetes Mellitus, Internal Medicine, medicine, Loss function, 030304 developmental biology, PCSK9, Genetic Variation, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Proprotein convertase, medicine.disease, prospective studies, Endocrinology, Diabetes Mellitus, Type 2, Gene Expression Regulation
Abstract

International audience; AIMS/HYPOTHESIS: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a critical regulator of cholesterol homeostasis. PCSK9 inhibitors are being actively developed to lower LDL-cholesterol levels. However, there are conflicting data regarding the consequences of Pcsk9 deficiency on glucose homeostasis in mouse models. Here, we analysed in humans the association between the PCSK9 p.R46L loss-of-function (LOF) variant and (1) glucose homeostasis variables; (2) type 2 diabetes status; and (3) the risk of 9 year incident type 2 diabetes in a prospective study. METHODS: PCSK9 p.R46L was genotyped in 4630 French participants from the Data from an Epidemiological Study on the Insulin Resistance Syndrome (DESIR) prospective study and in 1342 French participants with type 2 diabetes. The association between p.R46L and metabolic traits or type 2 diabetes risk was assessed through linear or logistic regression models adjusted for age, sex and BMI. The association between p.R46L and incident type 2 diabetes was assessed using a Cox regression model adjusted for sex, age and BMI at baseline. RESULTS: Significant associations (p \textless 10(-6)) were found between p.R46L and lower total cholesterol (-0.394 mmol/l), LDL-cholesterol (-0.393 mmol/l) and apolipoprotein B concentrations (-0.099 g/l). However, no significant association was observed between p.R46L and markers of glucose homeostasis (including fasting glucose, fasting insulin, HbA1c, HOMA-B, HOMA-IR) or type 2 diabetes risk. Furthermore, no significant association between p.R46L variant and risk of incident type 2 diabetes was observed in DESIR. CONCLUSIONS/INTERPRETATION: The PCSK9 p.R46L LOF variant was not associated with impaired glucose homeostasis in humans. These data are reassuring regarding the safety of PCSK9 inhibitors.

Published
2015

28. Septin 9 induces lipid droplets growth by a phosphatidylinositol-5-phosphate and microtubule-dependent mechanism hijacked by HCV

Author

Mickaël Marin, Abdelaziz Benjouad, Abdellah Akil, Sokhavuth Sar, Soumaya Benjelloun, Christian Bréchot, Cyntia Taveneau, Didier Samuel, Claire Gondeau, Philippe Briolotti, Valérie Thiers, Mohyeddine Omrane, Christophe Desterke, Stéphane Bressanelli, Hélène Tronchère, Patrick Maurel, Juan Peng, Ama Gassama-Diagne, Institut Pasteur du Maroc, Réseau International des Instituts Pasteur (RIIP), Laboratoire de biochimie et Immunologie, Faculté des Sciences, Université Mohammed V de Rabat [Agdal] (UM5), Physiopathologie et traitement des maladies du foie, Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), Hepatinov (DHU), Université Paris-Sud - Paris 11 (UP11)-Centre Hépato-Biliaire Paul Brousse, Service d'Hépatogastroentérologie, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Saint Eloi (CHRU Montpellier), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), 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), Centre hépato-biliaire (CHB), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Virologie Moléculaire et Structurale, Centre National de la Recherche Scientifique (CNRS), Université Internationale de Rabat (UIR), Institut Pasteur [Paris] (IP), A.A. was supported by a fellowship of RII Pasteur, University of Paris XI and CHB association. C.G. was supported by a grant from Agence nationale de recherches sur le sida et les hépatites virales (ANRS). This work was supported by a grant from Association pour la Recherche sur le Cancer (ARC/SUBV/CKLQ6) to AGD, Houel, Ludivine, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Mohammed V de Rabat [Agdal], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-CHU Saint-Eloi, Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), and Institut Pasteur [Paris]

Subjects
Liver Cirrhosis, 0301 basic medicine, General Physics and Astronomy, Hepacivirus, Virus Replication, Septin, Microtubules, Phosphatidylinositol Phosphates, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Lipid droplet, Cytoskeleton, Multidisciplinary, cytoskeleton, phosphoinositides, Hepatitis C, Hedgehog signaling pathway, 3. Good health, Cell biology, diacylglycerol acyltransferase-1, Host-Pathogen Interactions, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, biological phenomena, cell phenomena, and immunity, replication, Science, cell regulation, yeast septin, macromolecular substances, Biology, hepatitis-c virus, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Downregulation and upregulation, Microtubule, Cell Line, Tumor, core protein, Humans, Phosphatidylinositol 5-phosphate, fungi, biogenesis, metabolism, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Lipid Droplets, General Chemistry, Lipid Metabolism, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, eye diseases, 030104 developmental biology, Gene Expression Regulation, Septins, Biogenesis, Oleic Acid
Abstract

The accumulation of lipid droplets (LD) is frequently observed in hepatitis C virus (HCV) infection and represents an important risk factor for the development of liver steatosis and cirrhosis. The mechanisms of LD biogenesis and growth remain open questions. Here, transcriptome analysis reveals a significant upregulation of septin 9 in HCV-induced cirrhosis compared with the normal liver. HCV infection increases septin 9 expression and induces its assembly into filaments. Septin 9 regulates LD growth and perinuclear accumulation in a manner dependent on dynamic microtubules. The effects of septin 9 on LDs are also dependent on binding to PtdIns5P, which, in turn, controls the formation of septin 9 filaments and its interaction with microtubules. This previously undescribed cooperation between PtdIns5P and septin 9 regulates oleate-induced accumulation of LDs. Overall, our data offer a novel route for LD growth through the involvement of a septin 9/PtdIns5P signalling pathway., The accumulation of lipid droplets is often observed in hepatitis C virus infection, but the mechanism of their formation is not known. Here the authors show that septin 9 expression is increased in infected livers, and a septin 9/phosphatidylinositol 5-phosphate signalling pathway regulates the growth of lipid droplets.

Published
2016

29. Prevalence of gastrointestinal symptoms in patients with influenza, clinical significance, and pathophysiology of human influenza viruses in faecal samples: what do we know?

Author

Sylvie van der Werf, Thomas Hanslik, Thierry Blanchon, Alessandra Falchi, Pierre-Emmanuel Ceccaldi, Rémi N. Charrel, Laëtitia Minodier, Laboratoire de Virologie, Université Pascal Paoli (UPP), Cellule Pasteur, Université Paris Diderot - Paris 7 (UPD7)-PRES Sorbonne Paris Cité, Epidémiologie et Physiopathologie des Virus Oncogènes (EPVO (UMR_3569 / U-Pasteur_3)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Institut Pasteur [Paris], Génétique Moléculaire des Virus à ARN - Molecular Genetics of RNA Viruses (GMV-ARN (UMR_3569 / U-Pasteur_2)), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Centre National de Référence des virus influenzae (Grippe) (CNR), Institut Pasteur [Paris], Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Médecine Interne, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Ambroise Paré [AP-HP], Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), PRES Sorbonne Paris Cité-Université Paris Diderot - Paris 7 (UPD7), Centre National de Référence des virus influenzae (Grippe)-Génétique moléculaire des virus à ARN (CNR), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Ambroise Paré, Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), and Institut Pasteur [Paris] (IP)

Subjects
Gastrointestinal Diseases, Human influenza, Orthomyxoviridae, Review, Biology, Gastrointestinal symptoms, Virus, Feces, Respiratory infection, Virology, Influenza, Human, Prevalence, Humans, Clinical significance, Transmission (medicine), virus diseases, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, biology.organism_classification, Influenza, Pathophysiology, Intestine, 3. Good health, Intestines, Infectious Diseases, Stool, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, RNA, Seasons
Abstract

This review provides for the first time an assessment of the current understanding about the occurrence and the clinical significance of gastrointestinal (GI) symptoms in influenza patients, and their correlation with the presence of human influenza viruses in stools of patients with confirmed influenza virus infection. Studies exploring how human influenza viruses spread to the patient’s GI tract after a primary respiratory infection have been summarized. We conducted a systematic search of published peer-reviewed literature up to June 2015 with regard to the above-mentioned aspects, focusing on human influenza viruses (A(H1N1), A(H1N1)pdm09, A(H3N2), and B). Forty-four studies were included in this systematic review and meta-analysis. The pooled prevalence of any digestive symptoms ranged from 30.9 % (95 % CI, 9.8 to 57.5; I2 = 97.5 %) for A(H1N1)pdm09 to 2.8 % (95 % CI, 0.6 to 6.5; I2 = 75.4 %) for A(H1N1). The pooled prevalence of influenza viruses in stool was 20.6 % (95 % CI, 8.9 to 35.5; I2 = 96.8 %), but their correlation with GI symptoms has rarely been explored. The presence of viral RNA in stools because of haematogenous dissemination to organs via infected lymphocytes is likely, but the potential to cause direct intestinal infection and faecal–oral transmission warrants further investigation. This review highlights the gaps in our knowledge, and the high degree of uncertainty about the prevalence and significance of GI symptoms in patients with influenza and their correlation with viral RNA positivity in stool because of the high level of heterogeneity among studies. Electronic supplementary material The online version of this article (doi:10.1186/s12985-015-0448-4) contains supplementary material, which is available to authorized users.

Published
2015

30. EGFR and EphA2 are host factors for hepatitis C virus entry and possible targets for antiviral therapy

Author

Michel Doffoel, Marine Turek, Isabel Fofana, Olivier Poch, Muhammad N. Zahid, Patrick Pessaux, Thomas F. Baumert, Fei Xiao, Laetitia Zona, Christopher Davis, Sebastian Gorke, S. Michael Rothenberg, François-Loïc Cosset, Mirjam B. Zeisel, Laurent Brino, Dimitri Lavillette, Cathy Royer, Thomas Pietschmann, Wolfgang Raffelsberger, Benoit Fischer, Jane A. McKeating, Judith Fresquet, Christopher J. Mee, Arvind H. Patel, Joachim Lupberger, Christine Thumann, Baumert, Thomas F., Interaction virus-hôte et maladies du foie, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hepatitis C Research Group, Division of Immunity and Infection-University of Birmingham [Birmingham], Department of Medicine II, University of Freiburg [Freiburg], Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Virologie humaine, École normale supérieure - Lyon (ENS Lyon)-IFR128-Institut National de la Santé et de la Recherche Médicale (INSERM), Massachusetts General Hospital Cancer Center, Howard Hughes Medical Institute (HHMI)-Harvard Medical School [Boston] (HMS), Division of Experimental Virology, Centre for Experimental and Clinical Infection Research (TWINCORE), Helmholtz Centre for Infection Research (HZI)-Medizinische Hochschule Hannover (MHH)-Helmholtz Centre for Infection Research (HZI)-Medizinische Hochschule Hannover (MHH), MRC Virology Unit, University of Glasgow, Service d'Hépato-gastroentérologie, Hôpitaux Universitaires de Strasbourg-Nouvel Hôpital Civil, ERC-2008-AdG-233130-HEPCENT, INTERREG-IV-Rhin Supérieur-FEDER-Hepato-Regio-Net 2009, ANR-05-CEXC-008, ANRS 2008/354, Région Alsace, INCa, NIH, MRC and the Wellcome Trust., École normale supérieure de Lyon (ENS de Lyon)-IFR128-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)

Subjects
MESH: Virus Internalization, Hepacivirus, MESH: Base Sequence, Ligands, medicine.disease_cause, Receptor tyrosine kinase, Mice, Cell-cell transmission, 0302 clinical medicine, Claudin-1, MESH: RNA, Small Interfering, MESH: Ligands, MESH: Protein Kinase Inhibitors, MESH: Animals, MESH: Hepacivirus, Epidermal growth factor receptor, RNA, Small Interfering, MESH: Antigens, CD, MESH: Receptor, EphA2, 0303 health sciences, Phosphotyrosine kinase, biology, Receptor, EphA2, virus diseases, General Medicine, EPH receptor A2, Hepatitis C, 3. Good health, ErbB Receptors, MESH: Quinazolines, Liver, Host-Pathogen Interactions, RNA Interference, 030211 gastroenterology & hepatology, MESH: Membrane Proteins, Tyrosine kinase, MESH: Antiviral Agents, Hepatitis C virus, MESH: RNA Interference, MESH: Receptor, Epidermal Growth Factor, Sciences du Vivant [q-bio]/Médecine humaine et pathologie, Antiviral Agents, Article, General Biochemistry, Genetics and Molecular Biology, Cell Line, Tetraspanin 28, Erlotinib Hydrochloride, 03 medical and health sciences, MESH: Antigens, CD81, Antigens, CD, Viral entry, medicine, Animals, Humans, Antiviral, Kinase activity, Protein Kinase Inhibitors, MESH: Mice, 030304 developmental biology, MESH: Hepatitis C, MESH: Humans, Base Sequence, MESH: Host-Pathogen Interactions, Erythropoietin-producing hepatocellular (Eph) receptor, Membrane Proteins, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Virus Internalization, Virology, digestive system diseases, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, MESH: Cell Line, HCV escape variants, Quinazolines, biology.protein
Abstract

International audience; Hepatitis C virus (HCV) is a major cause of liver disease, but therapeutic options are limited and there are no prevention strategies. Viral entry is the first step of infection and requires the cooperative interaction of several host cell factors. Using a functional RNAi kinase screen, we identified epidermal growth factor receptor and ephrin receptor A2 as host cofactors for HCV entry. Blocking receptor kinase activity by approved inhibitors broadly impaired infection by all major HCV genotypes and viral escape variants in cell culture and in a human liver chimeric mouse model in vivo. The identified receptor tyrosine kinases (RTKs) mediate HCV entry by regulating CD81-claudin-1 co-receptor associations and viral glycoprotein-dependent membrane fusion. These results identify RTKs as previously unknown HCV entry cofactors and show that tyrosine kinase inhibitors have substantial antiviral activity. Inhibition of RTK function may constitute a new approach for prevention and treatment of HCV infection.

Published
2011

31. A multicentric randomized controlled trial on the impact of lengthening the interval between neoadjuvant radiochemotherapy and surgery on complete pathological response in rectal cancer (GRECCAR-6 trial): rationale and design

Author

Magali Svrcek, Emmanuel Tiret, Jérémie H. Lefevre, Alexandra Rousseau, Tabassome Simon, Yann Parc, Université Pierre et Marie Curie - Paris 6 (UPMC), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de chirurgie générale et digestive [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), Pôle de Pharmacie - Santé Publique - Information médicale [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)-Université Pierre et Marie Curie - Paris 6 (UPMC), and Service de Pathologie [CHU Saint-Antoine]

Subjects
Cancer Research, medicine.medical_specialty, Time Factors, Colorectal cancer, medicine.medical_treatment, Rectum, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.MHEP.CHI]Life Sciences [q-bio]/Human health and pathology/Surgery, law.invention, Study Protocol, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, Procedure, law, Surgical oncology, Genetics, medicine, Humans, Rectal cancer, Radiochemotherapy, Neoadjuvant therapy, Rectal Neoplasms, business.industry, Remission Induction, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Retrospective cohort study, Chemoradiotherapy, medicine.disease, Neoadjuvant Therapy, 3. Good health, Surgery, Clinical trial, Treatment Outcome, medicine.anatomical_structure, Oncology, Research Design, 030220 oncology & carcinogenesis, 030211 gastroenterology & hepatology, Complete histological response, business, Follow-Up Studies
Abstract

The French Research Group of Rectal Cancer Surgery (GRECCAR); International audience; Background: Neoadjuvant radiochemotherapy (RCT) is now part of the armamentarium of cancer of the lower and middle rectum. It is recommended in current clinical practice prior to surgical excision if the lesion is classified T3/T4 or N+. Histological complete response, defined by the absence of persistent tumor cell invasion and lymph node (ypT0N0) after pathological examination of surgical specimen has been shown to be an independent prognostic factor of overall survival and disease-free survival. Surgical excision is usually performed between 6 and 8 weeks after completion of CRT and pathological complete response rate ranges around 12%. In retrospective studies, a lengthening of the interval after RCT beyond 10 weeks was found as an independent factor increasing the rate of pathological complete response (between 26% and 31%), with a longer disease-free survival and without increasing the operative morbidity. The aim of the present study is to evaluate in 264 patients the rate of pathological complete response rate of rectal cancer after RCT by lengthening the time between RCT and surgery.Methods/design: The current study is a multicenter randomized trial in two parallel groups comparing 7 and 11 weeks of delay between the end of RCT and cancer surgery of rectal tumors.At the end of the RCT, surgery is planified and randomization is performed after patient’s written consent for participation. The histological complete response (ypT0N0) will be determined with analysis of the complete residual tumor and double reading by two pathologists blinded of the group of inclusion. Patients will be followed in clinics for 5 years after surgery. Participation in this trial does not change patient’s management in terms of treatment, investigations or visits. Secondary endpoints will include overall and disease free survival, rate of sphincter conservation and quality of mesorectal excision. The number of patients needed is 264.

Published
2013

32. Applicability and precautions of use of liver injury biomarker FibroTest. A reappraisal at 7 years of age

Author

Françoise Imbert-Bismut, F. Drane, Djamila Messous, Mona Munteanu, Vlad Ratziu, Chantal Housset, J.M. Castille, Yen Ngo, Thierry Poynard, Olivier Deckmyn, BMC, Ed., 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), Biopredictive, Biopredictive has supported this study as well as the 'Association pour la Recherche sur les Maladies Virales et Hépatiques'., 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, Liver Cirrhosis, Male, medicine.medical_specialty, Adolescent, Tertiary care, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, False positive paradox, Humans, False Positive Reactions, alpha-Macroglobulins, lcsh:RC799-869, Young adult, Child, False Negative Reactions, Aged, Aged, 80 and over, Apolipoprotein A-I, Haptoglobins, Low haptoglobin, business.industry, FibroTest, Gastroenterology, Infant, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Bilirubin, gamma-Glutamyltransferase, General Medicine, Middle Aged, Hepatology, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, 3. Good health, Surgery, Child, Preschool, 030220 oncology & carcinogenesis, Biomarker (medicine), lcsh:Diseases of the digestive system. Gastroenterology, Female, 030211 gastroenterology & hepatology, business, Algorithms, Biomarkers, Software, Research Article
Abstract

Background FibroTest (FT) is a validated biomarker of fibrosis. To assess the applicability rate and to reduce the risk of false positives/negatives (RFPN), security algorithms were developed. The aims were to estimate the prevalence of RFPN and of proven failures, and to identify factors associated with their occurrences. Methods Four populations were studied: 954 blood donors (P1), 7,494 healthy volunteers (P2), 345,695 consecutive worldwide sera (P3), including 24,872 sera analyzed in a tertiary care centre (GHPS) (P4). Analytical procedures of laboratories with RFPN > 5% and charts of P4 patients in with RFPN were reviewed. Results The prevalence of RFPN was 0.52% (5/954; 95%CI 0.17-1.22) in P1, 0.51% (38/7494; 0.36-0.70) in P2, and 0.97% (3349/345695; 0.94-1.00) in P3. Three a priori high-risk populations were confirmed: 1.97% in P4, 1.77% in HIV centre and 2.61% in Sub-Saharan origin subjects. RFPN was mostly associated with low haptoglobin (0.46%), and high apolipoproteinA1 (0.21%). A traceability study of a P3 laboratory with RFPFN > 5% permitted to correct analytical procedures. Conclusion The mean applicability rate of Fibrotest was 99.03%. Independent factors associated with the high risk of false positives/negatives were HIV center, subSaharan origin, and a tertiary care reference centre, although the applicability rate remained above 97%.

Published
2011

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