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Your search keyword '"Hôpital Erasmes"' showing total 11 results
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11 results on '"Hôpital Erasmes"'

1. Stratification of Pancreatic Ductal Adenocarcinomas Based on Tumor and Microenvironment Features

Author

Rémy Nicolle, Pieter Demetter, Pierre Laurent-Puig, Aurélien de Reyniès, Juan L. Iovanna, Jean-Luc Van Laethem, Magali Svrcek, Jacques Devière, Maria Gomez Galdon, Raphaël Maréchal, Nabila Elarouci, Laetitia Marisa, Francesco Puleo, Laurine Verset, Jean-Baptiste Bachet, Denis Franchimont, Yuna Blum, Eric Quertinmont, Jérôme Cros, Ligue Nationale Contre le Cancer - Paris, Ligue Nationale Contre le Cancer (LNCC), Compartimentation et dynamique cellulaires (CDC), Institut Curie [Paris]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Université Paris sciences et lettres (PSL), (le programme) Cartes d'identité des tumeurs (CIT), Ligue Nationales Contre le Cancer (LNCC), Laboratoire électrotechnique et électronique industrielle (LEEI), Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Université de Toulouse (UT), Department of Pathology, Hôpital Erasmes, 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), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), 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), Médecine Personnalisée, Pharmacogénomique, Optimisation Thérapeutique (MEPPOT - U1147), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Erasme [Bruxelles] (ULB), Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), CHU Pitié-Salpêtrière [AP-HP], Service de Gastro-Entérologie, d'Hépato-Pancréatologie et d'Oncologie Digestive - Endoscopie Digestive (hôpital Erasme), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB)-Faculté de Médecine [Bruxelles] (ULB), Ligue Nationnale Contre le Cancer, Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), 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), Service d'Anatomie Pathologique [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), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), Service d'Hépato-Gastro-Entérologie [CHU Pitié-Salpêtrière], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Curie-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), PSL Research University (PSL), Physiologie, Environnement et Génétique pour l'Animal et les Systèmes d'Elevage [Rennes] (PEGASE), AGROCAMPUS OUEST-Institut National de la Recherche Agronomique (INRA), Programme 'Cartes d'Identité des Tumeurs' [Paris] (CIT), Ligue Nationale Contre le Cancer, Pathologies biliaires, fibrose et cancer du foie (Inserm UMR_S 938), CHU Saint-Antoine [APHP]-Centre de Recherche Saint-Antoine (CR Saint-Antoine), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Saint-Antoine [APHP], Programme Cartes d'Identité des Tumeurs (CIT), Hôpital Erasme (Bruxelles), Service de Gastroentérologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], and Université Libre de Bruxelles [Bruxelles] (ULB)-Hôpital Erasme (Bruxelles)

Subjects
Adult, Male, 0301 basic medicine, [SDV]Life Sciences [q-bio], education, Gene Expression, Acinar Cells, Adenocarcinoma, Biology, Disease-Free Survival, DNA sequencing, Transcriptome, 03 medical and health sciences, 0302 clinical medicine, Stroma, Pancreatic cancer, Tumor Microenvironment, medicine, Acinar cell, Humans, Prospective Studies, RNA, Neoplasm, Pancreas, Aged, Proportional Hazards Models, Aged, 80 and over, Tumor microenvironment, Hepatology, Gastroenterology, DNA, Neoplasm, Sequence Analysis, DNA, Middle Aged, medicine.disease, Pancreas, Exocrine, Progression-Free Survival, 3. Good health, Editorial Commentary, 030104 developmental biology, 030220 oncology & carcinogenesis, Cancer cell, Cancer research, Regression Analysis, Immunohistochemistry, Female, Carcinoma, Pancreatic Ductal
Abstract

International audience; BACKGROUND & AIMS: Genomic studies have revealed subtypes of pancreatic ductal adenocarcinoma (PDA) based on their molecular features, but different studies have reported different classification systems. It is a challenge to obtain high-quality, freshly frozen tissue for clinical analysis and determination of PDA subtypes. We aimed to redefine subtypes of PDA using a large number of formalin-fixed and paraffin-embedded PDA samples, which are more amenable to routine clinical evaluation. METHODS: We collected PDA samples from 309 consecutive patients who underwent surgery from September 1996 through December 2010 at 4 academic hospitals in Europe; nontumor tissue samples were not included. Samples were formalin fixed and paraffin embedded. DNA and RNA were isolated; gene expression, targeted DNA sequencing, and immunohistochemical analyses were performed. We used independent component analysis to deconvolute normal, tumor, and microenvironment transcriptome patterns in samples. We devised classification systems from an unsupervised analysis using a consensus clustering approach of our data set after removing normal contamination components. We associated subtypes with overall survival and disease-free survival of patients using Cox proportional hazards regression with estimation of hazard ratios and 95% confidence interval. We used The Cancer Genome Consortium and International Cancer Genome Consortium PDA data sets as validation cohorts. RESULTS: We validated the previously reported basal-like and classical tumor-specific subtypes of PDAs. We identified features of the PDA, including microenvironment gene expression patterns, that allowed tumors to be categorized into 5 subtypes, called pure basal like, stroma activated, desmoplastic, pure classical, and immune classical. These PDA subtypes have features of cancer cells and immune cells that could be targeted by pharmacologic agents. Tumor subtypes were associated with patient outcomes, based on analysis of our data set and the International Cancer Genome Consortium and The Cancer Genome Consortium PDA data sets. We also observed an exocrine signal associated with acinar cell contamination (from pancreatic tissue). CONCLUSIONS: We identified a classification system based on gene expression analysis of formalin-fixed PDA samples. We identified 5 PDA subtypes, based on features of cancer cells and the tumor microenvironment. This system might be used to select therapies and predict patient outcomes. We found evidence that the previously reported exocrine-like (called ADEX) tumor subtype resulted from contamination with pancreatic acinar cells. ArrayExpress accession number: E-MTAB-6134.

Published
2018

2. Prevalence of Microsatellite Instability in Intraductal Papillary Mucinous Neoplasms of the Pancreas

Author

Jean-Christophe Vaillant, Nelson Dusetti, Jean-François Emile, Jean-Baptiste Bachet, Pascal Hammel, Anastasia R. Goloudina, Aurelie Scriva, Jean-Robert Delpero, Jean-François Fléjou, François Paye, Juan L. Iovanna, Christophe Louvet, Thierry André, Jean Closset, Jean-Luc Van Laethem, Alex Duval, Renato Micelli Lupinacci, Martine Antoine, Alain Sauvanet, Issam Abd Alsamad, Jérôme Cros, Vincent Jonchère, Olivier Buhard, Sylvie Dumont, Armelle Bardier-Dupas, Ada Collura, Raphaël Maréchal, Pieter Demetter, Anita Rodenas, Pascale Cervera, Magali Svrcek, Zayed Military Hospital, Department of Pathology, Hôpital Erasmes, Laboratoire électrotechnique et électronique industrielle (LEEI), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Assistance publique-Hôpitaux de Paris - Espace éthique (AP-HP Espace éthique), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Unité Mixte de Service d'Imagerie et de Cytométrie (UMS LUMIC), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Beaujon, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Diderot - Paris 7 (UPD7)-Hôpital Beaujon, Service de chirurgie hepato-pancreato-biliaire, Hôpital Beaujon-Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Service d'Oncologie Médicale [Montsouris], Institut Mutualiste de Montsouris (IMM), Laboratoire épidémiologie et oncogénèse des tumeurs digestives, Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Erasme Hospital, Brussels, Service d’Anatomie et cytologie pathologiques [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Tenon [APHP], Service d'anatomie pathologique [CHU Tenon], Service d'anatomie et cytologie pathologiques [CHU Saint-Antoine], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Saint-Antoine [APHP], Centre de Recherche en Cancérologie de Marseille (CRCM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), Physiopathologie du stress pancréatique, Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Saint-Antoine (CR Saint-Antoine), Pathologies biliaires, fibrose et cancer du foie (Inserm UMR_S 938), CHU Saint-Antoine [APHP]-Centre de Recherche Saint-Antoine (CR Saint-Antoine), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'Excellence : Lipoprotéines et Santé : prévention et Traitement des maladies Inflammatoires et du Cancer (LabEx LipSTIC), Institut National de la Recherche Agronomique (INRA)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Paris-Sud - Paris 11 (UP11)-École pratique des hautes études (EPHE)-Institut Gustave Roussy (IGR)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc (CRLCC - CGFL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Fédération Francophone de la Cancérologie Digestive, FFCD-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-France-Comté] (EFS [Bourgogne-France-Comté])-Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Université de Franche-Comté (UFC)-Université de Montpellier (UM), Service de chirurgie générale et digestive [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Saint-Antoine [APHP], Service d'Oncologie Médicale [CHU Saint -Antoine], Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Hôpital Beaujon [AP-HP], Biomarqueurs et essais cliniques en Cancérologie et Onco-Hématologie (BECCOH), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay, Hôpital Erasme [Bruxelles] (ULB), Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Tenon [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Sorbonne Université, Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université, Institut National de la Recherche Agronomique (INRA)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Paris-Sud - Paris 11 (UP11)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Gustave Roussy (IGR)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM)-Fédération Francophone de la Cancérologie Digestive, FFCD-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-France-Comté] (EFS [Bourgogne-France-Comté])-Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université de Montpellier (UM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], 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), Groupe Hospitalier Diaconesses Croix Saint-Simon, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 (UPMC), Hôpital Erasme [Bruxelles], Hôpital Beaujon [AP-HP], Université Paris Diderot - Paris 7 (UPD7), CHU Saint-Antoine [AP-HP], Hôpitaux Universitaires de l'Est Parisien [Paris] (HUEP), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Hôpital Ambroise Paré [AP-HP], CHI Créteil, CHU Tenon [AP-HP], 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), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [APHP], Laboratoire électrotechnique et électronique industrielle ( LEEI ), Institut National Polytechnique [Toulouse] ( INP ) -Centre National de la Recherche Scientifique ( CNRS ), Assistance publique-Hôpitaux de Paris - Espace éthique ( AP-HP Espace éthique ), Assistance publique - Hôpitaux de Paris (AP-HP), Unité Mixte de Service d'Imagerie et de Cytométrie ( UMS LUMIC ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Diderot - Paris 7 ( UPD7 ) -Hôpital Beaujon, Institut Mutualiste de Montsouris ( IMM ), Laboratoire de Mathématiques Informatique et Applications ( LAMIA ), Université des Antilles et de la Guyane ( UAG ), Université de Versailles Saint-Quentin-en-Yvelines ( UVSQ ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Tenon [APHP], Service d'anatomie et cytologie pathologiques, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Saint-Antoine [APHP], Centre de Recherche en Cancérologie de Marseille ( CRCM ), Aix Marseille Université ( AMU ) -Institut Paoli-Calmettes-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre de Recherche Saint-Antoine ( CR Saint-Antoine ), Pathologies biliaires, fibrose et cancer du foie ( Inserm UMR_S 938 ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -CHU Saint-Antoine [APHP], Laboratoire d'Excellence : Lipoprotéines et Santé : prévention et Traitement des maladies Inflammatoires et du Cancer ( LabEx LipSTIC ), Institut National de la Recherche Agronomique ( INRA ) -Université Montpellier 2 - Sciences et Techniques ( UM2 ) -Université Paris-Sud - Paris 11 ( UP11 ) -École pratique des hautes études ( EPHE ) -Institut Gustave Roussy ( IGR ) -Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ) -Université de Bourgogne ( UB ) -Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ) -Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Fédération Francophone de la Cancérologie Digestive, FFCD-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-France-Comté] ( EFS [Bourgogne-France-Comté] ) -Centre National de la Recherche Scientifique ( CNRS ) -Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Université de Franche-Comté ( UFC ), and Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Saint-Antoine [APHP]

Subjects
0301 basic medicine, Oncology, Male, Time Factors, endocrine system diseases, [SDV]Life Sciences [q-bio], CD8-Positive T-Lymphocytes, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, 0302 clinical medicine, PMS2, Cytokine Production, Mismatch Repair Endonuclease PMS2, Aged, 80 and over, Gastroenterology, Middle Aged, Lynch syndrome, 3. Good health, DNA-Binding Proteins, MutS Homolog 2 Protein, Phenotype, 030220 oncology & carcinogenesis, Female, Microsatellite Instability, MutL Protein Homolog 1, Carcinoma, Pancreatic Ductal, Adult, medicine.medical_specialty, congenital, hereditary, and neonatal diseases and abnormalities, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, MLH1, Disease-Free Survival, 03 medical and health sciences, Pancreatic Cancer, Lymphocytes, Tumor-Infiltrating, Internal medicine, Pancreatic cancer, medicine, Biomarkers, Tumor, Humans, Genetic Predisposition to Disease, neoplasms, Aged, Hepatology, Intraductal papillary mucinous neoplasm, [ SDV ] Life Sciences [q-bio], T-cell Activation, Microsatellite instability, nutritional and metabolic diseases, Marker, medicine.disease, digestive system diseases, MSH6, Pancreatic Neoplasms, 030104 developmental biology, MSH2, Neoplasms, Cystic, Mucinous, and Serous
Abstract

International audience; Microsatellite instability (MSI) caused by mismatch repair deficiency (dMMR) is detected in a small proportion of pancreatic ductal adenocarcinomas (PDACs). dMMR and MSI have been associated with responses of metastatic tumors, including PDACs, to immune checkpoint inhibitor therapy. We performed immunohistochemical analyses of a 445 PDAC specimens, collected from consecutive patients at multiple centers, to identify those with dMMR, based on loss of mismatch repair proteins MLH1, MSH2, MSH6, and/or PMS2. We detected dMMR in 1.6% of tumor samples; we found dMMR in a larger proportion of intraductal papillary mucinous neoplasms-related tumors (4/58, 6.9%) than non- intraductal papillary mucinous neoplasms PDAC (5/385, 1.3%) (P = .02). PDACs with dMMR contained potentially immunogenic mutations because of MSI in coding repeat sequences. PDACs with dMMR or MSI had a higher density of CD8+ T cells at the invasive front than PDACs without dMMR or MSI (P = .08; Fisher exact test). A higher proportion of PDACs with dMMR or MSI expressed the CD274 molecule (PD-L1, 8/9) than PDACs without dMMR or MSI (4/10) (P = .05). Times of disease-free survival and overall survival did not differ significantly between patients with PDACs with dMMR or MSI vs without dMMR or MSI. Studies are needed to determine whether these features of PDACs with dMMR or MSI might serve as prognostic factors.

Published
2017

3. Genome-Wide Association Study of Acute Renal Graft Rejection

Author

Yvon Lebranchu, Christian Noel, Annick Massart, Elisa Docampo, Guy Touchard, Anne Grall-Jezequel, Daniel Abramowicz, Maarten Naesens, Marie Essig, A Konarikova, Michel Georges, Judith Racapé, T Antoine, Pierre Merville, Jean-Luc Taupin, Dany Anglicheau, Y. Le Meur, François Glowacki, Ondrej Viklický, Lidia Ghisdal, Marc Abramowicz, M. Dinic, Ch. Legendre, Christophe Baron, Wouter Coppieters, Z. Ajarchouh, Dirk Kuypers, Jean-Philippe Rerolle, Eric Alamartine, Nilufer Broeders, Department of Nephrology - Dialysis and Renal Transplantation, Hôpital Erasmes, Service de néphrologie et immunologie clinique, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau-Université de Tours, Department of Nephrology, Intitute for clinical and Experimental Medicine, Department of microbiology and Immunology, University of Leuven K.U.Leuven, Department of Nephrology and Renal Transplantation, University Hospitals Leuven [Leuven]-Catholic University Leuven, CHU de Saint-Etienne, CHU de Saint-Etienne-CHU de Saint-Etienne, Département de Néphrologie, Centre hospitalier universitaire de Poitiers (CHU Poitiers), Lebanese University [Beirut] (LU), Hydrosciences Montpellier (HSM), Institut national des sciences de l'Univers (INSU - CNRS)-Institut de Recherche pour le Développement (IRD)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Lymphocyte B et Auto-immunité (LBAI), Université de Brest (UBO)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHRU - Service de néphrologie, dialyse et transplantation rénale, Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), LabEX IGO Immunothérapie Grand Ouest, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Impact de l'environnement chimique sur la santé humaine - ULR 4483 (IMPECS), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut national de recherche et de sécurité (Vandoeuvre lès Nancy) (INRS ( Vandoeuvre lès Nancy)), Service de néphrologie adultes [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA-Research), Université de Liège, Science des Procédés Céramiques et de Traitements de Surface (SPCTS), Université de Limoges (UNILIM)-Ecole Nationale Supérieure de Céramique Industrielle (ENSCI)-Institut des Procédés Appliqués aux Matériaux (IPAM), Université de Limoges (UNILIM)-Université de Limoges (UNILIM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut de Recherche Interdisciplinaire en Biologie Humaine et moléculaire = Insitute of Interdisciplinary Research [Bruxelles, Belgique] (IRIBHM), Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Centre of Epidemiology Biostatistic and Clinical Research, Université libre de Bruxelles (ULB), Department of Nephrology Antwerp, University of Antwerp (UA), Medical Genetics Department, Brussels, Hôpital Erasme [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB)-Faculté de Médecine [Bruxelles] (ULB), Service de néphrologie et immunologie clinique [CHRU Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau-Université de Tours (UT), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Lymphocytes B, Autoimmunité et Immunothérapies (LBAI), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-LabEX IGO Immunothérapie Grand Ouest, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Nantes Université (Nantes Univ), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Hôpital Bretonneau-Université de Tours-CHRU Tours, Centre hospitalier universitaire de Poitiers ( CHU Poitiers ), Lebanese University [Beirut], Hydrosciences Montpellier ( HSM ), Institut de Recherche pour le Développement ( IRD ) -Université Montpellier 2 - Sciences et Techniques ( UM2 ) -Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), Lymphocyte B et Auto-immunité ( LBAI ), Université de Brest ( UBO ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre Hospitalier Régional Universitaire de Brest ( CHRU Brest ), Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Impact de l'environnement chimique sur la santé humaine ( IMPECS ), Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ) -Université de Lille, Institut national de recherche et de sécurité (Vandoeuvre lès Nancy) ( INRS ( Vandoeuvre lès Nancy) ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Institut Necker Enfants-Malades (INEM) ( INEM - UM 111 (UMR 8253 / U1151) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Groupe Interdisciplinaire de Génoprotéomique Appliquée ( GIGA-Research ), Université de Liège-Faculté de médecine vétérinaire, Science des Procédés Céramiques et de Traitements de Surface ( SPCTS ), Université de Limoges ( UNILIM ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Chimie du CNRS ( INC ) -Ecole Nationale Supérieure de Céramique Industrielle ( ENSCI ) -Institut des Procédés Appliqués aux Matériaux ( IPAM ), Université de Limoges ( UNILIM ) -Université de Limoges ( UNILIM ), Insitute of Interdisciplinary Research in Molecular and Human Biology (IRIBHM), Université Libre de Bruxelles [Bruxelles] ( ULB ), University of Antwerp ( UA ), Hôpital Erasme (Bruxelles), Hôpital Bretonneau-Université de Tours-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Institut de Recherche pour le Développement (IRD)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Impact de l'environnement chimique sur la santé humaine (IMPECS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Université Libre de Bruxelles [Bruxelles] (ULB), Service de Néphrologie et d’Immunologie Clinique, Hôpital Bretonneau-CHU Tours, Pharmacologie des Immunosuppresseurs et de la Transplantation ( PIST ), Université de Limoges ( UNILIM ) -CHU Limoges-Génomique, Environnement, Immunité, Santé, Thérapeutique ( GEIST FR CNRS 3503 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service de Néphrologie, Dialyse, Transplantations [CHU Limoges], CHU Limoges, Service de Néphrologie-transplantation-dialyse [Bordeaux], CHU Bordeaux [Bordeaux], Département d'Immunologie et Histocompatiblité, Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Immunologie et Pathologie ( EA2216 ), Université de Brest ( UBO ) -IFR148, Department of Nephrology, University Hospital, Lille, France., Department of Nephrology, University Hospital, Service de Néphrologie et Transplantation rénale [CHRU-lille], CHU Necker - Enfants Malades [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP), Instiitut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire ( IRIBHM ), Medical Genetics Department, Hopital Erasme, Université Libre de Bruxelles [Bruxelles] ( ULB ) -Université Libre de Bruxelles [Bruxelles] ( ULB ), Institut des Procédés Appliqués aux Matériaux (IPAM), and Université de Limoges (UNILIM)-Université de Limoges (UNILIM)-Ecole Nationale Supérieure de Céramique Industrielle (ENSCI)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Limoges (UNILIM)

Subjects
Graft Rejection, Male, 0301 basic medicine, basic (laboratory) research/science, Génétique clinique, rejection: T cell mediated (TCMR), Genome-wide association study, kidney transplantation/nephrology, Immunogenetics, immunosuppression/immune modulation, 030230 surgery, 0302 clinical medicine, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, Immunology and Allergy, Medicine, Pharmacology (medical), genetics, ComputingMilieux_MISCELLANEOUS, Néphrologie - urologie, Receptor-Like Protein Tyrosine Phosphatases, Class 3, T cell mediated (TCMR) [rejection], Clinical Science, Middle Aged, Prognosis, 3. Good health, Acute Disease, Cohort, biomarker, [SDV.IMM]Life Sciences [q-bio]/Immunology, Original Article, Female, Microtubule-Associated Proteins, Adult, Genetic Markers, Locus (genetics), Genomics, Single-nucleotide polymorphism, Polymorphism, Single Nucleotide, 03 medical and health sciences, microarray/gene array, genomics, Humans, Gene, Transplantation, business.industry, Tumor Suppressor Proteins, Original Articles, Transplantation d'organes, Kidney Transplantation, Sciences biomédicales, immunogenetics, 030104 developmental biology, Case-Control Studies, Immunology, Kidney Failure, Chronic, Human medicine, business, Genome-Wide Association Study
Abstract

Acute renal rejection is a major risk factor for chronic allograft dysfunction and long-term graft loss. We performed a genome-wide association study to detect loci associated with biopsy-proven acute T cell-mediated rejection occurring in the first year after renal transplantation. In a discovery cohort of 4127 European renal allograft recipients transplanted in eight European centers, we used a DNA pooling approach to compare 275 cases and 503 controls, on Illumina 2·5 M arrays. In an independent replication cohort of 2765 patients transplanted in two European countries, we identified 313 cases and 531 controls, in whom we genotyped individually the most significant SNPs from the discovery cohort. In the discovery cohort, we found 5 candidate loci tagged by a number of contiguous SNPs (>5) that was never reached in iterative in silico permutations of our experimental data. In the replication cohort, two loci remained significantly associated with acute rejection in both univariate and multivariate analysis. One locus encompasses PTPRO, coding for a receptor-type tyrosine kinase essential for B cell receptor signalling. The other locus involves ciliary gene CCDC67, in line with the emerging concept of a shared building design between the immune synapse and the primary cilium. This article is protected by copyright. All rights reserved., FLWOA, SCOPUS: ar.j, info:eu-repo/semantics/published

Published
2017

4. Blocking TGF-β Signaling Pathway Preserves Mitochondrial Proteostasis and Reduces Early Activation of PDGFRβ+ Pericytes in Aristolochic Acid Induced Acute Kidney Injury in Wistar Male Rats

Author

Joëlle Nortier, Jean Michel Goujon, Anne-Emilie Decleves, Nathalie Quellard, Cécile Husson, Gang Li, Eric De Prez, Laetitia Giordano, M. H. Antoine, Agnieszka Pozdzik, Volker M. Arlt, Nathalie Caron, Isabelle Brochériou-Spelle, Julie Godet, Steven R. Ledbetter, Department of Nephrology - Dialysis and Renal Transplantation, Hôpital Erasmes, Hulunber Grassland Ecosystem Observation and Research Station (IARRP), Institute of Agricultural Resources and regional Planning-Chinese Academy of Agricultural Sciences (CAAS), Service d’Anapathomopathologie, Centre hospitalier universitaire de Poitiers (CHU Poitiers), Ischémie Reperfusion en Transplantation d’Organes Mécanismes et Innovations Thérapeutiques ( IRTOMIT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Poitiers, Département d'Anatomocytopathologie, Université de Poitiers-Institut National de la Santé et de la Recherche Médicale (INSERM), and Steichen, Clara

Subjects
0301 basic medicine, Male, Cell signaling, Time Factors, Physiology, [SDV]Life Sciences [q-bio], 030232 urology & nephrology, Psychologie appliquée, lcsh:Medicine, Smad Proteins, Mitochondrion, Signal transduction, Biochemistry, Epithelium, Kidney Tubules, Proximal, chemistry.chemical_compound, 0302 clinical medicine, Endocrinology, Animal Cells, Transforming Growth Factor beta, Medicine and Health Sciences, Homeostasis, Receptor, lcsh:Science, Myofibroblasts, Energy-Producing Organelles, Cells, Cultured, ComputingMilieux_MISCELLANEOUS, Connective Tissue Cells, Kidney, Multidisciplinary, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Acute kidney injury, Signaling cascades, Sciences bio-médicales et agricoles, Acute Kidney Injury, 3. Good health, Cell biology, Mitochondria, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, Connective Tissue, Aristolochic Acids, Anatomy, Cellular Types, Cellular Structures and Organelles, Myofibroblast, Biologie, Research Article, Blotting, Western, Aristolochic acid, Biology, Bioenergetics, Models, Biological, Cell Line, Mitochondrial Proteins, Receptor, Platelet-Derived Growth Factor beta, 03 medical and health sciences, Growth factor receptor, Growth Factors, medicine, Animals, Humans, Rats, Wistar, Biology and life sciences, Endocrine Physiology, lcsh:R, Endothelial Cells, Kidneys, Epithelial Cells, Renal System, Fibroblasts, medicine.disease, Fibrosis, Antibodies, Neutralizing, 030104 developmental biology, Proteostasis, Biological Tissue, chemistry, TGF-beta signaling cascade, Immunology, lcsh:Q, Pericytes, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Developmental Biology
Abstract

Background: The platelet-derived growth factor receptor β (PDGFRβ)+ perivascular cell activation becomes increasingly recognized as a main source of scar-associated kidney myofibroblasts and recently emerged as a new cellular therapeutic target. Aims: In this regard, we first confirmed the presence of PDGFRβ+ perivascular cells in a human case of end-stage aristolochic acid nephropathy (AAN) and thereafter we focused on the early fibrosis events of transforming growth factor β (TGFβ) inhibition in a rat model of AAN. Materials and Methods: Neutralizing anti-TGFβ antibody (1D11) and its control isotype (13C4) were administered (5 mg/kg, i.p.) at Days -1, 0, 2 and 4; AA (15 mg/kg, sc) was injected daily. Results: At Day 5, 1D11 significantly suppressed p-Smad2/3 signaling pathway improving renal function impairment, reduced the score of acute tubular necrosis, peritubular capillaritis, interstitial inflammation and neoangiogenesis. 1D11 markedly decreased interstitial edema, disruption of tubular basement membrane loss of brush border, cytoplasmic edema and organelle ultrastructure alterations (mitochondrial disruption and endoplasmic reticulum edema) in proximal tubular epithelial cells. Moreover, 1D11 significantly inhibited p-PERK activation and attenuated dysregulation of unfolded protein response (UPR) pathways, endoplasmic reticulum and mitochondrial proteostasis in vivo and in vitro. Conclusions: The early inhibition of p-Smad2/3 signaling pathway improved acute renal function impairment, partially prevented epithelial-endothelial axis activation by maintaining PTEC proteostasis and reduced early PDGFRβ+ pericytes-derived myofibroblasts accumulation., SCOPUS: ar.j, info:eu-repo/semantics/published

Published
2016

5. Infrared Microspectroscopy using Synchrotron Radiation (Sr Μftir) and Infrared Microspectroscopy as New Tools for Rapid Detection of Ectopic Calcifications Associated with Peritoneal Dialysis

Author

Monika Tooulou, Agnieszka Pozdzik, Dominique Bazin, Anwar Hamade, Pieter Demetter, Joëlle Nortier, Michel Daudon, Department of Nephrology - Dialysis and Renal Transplantation, Hôpital Erasmes, Laboratory of Experimental Nephrology - Department of Biochimie, Université libre de Bruxelles (ULB), Department of Pathology, Spectroscopie, Modélisation, Interfaces pour L'Environnement et la Santé (SMiLES), Laboratoire de Chimie de la Matière Condensée de Paris (LCMCP), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Collège de France (CdF (institution))-Institut de Chimie du CNRS (INC)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Collège de France (CdF (institution))-Institut de Chimie du CNRS (INC), Laboratoire de Physique des Solides, Université Paris XI - Orsay, Service d'Explorations fonctionnelles multidisciplinaires [CHU Tenon], CHU Tenon [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), Université Pierre et Marie Curie - Paris 6 (UPMC)-Collège de France (CdF (institution))-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Collège de France (CdF (institution))-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
Cardiovascular calcifications, Pathology, medicine.medical_specialty, Materials science, medicine.medical_treatment, Biomedical Engineering, Pharmaceutical Science, Medicine (miscellaneous), Bioengineering, Nanotechnology, Peritoneal dialysis, Hyperphosphatemia, Biopsy, medicine, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Von Kossa stain, Microspectroscopy, Ultrasonography, medicine.diagnostic_test, business.industry, medicine.disease, 3. Good health, Staining, Echocardiography, Infrared microscopy, business, Kidney disease
Abstract

International audience; The cardiovascular calcifications (CVC) represent a central complication of chronic kidney disease (CKD) responsible of high cardiovascular mortality particularly in patients on peritoneal dialysis. Unfortunately, electron beam and multislice computed tomography, planar X-ray, ultrasonography or cardiac echocardiography methods are not accurate to detect calcium phosphate microcrystals since of its small size. We investigated the ectopic calcifications by Von Kossa staining and infrared microspectroscopy using synchrotron radiation (SR μFTIR) and infrared microspectroscopy in formalin-fixed peritoneal tissues from 3 cases. Von Kossa staining allowed us to detect vascular calcifications only in one of 3 studied peritoneal biopsies. Vascular calcifications contained mainly carbapatite accordingly to the presence of the IR absorption bands positioned at 1030 cm-1 (ν3), 960 cm-1 (ν1). In all studied biopsy, we found several tissue microcrystals also composed by carbapatite. To our knowledge, we report for the first time the usefulness of infrared microscopy and SR μFTIR for the assessment of calcium phosphate microcrystals and identification of biochemical composition of VC associated with CKD in peritoneal membrane from patients on peritoneal dialysis. SR μFTIR technique and infrared microspectroscopy are new, remarkable, and rapid tools for detection of early stage of ectopic calcifications associated with peritoneal dialysis. Investigation of calcium phosphate microcrystals by both methods might improve our understanding of early stage of CVC pathophysiology. Citation: Pozdzik AA, Demetter P, Tooulou M, Hamade A, Nortier J, et al. (2015) Infrared Microspectroscopy using Synchrotron Radiation (Sr Μftir) and Infrared Microspectroscopy as New Tools for Rapid Detection of Ectopic Calcifications Associated with Peritoneal Dialysis.

Published
2015

6. Aberrant expression of serotonin receptors in an aldosterone- and cortisol-producing adenoma

Author

Céline Duparc, Camilo Garcia, Natacha Driessens, Rodrigo Moreno-Reyes, Maria Lytrivi, Estelle Louiset, Valerio Lucidi, Pieter Demetter, Julien Wils, Bernard Corvilain, Denis Brisbois, Stella Vudu, Hervé Lefebvre, Department of Pathology, Hôpital Erasmes, Institut Jules Bordet [Bruxelles], Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Department of Abdominal Surgery [Brussels, Belgium], Hôpital Erasme [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB)-Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB)-Centre de Chirurgie Hépato-Biliaire de l'ULB [Brussels, Belgium], Différenciation et communication neuronale et neuroendocrine (DC2N), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Normandie Université (NU), CHU Rouen, Département d'Endocrinologie, Diabète et Maladies Métaboliques [CHU Rouen], and Normandie Université (NU)-Normandie Université (NU)

Subjects
medicine.medical_specialty, Adenoma, 030209 endocrinology & metabolism, Stimulation, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, 030204 cardiovascular system & hematology, Adrenocortical adenoma, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Primary aldosteronism, Internal medicine, medicine, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], 5-HT receptor, Aldosterone, Adrenal cortex, business.industry, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, medicine.disease, 3. Good health, Endocrinology, medicine.anatomical_structure, chemistry, Serotonin, business
Abstract

Aberrant expression of serotonin receptors in an aldosterone- and cortisol-producing adenoma Introduction Aberrant expression of serotonin receptors has been described to be involved in the pathophysiology of both aldosterone-producing and cortisol-producing adrenal adenomas. Case report A 46-year-old woman was referred for evaluation of severe hypertension associated with hypokalaemia. Primary aldosteronism with concurrent subclinical Cushing’s syndrome was diagnosed. A CT-scan identified a lesion of 4 cm in the right adrenal gland and a second lesion of 1 cm in the left adrenal gland, both displaying benign imaging phenotype. Following dexamethasone suppression, we explored the potential aberrant expression of serotonin receptors in the adrenal cortex by intravenous administration of metoclopramide, a serotonin type 4 receptor (5-HT4-R) agonist. This led to abnormal cortisol increase and physiological response of aldosterone in peripheral blood. Adrenal venous sampling was then performed in basal conditions and after metoclopramide stimulation. An increase in cortisol level was observed in the left adrenal vein after stimulation. 131I-19-Iodocholesterol scintigraphy showed intense radiotracer uptake in the right adrenal mass and weak uptake in the contralateral mass. Right laparoscopic adrenalectomy was performed. Histological examination revealed an adrenocortical adenoma. In vitro, cultured adrenocortical cells derived from the tumoural tissue exhibited aldosterone and cortisol co-secretion. Administration of 5-HT or metoclopramide to the cells induced a dose-dependent increase in cortisol production. These effects were inhibited by concomitant administration of the 5-HT4-R antagonist GR113808. Incubation of tumour tissue fragments with 5-HT induced a significant increase in aldosterone production which was abrogated in the presence of GR113808. These data were suggestive of aberrant expression of 5HT4-R in the tumoural tissue. Conclusion We report a rare case of an aldosterone- and cortisol-co-producing adenoma in a patient with severe hypertension and bilateral adrenal masses exhibiting an abnormal plasma cortisol response to metoclopramide. In vitro studies revealed enhanced sensitivity of the tumour tissue to 5-HT indicative of illicit expression of 5-HT4 receptors.

Published
2015

7. Spectrum and Prognosis of Noninfectious Renal Mixed Cryoglobulinemic GN

Author

Mohamad, Zaidan, Benjamin, Terrier, Agnieszka, Pozdzik, Thierry, Frouget, Nathalie, Rioux-Leclercq, Christian, Combe, Sébastien, Lepreux, Aurélie, Hummel, Laure-Hélène, Noël, Isabelle, Marie, Bruno, Legallicier, Arnaud, François, Antoine, Huart, David, Launay, Gilles, Kaplanski, Frank, Bridoux, Philippe, Vanhille, Raifah, Makdassi, Jean-François, Augusto, Philippe, Rouvier, Alexandre, Karras, Chantal, Jouanneau, Marie-Christine, Verpont, Patrice, Callard, Fabrice, Carrat, Olivier, Hermine, Jean-Marc, Léger, Xavier, Mariette, Patricia, Senet, David, Saadoun, Pierre, Ronco, Isabelle, Brochériou, Patrice, Cacoub, Emmanuelle, Plaisier, Thierry, Zénone, CHU Necker - Enfants Malades [AP-HP], Departement Hospitalo- Universitaire - Inflammation, Immunopathologie, Biothérapie [Paris] (DHU - I2B), Université Pierre et Marie Curie - Paris 6 (UPMC)-CHU Pitié-Salpêtrière [APHP], Service de médecine interne et centre de référence des maladies rares [CHU Cochin], CHU Cochin [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Department of Nephrology - Dialysis and Renal Transplantation, Hôpital Erasmes, Laboratory of Experimental Nephrology - Department of Biochimie, Université Libre de Bruxelles [Bruxelles] (ULB), Service de néphrologie, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service de Néphrologie-transplantation-dialyse [Bordeaux], CHU Bordeaux [Bordeaux], Centre de compétences des microangiopathies thrombotiques, Université Bordeaux Segalen - Bordeaux 2, Centre de recherche Croissance et signalisation (UMR_S 845), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'anatomie pathologique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Service de Médecine Interne [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Service d'Anatomie et Cytologie Pathologique [Rouen], Service de Néphrologie et Immunopathologie Clinique, Centre Hospitalier Universitaire de Toulouse, PRES Université de Toulouse, Laboratoire d'Immunologie (EA 2686), Université de Lille, Droit et Santé, Inflammation: mécanismes et régulation et interactions avec la nutrition et les candidoses, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, Service de Médecine Interne et d'Immunologie clinique, Centre National de Référence Maladies rares-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service de néphrologie - hémodialyse et transplantation rénale, Centre hospitalier universitaire de Poitiers (CHU Poitiers), Service de médecine interne et néphrologie, CH Valenciennes, Université d'Angers - Faculté de médecine (UA UFR Médecine), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Université d'Angers (UA), Service de Néphrologie et Hémodialyse [CHU HEGP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Des Maladies Rénales Rares aux Maladies Fréquentes, Remodelage et Réparation, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Tenon [APHP], Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), CHU Saint-Antoine [APHP], Centre de référence des mastocytoses, Service d'Hématologie Adulte, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Centre d'Immunologie et de Maladies Infectieuses (CIMI), 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), Régulation de la réponse immune, infection VIH-1 et autoimmunité, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Dermatologie [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Tenon [APHP], Immunologie - Immunopathologie - Immunothérapie (I3), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Service d'immunologie [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Sorbonne Universités, Service de Néphrologie et Dialyses [CHU Tenon], Departement Hospitalo- Universitaire - Inflammation, Immunopathologie, Biothérapie [Paris] ( DHU - I2B ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -CHU Pitié-Salpêtrière [APHP], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Cochin [AP-HP], Université Libre de Bruxelles [Bruxelles] ( ULB ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Institut de Génétique et Développement de Rennes ( IGDR ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Centre National de la Recherche Scientifique ( CNRS ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre de recherche Croissance et signalisation ( UMR_S 845 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), CHU Necker - Enfants Malades [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP), CHU Rouen-Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ), Laboratoire d'Immunologie ( EA 2686 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Lille, Droit et Santé, Centre National de Référence Maladies rares-Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Université de Poitiers-Centre hospitalier universitaire de Poitiers ( CHU Poitiers ), Centre de Recherche en Cancérologie / Nantes - Angers ( CRCNA ), CHU Angers-Centre hospitalier universitaire de Nantes ( CHU Nantes ) -Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Hôpital Laennec-Centre National de la Recherche Scientifique ( CNRS ) -Faculté de Médecine d'Angers, Université d'Angers - Faculté de médecine ( UA UFR Médecine ), Université d'Angers ( UA ) -CHU Angers, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service de Pathologie, Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Tenon [APHP], Institut Pierre Louis d'Epidémiologie et de Santé Publique ( iPLESP ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ), Département de santé publique, Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Imagine - Institut des maladies génétiques ( IMAGINE - U1163 ), Centre d'Immunologie et de Maladies Infectieuses ( CIMI ), 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 ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Immunologie - Immunopathologie - Immunothérapie ( I3 ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Anatomopathologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Pierre et Marie Curie - Paris 6 (UPMC)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Université libre de Bruxelles (ULB), Service de néphrologie [Rennes], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Service de Médecine Interne [CHU Rouen], Service d'Anatomie et Cytologie Pathologique [CHU Rouen], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), 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)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), CHU Tenon [AP-HP], CHU Saint-Antoine [AP-HP], Centre de référence des mastocytoses (CEREMAST), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de dermatologie et allergologie [CHU Tenon], Service d'Immunologie [CHU Pitié-Salpétrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Tenon [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)-Université Pierre et Marie Curie - Paris 6 (UPMC), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université de Rennes (UR)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service Médecine interne et immunopathologie clinique [CHU Toulouse], Pôle IUCT [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), CHU Pitié-Salpêtrière [APHP]-Université Pierre et Marie Curie - Paris 6 (UPMC), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Cochin [AP-HP], Université de Lille, Droit et Santé-Institut National de la Santé et de la Recherche Médicale (INSERM), and Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)

Subjects
Male, medicine.medical_specialty, Pathology, Cyclophosphamide, Glomerulonephritis, Membranoproliferative, [SDV]Life Sciences [q-bio], 030232 urology & nephrology, Lymphoproliferative disorders, Gastroenterology, 03 medical and health sciences, 0302 clinical medicine, Clinical Research, Internal medicine, medicine, Humans, Cause of death, Retrospective Studies, 030203 arthritis & rheumatology, Proteinuria, [ SDV ] Life Sciences [q-bio], business.industry, General Medicine, membranoproliferative GN, Middle Aged, medicine.disease, Prognosis, Cryoglobulinemia, 3. Good health, Lymphoma, Regimen, Nephrology, histopathology, Rituximab, Female, medicine.symptom, business, Immunosuppressive Agents, medicine.drug
Abstract

International audience; Noninfectious mixed cryoglobulinemic GN (MCGN) has been poorly investigated. We analyzed presentation and outcome of 80 patients with biopsy-proven MCGN, which were identified in the retrospective French CryoVas survey. MCGN was related to primary Sjögren's syndrome in 22.5% of patients and to lymphoproliferative disorders in 28.7% of patients, and was defined as essential in 48.8% of patients. At presentation, hematuria, proteinuria ≥1 g/d, hypertension, and renal failure were observed in 97.4%, 84.8%, 85.3%, and 82.3% of cases, respectively. Mean±eGFR was 39.5±20.4 ml/min per 1.73 m2. Membranoproliferative GN was the predominant histologic pattern, observed in 89.6% of cases. Renal interstitium inflammatory infiltrates were observed in 50% of cases. First-line treatment consisted of steroids alone (27.6%) or in association with rituximab (21.1%), alkylating agents (36.8%) or a combination of cyclophosphamide and rituximab (10.5%). After a mean follow-up of 49.9±45.5 months, 42.7% of patients relapsed with a renal flare in 75% of cases. At last follow-up, mean eGFR was 50.2±26.1 ml/min per 1.73 m2 with 9% of patients having reached ESRD; 59% and 50% of patients achieved complete clinical and renal remission, respectively. A rituximab+steroids regimen prevented relapses more effectively than steroids alone or a cyclophosphamide+steroids combination did, but was associated with a higher rate of early death when used as first-line therapy. Severe infections and new-onset B-cell lymphoma occurred in 29.1% and 8.9% of cases, respectively; 24% of patients died. In conclusion, noninfectious MCGN has a poor long-term outcome with severe infections as the main cause of death

Published
2015

8. Results of the HepZero study comparing heparin-grafted membrane and standard care show that heparin-grafted dialyzer is safe and easy to use for heparin-free dialysis

Author

Joan Fort Ros, Nathalie Loughraieb, Marc Dorval, Renaud Fay, Damien Thibaudin, Joëlle Cridlig, Maurice Laville, Loreto Fernandez Lorente, Frédérique Moureau, Michael Schulz, Laurent Juillard, Patrick Rossignol, Alicja Dębska-Ślizień, Joëlle Nortier, Casper F. M. Franssen, Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Néphrologie [Lyon], Hospices Civils de Lyon (HCL)-Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Association pour l'Utilisation du Rein Artificiel Région Lyonnaise (AURAL), Department of Nephrology [CHUDGLD], Dr. Georges-L.-Dumont University Hospital Centre (CHUDGLD), Nephrology Department, Vall d'Hebron University Hospital [Barcelona]-Autonomous University of Barcelona, Centre d'investigation clinique plurithématique Pierre Drouin (CIC-P), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Service de Néphrologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Department of Nephrology - Dialysis and Renal Transplantation, Hôpital Erasmes, Service de néphrologie, Groupement Hospitalier Edouard Herriot, Hospices Civils de Lyon, France (Service de néphrologie, Groupement Hospitalier Edouard Herriot, Hospices Civils de Lyon, France), Medical University of Gdansk, Germans Trias i Pujol Hospital, Barcelona Autonomous University, Service de Néphrologie, Hôpital Nord, CHU Saint Etienne, Saint Etienne, France, Groningen University Medical Centre, Royal Liverpool and Broadgreen University Hospital NHS Trust, Hospal, Le Groupe Gambro, Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National de la Recherche Agronomique (INRA), Centre d'investigation clinique plurithématique Pierre Drouin [Nancy] (CIC-P), Centre d'investigation clinique [Nancy] (CIC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), and Autonomous University of Barcelona-Vall d'Hebron University Hospital [Barcelona]

Subjects
Male, MESH: Heparin, medicine.medical_treatment, 030232 urology & nephrology, MESH: Equipment Failure, 030204 cardiovascular system & hematology, Sodium Chloride, law.invention, No-heparin, 0302 clinical medicine, MESH: Aged, 80 and over, Randomized controlled trial, Coated Materials, Biocompatible, MESH: Coated Materials, Biocompatible, law, MESH: Renal Insufficiency, ORAL ANTICOAGULATION, MESH: Renal Dialysis, Prospective Studies, Renal Insufficiency, Prospective cohort study, anticoagulation, Saline, MESH: Treatment Outcome, Aged, 80 and over, MESH: Aged, hemodialysis, MESH: Middle Aged, Néphrologie - urologie, heparin-grafted membrane, Heparin, Middle Aged, 3. Good health, Treatment Outcome, Nephrology, Hemodialysis, Equipment Failure, Female, Heparin-grafted membrane, MESH: Membranes, Artificial, MESH: Hemorrhage, medicine.drug, medicine.medical_specialty, SYSTEMIC ANTICOAGULATION, MESH: Sodium Chloride, Hemorrhage, MESH: Anticoagulants, 03 medical and health sciences, Anticoagulation, Standard care, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Renal Dialysis, REGIONAL CITRATE ANTICOAGULATION, medicine, Humans, Dialysis, Aged, no-heparin, MESH: Humans, business.industry, Anticoagulants, Médecine pathologie humaine, Membranes, Artificial, Confidence interval, Sciences biomédicales, MESH: Prospective Studies, MESH: Male, Surgery, Ingénierie biomédicale, FREE HEMODIALYSIS, HIGH-RISK, randomized controlled trial, business, MESH: Female
Abstract

Heparin is used to prevent clotting during hemodialysis, but heparin-free hemodialysis is sometimes needed to decrease the risk of bleeding. The HepZero study is a randomized, multicenter international controlled open-label trial comparing no-heparin hemodialysis strategies designed to assess non-inferiority of a heparin grafted dialyzer (NCT01318486). A total of 251 maintenance hemodialysis patients at increased risk of hemorrhage were randomly allocated for up to three heparin-free hemodialysis sessions using a heparin-grafted dialyzer or the center standard-of-care consisting of regular saline flushes or pre-dilution. The first heparin-free hemodialysis session was considered successful when there was neither complete occlusion of air traps or dialyzer, nor additional saline flushes, changes of dialyzer or bloodlines, or premature termination. The current standard-of-care resulted in high failure rates (50%). The success rate in the heparin-grafted membrane arm was significantly higher than in the control group (68.5% versus 50.4%), which was consistent for both standard-of-care modalities. The absolute difference between the heparin-grafted membrane and the controls was 18.2%, with a lower bound of the 90% confidence interval equal to plus 7.9%. The hypothesis of the non-inferiority at the minus 15% level was accepted, although superiority at the plus 15% level was not reached. Thus, use of a heparin-grafted membrane is a safe, helpful, and easy-to-use method for heparin-free hemodialysis in patients at increased risk of hemorrhage.Kidney International advance online publication, 9 July 2014; doi:10.1038/ki.2014.225., JOURNAL ARTICLE, SCOPUS: ar.j, info:eu-repo/semantics/published

Published
2014

9. Consensus Conference on a Composite Endpoint for Clinical Trials on Immunosuppressive Drugs in Lung Transplantation

Author

Monchaud, Caroline, Marin, Benoît, Estenne, Marc, Preux, Pierre-Marie, Pison, Christophe, Marquet, Pierre, Pharmacologie des Immunosuppresseurs et de la Transplantation (PIST), Université de Limoges (UNILIM)-CHU Limoges-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neuroépidémiologie Tropicale (NET), Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM)-CHU Limoges-Institut d'Epidémiologie Neurologique et de Neurologie Tropicale-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de l'Information Médicale et de l'Évaluation [CHU Limoges] (SIME), CHU Limoges, Laboratoire de Biostatistique et d'Informatique Médicale, Université de Limoges (UNILIM), Service de pneumologie, Hôpital Erasmes, Institut National de la Santé et de la Recherche Médicale (INSERM)-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-Université de Limoges (UNILIM)-CHU Limoges, CHU Limoges-Institut d'Epidémiologie Neurologique et de Neurologie Tropicale-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM), Laboratoire de bioénergétique fondamentale et appliquée [1990-2015] (LBFA [1990-2015]), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Centre Hospitalier Universitaire [Grenoble] (CHU)

Subjects
Lung Diseases, Research design, Pathology, medicine.medical_specialty, Consensus, Delphi Technique, Endpoint Determination, [SDV]Life Sciences [q-bio], International Cooperation, medicine.medical_treatment, MEDLINE, Psychological intervention, Delphi method, immunosuppressive drugs, 030230 surgery, Delphi, 03 medical and health sciences, 0302 clinical medicine, Surveys and Questionnaires, Pulmonary Medicine, medicine, Humans, Lung transplantation, Intensive care medicine, Societies, Medical, clinical trials, Clinical Trials as Topic, Transplantation, business.industry, 3. Good health, Clinical trial, Immunosuppressants, Treatment Outcome, Immunosuppressive drug, Research Design, Consensus conferences, 030211 gastroenterology & hepatology, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Immunosuppressive Agents, Composite endpoints
Abstract

Background. In lung transplantation, diverse clinical events may impact patient outcome. In clinical trials comparing intervention strategies, single primary endpoints require large populations, or long study durations, whereas composite endpoints (CEPs) do not take into account the respective impact of their components on patient survival. The objective of this study was to propose consensus recommendations on endpoints for clinical trials on immunosuppressants in lung transplantation. Methods. The consensus process was managed through the Internet using the Delphi method. Forty experts were invited by the pilot group with the help of the International Society for Heart and Lung Transplantation and The Transplantation Society. In the first round, a questionnaire was made available to the experts to complete, and the responses were analyzed. In each next round, a new questionnaire was developed from the previous responses and sent to the panel members. Results. Consensus between 17 experts was achieved after five rounds. Two score-type CEPs were defined for immunosuppressive drug efficacy (7 items) and for toxicity (15 items). Death related to graft loss or immunosuppressive drug toxicity was attributed a maximum weight of 100. The weights of the items included in the efficacy and toxicity CEPs ranged between 10 and 80 and between 25 and 70, respectively. The CEP scores are calculated by adding the weights of all the items composing them, without exceeding 90 as long as the patient is alive. Conclusion. This consensus conference proposed two score-type CEPs including relevant endpoints. After validation, they should allow clinical trials with higher statistical power, improving the evaluation of the interventions tested.

Published
2014

10. Population pharmacokinetic modelling and design of a Bayesian estimator for therapeutic drug monitoring of tacrolimus in lung transplantation

Author

Martine Reynaud-Gaubert, Romain Kessler, Marc Stern, Pierre Marquet, Caroline Monchaud, Annick Rousseau, Romain Guillemain, Christophe Pison, Brenda C. M. de Winter, Christiane Knoop, Marc Estenne, Pharmacologie des Immunosuppresseurs et de la Transplantation (PIST), Université de Limoges (UNILIM)-CHU Limoges-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de chirurgie cardiovasculaire, 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)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Service de pneumologie, Hôpital Erasmes, Service de chirurgie thoracique, Assistance Publique - Hôpitaux de Marseille (APHM)-Hôpital nord, Clinique de pneumologie, CHU Grenoble, Service de pneumologie [Hôpital Foch], Hôpital Foch [Suresnes], Service de Pneumologie, Nouvel Hôpital Civil Strasbourg, Service de Pharmacologie, toxicologie et pharmacovigilance [CHU Limoges], CHU Limoges, and Marquet, Pierre

Subjects
Graft Rejection, Male, Oncology, medicine.medical_treatment, Pharmacology, 030226 pharmacology & pharmacy, MESH: Genotype, 0302 clinical medicine, Belgium, MESH: Belgium, MESH: Drug Monitoring, Cytochrome P-450 CYP3A, Pharmacology (medical), Prospective Studies, Prospective cohort study, MESH: Treatment Outcome, MESH: Biological Availability, MESH: Aged, MESH: Cytochrome P-450 CYP3A, education.field_of_study, MESH: Middle Aged, medicine.diagnostic_test, MESH: Polymorphism, Single Nucleotide, Middle Aged, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, 3. Good health, [SDV.SP] Life Sciences [q-bio]/Pharmaceutical sciences, MESH: Reproducibility of Results, MESH: Nonlinear Dynamics, Phenotype, Treatment Outcome, surgical procedures, operative, MESH: Young Adult, Area Under Curve, 030220 oncology & carcinogenesis, Drug Therapy, Combination, Female, France, MESH: Immunosuppressive Agents, Drug Monitoring, Immunosuppressive Agents, Lung Transplantation, Adult, medicine.medical_specialty, Adolescent, Genotype, Metabolic Clearance Rate, MESH: Bayes Theorem, Population, MESH: Pharmacogenetics, Biological Availability, MESH: Graft Rejection, MESH: Phenotype, Models, Biological, Polymorphism, Single Nucleotide, Tacrolimus, Young Adult, 03 medical and health sciences, Pharmacokinetics, Internal medicine, medicine, MESH: Tacrolimus, Humans, Lung transplantation, education, Aged, MESH: Adolescent, MESH: Metabolic Clearance Rate, MESH: Humans, business.industry, MESH: Models, Biological, Reproducibility of Results, Bayes Theorem, MESH: Adult, MESH: Male, MESH: Prospective Studies, Bioavailability, MESH: France, MESH: Drug Therapy, Combination, Nonlinear Dynamics, Pharmacogenetics, Therapeutic drug monitoring, MESH: Area Under Curve, MESH: Lung Transplantation, business, MESH: Female
Abstract

International audience; BACKGROUND: Therapeutic drug monitoring of tacrolimus is a major support to patient management and could help improve the outcome of lung transplant recipients, by minimizing the risk of rejections and infections. However, despite the wide use of tacrolimus as part of maintenance immunosuppressive regimens after lung transplantation, little is known about its pharmacokinetics in this population. Better knowledge of the pharmacokinetics of tacrolimus in lung transplant recipients, and the development of tools dedicated to its therapeutic drug monitoring, could thus help improve their outcome. OBJECTIVES: The aims of this study were (i) to characterize the population pharmacokinetics of tacrolimus in lung transplant recipients, including the influence of biological and pharmacogenetic covariates; and (ii) to develop a Bayesian estimator of the tacrolimus area under the blood concentration-time curve from time zero to 12 hours (AUC(12)) for its therapeutic drug monitoring in lung transplant recipients. METHODS: A population pharmacokinetic model was developed by nonlinear mixed-effects modelling using NONMEM® version VI, from 182 tacrolimus full concentration-time profiles collected in 78 lung transplant recipients within the first year post-transplantation. Patient genotypes for the cytochrome P450 3A5 (CYP3A5) A6986G single nucleotide polymorphism (SNP) were characterized by TaqMan allelic discrimination. Patients were divided into an index dataset (n = 125 profiles) and a validation dataset (n = 57 profiles). A Bayesian estimator was derived from the final model using the index dataset, in order to determine the tacrolimus AUC(12) on the basis of a limited number of samples. The predictive performance of the Bayesian estimator was evaluated in the validation dataset by comparing the estimated AUC(12) with the trapezoidal AUC(12). RESULTS: Tacrolimus pharmacokinetics were described using a two-compartment model with Erlang absorption and first-order elimination. The model included cystic fibrosis (CF) and CYP3A5 polymorphism as covariates. The relative bioavailability in patients with CF was approximately 60% of the relative bioavailability observed in patients without CF, and the transfer rate constant between the transit compartments was 2-fold smaller in patients with CF than in those without CF (3.32 vs 7.06 h-1). The apparent clearance was 40% faster in CYP3A5 expressers than in non-expressers (24.5 vs 17.5 L/h). Good predictive performance was obtained with the Bayesian estimator developed using the final model and concentrations measured at 40 minutes and at 2 and 4 hours post-dose, as shown by the mean bias (1.1%, 95% CI -1.4, 3.7) and imprecision (9.8%) between the estimated and the trapezoidal AUC(12). The bias was >20% in 1.8% of patients. CONCLUSION: Population pharmacokinetic analysis showed that lung transplant patients with CF displayed lower bioavailability and a smaller transfer rate constant between transit compartments than those without CF, while the apparent clearance was faster in CYP3A5 expressers than in non-expressers. The Bayesian estimator developed in this study provides an accurate prediction of tacrolimus exposure in lung transplant patients, with and without CF, throughout the first year post-transplantation. This tool may allow routine tacrolimus dose individualization and may be used to conduct clinical trials on therapeutic drug monitoring of tacrolimus after lung transplantation.

Published
2012

11. Bayesian estimation of mycophenolate mofetil in lung transplantation, using a population pharmacokinetic model developed in kidney and lung transplant recipients

Author

Christiane Knoop, Brenda C. M. de Winter, Romain Guillemain, Caroline Monchaud, Marc Estenne, Christophe Pison, Annick Rousseau, Romain Kessler, Claire Dromer, Pierre Marquet, Martine Reynaud-Gaubert, Marc Stern, Aurélie Prémaud, Marquet, Pierre, Pharmacologie des Immunosuppresseurs et de la Transplantation (PIST), Université de Limoges (UNILIM)-CHU Limoges-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de bioénergétique fondamentale et appliquée (LBFA), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Pneumologie, Nouvel Hôpital Civil Strasbourg, Service de chirurgie thoracique, Assistance Publique - Hôpitaux de Marseille (APHM)-Hôpital nord, CHU Bordeaux [Bordeaux]-Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], Service de pneumologie [Hôpital Foch], Hôpital Foch [Suresnes], Service de chirurgie cardiovasculaire, 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)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Service de pneumologie, Hôpital Erasmes, and The STIMMUGREP trial was sponsored by the Direction de la Recherche Clinique et de l'Innovation, Limoges University Hospital, and co- funded by the Programme Hospitalier de Recherche Clinique (PHRC) Re ́ gional, Vaincre la Mucoviscidose and Agence de la Biome ́ decine (France).

Subjects
Male, Cystic Fibrosis, medicine.medical_treatment, Pharmacology, 030226 pharmacology & pharmacy, Organ transplantation, MESH: Kidney Transplantation, 0302 clinical medicine, Pharmacology (medical), immunosuppressor, pharmacokinetic, Kidney transplantation, MESH: Biological Availability, MESH: Aged, education.field_of_study, MESH: Middle Aged, medicine.diagnostic_test, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, Middle Aged, 3. Good health, [SDV.SP] Life Sciences [q-bio]/Pharmaceutical sciences, MESH: Reproducibility of Results, MESH: Young Adult, 030220 oncology & carcinogenesis, Area Under Curve, Female, MESH: Immunosuppressive Agents, Immunosuppressive Agents, medicine.drug, Lung Transplantation, Adult, medicine.medical_specialty, MESH: Cystic Fibrosis, Adolescent, MESH: Bayes Theorem, Population, Urology, Biological Availability, transplantatation, Models, Biological, Mycophenolic acid, 03 medical and health sciences, Young Adult, Pharmacokinetics, medicine, Lung transplantation, Humans, education, MESH: Mycophenolic Acid, Aged, MESH: Adolescent, MESH: Humans, business.industry, MESH: Models, Biological, Reproducibility of Results, MESH: Adult, Bayes Theorem, Mycophenolic Acid, Ciclosporin, medicine.disease, Kidney Transplantation, MESH: Male, Therapeutic drug monitoring, MESH: Area Under Curve, MESH: Lung Transplantation, business, MESH: Female
Abstract

International audience; BACKGROUND AND OBJECTIVES: The immunosuppressive drug mycophenolate mofetil is used to prevent rejection after organ transplantation. In kidney transplant recipients, it has been demonstrated that adjustment of the mycophenolate mofetil dose on the basis of the area under the concentration-time curve (AUC) of mycophenolic acid (MPA), the active moiety of mycophenolate mofetil, improves the clinical outcome. Because of the high risks of rejections and infections in lung transplant recipients, therapeutic drug monitoring of the MPA AUC might be even more useful in these patients. The aims of this study were to characterize the pharmacokinetics of MPA in lung and kidney transplant recipients, describe the differences between the two populations and develop a Bayesian estimator of the MPA AUC in lung transplant recipients. METHODS: In total, 460 MPA concentration-time profiles from 41 lung transplant recipients and 116 kidney transplant recipients were included. Nonlinear mixed-effects modelling was used to develop a population pharmacokinetic model. Patients were divided into an index dataset and a validation dataset. The pharmacokinetic model derived from the index dataset was used to develop a Bayesian estimator, which was validated using the 35 lung transplant recipients' profiles from the validation dataset. RESULTS: MPA pharmacokinetics were described using a two-compartment model with lag time, first-order absorption and first-order elimination. The influence of ciclosporin co-treatment and the changes over time post-transplantation were included in the model. Lung transplant recipients had, on average, a 53% slower absorption rate and 50% faster MPA apparent oral clearance than kidney transplant recipients (p

Published
2011

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