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1. The microenvironment of DLBCL is characterized by noncanonical macrophages recruited by tumor-derived CCL5

Author: Michel Aurrand-Lions, Mélanie Quintero, Christian Righini, Jean-François Mayol, Nathalie Sturm, Benoit Manfroi, Sébastien Tabruyn, Jérôme Moreaux, Bertrand Huard, Maria De Grandis, Anthropologie bio-culturelle, Droit, Ethique et Santé (ADES), Aix Marseille Université (AMU)-EFS ALPES MEDITERRANEE-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, and 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)
Subjects: CCR1, Chemokine, [SDV]Life Sciences [q-bio], Biology, medicine.disease_cause, CCL5, Monocytes, Leukocyte Count, stomatognathic system, immune system diseases, hemic and lymphatic diseases, medicine, Tumor Microenvironment, Neoplasm, Humans, skin and connective tissue diseases, Chemokine CCL5, Lymphoid Neoplasia, Macrophages, Hematology, Gene signature, Tumor-Derived, medicine.disease, Germinal Center, Lymphoma, Cancer research, biology.protein, Lymphoma, Large B-Cell, Diffuse, Carcinogenesis, hormones, hormone substitutes, and hormone antagonists
Abstract: Key Points CCL5 is differentially expressed by DLBCL cells and efficiently recruits TAMs through their expression of CCR1/CCR5.Most DLBCL TAMs have a noncanonical gene signature., Visual Abstract, Tissue invasion by tumor cells induces a host inflammatory response that variably impacts tumorigenesis. This has been well documented for tumor-associated macrophages (TAMs) that could play a pro/M2- or an anti/M1-tumoral function. TAMs frequently infiltrate diffuse large B-cell lymphoma (DLBCL), an aggressive neoplasm arising from germinal center–experienced B cells. However, the pathway leading to the presence of TAMs in DLBCL remains unknown, and their impact is unclear. Here, we show that some DLBCL tumor cells expressed the chemokine CCL5, enabling the differential recruitment of blood monocytes through their expression of CCR1 and CCR5. CCL5 expression by DLBCL was not related to molecular subtypes, and healthy tonsillar B cells did not produce this chemokine, implying a posttransformation event. A single-cell analysis revealed that most DLBCL TAMs had a noncanonical gene signature with the concomitant expression of M1 and M2 genes. The presence of noncanonical TAMs may explain the lack of impact of macrophages on DLBCL development reported in some survival studies.
Published: 2021
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2. Dysfunctional BTN3A together with deregulated immune checkpoints and type I/II IFN dictate defective interplay between pDCs and γδ T cells in melanoma patients, which impacts clinical outcomes

Author: Benedicte Ponsard, Pauline Girard, H. Gil, Olivier Manches, Stéphane Mouret, Nathalie Sturm, Florence de Fraipont, Edwige Col, Eleonora Sosa Cuevas, Julie Charles, Laurence Chaperot, Caroline Aspord, Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Etablissement français du sang - Auvergne-Rhône-Alpes (EFS), Centre Hospitalier Universitaire [Grenoble] (CHU), and Chaperot, Laurence
Subjects: [SDV.IMM] Life Sciences [q-bio]/Immunology, medicine.medical_treatment, Immunology, Context (language use), immune subversion, Immune control, γδ T cells, Immune system, medicine, melanoma, Immunology and Allergy, General Nursing, business.industry, Melanoma, pDCs, hemic and immune systems, Original Articles, RC581-607, medicine.disease, Immune checkpoint, Pathophysiology, Crosstalk (biology), Cytokine, BTN3A, [SDV.IMM]Life Sciences [q-bio]/Immunology, Original Article, Immunologic diseases. Allergy, business
Abstract: Objectives pDCs and γδ T cells emerge as potent immune players participating in the pathophysiology of cancers, yet still remaining enigmatic while harbouring a promising potential for clinical translations. Despite strategic and closed missions, crosstalk between pDCs and γδ T cells has not been deciphered yet in cancers, especially in melanoma where the long‐term control of the tumor still remains a challenge. Methods This prompted us to explore the interplay between pDCs and γδ T cells in the context of melanoma, investigating the reciprocal features of pDCs or γδ T cells, the underlying molecular mechanisms and its impact on clinical outcomes. Results TLRL‐activated pDCs from the blood and tumor infiltrate of melanoma patients displayed an impaired ability to activate, to modulate immune checkpoints and trigger the functionality of γδ T cells. Conversely, γδ T cells from the blood or tumor infiltrate of melanoma patients activated by PAg were defective in triggering pDCs’ activation and modulation of immune checkpoints, and failed to elicit the functionality of pDCs. Reversion of the dysfunctional cross‐talks could be achieved by specific cytokine administration and immune checkpoint targeting. Strikingly, we revealed an increased expression of BTN3A on circulating and tumor‐infiltrating pDCs and γδ T cells from melanoma patients, but stressed out the potential impairment of this molecule. Conclusion Our study uncovered that melanoma hijacked the bidirectional interplay between pDCs and γδ T cells to escape from immune control, and revealed BTN3A dysfunction. Such understanding will help harness and synergise the power of these potent immune cells to design new therapeutic approaches exploiting their antitumor potential while counteracting their skewing by tumors to improve patient outcomes., Our study reveals, for the first time, crucial impairments of the bidirectional interactions between pDCs and γδ T cells in melanoma, and uncovered the dysfunction of BTN3A together with deregulation of specific immune checkpoints and type I/II IFNs in dictating defective pDC / γδT cell interplays. Such advances pave the way to harness these potent and promising cell partners to design novel immunotherapeutic strategies.
Published: 2021
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3. Multi-organ failure induced by Nivolumab in the context of allo-stem cell transplantation

Author: Olivier Manches, Nicolas Terzi, Dominique Masson, Laurence Chaperot, Claude-Eric Bulabois, Nathalie Sturm, Carole Schwebel, Jean-Yves Cahn, Diane Giovannini, Julie Charles, Marie-Thérèse Leccia, Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Institut National de la Santé et de la Recherche Médicale (INSERM)-EFS-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF), Laboratoire de Cytologie, Département d'Anatomie et de Cytologie Pathologiques, CHU Grenoble-Hôpital Michallon, Service de réanimation médicale [CHU Caen], CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Université de Caen Normandie (UNICAEN), Normandie Université (NU), CHU Grenoble, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble, Département d'anatomie et cythologie pathologique, Laboratoire HLA [EFS - Auvergne-Rhônes-Alpes], Etablissement français du sang - Auvergne-Rhône-Alpes (EFS), Département Pluridisciplinaire de Médecine, Dermatologie, Centre Hospitalier Universitaire [Grenoble] (CHU), Laboratoire recherche et développement, EFS, Hematology, Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), and Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])
Subjects: 0301 basic medicine, Cancer Research, medicine.medical_specialty, GVHD, Case Report, lcsh:RC254-282, Polymyositis, Gastroenterology, 03 medical and health sciences, 0302 clinical medicine, Autologous stem-cell transplantation, Immune-related adverse events, Internal medicine, Medicine, Myositis, ComputingMilieux_MISCELLANEOUS, lcsh:RC633-647.5, business.industry, lcsh:Diseases of the blood and blood-forming organs, Hematology, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, medicine.disease, Immune checkpoint, 3. Good health, Lymphoma, Allogeneic stem cell transplantation, Transplantation, PD1, 030104 developmental biology, Nivolumab, Oncology, 030220 oncology & carcinogenesis, [SDV.IMM]Life Sciences [q-bio]/Immunology, Stem cell, business, Hodgkin lymphoma
Abstract: Background Immune checkpoint inhibitors have radically changed the landscape of anti-tumor therapies in several malignancies. However the adverse events associated with immune checkpoint blockade in combination with other treatments remains to be thoroughly documented. Here we report the case of a 33-year-old male with classical Hodgkin lymphoma who was successfully treated for lymphoma but experienced serious and eventually fatal multisystem organ failure following nivolumab administration and allogeneic stem cell transplantation. Case presentation The patient was diagnosed with stage IIIa nodular sclerosing Hodgkin lymphoma. Originally treated by chemotherapy and autologous stem cell transplantation, he subsequently received two allogeneic stem cell transplants from matched and haplo-identical siblings upon successive disease recurrences. Nivolumab treatment was administered prior to the second allograft, after which complete remission of lymphoma was achieved (year 10), as evidenced by clinical and radiographic examination. However within the next 3 months, the patient went on to develop a constellation of symptoms affecting multiple organs, including acute pneumonia with no evidence of bacterial infection, widespread cutaneous eruptions on trunk and lower limbs, mucosal ulcerations, myositis, diarrhea and colitis. Further complications included hepatic cytolysis, acute renal failure, pancreatitis, as well as complete heart block. Some of these injuries being suggestive of graft-versus-host disease, the patient was administered immunosuppressive therapy (mycophenolate, steroids and polyvalent immunoglobulins), but died shortly afterwards. Tissue biopsies revealed extensive lymphocytic infiltration (mostly CD3 + T cells) in skin, liver, and most peculiarly in muscles, including the myocardium. Massive lymphoid-histiocytic infiltration of muscle fibers was accompanied by acute necrotizing myositis and endomysial inflammation. Conclusions Multi-organ failure represents a rare but potentially fatal outcome of immune checkpoint blockade in patients receiving allogeneic stem cell grafts. Nivolumab may induce atypical immune-mediated tissue inflammation and damage, such as the extensive muscular polymyositis described here in a patient with Hodgkin lymphoma. Nivolumab might also worsen GVHD symptoms in the context of allogeneic stem cell transplantation. Irrespective of the actual pathological mechanisms, clinicians should be alerted to these fatal drug-related toxicities. Electronic supplementary material The online version of this article (10.1186/s40164-019-0132-2) contains supplementary material, which is available to authorized users.
Published: 2019
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4. Nanoparticles in foods? A multiscale physiopathological investigation of iron oxide nanoparticle effects on rats after an acute oral exposure: Trace element biodistribution and cognitive capacities

Author: Salem Amara, Dalel Askri, Sylvia G. Lehmann, Benoit Chovelon, Nathalie Sturm, Souhir Ouni, Michel Seve, Mohsen Sakly, Josiane Arnaud, Said Galai, PROteomics and METabolomics Platform [Grenoble] (PROMETHEE), Laboratory of Fundamental and Applied Bioenergetics = Laboratoire de bioénergétique fondamentale et appliquée (LBFA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Département de pharmacochimie moléculaire (DPM ), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), CHU Grenoble, Institut des Sciences de la Terre (ISTerre), and Institut Français des Sciences et Technologies des Transports, de l'Aménagement et des Réseaux (IFSTTAR)-Institut national des sciences de l'Univers (INSU - CNRS)-Institut de recherche pour le développement [IRD] : UR219-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])
Subjects: Male, Biodistribution, [SDV]Life Sciences [q-bio], Iron oxide, Metal Nanoparticles, Clinical Chemistry Tests, Pharmacology, Toxicology, Ferric Compounds, Dietary Exposure, 03 medical and health sciences, chemistry.chemical_compound, Cognition, 0404 agricultural biotechnology, Oral administration, Toxicity Tests, Acute, Animals, Homeostasis, Distribution (pharmacology), Ingestion, Tissue Distribution, Rats, Wistar, 030304 developmental biology, 0303 health sciences, Hematologic Tests, Behavior, Animal, Body Weight, Organ Size, 04 agricultural and veterinary sciences, General Medicine, 040401 food science, Trace Elements, 3. Good health, Liver, chemistry, Blood chemistry, Toxicity, Iron oxide nanoparticles, Food Science
Abstract: Iron Oxide Nanoparticles (IONPs) are used in several fields of application, mainly in the biomedical field for their magnetic properties and in food additive known as “E172” for their colour. In the present investigation, we focused on IONP effects on Wistar rat following acute oral exposure. We performed a multiscale physiopathological investigation in order to elucidate potential toxic effects linked to IONP ingestion, especially on cognitive capacities, trace element distribution, blood constituents, organ functions, organ structure and iron deposit. We demonstrated that oral exposure to IONPs induces disturbances of certain parameters depending on the dose. Interestingly, the histopathological examination evidenced inflammatory effects of IONPs in the liver with iron deposits in hepatocytes and Kuppfer cells. Neurobehavioral examination showed that oral exposure to IONPs did not affect nor rat emotions, exploration and locomotion capacities, nor spatial reference memory status. Furthermore, oral administration of IONPs did not disrupt the trace element homeostasis nor in the liver neither in the stomach. Altogether, our study evidenced low signs of toxicity, but some effects lead us to a careful use of these NPs. Thereby, their use in foods should be further studied to better evaluate the potential toxic risks of the oral exposure to IONPs.
Published: 2019
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5. A proliferation‐inducing ligand–mediated anti‐inflammatory response of astrocytes in multiple sclerosis

Author: Mahdia Benkhoucha, Mashal Claude Ahmed, Dominique Baeten, Romain Marignier, Jose Boucraut, Olivier Casez, Michael Hahne, Jean Boutonnat, Corinne Sonrier, Benoit Manfroi, Laurie Baert, Patrice N. Marche, Nathalie Sturm, Marine Tessier, Patrice H. Lalive, Romain R. Vivès, Bertrand Huard, Cyril Rivat, Catherine Ghezzi, Hans Lassmann, Pascal Schneider, Natalia Popa, Gilda Raguenez, Alexis Broisat, Hugues Lortat-Jacob, Mitra Ahmadi, Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Department of Pathology and Immunology [Geneva, Switzerland] (Clinical Pathology Division), University of Geneva [Switzerland]-Geneva University Hospitals - HUG [Switzerland], Centre de recherche en neurobiologie - neurophysiologie de Marseille (CRN2M), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Département d'anatomie et cythologie pathologique, CHU Grenoble-Hôpital Michallon, Centre Hospitalier Universitaire [Grenoble] (CHU), Centre de recherche en neurosciences de Lyon (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Radiopharmaceutiques biocliniques (LRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Department of Clinical Immunology and Rheumatology [Academic Medical Center, Amsterdam], University of Amsterdam [Amsterdam] (UvA), Institut de biologie structurale (IBS - UMR 5075 ), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Department of Biochemistry [Lausanne], Université de Lausanne (UNIL), University of Vienna [Vienna], Department of Clinical Neurosciences [Geneva, Switzerland], Unit of Neuroimmunology and Neuromuscular Diseases [Geneva, Switzerland] (Division of Neurology), Geneva University Hospitals - HUG [Switzerland]-Geneva University Hospitals - HUG [Switzerland], This work was supported by Grenoble Alpes University (B.H.), the National Institute of Health and Medical Research (B.H.), the Association for Aid to Multiple Sclerosis Research (B.H.), the National Agency for Research (program center of excellence in neurodegeneration obtained within the Grenoble excellence in neurodegeneration network, B.H.), the Swiss National Science Foundation (310030_156961/310030_176256 to PS and 310030_153164/310030_176678 to PL), and the Swiss Multiple Sclerosis Society (P.L.)., Clinical Immunology and Rheumatology, AII - Inflammatory diseases, Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Université de Genève = University of Geneva (UNIGE)-Geneva University Hospitals - HUG [Switzerland], Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut des Neurosciences de Montpellier (INM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Université de Lausanne = University of Lausanne (UNIL), Grenoble Alpes University, the National Institute of Health and Medical Research, the Association for Aid to Multiple Sclerosis Research), the National Agency for Research (program center of excellence in neurodegeneration obtained within the Grenoble excellence in neurodegeneration network, the Swiss National Science Foundation (310030_156961/310030_176256 to PS and 310030_153164/310030_176678 )The Swiss Multiple Sclerosis Society, and MARCHE, Patrice
Subjects: Male, 0301 basic medicine, T-Lymphocytes, Mice, chemistry.chemical_compound, 0302 clinical medicine, B-Cell Activating Factor, Medicine, Mice, Knockout, Reverse Transcriptase Polymerase Chain Reaction, Chondroitin Sulfates, Middle Aged, Immunohistochemistry, Interleukin-10, 3. Good health, Interleukin 10, Neurology, Adult, Aged, Animals, Astrocytes/immunology, Astrocytes/metabolism, Astrocytes/pathology, B-Cell Activating Factor/metabolism, Cell Proliferation, Chondroitin Sulfate Proteoglycans/metabolism, Chondroitin Sulfates/metabolism, Cytokines/immunology, Disease Models, Animal, Encephalomyelitis, Autoimmune, Experimental/immunology, Encephalomyelitis, Autoimmune, Experimental/metabolism, Encephalomyelitis, Autoimmune, Experimental/pathology, Female, Humans, Interleukin-10/immunology, Macrophages/pathology, Multiple Sclerosis/immunology, Multiple Sclerosis/metabolism, Multiple Sclerosis/pathology, T-Lymphocytes/immunology, Tumor Necrosis Factor Ligand Superfamily Member 13/genetics, Tumor Necrosis Factor Ligand Superfamily Member 13/metabolism, Tumor Necrosis Factor Ligand Superfamily Member 13/pharmacology, Cytokines, [SDV.IMM]Life Sciences [q-bio]/Immunology, Tumor necrosis factor alpha, medicine.symptom, Encephalomyelitis, Autoimmune, Experimental, Multiple Sclerosis, [SDV.IMM] Life Sciences [q-bio]/Immunology, Tumor Necrosis Factor Ligand Superfamily Member 13, Inflammation, 03 medical and health sciences, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, B-cell activating factor, Autoimmune encephalitis, business.industry, Macrophages, Multiple sclerosis, medicine.disease, 030104 developmental biology, Chondroitin Sulfate Proteoglycans, chemistry, Chondroitin sulfate proteoglycan, Astrocytes, Immunology, Cytokine secretion, Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract: International audience; OBJECTIVE:The two related tumor necrosis factor members a proliferation-inducing ligand (APRIL) and B-cell activation factor (BAFF) are currently targeted in autoimmune diseases as B-cell regulators. In multiple sclerosis (MS), combined APRIL/BAFF blockade led to unexpected exacerbated inflammation in the central nervous system (CNS) of patients. Here, we investigate the role of the APRIL/BAFF axis in the CNS.METHODS:APRIL expression was analyzed in MS lesions by immunohistochemistry. The in vivo role of APRIL was assessed in the murine MS model, experimental autoimmune encephalitis (EAE). Functional in vitro studies were performed with human and mouse astrocytes.RESULTS:APRIL was expressed in lesions from EAE. In its absence, the disease was worst. Lesions from MS patients also showed APRIL expression upon infiltration of macrophages. Notably, all the APRIL secreted by these macrophages specifically targeted astrocytes. The upregulation of chondroitin sulfate proteoglycan, sometimes bearing chondroitin sulfate of type E sugar moieties, binding APRIL, in reactive astrocytes explained the latter selectivity. Astrocytes responded to APRIL by producing a sufficient amount of IL-10 to dampen antigen-specific T-cell proliferation and pathogenic cytokine secretion. Finally, an intraspinal delivery of recombinant APRIL before disease onset, shortly reduced EAE symptoms. Repeated intravenous injections of recombinant APRIL before and even at disease onset also had an effect.INTERPRETATION:Our data show that APRIL mediates an anti-inflammatory response from astrocytes in MS lesions. This protective activity is not shared with BAFF. ANN NEUROL 2019;85:406-420.© 2019 American Neurological Association.
Published: 2019
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6. Immunologic Features of Patients With Advanced Hepatocellular Carcinoma Before and During Sorafenib or Anti-programmed Death-1/Programmed Death-L1 Treatment

Author: Christian Sengel, Patrice N. Marche, Keerthi Kurma, Thomas Decaens, Zuzana Macek Jilkova, Caroline Aspord, Nathalie Sturm, Anouck Granon, Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Service d'hépato-gastroentérologie [CHU Grenoble Alpes], Centre Hospitalier Universitaire Grenoble Alpes (CHU Grenoble Alpes), Etablissement français du sang - Auvergne-Rhône-Alpes (EFS), Service de Radiologie [CHU Grenoble Alpes], Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Service d'Anatomopathologie [CHU Grenoble Alpes], MARCHE, Patrice, Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), and Centre Hospitalier Universitaire [Grenoble] (CHU)
Subjects: Sorafenib, CD4-Positive T-Lymphocytes, Male, Carcinoma, Hepatocellular, Programmed Cell Death 1 Receptor, [SDV.CAN]Life Sciences [q-bio]/Cancer, CD8-Positive T-Lymphocytes, Article, 03 medical and health sciences, 0302 clinical medicine, Immune system, [SDV.CAN] Life Sciences [q-bio]/Cancer, Antigens, CD, Predictive Value of Tests, Medicine, Humans, Hepatitis A Virus Cellular Receptor 2, Protein Kinase Inhibitors, Aged, Neoplasm Staging, business.industry, Liver Neoplasms, Gastroenterology, biochemical phenomena, metabolism, and nutrition, medicine.disease, Prognosis, Lymphocyte Activation Gene 3 Protein, digestive system diseases, Immune checkpoint, 3. Good health, Up-Regulation, Liver, 030220 oncology & carcinogenesis, Hepatocellular carcinoma, Cancer research, Disease Progression, Treatment strategy, 030211 gastroenterology & hepatology, Female, Programmed death 1, Immunotherapy, business, medicine.drug, Programmed death
Abstract: International audience; INTRODUCTION: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide. Today, a promising treatment strategy is focused on the enhancement of antitumor immune responses by immune checkpoint modification. However, as only 20% of patients with HCC are responders, identification of predictive factors is urgently required. Therefore, for the first time, the features of the intrahepatic and circulating immune system in patients with advanced-stage HCC, before and during the treatment, were analyzed. METHODS: We collected fresh HCC biopsies, along with adjacent tumor-free liver tissues and peripheral blood samples, from 21 patients with advanced HCC. Furthermore, we performed an extensive immunomonitoring of patients with HCC treated with sorafenib or programmed death (PD)-1/PD-L1 pathway blockade using multiparametric flow cytometry. RESULTS: We observed that regardless of the treatment, low baseline intratumoral CD4 1 /CD8 1 T-cell ratio was associated with better overall survival (P 5 0.0002). The baseline frequency of intratumoral PD-1 high CD8 1 T cells was significantly lower in patients responding to sorafenib treatment than in the nonresponders (P 5 0.0117), and the frequency of circulating PD-1 high T cells increased with tumor progression (P 5 0.0329). By contrast, responders to PD-1/PD-L1 pathway blockade showed a trend of high baseline frequency of intratumoral PD-1 high CD8 1 T cells. Moreover, we observed a trend of LAG3 and TIM3 upregulation on circulating T cells in nonresponding patients to PD-1/PD-L1 pathway blockade. DISCUSSION: Immunosuppressive state, characterized by an enhanced intratumoral CD4 1 /CD8 1 T-cell ratio, was associated with poor prognosis. Additionally, our results suggest that the frequency of intratumoral PD-1 high CD8 1 T cells may serve as a biomarker to identify which individuals will benefit from which treatment and support the use of combination strategies. SUPPLEMENTARY MATERIAL accompanies this paper at
Published: 2019
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7. Combination of AKT inhibitor ARQ 092 and sorafenib potentiates inhibition of tumor progression in cirrhotic rat model of hepatocellular carcinoma

Author: Brian Schwartz, Pierre Hainaut, Zuzana Macek Jilkova, Gaël S. Roth, Thomas Decaens, Giovanni Abbadessa, Yi Yu, Ayca Zeybek Kuyucu, Patrice N. Marche, Keerthi Kurma, Ahmad Pour, Séyédéh Tayébéh, Nathalie Sturm, Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Department of Bioengineering [Izmir, Turkey], Izmir Institute of Technology (IZTECH), Département de Gastroentérologie et hépatologie, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-Hôpital Michallon, ArQule Inc. [Woburn, MA, USA], Anatomie et de Cytologie Pathologiques [CHU Grenoble], Centre Hospitalier Universitaire [Grenoble] (CHU), Work was funded by la Ligue contre le Cancer CD63 (2016-R16145CC), AZK was supported by The Scientific and Technological Research Council of Turkey (TUBITAK 2214B)., Zeybek Kuyucu, Ayça, Izmir Institute of Technology. Biotechnology and Bioengineering, MARCHE, Patrice, and Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])
Subjects: 0301 basic medicine, Sorafenib, [SDV.CAN]Life Sciences [q-bio]/Cancer, AKT inhibitor, liver cancer, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Fibrosis, medicine, neoplasms, Liver cancers, AKT Inhibitor ARQ 092, CD63, business.industry, fibrosis, Cancer, [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, digestive system diseases, 3. Good health, 030104 developmental biology, Oncology, Tumor progression, 030220 oncology & carcinogenesis, Hepatocellular carcinoma, Combination treatment, DEN-induced model, Cancer research, combination treatment, Liver cancer, business, Research Paper, medicine.drug
Abstract: The prognosis of patients with advanced hepatocellular carcinoma (HCC) is very poor. The AKT pathway is activated in almost half of HCC cases and in addition, long term exposure to conventional drug treatment of HCC, sorafenib, often results in overactivation of AKT, leading to HCC resistance. Therefore, it is important to assess the safety and the efficacy of selective allosteric AKT inhibitor ARQ 092 (Miransertib) in combination with sorafenib. Here, we demonstrated in vitro that the combination of ARQ 092 with sorafenib synergistically suppressed proliferation, promoted apoptosis, and reduced migration. To test the effect of the combination in vivo, rats with diethylnitrosamine-induced cirrhosis and fully developed HCC were randomized and treated with vehicle, sorafenib, ARQ 092 or the combination of ARQ 092 with sorafenib; (n=7/group) for 6 weeks. Tumor progression, size of tumors and the mean tumor number were significantly reduced by the combination treatment compared to the control or single treatments. This effect was associated with a significant increase in apoptotic response and reduction in proliferation and angiogenesis. Sirius red staining showed a decrease in liver fibrosis. Moreover, treatments improved immune response in blood and in tumor microenvironment. Thus, the combination of ARQ 092 with sorafenib potentiates inhibition of tumor progression and gives the possibility of therapeutic improvement for patients with advanced HCC., Ligue contre le Cancer CD63 (2016-R16145CC), The Scientific and Technological Research Council of Turkey (TUBITAK 2214B)
Published: 2018
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8. Influence of Progenitor-Derived Regeneration Markers on Hepatitis C Virus-Related Cirrhosis Outcome (ANRS CO12 CirVir Cohort)

Author: Carole Cagnot, Marianne Ziol, Nathalie Ganne-Carrié, Fatiha Merabtene, Françoise Roudot-Thoraval, Richard Layese, Christophe Sattonnet, Pierre Bedossa, Valérie Bourcier, Pierre Nahon, Benoit Terris, Paulette Bioulac-Sage, Dominique Wendum, Nathalie Barget, Janick Selves, Emmanuel Sauce, Nathalie Sturm, Service d'Anatomie et cytologie pathologiques [CHU Saint-Antoine], 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 - Faculté de Médecine (SU FM), Sorbonne Université (SU), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Clinical Epidemiology and Ageing : Geriatrie Soins Primaires et Santé Publique (CEpiA), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Hôpital Henri Mondor, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service de santé publique [Mondor], Université Paris-Est Créteil Val-de-Marne - Faculté de médecine (UPEC Médecine), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Hôpital Jean Verdier [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Sorbonne Paris Cité (USPC), Génomique Fonctionnelle des Tumeurs Solides (U1162), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité Mixte de Service d'Imagerie et de Cytométrie [CHU Saint-Antoine] (UMS LUMIC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), ANRS France Recherche Nord & sud Sida-hiv hépatites, Hôpital Beaujon [AP-HP], Service d'Anatomie et de cytologie pathologiques [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Bordeaux [Bordeaux], Centre Hospitalier Universitaire [Grenoble] (CHU), Gestionnaire, Hal Sorbonne Université, Service d'Anatomie Pathologique [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], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0301 basic medicine, Liver Cirrhosis, Male, Cirrhosis, Hepacivirus, medicine.disease_cause, Gastroenterology, Cohort Studies, chemistry.chemical_compound, 0302 clinical medicine, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Prospective Studies, intermediate hepatobiliary cells, liver decompensation, medicine.diagnostic_test, Stem Cells, Hazard ratio, Biopsy, Needle, Epithelial cell adhesion molecule, hepatocellular carcinoma, Middle Aged, Epithelial Cell Adhesion Molecule, Prognosis, Hepatitis C, Immunohistochemistry, 3. Good health, Survival Rate, Hepatocellular carcinoma, Liver biopsy, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Keratins, 030211 gastroenterology & hepatology, Female, Adult, medicine.medical_specialty, Hepatitis C virus, Risk Assessment, 03 medical and health sciences, Internal medicine, medicine, Humans, Decompensation, Aged, Proportional Hazards Models, Hepatology, business.industry, Keratin7, [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, Liver Regeneration, 030104 developmental biology, chemistry, EpCAM, Multivariate Analysis, business, Biomarkers
Abstract: Progenitor-derived regeneration gives rise to the aberrant expression of biliary markers such as cytokeratin 7 (K7) and epithelial cell adhesion molecule (EpCAM) in hepatocytes. We aimed to describe the expression of these molecules in patients with compensated hepatitis C virus (HCV)-related cirrhosis and to investigate its potential influence on cirrhosis complications. Among patients with Child-Pugh A uncomplicated HCV-related cirrhosis enrolled in the prospective ANRS CO12 CirVir cohort, we selected individuals with a liver biopsy collected within 2 years before inclusion in the study. K7 and EpCAM immunostaining identified intermediate hepatobiliary cells. The influence of biliary marker expres-sion in hepatocytes on decompensation events and the occurrence of hepatocellular carcinoma (HCC) was studied using a multivariate Cox proportional hazards regression model. Among the 337 patients eligible for the study (men, 67%; median age, 52 years), 198 (58.8%) had biopsies with K7-positive hepatocytes including extensive staining in 40 (11.9%) and 203 had EpCAM-positive hepatocytes (60.6%). During follow-up (median, 54.2 months), 47 patients (14%) experienced a decompensation event, and HCC was diagnosed in 37 patients (11%). Extensive K7 staining was independently associated with the occurrence of a decompensation event (hazard ratio [HR], 3.00; 95% confidence interval [CI], 1.30-6.89; P = 0.010). EpCAM expression was independently associated with HCC occurrence (HR, 2.37; 95% CI, 1.07-5.23; P =0.033) along with age and a low prothrombin ratio. CONCLUSION Progenitor-derived regeneration depicted by K7 and EpCAM immunostaining of hepatocytes in liver biopsies of patients with compensated HCV-related cirrhosis marks a cirrhosis stage more prone to develop complications. (HEPATOLOGY 2018; 68:1534-1548).
Published: 2018
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9. Clinicopathological description of 43 oncocytic adrenocortical tumors: importance of Ki-67 in histoprognostic evaluation

Author: Delphine Vezzosi, Abir Al Ghuzlan, Delphine Drui, Matthieu Wargny, Sébastien Aubert, Sarra Smati, Olivier Chabre, Laurence Amar, Claire Briet, François Pattou, Rossella Libé, Martine Patey, Bertrand Cariou, Frédérique Tissier, Karine Renaudin, Nathalie Sturm, Jérôme Bertherat, Magalie Haissaguerre, Peggy Pierre, Mathilde Sibony, Jean Christophe Lifante, Claudine Berthozat, Emmanuelle Leteurtre, Christine Do Cao, Eric Baudin, Eric Mirallié, Service de Pathologie [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), 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), Centre d’Investigation Clinique de Nantes (CIC Nantes), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes), Département de biologie et pathologie médicales [Gustave Roussy], Institut Gustave Roussy (IGR), Service de pathologie [CHU Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, 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 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), Laboratoire d’anatomie et cytologie pathologique, Hôpital Robert Debré, CHU de Reims, Service d'anatomie pathologique [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Département de Gastroentérologie et hépatologie, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-Hôpital Michallon, Centre Hospitalier Universitaire Grenoble Alpes (CHU Grenoble Alpes), Université Paris-Sorbonne (UP4), Service d'HYPERVASC [CHU HEGP), 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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Service d'Endocrinologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre de Référence pour les Maladies Rares, Université Grenoble Alpes - UFR Médecine (UGA UFRM), Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Service d'endocrinologie-diabétologie-nutrition [CHU Grenoble-Alpes], Service d’endocrinologie, diabétologie et maladies métaboliques [CHRU LIlle], Département d'endocrinologie - Bordeaux 2, Université Bordeaux Segalen - Bordeaux 2, Service d'Endocrinologie (TOURS - Endocrino), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'Endocrinologie (TOULOUSE - Endocrino), CHU Toulouse [Toulouse], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Service de Chirurgie Générale et Endocrinienne [Lyon], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Health Service and Performance Research (HESPER), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Service de chirurgie générale et endocrinienne, Hôpital Claude Huriez [Lille], CHU Lille-CHU Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service de Chirurgie Digestive et Endocrinienne [Nantes], Médecine nucléaire, Département d'imagerie médicale [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5), Service d'Endocrinologie [Nantes], Unité de recherche de l'institut du thorax (ITX-lab), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Université de Lille-UNICANCER-Université de Lille-UNICANCER-Cancéropole Nord-Ouest-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier Universitaire [Grenoble] (CHU), MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Service Endocrinologie, maladies métaboliques et nutrition [CHU Toulouse], Pôle Cardiovasculaire et Métabolique [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université Paris Descartes - Paris 5 (UPD5)-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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille
Subjects: 0301 basic medicine, Oncology, Adult, Male, medicine.medical_specialty, Pathology, Proliferation index, Adenoma, [SDV]Life Sciences [q-bio], Malignancy, Pathology and Forensic Medicine, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Carcinoma, Biomarkers, Tumor, Adenoma, Oxyphilic, Humans, Stage (cooking), Retrospective Studies, biology, business.industry, Retrospective cohort study, Middle Aged, medicine.disease, Prognosis, Adrenal Cortex Neoplasms, 3. Good health, 030104 developmental biology, Ki-67 Antigen, 030220 oncology & carcinogenesis, Ki-67, Cohort, biology.protein, Female, business
Abstract: International audience; Oncocytic adrenocortical tumors are a rare subtype of adrenal tumors with challenging diagnosis and histoprognostic assessment. It is usually believed that oncocytic adrenocortical tumors have a more indolent clinical behavior than conventional adrenocortical tumors. As the Weiss score overestimates the malignancy of oncocytic adrenocortical tumors owing to intrinsic parameters, alternative scores have been proposed. The Lin-Weiss-Bisceglia score is currently recommended. We performed a large nationwide multicenter retrospective clinicopathologic study of oncocytic adrenocortical tumors. Among the 43 patients in our cohort, 40 patients were alive without disease, 2 patients died of their disease and 1 patient was alive with relapse after a median follow-up of 38 months (20-59). Our data revealed that over 50% of the oncocytic adrenocortical tumor cases were diagnosed as carcinoma whatever the classification systems used, including the Lin-Weiss-Bisceglia score. The exception is the Helsinki score, which incorporates the Ki-67 proliferation index and was the most specific prognostic score for oncocytic adrenocortical tumor malignancy without showing a loss in sensitivity. A comparison of malignant oncocytic adrenocortical tumors with conventional adrenocortical carcinomas matched for age, sex, ENS@T stage and surgical resection status showed significant better overall survival of malignant oncocytic adrenocortical tumors.
Published: 2018
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10. Molecular Classification of Hepatocellular Adenoma Associates With Risk Factors, Bleeding, and Malignant Transformation

Author: Viviane Gnemmi, Gabrielle Couchy, Jean-Frédéric Blanc, Eric Savier, Jean Saric, Georges-Philippe Pageaux, Christophe Letoublon, Jean-Charles Nault, Guillaume Morcrette, Valérie Vilgrain, Brigitte Le Bail, Denis Castaing, Christophe Laurent, Anne de Muret, Vincenzo Mazzaferro, Yannick Bacq, Alain Luciani, Julien Calderaro, Valérie Paradis, Laurence Chiche, Nora Frulio, Luigi Terraciano, Emmanuel Jacquemin, Emmanuel Boleslawski, Jeanne Ramos, Sandrine Imbeaud, Benoit Terris, Marie Christine Saint Paul, Brigitte Bancel, Jean-Christophe Vaillant, François Paye, Catherine Guettier, Jacques Belghiti, Janick Selves, Daniel Azoulay, Camilla Pilati, Eric Letouzé, Dominique Wendum, Stefano Caruso, Charles Balabaud, Pascal Bourlier, Claire Castain, Jean-Michel Fabre, Jessica Zucman-Rossi, Alexis Laurent, Sophie Prevot, Zin Benchellal, Fanny Dujardin, Monique Fabre, Sandra Rebouissou, Paulette Bioulac-Sage, Nathalie Sturm, Philippe Labrune, Jean-Marie Péron, Alberto Quaglia, Jean-Yves Scoazec, Université Paris 13 (UP13), Génomique Fonctionnelle des Tumeurs Solides (U1162), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiopathologie du cancer du foie, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], Département d'hépato-gastro-entérologie [Hôpital Trousseau : CHRU Tours], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service d'Anatomo-Pathologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut Gustave Roussy (IGR), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Département d'anatomie et cythologie pathologique, CHU Grenoble-Hôpital Michallon, 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), Service d'anatomie pathologique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Service de Chirurgie Digestive, Hépato-Bilio-pancréatique et Transplantation Hépatique [CHU Pitié-Salpétrière], CHU Pitié-Salpêtrière [AP-HP], Thérapie génique, Génomique et Epigénomique (U 1169), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, 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), Service d'Anatomie Pathologique [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Service d'Anatomopathologie [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Service de pathologie [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Service d'oncologie médicale [CHU HEGP], 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), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service d'Anatomie et cytologie pathologiques [CHU Saint-Antoine], CHU Saint-Antoine [AP-HP], Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS)-CHU Trousseau [APHP], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Paul Brousse-Université Paris-Sud - Paris 11 (UP11), CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-CHU Trousseau [APHP], Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), CHU Necker - Enfants Malades [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), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Male, Malignant transformation, 0302 clinical medicine, Risk Factors, Cytokine Receptor gp130, GTP-Binding Protein alpha Subunits, Gs, Hepatocyte Nuclear Factor 1-alpha, Child, Telomerase, beta Catenin, Inhibin-beta Subunits, Aged, 80 and over, biology, Liver Neoplasms, Gastroenterology, hepatocellular carcinoma, Middle Aged, Protein-Tyrosine Kinases, Neoplasm Proteins, 3. Good health, HNF1A, Cell Transformation, Neoplastic, 030220 oncology & carcinogenesis, Fyn-related kinase, Female, 030211 gastroenterology & hepatology, Gene Fusion, Signal Transduction, Adenoma, Adult, STAT3 Transcription Factor, Carcinoma, Hepatocellular, Adolescent, hepatocellular adenoma, Hemorrhage, Zinc Finger Protein GLI1, Young Adult, 03 medical and health sciences, sonic hedgehog, Chromogranins, GNAS complex locus, medicine, [SDV.MHEP.AHA]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Humans, Hedgehog Proteins, benign liver tumor, Unclassified Hepatocellular Adenoma, Aged, Hepatology, Sequence Analysis, RNA, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Janus Kinase 2, Hepatocellular adenoma, medicine.disease, Mutation, biology.protein, Cancer research, Inflammatory Hepatocellular Adenoma, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Transcriptome
Abstract: International audience; BACKGROUND & AIMS: Hepatocellular adenomas (HCAs) are benign liver tumors that can be assigned to molecular subtypes based on inactivating mutations in hepatocyte nuclear factor 1A, activating mutations in β-catenin, or activation of inflammatory signaling pathways. We aimed to update the classification system for HCA and associate the subtypes with disease risk factors and complications.METHODS: We analyzed expression levels of 20 genes and sequenced exon regions of 8 genes (HNF1A, IL6ST, CTNNB1, FRK, STAT3, GNAS, JAK1, and TERT) in 607 samples of 533 HCAs from 411 patients, collected from 28 centers mainly in France from 2000 and 2014. We performed gene expression profile, RNA sequence, whole-exome and genome sequence, and immunohistochemical analyses of select samples. Molecular data were associated with risk factors, histopathology, bleeding, and malignant transformation.RESULTS: Symptomatic bleeding occurred in 14% of the patients (85% of cases were female, median age, 38 years); 7% of the nodules were borderline between HCA and hepatocellular carcinoma, and 3% of patients developed hepatocellular carcinoma from HCA. Based on molecular features, we classified HCA into 8 subgroups. One new subgroup, composed of previously unclassified HCA, represented 4% of HCAs overall and was associated with obesity and bleeding. These tumors were characterized by activation of sonic hedgehog signaling, due to focal deletions that fuse the promoter of INHBE with GLI1. Analysis of genetic heterogeneity among multiple HCAs, from different patients, revealed a molecular subtype field effect; multiple tumors had different mutations that deregulated similar pathways. Specific molecular subtypes of HCA associated with various HCA risk factors, including imbalances in estrogen or androgen hormones. Specific molecular subgroup of HCA with β-catenin and sonic hedgehog activation associated with malignant transformation and bleeding, respectively.CONCLUSIONS: Using sequencing and gene expression analyses, we identified a subgroup of HCA characterized by fusion of the INHBE and GLI1 genes and activation of sonic hedgehog pathway. Molecular subtypes of HCAs associated with different patients' risk factors for HCA, disease progression, and pathology features of tumors. This classification system might be used to select treatment strategies for patients with HCA.
Published: 2017
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11. A Single Test Combining Blood Markers and Elastography is More Accurate Than Other Fibrosis Tests in the Main Causes of Chronic Liver Diseases

Author: Dominique Salmon, Paul Calès, Victor de Ledinghen, Brigitte Le Bail, Alexandra Ducancelle, Julien Vergniol, Jean-Pierre Zarski, Vincent Leroy, Eric Nguyen Khac, Nathalie Sturm, Hémodynamique, Interaction Fibrose et Invasivité tumorales Hépatiques (HIFIH), Université d'Angers (UA), Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'hépato-gastroentérologie [CHU Grenoble Alpes], Centre Hospitalier Universitaire Grenoble Alpes (CHU Grenoble Alpes), Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], Département d'anatomie et cythologie pathologique, CHU Grenoble-Hôpital Michallon, Laboratoire d'anatomie pathologique, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Département d'hépato-gastroentérologie, CHU Grenoble-Université Grenoble Alpes (UGA), Service d'Hépato-gastroentérologie [CHU Amiens-Picardie], CHU Amiens-Picardie, Service Maladies infectieuses et tropicales [AP-HP Hôpital Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Descartes - Paris 5 (UPD5), Centre d'investigation de la fibrose hépatique [CHU de Bordeaux] (Hôpital Haut-Lévêque ), Hôpital Haut-Lévêque [CHU de Bordeaux], Institut National de la Santé et de la Recherche Médicale (INSERM)-EFS-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF), and Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble
Subjects: Adult, Liver Cirrhosis, Male, Pathology, medicine.medical_specialty, [SDV]Life Sciences [q-bio], Disease, Severity of Illness Index, End Stage Liver Disease, 03 medical and health sciences, 0302 clinical medicine, Fibrosis, Severity of illness, Medicine, Blood test, Humans, Aspartate Aminotransferases, Prospective Studies, Stage (cooking), Prospective cohort study, Retrospective Studies, medicine.diagnostic_test, business.industry, Platelet Count, Liver Diseases, Fatty liver, Gastroenterology, Middle Aged, medicine.disease, 3. Good health, Liver, ROC Curve, 030220 oncology & carcinogenesis, Elasticity Imaging Techniques, 030211 gastroenterology & hepatology, Female, Elastography, business, Biomarkers
Abstract: International audience; BACKGROUND AND GOAL: International guidelines suggest combining a blood test and liver stiffness measurement (LSM) to stage liver fibrosis in chronic hepatitis C (CHC) and non-alcoholic fatty liver disease (NAFLD). Therefore, we compared the accuracies of these tests between the main etiologies of chronic liver diseases.STUDY: Overall, 1968 patients were included in 5 etiologies: CHC: 698, chronic hepatitis B: 152, human immunodeficiency virus/CHC: 628, NAFLD: 225, and alcoholic liver disease (ALD): 265. Sixteen tests [13 blood tests, LSM (Fibroscan), 2 combined: FibroMeters] were evaluated. References were Metavir staging and CHC etiology. Accuracy was evaluated mainly with the Obuchowski index (OI) and accessorily with area under the receiver operating characteristics (F≥2, F≥3, cirrhosis).RESULTS: OIs in CHC were: FibroMeters: 0.812, FibroMeters: 0.785 to 0.797, Fibrotest: 0.762, CirrhoMeters: 0.756 to 0.771, LSM: 0.754, Hepascore: 0.752, FibroMeter: 0.750, aspartate aminotransferase platelet ratio index: 0.742, Fib-4: 0.741. In other etiologies, most tests had nonsignificant changes in OIs. In NAFLD, CHC-specific tests were more accurate than NAFLD-specific tests. The combined FibroMeters had significantly higher accuracy than their 2 constitutive tests (FibroMeters and LSM) in at least 1 diagnostic target in all etiologies, except in ALD where LSM had the highest OI, and in 3 diagnostic targets (OIs and 2 area under the receiver operating characteristics) in CHC and NAFLD.CONCLUSIONS: Some tests developed in CHC outperformed other tests in their specific etiologies. Tests combining blood markers and LSM outperformed single tests, validating recent guidelines and extending them to main etiologies. Noninvasive fibrosis evaluation can thus be simplified in the main etiologies by using a unique test: either LSM alone, especially in ALD, or preferably combined to blood markers.
Published: 2017
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12. Progression of fibrosis in patients with chronic viral hepatitis is associated with IL-17 + neutrophils

Author: Bertrand Huard, Samia Afzal, Zuzana Macek Jilkova, Patrice N. Marche, Thomas Decaens, Nathalie Sturm, Evelyne Jouvin-Marche, Hélène Marche, Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), National Center of Excellence in Molecular Biology [ Lahore, Pakistan], University of the Punjab, Département de Gastroentérologie et hépatologie, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-Hôpital Michallon, Anatomie et de Cytologie Pathologiques [CHU Grenoble], Centre Hospitalier Universitaire [Grenoble] (CHU), This work was supported by grants from Institut National de la Santé et de la Recherche Médicale (INSERM) and the Agence Nationale de Recherches sur le Sida et les hepatites virales (ANRS). Part of the works was supported by the Ligue contre le Cancer (CD38 & CD73). ZMJ received financial support from Foundation Finovi and ANRS. SA was supported by a fellowship from the Higher Education Commission of Pakistan and French Embassy in Pakistan., MARCHE, Patrice, and Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])
Subjects: Liver Cirrhosis, Male, 0301 basic medicine, Pathology, medicine.medical_specialty, Hepatitis, Viral, Human, [SDV.IMM] Life Sciences [q-bio]/Immunology, Biopsy, medicine.medical_treatment, Fluorescent Antibody Technique, Immunofluorescence, liver, Flow cytometry, 03 medical and health sciences, neutrophils, Fibrosis, medicine, Humans, Aged, Hepatology, medicine.diagnostic_test, business.industry, Macrophages, Interleukin-17, fibrosis, [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, 3. Good health, IL-17, 030104 developmental biology, Cytokine, Disease Progression, Th17 Cells, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, France, Interleukin 17, Hepatic fibrosis, Viral hepatitis, business
Abstract: International audience; BACKGROUND & AIMS:The pro-inflammatory cytokine IL-17 plays a crucial role in liver diseases associated with hepatic fibrosis and increased risk of cancer development. Nevertheless, the cellular source of this cytokine has never been characterized in patients with liver fibrosis.METHODS:In this study, we investigated liver biopsies from 49 patients with chronic viral hepatitis at different stages of liver fibrosis. We monitored IL-17 production by intracellular flow cytometry, immunofluorescence and immunohistochemical in situ stainings, allowing a precise quantification, characterization and localization of IL-17(+) cells.RESULTS:Density of IL-17(+) cells increased with the stage of liver fibrosis specifically in fibrotic septa and portal areas (correlation coefficient r = 0.7373; P < 0.0001). Data clearly show that the frequency of intrahepatic IL-17(+) lymphocytes (including T, NKT and NK cells) was independent on stage of liver fibrosis, and we observed no statistical differences in number of IL-17(+) macrophages during progression of fibrosis. On the other hand, the number of IL-17(+) neutrophils in fibrotic septa and portal areas strongly correlated with the stages of fibrosis (correlation coefficient r = 0.6986; P < 0.0001), contributing significantly to total IL-17 production in liver tissue.CONCLUSIONS:Our data indicate that neutrophils represent an important source of IL-17 in the human liver, especially in late fibrosis stages. Inhibition of this specific harmful subset of neutrophils may offer therapeutic opportunities in fibrotic liver.© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
Published: 2016
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13. Liver-infiltrating CD8+ lymphocytes as prognostic factor for tumour recurrence in hepatitis C virus-related hepatocellular carcinoma

Author: Evelyne Jouvin-Marche, Nathalie Sturm, Paulette Bioulac-Sage, Christian Letoublon, Rémy Slama, Vincent Leroy, Jeanne Tran Van Nhieu, Muhammad Ramzan, Jean-Pierre Zarski, Patrice N. Marche, Brigitte Bancel, Philippe Merle, Thomas Decaens, Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Département d'anatomie et cythologie pathologique, CHU Grenoble-Hôpital Michallon, Centre Hospitalier Universitaire [Grenoble] (CHU), Hôpital Pellegrin, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'Hépatologie [Hôpital de la Croix-Rousse - HCL], Hôpital de la Croix-Rousse [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Département de pathologie [Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Département de chirurgie digestive et de l'urgence, and Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Liver Cirrhosis, Male, 0301 basic medicine, Pathology, Cirrhosis, Survival, analysis, Gene Expression, Kaplan-Meier Estimate, CD8-Positive T-Lymphocytes, Hepatitis, surgery, 0302 clinical medicine, Risk Factors, Recurrence, Tumor Microenvironment, Lymphocytes, Liver Neoplasms, FOXP3, Hepatitis C, Middle Aged, Immunohistochemistry, 3. Good health, medicine.anatomical_structure, Liver, 030220 oncology & carcinogenesis, Hepatocellular carcinoma, Female, France, Inflammation Mediators, Adult, medicine.medical_specialty, Carcinoma, Hepatocellular, Patients, Cells, chemical and pharmacologic phenomena, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Real-Time Polymerase Chain Reaction, Natural killer cell, 03 medical and health sciences, Lymphocytes, Tumor-Infiltrating, Predictive Value of Tests, Parenchyma, Biomarkers, Tumor, Carcinoma, medicine, Humans, Aged, Inflammation, Hepatology, Perforin, medicine.disease, digestive system diseases, 030104 developmental biology, Neoplasm Recurrence, Local
Abstract: International audience; BACKGROUND: Chronic liver inflammation and immune/inflammatory response promote hepatocellular carcinoma. The aim of this study was to characterize the immune status of HCV-related cirrhosis in patients with hepatocellular carcinoma (HCV-HCC) as compared to HCV patients without hepatocellular carcinoma. METHOD: Immune markers (CD3, CD4, CD8, CD20, CD56, TCRgammadelta, FoxP3) and gene expression profiles (CD8alpha, CD8beta, FoxP3, IL-6, IFN-gamma, perforin, RANTES) were analysed in a test cohort by immunohistochemistry and quantitative RT-PCR analysis on serial non-tumorous and tumorous tissues. RESULTS: Immune micro-environment was more inflammatory in HCV-HCC than HCV cirrhotic livers. The number of CD3(+) , CD4(+) , CD8(+) and CD20(+) liver-infiltrating lymphocytes was significantly higher, whereas the number of CD56(+) cells was significantly lower in HCV-HCC compared to HCV cirrhotic parenchyma. These differences were restricted to fibrous septa for CD4(+) and CD20(+) cells and to nodular parenchyma for CD8(+) cells. Gene expressions of CD8alpha, FoxP3 and RANTES were also significantly higher in HCV-HCC than in HCV cirrhosis. Interestingly, in a large cohort of 63 HCV-HCC patients. The number of CD8(+) cells \\textgreater/=100/field was associated with significant higher tumour recurrence (P = 0.003) and lower overall survival (P = 0.05) at 5 years. CONCLUSION: High densities of liver-infiltrating lymphocytes in HCV-HCC cirrhotic parenchyma prevail inflammatory conditions and could contribute to tumorigenesis and tumour recurrence. These results could contribute towards better clinical evaluation of patients susceptible for HCC recurrence after curative surgery
Published: 2016
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14. Precise evaluation of liver histology by computerized morphometry shows that steatosis influences liver stiffness measured by transient elastography in chronic hepatitis C

Author: Jérôme, Boursier, Victor, de Ledinghen, Nathalie, Sturm, Laïla, Amrani, Yannick, Bacq, Jérémy, Sandrini, Brigitte, Le Bail, Julien, Chaigneau, Jean-Pierre, Zarski, Yves, Gallois, Vincent, Leroy, Zaytouna, Al Hamany, Frédéric, Oberti, Isabelle, Fouchard-Hubert, Nina, Dib, Sandrine, Bertrais, Marie-Christine, Rousselet, Paul, Calès, A, Plages, Service d’Hépato-Gastroentérologie [CHU Angers], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Hémodynamique, Interaction Fibrose et Invasivité tumorales Hépatiques (HIFIH), Université d'Angers (UA), Fibrose hépatique et cancer du foie, Université Bordeaux Segalen - Bordeaux 2-IFR66-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'hépato-gastro-entérologie, CHU Bordeaux [Bordeaux]-Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], Département d'anatomie et cythologie pathologique, CHU Grenoble-Hôpital Michallon, Université Mohammed V Souissi, Département d'hépato-gastro-entérologie [Hôpital Trousseau : CHRU Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Département de Pathologie Cellulaire et Tissulaire [Angers], Laboratoire d'anatomie pathologique, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Département de Gastroentérologie et hépatologie, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-Hôpital Michallon, Equipe d'Épidémiologie Environnementale appliquée à la Reproduction et la Santé Respiratoire (CRI INSERM/UJF - U823 ), Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de Biochimie et Génétique [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), and Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS)-CHU Trousseau [APHP]
Subjects: Adult, Male, medicine.medical_specialty, Pathology, Steatosis, Biopsy, [SDV]Life Sciences [q-bio], Chronic hepatitis C, Gastroenterology, Stiffness, Fibrosis, Internal medicine, medicine, Computerized morphometry, Humans, Diagnosis, Computer-Assisted, medicine.diagnostic_test, business.industry, Fatty liver, Hepatitis C, Hepatology, Hepatitis C, Chronic, Middle Aged, medicine.disease, 3. Good health, Fatty Liver, Fibroscan, Liver, Elasticity Imaging Techniques, Female, Transient elastography, business, Viral hepatitis
Abstract: International audience; BackgroundLiver stiffness evaluation (LSE) by Fibroscan is now widely used to assess liver fibrosis in chronic hepatitis C. Liver steatosis is a common lesion in chronic hepatitis C as in other chronic liver diseases, but its influence on LSE remains unclear. We aimed to precisely determine the influence of steatosis on LSE by using quantitative and precise morphometric measurements of liver histology.Methods650 patients with chronic hepatitis C, liver biopsy, and LSE were included. Liver specimens were evaluated by optical analysis (Metavir F and A, steatosis grading) and by computerized morphometry to determine the area (%, reflecting quantity) and fractal dimension (FD, reflecting architecture) of liver fibrosis and steatosis.ResultsThe relationships between LSE and liver histology were better described using morphometry. LSE median was independently linked to fibrosis (area or FD), steatosis (area or FD), activity (serum AST), and IQR/LSE median. Steatosis area ≥4.0 % induced a 50 % increase in LSE result in patients with fibrosis area
Published: 2014
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15. ESM-1 expression in stromal cells is predictive of recurrence after radiofrequency ablation in early hepatocellular carcinoma

Author: Julien Calderaro, Nathalie Sturm, Pierre Nahon, Michel Beaugrand, Jean-Charles Nault, Eric Vicaut, Maryse Delehedde, Nathalie Barget, Jean-Frédéric Blanc, Jean-Claude Trinchet, Mounir Aout, Paulette Bioulac-Sage, Nathalie Ganne-Carrié, Angela Sutton, N. Charnaux, Marianne Ziol, Vincent Leroy, Olivier Seror, Gisèle N'Kontchou, Hôpital Jean Verdier [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris 13 (UP13), Service de Pathologie [Créteil], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Henri Mondor, Service de cardiologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), As Scalable As Possible: foundations of large scale dynamic distributed systems (ASAP), SYSTÈMES LARGE ÉCHELLE (IRISA-D1), Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Institut National de Recherche en Informatique et en Automatique (Inria)-Télécom Bretagne-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Institut National de Recherche en Informatique et en Automatique (Inria)-Télécom Bretagne-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Institut National de Recherche en Informatique et en Automatique (Inria)-Télécom Bretagne-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-Inria Rennes – Bretagne Atlantique, Institut National de Recherche en Informatique et en Automatique (Inria), Inserm, UMR-1053, Université de Bordeaux, Bordeaux, F-33076, France, Institut Albert Bonniot - Ontogénèse et oncogénèse moléculaires, CHU Grenoble-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de pathologie [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Service d'Hépato-gastroentérologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Jean Verdier [AP-HP], Université Paris Descartes - Paris 5 (UPD5), Génomique fonctionnelle des tumeurs solides (U674), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7), Université Sorbonne Paris Cité (USPC), Université Paris Descartes - Faculté de Médecine (UPD5 Médecine), UFR Santé, Médecine et Biologie Humaine (UFR SMBH), School of Biological Sciences, Biosciences Building, University of Liverpool, Unité de Recherche Clinique Saint-Louis Lariboisère Fernand Widal, Clinique Saint-Louis Lariboisère Fernand Widal, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Henri Mondor [Créteil], Inria Rennes – Bretagne Atlantique, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-SYSTÈMES LARGE ÉCHELLE (IRISA-D1), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Institut National de Recherche en Informatique et en Automatique (Inria)-Télécom Bretagne-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Institut National de Recherche en Informatique et en Automatique (Inria)-Télécom Bretagne-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Télécom Bretagne-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Jean Verdier [Bondy], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Hôpital Jean Verdier AP-HP Bondy, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Henri Mondor, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Université de Bretagne Sud (UBS)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Rennes (ENS Rennes)-Institut National de Recherche en Informatique et en Automatique (Inria)-Télécom Bretagne-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-CentraleSupélec-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Université de Rennes (UNIV-RENNES)-CentraleSupélec-Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Université de Bretagne Sud (UBS)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Rennes (ENS Rennes)-Télécom Bretagne-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-CentraleSupélec, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Jean Verdier [Bondy], Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Télécom Bretagne-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS), CentraleSupélec-Télécom Bretagne-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de Recherche en Informatique et en Automatique (Inria)-École normale supérieure - Rennes (ENS Rennes)-Université de Bretagne Sud (UBS)-Centre National de la Recherche Scientifique (CNRS)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-CentraleSupélec-Télécom Bretagne-Université de Rennes 1 (UR1), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), and Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Inria Rennes – Bretagne Atlantique
Subjects: Adult, Male, Pathology, medicine.medical_specialty, Carcinoma, Hepatocellular, Radiofrequency ablation, [SDV]Life Sciences [q-bio], Gastroenterology, law.invention, 03 medical and health sciences, chemistry.chemical_compound, Cytokeratin, 0302 clinical medicine, law, Internal medicine, Biopsy, medicine, Humans, Early Hepatocellular Carcinoma, ComputingMilieux_MISCELLANEOUS, Aged, 030304 developmental biology, Aged, 80 and over, 0303 health sciences, Hepatology, medicine.diagnostic_test, business.industry, Liver Neoplasms, Epithelial cell adhesion molecule, Middle Aged, medicine.disease, Neoplasm Proteins, 3. Good health, chemistry, 030220 oncology & carcinogenesis, Hepatocellular carcinoma, Liver biopsy, Catheter Ablation, Biomarker (medicine), Female, Proteoglycans, Neoplasm Recurrence, Local, Stromal Cells, business
Abstract: Background & Aims The prognosis of hepatocellular carcinoma (HCC) treated by radiofrequency ablation (RFA) is mainly linked to tumor recurrence. So far, no tissue biomarker of recurrence has been validated in biopsy samples. We aimed at investigating the prognostic value of tissue biomarkers in HCC biopsy samples of patients treated with RFA. Methods All consecutive naive patients from 3 university hospitals, with compensated cirrhosis, early-stage (BCLC 0/A) uninodular HCC treated with RFA, and available tumor biopsy, were included. Edmondson's grade, and the expression of cytokeratin 19, glutamine synthase, beta-catenin, epithelial cell adhesion molecule (EpCAM), and endothelial cell-specific molecule 1 (ESM-1) were assessed. Main clinical end points were overall and early recurrence. Statistical analyses were performed using Kaplan Meier, Log-rank test, and Cox models. Results 150 patients were included. Recurrence, death or liver transplantation occurred in 85, 51, and 12 patients, respectively. Median follow-up was 27months. ESM-1 expression by HCC stromal endothelial cells was observed in 58 patients (40%) and was associated with higher serum AFP levels, larger tumor, and more frequent expression of EpCAM and surrogate markers of activation of the Wnt-s-catenin pathway. The 2 independent predictive factors of overall recurrence were serum AFP (HR 1.11 [1.002; 1.22], p =0.045) and ESM-1 expression (HR 1.56 [1.004; 2.43], p =0.048). ESM-1 expression was also an independent predictive factor of early recurrence (HR 1.81 [1.02; 3.21], p =0.042). Conclusions ESM-1 expression by stromal endothelial cells, in tumor biopsy samples, has an independent predictive value of early recurrence after RFA.
Published: 2013
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16. Determination of reliability criteria for liver stiffness evaluation by transient elastography

Author: Brigitte Le-Bail, Sandrine Bertrais, Marie-Christine Rousselet, Jérôme Boursier, Paul Calès, Isabelle Fouchard-Hubert, Victor de Ledinghen, Jean-Pierre Zarski, Frédéric Oberti, Yves Gallois, Nathalie Sturm, Service d'Hépato-gastroentérologie, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Département de Gastroentérologie et hépatologie, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-Hôpital Michallon, Département d'hépatologie et de gastroentérologie [CHU Bordeaux], Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], Département de Pathologie Cellulaire et Tissulaire [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Service de pathologie [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Service d'Hépato-gastroentérologie [CHU Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Remodelage osseux et biomatériaux, Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hémodynamique, Interaction Fibrose et Invasivité tumorales Hépatiques (HIFIH), Université d'Angers (UA), the Multicentric Group from ANRS/HC/EP23 FIBROSTAR Studies, Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), and Groupe d'Études Remodelage Osseux et bioMatériaux (GEROM)
Subjects: Adult, Liver Cirrhosis, Male, Pathology, medicine.medical_specialty, Multivariate analysis, Biopsy, Large population, Chronic liver disease, Severity of Illness Index, 03 medical and health sciences, Hepatitis B, Chronic, 0302 clinical medicine, Non-alcoholic Fatty Liver Disease, Predictive Value of Tests, Liver stiffness, Interquartile range, Humans, Medicine, Reliability (statistics), ComputingMilieux_MISCELLANEOUS, Hepatology, medicine.diagnostic_test, business.industry, Reproducibility of Results, Hepatitis C, Chronic, Middle Aged, medicine.disease, 3. Good health, Fatty Liver, Liver, 030220 oncology & carcinogenesis, Liver biopsy, Elasticity Imaging Techniques, Female, 030211 gastroenterology & hepatology, Radiology, business, Transient elastography, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Liver stiffness evaluation (LSE) is usually considered as reliable when it fulfills all the following criteria: ≥10 valid measurements, ≥60% success rate, and interquartile range / median ratio (IQR/M) ≤0.30. However, such reliable LSE have never been shown to be more accurate than unreliable LSE. Thus, we aimed to evaluate the relevance of the usual definition for LSE reliability, and to improve reliability by using diagnostic accuracy as a primary outcome in a large population. 1,165 patients with chronic liver disease from 19 French centers were included. All patients had liver biopsy and LSE. 75.7% of LSE were reliable according to the usual definition. However, these reliable LSE were not significantly more accurate than unreliable LSE with, respectively: 85.8% versus 81.5% well-classified patients for the diagnosis of cirrhosis (P = 0.082). In multivariate analyses with different diagnostic targets, LSE median and IQR/M were independent predictors of fibrosis staging, with no significant influence of ≥10 valid measurements or LSE success rate. These two reliability criteria determined three LSE groups: "very reliable" (IQR/M ≤0.10), "reliable" (0.10IQR/M ≤0.30, or IQR/M0.30 with LSE median7.1 kPa), and "poorly reliable" (IQR/M0.30 with LSE median ≥7.1 kPa). The rates of well-classified patients for the diagnosis of cirrhosis were, respectively: 90.4%, 85.8%, and 69.5% (P10(-3) ). According to these new reliability criteria, 9.1% of LSE were poorly reliable (versus 24.3% unreliable LSE with the usual definition, P10(-3) ), 74.3% were reliable, and 16.6% were very reliable.The usual definition for LSE reliability is not relevant. LSE reliability depends on IQR/M according to liver stiffness median level, defining thus three reliability categories: very reliable, reliable, and poorly reliable LSE. (HEPATOLOGY 2013).
Published: 2013
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17. AST/ALT ratio is not an index of liver fibrosis in chronic hepatitis C when aminotransferase activities are determinate according to the international recommendations

Author: Jérôme, Guéchot, Renée Claude, Boisson, Jean-Pierre, Zarski, Nathalie, Sturm, Paul, Calès, Elisabeth, Lasnier, E-S, Zafrani, CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Laboratoire de Biochimie et Toxicologie [Centre Hospitalier Lyon Sud - HCL], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Pôle Digidune, Pôle DigiDune, Laboratoire de Cytologie, Département d'Anatomie et de Cytologie Pathologiques, CHU Grenoble-Hôpital Michallon, Hémodynamique, Interaction Fibrose et Invasivité tumorales Hépatiques (HIFIH), and Université d'Angers (UA)
Subjects: Liver Cirrhosis, Male, medicine.medical_specialty, Cirrhosis, Organ Dysfunction Scores, Biopsy, [SDV]Life Sciences [q-bio], Biopsy, Fine-Needle, Gastroenterology, digestive system, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Internal medicine, medicine, Humans, Aspartate Aminotransferases, Prospective Studies, Pyridoxal phosphate, Chronic, Prospective cohort study, Pyridoxal, Hepatology, medicine.diagnostic_test, business.industry, AST/ALT ratio, Alanine Transaminase, Hepatitis C, Chronic, Middle Aged, medicine.disease, Hepatitis C, digestive system diseases, 3. Good health, chemistry, Liver, ROC Curve, 030220 oncology & carcinogenesis, Liver biopsy, Pyridoxal Phosphate, Cohort, Fine-Needle, 030211 gastroenterology & hepatology, Female, business, Hepatic fibrosis
Abstract: International audience; OBJECTIVE: The aspartate aminotransferase activity (AST)/alanine aminotransferase activity (ALT) ratio is used as liver fibrosis index whereas the reported data are conflicting. In chronic hepatitis C (CHC), reported diagnostic accuracies range from none to good for significant fibrosis and to excellent for cirrhosis. Assuming that AST/ALT increases are mainly due to vitamin B6 defects since pyridoxal phosphate (PLP), active form of B6, acts as coenzyme in transamination reactions, we evaluated the diagnostic accuracy of the AST/ALT ratio using standardized methods for AST and ALT activities, with PLP addition as recommended, in a prospective multicenter cohort of CHC patients.METHODS: ALT and AST activities were measured using the recommended IFCC methods with addition of pyridoxal 5'-phosphate. We evaluated the AST/ALT ratio for the diagnosis of liver fibrosis or cirrhosis in a cohort of CHC patients included in a multicenter prospective study. A liver biopsy was performed in each patient and reviewed by two independent pathologists in order to determine the fibrosis stage according to Metavir classification which was the reference standard.RESULTS: AST/ALT ratio significantly increased with histological stage of liver fibrosis and there was a significant correlation between Metavir fibrosis stage and AST/ALT ratio (r=0.129, PCONCLUSION: AST/ALT ratio is not a good and discriminative index of liver fibrosis in CHC when aminotransferase activities are determinate according to the international recommendations.
Published: 2013
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18. Including osteoprotegerin and collagen IV in a score-based blood test for liver fibrosis increases diagnostic accuracy

Author: Chantal Housset, Nathalie Sturm, Sophie Thoret, Ludmia Taibi, Michel Vaubourdolle, Jérôme Guéchot, Elisabeth Lasnier, Jean-Pierre Zarski, Nelly Bosselut, Bernard Poggi, Marie-Christine Gelineau, Bruno Baudin, Physiopathogenèse et Traitement des Maladies du Foie [Villejuif], Université Paris-Sud - Paris 11 (UP11)-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), Département de Gastroentérologie et hépatologie, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-Hôpital Michallon, Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Centre d'Investigation Clinique [Grenoble] (CIC Grenoble), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-Hôpital Michallon-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), the ANRS HCEP 23 Fibrostar Group, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Sud - Paris 11 (UP11), Pôle de Biologie, Hôpitaux Universitaires Est Parisien, Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Université Grenoble Alpes (UGA)-Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Michallon, CHU Saint-Antoine [APHP], Centre de Recherche Saint-Antoine (CR Saint-Antoine), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Physiopathogénèse et Traitement des Maladies du Foie, Hôpital Paul Brousse-Université Paris-Saclay, Laboratoire Adaptation et pathogénie des micro-organismes [Grenoble] (LAPM), and Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Adult, Collagen Type IV, Liver Cirrhosis, Male, medicine.medical_specialty, Pathology, Liver fibrosis, Clinical Biochemistry, Diagnostic accuracy, Hepacivirus, Sensitivity and Specificity, Severity of Illness Index, Biochemistry, Gastroenterology, 03 medical and health sciences, 0302 clinical medicine, Osteoprotegerin, Internal medicine, medicine, Humans, Blood test, alpha-Macroglobulins, Aspartate Aminotransferases, Prospective Studies, Blood markers, Prospective cohort study, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, Apolipoprotein A-I, medicine.diagnostic_test, business.industry, Biochemistry (medical), Fibrosis stage, General Medicine, Hepatitis C, Chronic, Middle Aged, 3. Good health, Research Design, Female, 030211 gastroenterology & hepatology, Transient elastography, business, Biomarkers, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Background Noninvasive methods for liver fibrosis evaluation in chronic liver diseases have been recently developed, i.e. transient elastography (Fibroscan™) and blood tests (Fibrometer®, Fibrotest®, and Hepascore®). In this study, we aimed to design a new score in chronic hepatitis C (CHC) by selecting blood markers in a large panel and we compared its diagnostic performance with those of other noninvasive methods. Methods Sixteen blood tests were performed in 306 untreated CHC patients included in a multicenter prospective study (ANRS HC EP 23 Fibrostar) using METAVIR histological fibrosis stage as reference. The new score was constructed by non linear regression using the most accurate biomarkers. Results Five markers (alpha-2-macroglobulin, apolipoprotein-A1, AST, collagen IV and osteoprotegerin) were included in the new function called Coopscore©. Using the Obuchowski Index, Coopscore© shows higher diagnostic performances than for Fibrometer®, Fibrotest®, Hepascore® and Fibroscan™ in CHC. Association between Fibroscan™ and Coopscore© might avoid 68% of liver biopsies for the diagnosis of significant fibrosis. Conclusion Coopscore© provides higher accuracy than other noninvasive methods for the diagnosis of liver fibrosis in CHC. The association of Coopscore© with Fibroscan™ increases its predictive value.
Published: 2013
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19. Immunohistochemical markers on needle biopsies are helpful for the diagnosis of focal nodular hyperplasia and hepatocellular adenoma subtypes

Author: François Paraf, Marie Christine Saint Paul, Saïd Taouji, Jeanne Ramos, Nathalie Sturm, Brigitte Bancel, Valérie Paradis, Dominique Wendum, Emmanuelle Leteurtre, Monique Fabre, Jean-Yves Scoazec, Paulette Bioulac-Sage, Charles Balabaud, Jessica Zucman-Rossi, Gaelle Cubel, Brigitte Le Bail, Sophie Michalak, Catherine Guettier, Jeanne Tran Van Nhieu, Service de pathologie [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Physiopathologie du cancer du foie, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Fibrose hépatique et cancer du foie, Université Bordeaux Segalen - Bordeaux 2-IFR66-Institut National de la Santé et de la Recherche Médicale (INSERM), equipe 4, Laboratoire Central d'Anatomie et de Cytologie Pathologiques [Hôpital Edouard Herriot - HCL], Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL)-Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL)-Centre de Recherche en Cancérologie de Lyon (CRCL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer (JPArc - U837 Inserm), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université Lille 2 - Faculté de Médecine, Centre de recherche biomédicale Bichat-Beaujon (CRB3), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Albert Bonniot - Ontogénèse et oncogénèse moléculaires, CHU Grenoble-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Département de pathologie [Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), 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], Equipe 16, Centre de Recherche en Cancérologie de Lyon (CRCL), Tumorothèque de Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Université de Limoges (UNILIM), Hôpital Pasteur [Nice] (CHU), Laboratoire de Pathologie Cellulaire et Tissulaire, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Hôpital Bicêtre, Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Bicêtre, Hôpital Paul Brousse, Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Paul Brousse, Laboratoire d'anatomie pathologique, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Génomique Fonctionnelle des Tumeurs Solides (U1162), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL)-Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), 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, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Université Pierre et Marie Curie - Paris 6 (UPMC)-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 de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse, Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Bordeaux Segalen - Bordeaux 2-IFR66-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Hospices Civils de Lyon ( HCL ) -Hospices Civils de Lyon ( HCL ) -Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon ( HCL ) -Hospices Civils de Lyon ( HCL ) -Centre de Recherche en Cancérologie de Lyon ( CRCL ), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Centre de recherche Jean-Pierre Aubert-Neurosciences et Cancer, Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Lille, Droit et Santé, Centre de recherche biomédicale Bichat-Beaujon ( CRB3 ), Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), CHU Grenoble-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), 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 Lyon ( CRCL ), Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ), Université de Limoges ( UNILIM ), Hôpital Pasteur [Nice] ( CHU ), CHU Angers, Université Paris-Sud - Paris 11 ( UP11 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Bicêtre, Université Paris-Sud - Paris 11 ( UP11 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Paul Brousse, Genomique Fonctionnelle des Tumeurs Solides, and Université Paris Diderot - Paris 7 ( UPD7 ) -IFR105-Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM )
Subjects: Core needle, Male, MESH: Biopsy, Large-Core Needle, Pathology, MESH : Liver Neoplasms, MESH: Focal Nodular Hyperplasia, MESH: beta Catenin, MESH : Hepatocytes, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, MESH: Hepatocytes, MESH: Adenoma, Liver Cell, 0302 clinical medicine, MESH: Liver Neoplasms, MESH : Tumor Markers, Biological, MESH : Female, Hepatocyte Nuclear Factor 1-alpha, MESH : Algorithms, beta Catenin, medicine.diagnostic_test, Liver Neoplasms, Focal nodular hyperplasia, MESH : Adult, MESH : Biopsy, Large-Core Needle, MESH : Diagnosis, Differential, MESH: Predictive Value of Tests, 3. Good health, Focal Nodular Hyperplasia, 030220 oncology & carcinogenesis, Immunohistochemistry, 030211 gastroenterology & hepatology, MESH : Hepatocyte Nuclear Factor 1-alpha, Female, Anatomy, Algorithms, Adult, medicine.medical_specialty, MESH : Male, MESH: Algorithms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Pathology and Forensic Medicine, Adenoma, Liver Cell, Diagnosis, Differential, 03 medical and health sciences, MESH : Adenoma, Liver Cell, Glutamate-Ammonia Ligase, Predictive Value of Tests, MESH: Diagnosis, Differential, Biopsy, medicine, Biomarkers, Tumor, Humans, MESH: Glutamate-Ammonia Ligase, MESH : Predictive Value of Tests, MESH: Hepatocyte Nuclear Factor 1-alpha, MESH: Humans, business.industry, Significant difference, MESH : Humans, MESH: Adult, MESH : Glutamate-Ammonia Ligase, Hepatocellular adenoma, medicine.disease, MESH : beta Catenin, MESH: Male, Staining, MESH : Focal Nodular Hyperplasia, MESH: Tumor Markers, Biological, Hepatocytes, Surgery, Biopsy, Large-Core Needle, business, MESH: Female, Immunostaining
Abstract: International audience; Phenotypic identification of focal nodular hyperplasia (FNH) and hepatocellular adenoma (HCA) subtypes using immunohistochemical markers has been developed from their molecular characteristics. Our objective was to evaluate the sensitivity of these markers in the definitive diagnosis of these lesions by core needle biopsies. A total of 239 needle biopsies paired with their surgical resection specimen (group A) or without an associated resection specimen (group B) were reviewed. Using a step-by-step algorithm after standard staining, appropriate immunostaining analyses were performed to determine the certainty of diagnosis of FNH, HNF1α-inactivated HCA, inflammatory HCA, β-catenin-activated HCA, or unclassified HCA. The diagnosis of FNH was certain or probable on routine stains in 53% of needle biopsies of group A, whereas after glutamine synthetase staining, the diagnosis was certain in 86.7% as compared with 100% on the corresponding surgical specimen (P=0.04). In needle biopsies of group A, the diagnosis of HCA was certain on routine stains in 58.6% as compared with 94.3% on surgical specimens. After specific immunostaining, diagnosis was established on biopsies with 74.3% certainty, including all HCA subtypes, with similar distribution in surgical specimens. For each "certain diagnosis" paired diagnostic test (biopsy and surgical specimen), a positive correlation was observed (P
Published: 2012
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20. Comparison of nine blood tests and transient elastography for liver fibrosis in chronic hepatitis C: the ANRS HCEP-23 study

Author: Jean-Pierre Bronowicki, Elie-Serge Zafrani, Armelle Poujol-Robert, François Bailly, Dominique Larrey, Marc Bourlière, Albert Tran, Marie-Christine Gelineau, Jérôme Guéchot, Hélène Voitot, Victor de Ledinghen, I. Hubert, Michel Vaubourdolle, Adeline Paris, Dominique Guyader, Nathalie Sturm, Jean-Charles Renversez, Jean-Luc Bosson, Jean-Pierre Zarski, Candice Trocme, Maria Alessandra Rosenthal-Allieri, Tarik Asselah, Renée-Claude Boisson, Frédéric Ziegler, Elisabeth Lasnier, Département d'hépato-gastroentérologie, CHU Grenoble-Université Grenoble Alpes (UGA), Institut Albert Bonniot - Ontogénèse et oncogénèse moléculaires, CHU Grenoble-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Département de pathologie [Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service d'hépatologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CIC - Grenoble, Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Microenvironnement et remodelage, Foie, métabolismes et cancer, 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 )-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 )-Service d'hépato-gastro-entérologie [Rennes] = Gastroenterology [Rennes], CHU Pontchaillou [Rennes]-CHU Pontchaillou [Rennes], Département de biologie intégrée, CHU Grenoble-Hôpital Michallon, Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), Service d'Hépato-Gastro-Entérologie, CHU Bordeaux [Bordeaux]-Hôpital Saint-André, Service d'Hépato-Gastroentérologie, Hôpital St Joseph, Service de Biochimie et Génétique Moléculaire, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Saint Eloi (CHRU Montpellier), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Laboratoire d'Immunologie, Centre Hospitalier Universitaire de Nice (CHU Nice)-Hôpital l'Archet, Hôpital Hôtel Dieu, French Clinical Biology Society (Société Francaise de Biologie Clinique), Association for Liver Research (l'Association pour l'Etude du Foie), 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 )-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 d'hépato-gastro-entérologie [Rennes] = Gastroenterology [Rennes], Université Nice Sophia Antipolis (... - 2019) (UNS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-CHU Saint-Eloi, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Diderot - Paris 7 (UPD7)-Hôpital Beaujon, 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 d'hépato- gastro-entérologie, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes]-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], and Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Liver Cirrhosis, Male, Cirrhosis, Transient elastography, Biopsy, MESH: Elasticity Imaging Techniques, Chronic hepatitis C, Gastroenterology, MESH: Biopsy, 0302 clinical medicine, Prospective Studies, Prospective cohort study, 0303 health sciences, Hematologic Tests, MESH: Middle Aged, medicine.diagnostic_test, Hepatitis C, Middle Aged, MESH: Predictive Value of Tests, 3. Good health, MESH: Hepatitis C, Chronic, Liver biopsy, Predictive value of tests, Elasticity Imaging Techniques, 030211 gastroenterology & hepatology, Female, MESH: Liver Cirrhosis, Adult, medicine.medical_specialty, Liver fibrosis, MESH: Hematologic Tests, 03 medical and health sciences, Predictive Value of Tests, Internal medicine, medicine, Humans, 030304 developmental biology, Surrogate markers, Blood tests, MESH: Humans, Hepatology, Receiver operating characteristic, business.industry, MESH: Adult, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Hepatitis C, Chronic, medicine.disease, MESH: Prospective Studies, MESH: Male, Surgery, business, MESH: Female
Abstract: International audience; BACKGROUND & AIMS: Blood tests and transient elastography (Fibroscan™) have been developed as alternatives to liver biopsy. This ANRS HCEP-23 study compared the diagnostic accuracy of nine blood tests and transient elastography (Fibroscan™) to assess liver fibrosis, vs. liver biopsy, in untreated patients with chronic hepatitis C (CHC). METHODS: This was a multicentre prospective independent study in 19 French University hospitals of consecutive adult patients having simultaneous liver biopsy, biochemical blood tests (performed in a centralized laboratory) and Fibroscan™. Two experienced pathologists independently reviewed the liver biopsies (mean length=25±8.4 mm). Performance was assessed using ROC curves corrected by Obuchowski's method. RESULTS: Fibroscan™ was not interpretable in 113 (22%) patients. In the 382 patients having both blood tests and interpretable Fibroscan™, Fibroscan™ performed similarly to the best blood tests for the diagnosis of significant fibrosis and cirrhosis. Obuchowski's measure showed Fibrometer® (0.86), Fibrotest® (0.84), Hepascore® (0.84), and interpretable Fibroscan™ (0.84) to be the most accurate tests. The combination of Fibrotest®, Fibrometer®, or Hepascore® with Fibroscan™ or Apri increases the percentage of well classified patients from 70-73% to 80-83% for significant fibrosis, but for cirrhosis a combination offers no improvement. For the 436 patients having all the blood tests, AUROC's ranged from 0.82 (Fibrometer®) to 0.75 (Hyaluronate) for significant fibrosis, and from 0.89 (Fibrometer® and Hepascore®) to 0.83 (FIB-4) for cirrhosis. CONCLUSIONS: Contrarily to blood tests, performance of Fibroscan™ was reduced due to uninterpretable results. Fibrotest®, interpretable Fibroscan™, Fibrometer®, and Hepascore® perform best and similarly for diagnosis of significant fibrosis and cirrhosis.
Published: 2012
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21. A New Combination of Blood Test and Fibroscan for Accurate Non-Invasive Diagnosis of Liver Fibrosis Stages in Chronic Hepatitis C

Author: Sandrine Bertrais, Frédéric Oberti, Paul Calès, Nathalie Sturm, Isabelle Fouchard-Hubert, Victor de Ledinghen, Marie-Christine Rousselet, Jérôme Boursier, Juliette Foucher, Jean-Pierre Zarski, Vincent Leroy, Yves Gallois, Nina Dib, Hémodynamique, Interaction Fibrose et Invasivité tumorales Hépatiques (HIFIH), Université d'Angers (UA), Service d'Hépato-Gastro-Entérologie, CHU Bordeaux [Bordeaux]-Hôpital Saint-André, Département d'hépato-gastroentérologie, CHU Grenoble-Université Grenoble Alpes (UGA), Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Institut National de la Santé et de la Recherche Médicale (INSERM)-EFS-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF), Institut Albert Bonniot - Ontogénèse et oncogénèse moléculaires, CHU Grenoble-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Albert Bonniot, Département d'hépatologie et de gastroentérologie, Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], Yahoo! Research [Barcelona], Université Grenoble Alpes (UGA)-CHU Grenoble, and Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Adult, Liver Cirrhosis, Male, medicine.medical_specialty, Liver fibrosis, [SDV]Life Sciences [q-bio], Gastroenterology, Severity of Illness Index, 03 medical and health sciences, 0302 clinical medicine, Chronic hepatitis, Internal medicine, Severity of illness, Biopsy, medicine, Blood test, Humans, Prospective Studies, Prospective cohort study, Hematologic Tests, Hepatology, medicine.diagnostic_test, business.industry, Hepatitis C, Hepatitis C, Chronic, Middle Aged, medicine.disease, 3. Good health, Logistic Models, 030220 oncology & carcinogenesis, Elasticity Imaging Techniques, 030211 gastroenterology & hepatology, Female, Hepatic fibrosis, business
Abstract: International audience; OBJECTIVES: Precise evaluation of the level of liver fibrosis is recommended in patients with chronic hepatitis C (CHC). Blood fibrosis tests and Fibroscan are now widely used for the non-invasive diagnosis of liver fibrosis. Detailed fibrosis stage classifications have been developed to provide an estimation of the liver fibrosis stage from the results of these non-invasive tests. Our aim was to develop a new and more accurate fibrosis stage classification by using new scores combining non-invasive fibrosis tests.METHODS: In all, 729 patients with CHC (exploratory set: 349; validation set: 380) had liver biopsy for Metavir fibrosis (F) staging, and 6 fibrosis tests: Fibroscan, Fibrotest, FibroMeter, Hepascore, FIB-4, APRI. RESULTS: Exploratory set: Fibroscan and FibroMeter were the independent predictors of different diagnostic targets of liver fibrosis. New fibrosis indexes combining FibroMeter and Fibroscan were thus developed for the diagnosis of clinically significant fibrosis (CSF-index) or severe fibrosis (SF-index). The association of CSF- and SF-indexes provided a new fibrosis stage classification (CSF/SF classification): F0/1, F1/2, F2±1, F2/3, F3±1, F4. Validation set: CSF/SF classification had a high diagnostic accuracy (85.8% well-classified patients), significantly higher than the diagnostic accuracies of FibroMeter (69.7%, P
Published: 2011
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22. Temozolomide treatment in aggressive pituitary tumors and pituitary carcinomas: a French multicenter experience

Author: Olivier Chabre, Richard Assaker, Françoise Borson-Chazot, Patrick François, Florence de Fraipont, Dominique Figarella-Branger, Jean-Guy Passagia, Stephan Gaillard, Sylvie Salenave, Nathalie Sturm, Philippe Caron, Philippe Chanson, Emmanuel Jouanneau, Christine Cortet-Rudelli, Michèle Bernier, Henry Dufour, Gérald Raverot, Aurélie Cornelius, Jacqueline Trouillas, Thierry Brue, M. Muller, Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Département d'anatomie et cythologie pathologique, CHU Grenoble-Hôpital Michallon, INSERM U823, équipe 5 (cibles diagnostiques ou thérapeutiques et vectorisation de drogues dans le cancer du poumon), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)-UM Biochimie des Cancers et Biothérapies, CHU Grenoble-Institut de Biologie et Pathologie-Institut de Biologie et Pathologie, Laboratoire d'Imagerie Paramétrique (LIP), Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR58-Centre National de la Recherche Scientifique (CNRS), Centre de recherches métalexicographiques et dictionnairiques francophones (CRMDF), Université de Cergy Pontoise (UCP), Université Paris-Seine-Université Paris-Seine-Centre National de la Recherche Scientifique (CNRS), Département d'endocrino-diabétologie, maladies de la nutrition, Récepteurs stéroïdiens : physiopathologie endocrinienne et métabolique, Université Paris-Sud - Paris 11 (UP11)-IFR93-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Endocrinologie et Maladies de la reproduction, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Service de neurochirurgie [CHU Marseille], Université de la Méditerranée - Aix-Marseille 2-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Centre de recherche en neurobiologie - neurophysiologie de Marseille (CRN2M), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Littoral, Environnement, Télédétection, Géomatique (LETG - Nantes), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université de Brest (UBO)-Université de Rennes 2 (UR2)-Centre National de la Recherche Scientifique (CNRS)-Institut de Géographie et d'Aménagement Régional de l'Université de Nantes (IGARUN), Université de Nantes (UN)-Université de Nantes (UN), Galaxies, Etoiles, Physique, Instrumentation (GEPI), Institut national des sciences de l'Univers (INSU - CNRS)-Observatoire de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie des Substances Naturelles (ICSN), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Service de pathologie et neuropathologie, Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR93-Université Paris-Sud - Paris 11 (UP11), Service de neurochirurgie, Institut de Géographie et d'Aménagement Régional de l'Université de Nantes (IGARUN), Université de Nantes (UN)-Université de Nantes (UN)-Université de Rennes 2 (UR2), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université de Brest (UBO)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), and Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)
Subjects: Male, MESH: Carcinoma, Pituitary gland, MESH: Sequence Analysis, DNA, Endocrinology, Diabetes and Metabolism, Clinical Biochemistry, MESH: Antineoplastic Agents, Alkylating, Biochemistry, 0302 clinical medicine, Endocrinology, MESH: DNA Methylation, MESH: Middle Aged, MESH: Prolactinoma, Middle Aged, 3. Good health, Dacarbazine, ACTH-Secreting Pituitary Adenoma, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Female, France, hormones, hormone substitutes, and hormone antagonists, medicine.drug, Adult, endocrine system, medicine.medical_specialty, Adenoma, 030209 endocrinology & metabolism, Context (language use), MESH: Dacarbazine, O(6)-Methylguanine-DNA Methyltransferase, 03 medical and health sciences, Internal medicine, Temozolomide, medicine, Carcinoma, Humans, Neoplasm Invasiveness, Pituitary Neoplasms, Prolactinoma, MESH: Pituitary Neoplasms, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Antineoplastic Agents, Alkylating, neoplasms, Retrospective Studies, MESH: Humans, MESH: O(6)-Methylguanine-DNA Methyltransferase, business.industry, Biochemistry (medical), Pituitary tumors, O-6-methylguanine-DNA methyltransferase, MESH: Adult, MESH: Retrospective Studies, Sequence Analysis, DNA, MESH: Neoplasm Invasiveness, DNA Methylation, medicine.disease, MESH: Male, MESH: ACTH-Secreting Pituitary Adenoma, MESH: France, Pituitary carcinoma, business, MESH: Female
Abstract: International audience; CONTEXT: To date only 18 patients with aggressive pituitary tumors or carcinomas treated with temozolomide have been reported. Increased expression of O6-methylguanine-DNA-methyltranferase (MGMT) has been suggested to predict resistance to temozolomide. OBJECTIVES: The objective of the study was to describe the antitumoral efficacy and toxicity of temozolomide in patients with aggressive pituitary tumors or carcinomas and evaluate the possible prognostic value of MGMT promoter methylation and protein expression. PATIENTS: Eight patients, five with pituitary carcinomas (three prolactin (PRL) and two ACTH) and three with aggressive pituitary tumors (one PRL and two ACTH), all treated with temozolomide administered orally for four to 24 cycles, were included in our French multicenter study. DESIGN: MGMT expression was assessed by immunohistochemistry and MGMT promoter methylation by pyrosequencing. RESULTS: Three of the eight patients (two ACTH adenomas and one PRL carcinoma) responded to temozolomide as demonstrated by significant tumor shrinkage and reduced hormone secretion. Three cycles of temozolomide were sufficient to identify treatment-responsive patients. Additional cycles did not improve treatment efficacy in those not responding, even when associated with carboplatin and vepeside. MGMT expression did not predict tumoral response to temozolomide because it was positive in one responder and negative in two nonresponders. Similarly, MGMT promoter methylation (three of seven tumors) did not predict clinical response. Toxicity remained mild in all patients. CONCLUSION: Temozolomide treatment may be an effective option for some aggressive pituitary tumors or carcinomas. Response to a trial of three cycles of treatment seems sufficient to identify responders and more reliable than patient MGMT status.
Published: 2010
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23. Systematic Analysis of G Protein-Coupled Receptor Gene Expression in Adrenocorticotropin-Independent Macronodular Adrenocortical Hyperplasia Identifies Novel Targets for Pharmacological Control of Adrenal Cushing’s Syndrome

Author: Guillaume Assié, Hervé Lefebvre, Jérôme Bertherat, Nathalie Sturm, Eric Clauser, Jean-Jacques Feige, Fernande René-Corail, Michaël Thomas, Lionel Groussin, Estelle Louiset, Olivier Chabre, Nadia Cherradi, Institut Cochin (UMR_S567 / UMR 8104), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Différenciation et communication neuronale et neuroendocrine (DC2N), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Angiogenèse hormono-regulée et angiogenèse tumorale (LAPV), Université Joseph Fourier - Grenoble 1 (UJF)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), 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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Biologie du Cancer et de l'Infection (BCI ), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), CHU Cochin [AP-HP], Université Paris Descartes - Paris 5 (UPD5)-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)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Laboratoire Adaptation et pathogénie des micro-organismes [Grenoble] (LAPM), Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG)
Subjects: Cortisol secretion, medicine.medical_specialty, Adenoma, Endocrinology, Diabetes and Metabolism, Clinical Biochemistry, Gene Expression, Context (language use), 030209 endocrinology & metabolism, Biology, Biochemistry, Clonidine, G Protein-Coupled Receptor Gene, Receptors, G-Protein-Coupled, [SHS]Humanities and Social Sciences, 03 medical and health sciences, Translational Highlights from Jcem, Drug Delivery Systems, 0302 clinical medicine, Endocrinology, Adrenocorticotropic Hormone, Receptors, Adrenergic, alpha-2, Internal medicine, Adrenergic alpha-2 Receptor Agonists, medicine, Humans, Pituitary Neoplasms, Cushing Syndrome, Molecular Biology, Antihypertensive Agents, Cells, Cultured, Oligonucleotide Array Sequence Analysis, Hydrocortisone, G protein-coupled receptor, 030304 developmental biology, 0303 health sciences, Hyperplasia, 030219 obstetrics & reproductive medicine, Gene Expression Profiling, Biochemistry (medical), General Medicine, medicine.disease, 3. Good health, Gene expression profiling, ACTH-Secreting Pituitary Adenoma, Macronodular Adrenal Hyperplasia, Adrenal Cortex, hormones, hormone substitutes, and hormone antagonists, medicine.drug
Abstract: Stimulation of cortisol secretion through abnormally expressed G protein-coupled receptors (GPCRs) is a frequent feature of ACTH-independent macronodular adrenal hyperplasia (AIMAH). This has opened a pharmacological strategy that targets GPCRs for the treatment of Cushing's syndrome in AIMAH. However, only few drugs are available for the presently described GPCRs.The objective of the study was to identify new GPCR targets for the pharmacological treatment of adrenal Cushing's syndrome.We designed a cDNA chip containing 865 nucleotidic sequences of GPCRs. mRNAs were extracted from three normal adrenals, 18 AIMAHs, four adrenals from Cushing's disease patients, and 13 cortisol-secreting adenomas. A set of GPCR mRNAs that showed significantly higher or lower expression in AIMAH than in normal adrenal were studied by quantitative RT-PCR analysis. Analysis of protein expression and function were performed on selected GPCRs.The study was conducted at a tertiary care center and basic research laboratories.The ACTH MC2 receptor showed a low expression in 15 of 18 AIMAHs samples, whereas several previously undescribed GPCR genes were found highly expressed in a subset of AIMAH, such as the receptors for motilin (MLNR; three of 18 AIMAHs) and γ-aminobutyric acid (GABBR1; five of 18 AIMAHs), and the α2A adrenergic receptor (ADRA2A; 13 of 18 AIMAHs), on which we focused our attention. Western blot and immunochemistry analyses showed expression of ADRA2A protein in AIMAH but not in normal adrenal cortex. The ADRA2A agonist clonidine enhanced both basal and stimulated cortisol production. Clonidine-induced increase in basal cortisol levels was blocked by the ADRA2A antagonist yohimbine.ADRA2A is a potential target for pharmacological treatment of Cushing's syndrome linked to AIMAH.
Published: 2010
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24. Automation of the Hepascore and validation as a biochemical index of liver fibrosis in patients with chronic hepatitis C from the ANRS HC EP 23 Fibrostar cohort

Author: Jérôme, Guéchot, Elisabeth, Lasnier, Nathalie, Sturm, Adeline, Paris, Jean-Pierre, Zarski, M, Beaugrand, CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut Albert Bonniot - Ontogénèse et oncogénèse moléculaires, CHU Grenoble-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CIC - Grenoble, Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département d'hépato-gastroentérologie, CHU Grenoble-Université Grenoble Alpes (UGA), French de National Agency for Research, Société Française de Biologie Clinique (SFBC), and Association pour l'Étude du Foie (AFEF) References [1] Manning DS, Afdhal NH. Diagnosis and quantification of fibrosis. Gastroenterology
Subjects: Liver Cirrhosis, Male, Pathology, Cirrhosis, Liver fibrosis, Clinical Biochemistry, Biochemistry, Gastroenterology, Diagnostic accuracy, Cohort Studies, Automation, 0302 clinical medicine, MESH: Automation, Hepascore, Prospective cohort study, MESH: Cohort Studies, MESH: Aged, Blood marker, MESH: Middle Aged, medicine.diagnostic_test, General Medicine, Middle Aged, Hepatitis C, 3. Good health, MESH: Hepatitis C, Chronic, MESH: Young Adult, 030220 oncology & carcinogenesis, Liver biopsy, Cohort, 030211 gastroenterology & hepatology, Female, MESH: Liver Cirrhosis, Adult, medicine.medical_specialty, Adolescent, Sensitivity and Specificity, 03 medical and health sciences, Young Adult, Chronic hepatitis, Internal medicine, medicine, Humans, In patient, Aged, MESH: Adolescent, MESH: Humans, Receiver operating characteristic, business.industry, Biochemistry (medical), MESH: Adult, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Hepatitis C, Chronic, medicine.disease, MESH: Sensitivity and Specificity, MESH: Male, business, MESH: Female
Abstract: International audience; BACKGROUND: Hepascore combining serum bilirubin, gamma glutamyl transpeptidase, hyaluronic acid (HA) and alpha2-macroglobulin with age and sex, was reported as relevant in predicting liver fibrosis in patients with chronic HCV infection and was proposed as an alternative to liver biopsy. METHODS: Since an automated HA assay (Latex method, Wako, Japan) became available, we investigated to automate Hepascore by simultaneous measurements of components using an OLYMPUS AU640 analyzer (Tokyo, Japan). For its clinical evaluation, we considered a cohort of chronic HCV patients included in a multicenter prospective study (ANRS HC EP 23 Fibrostar). RESULTS: Automated Hepascore was not significantly different than assayed as previously described. An improvement in HA variability was evidenced. In 512 chronic HCV patients, automated Hepascore, using ROC curves analysis, showed good predictive performances for significant fibrosis (AUROC=0.81), severe fibrosis (AUROC=0.82), and cirrhosis (AUROC=0.88). For significant fibrosis, Hepascore (cut-off=0.5) had a sensitivity of 0.77, a specificity of 0.70, a positive predictive value of 0.71 and a negative predictive value (NPV) of 0.77. Hepascore
Published: 2010
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25. Features and distribution of CD8 T cells with human leukocyte antigen class I-specific receptor expression in chronic hepatitis C

Author: Paula Bonorino, Martine Pernollet, Nathalie Sturm, Evelyne Jouvin-Marche, Vincent Leroy, Stefania Tongiani-Dashan, Tania Dufeu-Duchesne, Jean-Pierre Zarski, Patrice N. Marche, Eric Vivier, Contrôle moléculaire de la réponse immune specifique, Université Joseph Fourier - Grenoble 1 (UJF)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de Gastroentérologie et hépatologie, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-Hôpital Michallon, Département d'anatomie et cythologie pathologique, CHU Grenoble-Hôpital Michallon, Laboratoire d'Immunologie, EFS, Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and specific grant from the Agence Nationale pour la Recherche sur le Sida et les hépatites virales (ANRS). P.B. was supported by fellowships from the French government and from the ANRS.
Subjects: Male, CD8-Positive T-Lymphocytes, NKG2A, MESH: Histocompatibility Antigens Class I, Interleukin 21, 0302 clinical medicine, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Cytotoxic T cell, IL-2 receptor, Receptors, Immunologic, MESH: Aged, 0303 health sciences, MESH: Middle Aged, ZAP70, Middle Aged, Natural killer T cell, MESH: CD8-Positive T-Lymphocytes, MESH: Case-Control Studies, 3. Good health, MESH: Hepatitis C, Chronic, medicine.anatomical_structure, Phenotype, Liver, Receptors, KIR2DL3, Receptors, KIR2DL1, Receptors, Natural Killer Cell, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, NK Cell Lectin-Like Receptor Subfamily C, KIRs, Adult, Biology, MESH: Phenotype, Natural killer cell, 03 medical and health sciences, Viral C hepatitis, medicine, Humans, Antigen-presenting cell, MESH: Receptors, Immunologic, 030304 developmental biology, Aged, CD40, MESH: Humans, Hepatology, Perforin, Histocompatibility Antigens Class I, MESH: Receptors, KIR2DL3, MESH: Adult, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, MESH: Receptors, KIR2DL1, Hepatitis C, Chronic, NK cell receptors, MESH: Male, MESH: Perforin, Case-Control Studies, Immunology, biology.protein, T cell subsets, MESH: Female, 030215 immunology, MESH: Liver
Abstract: UNLABELLED CD8(+) T cells represent a sizable component of the liver inflammatory infiltrate in chronic hepatitis C and are thought to contribute to immune-mediated tissue injury. Because chronic stimulation may promote the expression by CD8(+) T cells of distinct human leukocyte antigen class I-specific natural killer cell receptors (NKRs) susceptible to both inhibiting effector functions and promoting cell survival, we examined the distribution and characteristics of CD8(+) T cells with such receptors in chronic hepatitis C patients. NKR CD8(+) T cells were detectable in liver and peripheral blood from hepatitis C virus (HCV)-infected patients but were not major subsets. However, the frequency of NKG2A(+) CD8(+) in the liver and in a lesser extent in the peripheral blood was positively correlated to histological activity in HCV-infected patients. No such correlation was found with KIR(+) T cells in liver in HCV-infected patients and with the both NKR CD8(+) T cells in hepatitis B virus (HBV) infected patients. Circulating CD8(+) T cells expressing KIRs exhibited phenotypic features of memory T cells with exacerbated expression of the senescence marker CD57 in patients. NKG2A(+)CD8(+) T cells were committed T cells that appeared less differentiated than KIR(+)CD8(+) T cells. In HCV-infected patients, their content in perforin was low and similar to that observed in NKG2A(-)CD8(+) T cells; this scenario was not observed in healthy subjects and HBV-infected patients. Both NKG2A and KIRs could inhibit the response of HCV-specific CD8(+) T cells ex vivo. CONCLUSION These results support the concept that an accumulation in the liver parenchyma of NKR(+)CD8(+) T cells that have functional alterations could be responsible for liver lesions. They provide novel insights into the complexity of liver-infiltrating CD8(+) T cells in chronic hepatitis C and reveal that distinct subsets of antigen-experienced CD8(+) T cells are differentially sensitive to the pervasive influence of HCV.
Published: 2007
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26. Prospective comparison of six non-invasive scores for the diagnosis of liver fibrosis in chronic hepatitis C

Author: Vincent Leroy, Jean-Pierre Zarski, Jean-Charles Renversez, Marie-Noëlle Hilleret, Françoise Morel, Nathalie Sturm, Candice Trocmé, Patrice Faure, Département de Gastroentérologie et hépatologie, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-Hôpital Michallon, Contrôle moléculaire de la réponse immune specifique, Université Joseph Fourier - Grenoble 1 (UJF)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département d'anatomie et cythologie pathologique, CHU Grenoble-Hôpital Michallon, Laboratoire d'Enzymologie (DBPC), CHU Grenoble-GREPI EA 2938, Laboratoire de Biochimie (DBI), CHU Grenoble, Duperray, Alain, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Joseph Fourier - Grenoble 1 (UJF)
Subjects: Liver Cirrhosis, Male, FIBROMETER, Liver fibrosis, Logistic regression, Gastroenterology, Severity of Illness Index, MESH: gamma-Glutamyltransferase, 0302 clinical medicine, Liver Function Tests, Fibrosis, MESH: Bilirubin, MESH: Liver Function Tests, Prospective Studies, MESH: Fatty Liver, MESH: Middle Aged, medicine.diagnostic_test, Alanine Transaminase, gamma-Glutamyltransferase, Middle Aged, MESH: Predictive Value of Tests, 3. Good health, MESH: Hepatitis C, Chronic, Liver, 030220 oncology & carcinogenesis, Liver biopsy, Area Under Curve, 030211 gastroenterology & hepatology, Female, MESH: Liver Cirrhosis, Algorithms, Adult, medicine.medical_specialty, MESH: Algorithms, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Sensitivity and Specificity, 03 medical and health sciences, MESH: Aspartate Aminotransferases, Chronic hepatitis, Predictive Value of Tests, Internal medicine, MESH: Severity of Illness Index, medicine, Humans, Aspartate Aminotransferases, MESH: Platelet Count, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, MESH: Humans, Hepatology, FibroTest, business.industry, Platelet Count, MESH: Biological Markers, Bilirubin, MESH: Adult, Hepatitis C, Chronic, medicine.disease, MESH: Male, MESH: Prospective Studies, MESH: Sensitivity and Specificity, Fatty Liver, MESH: Alanine Transaminase, MESH: Area Under Curve, Hepatic fibrosis, business, MESH: Female, Biomarkers, MESH: Liver
Abstract: International audience; BACKGROUND/AIMS: Non-invasive markers of liver fibrosis have recently been developed as an alternative to liver biopsy. The aim of this study was to compare the diagnostic performance of 6 scores (MP3, Fibrotest, Fibrometer, Hepascore, Forns' score and APRI). METHODS: We studied 180 chronic hepatitis C patients. Liver fibrosis was staged according to the METAVIR scoring system. RESULTS: Overall diagnostic performance of scores determined by AUROCs ranged from 0.86 for Fibrometer to 0.78 for Forns' score (NS) for discriminating F0F1 versus F2F3F4. For discriminating F0F1F2 versus F3F4, AUROCs ranged from 0.91 for Fibrometer to 0.78 for Forns' score (p
Published: 2007
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27. Association of CYP1B1 Germ Line Mutations with Hepatocyte Nuclear Factor 1{alpha}-Mutated Hepatocellular Adenoma

Author: Emmanuelle Jeannot, Jean-Yves Scoazec, Nathalie Sturm, Laurence Chiche, Catherine Buffet, Christine Bellanné-Chantelot, Claudia de Toma, Yannick Bacq, Karine Poussin, Jessica Zucman-Rossi, Pierre Laurent-Puig, Paulette Bioulac-Sage, Jeanne Tran Van Nhieu, Génomique Fonctionnelle des Tumeurs Solides (U1162), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'Etude du Polymorphisme Humain (CEPH), Université Paris Diderot - Paris 7 (UPD7)-Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Fondation Jean Dausset, Département de Chirurgie [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Service de gastro-entérologie [CHU Trousseau], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Laboratoire de Pathologie Cellulaire, CHU Grenoble, Service d'hépato-gastro-entérologie, Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Département de pathologie [Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Bases moléculaires de la réponse aux xénobiotiques (U775 (IFR95)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Fibrose hépatique et cancer du foie, Université Bordeaux Segalen - Bordeaux 2-IFR66-Institut National de la Santé et de la Recherche Médicale (INSERM), This work was founded by the ARC grant n°5188, The Inserm 'Réseau de recherche clinique et en santé des populations', the SNFGE and the Fondation de France. EJ is recipient of an ARC fellowship., Genomique Fonctionnelle des Tumeurs Solides, Université Paris Diderot - Paris 7 ( UPD7 ) -IFR105-Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre d'Etude du Polymorphisme Humain ( CEPH ), Université Paris Diderot - Paris 7 ( UPD7 ) -Institut Universitaire d'Hématologie ( IUH ), Université Paris Diderot - Paris 7 ( UPD7 ) -Fondation Jean Dausset, Service de chirurgie, CHU Caen, Service de gastro-entérologie, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Trousseau [APHP], Université Paris-Sud - Paris 11 ( UP11 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Bicêtre, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), Service de Cytogénétique, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Saint-Antoine [APHP], Bases moléculaires de la réponse aux xénobiotiques ( U775 (IFR95) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Université Bordeaux Segalen - Bordeaux 2-IFR66-Institut National de la Santé et de la Recherche Médicale ( INSERM ), and Zucman-Rossi, Jessica
Subjects: Cancer Research, Somatic cell, medicine.disease_cause, Germline, 0302 clinical medicine, Cytochrome P-450 Enzyme System, Genotype, estrogen, Hepatocyte Nuclear Factor 1-alpha, tumor suppressor gene, Child, Genetics, Mutation, Liver Neoplasms, Middle Aged, 3. Good health, Pedigree, Oncology, 030220 oncology & carcinogenesis, Cytochrome P-450 CYP1B1, CYP1B1, 030211 gastroenterology & hepatology, Female, [ SDV.MHEP.HEG ] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Aryl Hydrocarbon Hydroxylases, Adult, endocrine system, Adenoma, Adolescent, cytochrome P450, hepatocellular adenoma, Biology, Adenoma, Liver Cell, 03 medical and health sciences, Germline mutation, medicine, Genetic predisposition, Humans, Genetic Predisposition to Disease, Alleles, Germ-Line Mutation, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Hepatocellular adenoma, medicine.disease, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Mutagenesis, Site-Directed, mutation, genetic predisposition, metabolism
Abstract: Biallelic somatic mutations of TCF1 coding for hepatocyte nuclear factor 1α (HNF1α) are found in 50% of the hepatocellular adenoma (HCA) cases usually associated with oral contraception. In rare cases, HNF1α germ line mutations could also predispose to familial adenomatosis. In order to identify new genetic factors predisposing to HNF1α-mutated HCA, we searched for mutations in genes involved in the metabolism of estrogen. For 10 genes (CYP1A1, CYP1A2, CYP3A4, CYP3A5, COMT, UGT2B7, NQO1, GSTM1, GSTP1, and GSTT1), we did not find mutations nor differences in the allele distribution among 32 women presenting HNF1α-mutated adenomas compared with 58 controls. In contrast, we identified a CYP1B1 germ line heterozygous mutation in 4 of 32 women presenting HNF1α-mutated adenomas compared with none in 58 controls. We confirmed these results with the identification of four additional CYP1B1 mutations in a second series of 26 cases. No mutations were found in the control group, which was extended to 98 individuals, and only a known rare genetic variant was observed in two controls (P = 0.0003). We did an ethoxyresorufin O-deethylase assay to evaluate the functional consequence of the CYP1B1 mutations. We found reduced enzymatic activity in each CYP1B1 variant. In addition, an E229K CYP1B1 mutation was found in a woman with a germ line HNF1α mutation in a familial adenomatosis context. In this large family, all three patients with adenomatosis bore both HNF1 and CYP1B1 germ line mutations. In conclusion, our data suggested that CYP1B1 germ line–inactivating mutations might increase the incidence of HCA in women with HNF1α mutations. [Cancer Res 2007;67(6):2611–6]
Published: 2007
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28. Inflammatory pseudotumour of the liver: a variant rich in giant atypical reactive dendritic cells

Author: Nathalie Sturm, Guillou L, Elisabeth Brambilla, Bosseray A, Laverrière Mh, Christian Letoublon, Pinel N, Département de chirurgie digestive et de l'urgence, CHU Grenoble-Hôpital Michallon, Department of Pathology, Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV)-University Institute of Pathology, Département de médecine aiguë spécialisée, Salas, Danielle, and University Institute of Pathology-Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV)
Subjects: MESH: Cell Nucleus, Pathology, medicine.medical_specialty, Histology, MESH: Liver Diseases, [SDV.CAN]Life Sciences [q-bio]/Cancer, Pathology and Forensic Medicine, MESH: Giant Cells, 03 medical and health sciences, 0302 clinical medicine, Text mining, [SDV.CAN] Life Sciences [q-bio]/Cancer, medicine, 030304 developmental biology, MESH: Treatment Outcome, 0303 health sciences, Inflammatory pseudotumour, MESH: Humans, MESH: Dendritic Cells, business.industry, MESH: Cytoplasm, MESH: Adult, General Medicine, MESH: Granuloma, Plasma Cell, MESH: Male, 030220 oncology & carcinogenesis, Immunology, MESH: Microscopy, Electron, Transmission, business
Published: 2007
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29. MacDuffie syndrome and primary sclerosing cholangitis: an exceptional association

Author: Frédéric Heluwaert, Jean-Marc Phelip, Bruno Bonaz, Marie Noelle Hilleret, Jean-Pierre Zarski, Nathalie Sturm, Xavier Roblin, Département de Gastroentérologie et hépatologie, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-Hôpital Michallon, and Sinniger, Valérie
Subjects: medicine.medical_specialty, Physiology, Gastroenterology, Primary sclerosing cholangitis, 03 medical and health sciences, 0302 clinical medicine, Transplant surgery, MESH: Diagnosis, Differential, Internal medicine, medicine, MESH: Syndrome, ComputingMilieux_MISCELLANEOUS, 030203 arthritis & rheumatology, MESH: Humans, MESH: Middle Aged, business.industry, MESH: Vasculitis, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, medicine.disease, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, MESH: Cholangitis, Sclerosing, MESH: Male, 3. Good health, 030211 gastroenterology & hepatology, business, Biliary tract disease
Abstract: International audience; No abstract
Published: 2006
Full Text: View/download PDF

30. Genotype-phenotype correlation in hepatocellular adenoma: new classification and relationship with HCC

Author: Emmanuelle Jeannot, Charles Balabaud, Yannick Bacq, Jeanne Tran Van Nhieu, Emmanuelle Leteurtre, Paulette Bioulac-Sage, Dominique Wendum, Lucille Mellottee, Denis Castaing, Laurence Chiche, Jessica Zucman-Rossi, Christian Partensky, Elie Serge Zafrani, Sandra Rebouissou, Christophe Laurent, Monique Fabre, Valérie Paradis, Jean-Yves Scoazec, Sophie Michalak, Pierre Laurent-Puig, Catherine Guettier, Génomique Fonctionnelle des Tumeurs Solides (U1162), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Henri Mondor, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Hôpital Paul Brousse, Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse, Service de gastro-entérologie [CHU Trousseau], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Hôpital Beaujon, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Hôpital Bicêtre, Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Hôpital Saint-André, Toxicologie Moleculaire (U490), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Fibrose hépatique et cancer du foie, Université Bordeaux Segalen - Bordeaux 2-IFR66-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Pellegrin, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, The authors thank Leigh Pascoe for critical reading of the manuscript. We thank all the other participants to the GENTHEP (Groupe d'e´tude Ge´ne´tique des Tumeurs He´patiques) network: Michel Beaugrand, Jordi Bruix, Christine Bellanne´e-Chantelot, Jacques Belghiti, Jean Fre´de´ric Blanc, Pascal Bourlier, Paul Cale`s, Chen Liu, Marie Pierre Chenard-Neu, Daniel Cherqui, Vale´rie Costes, Thong Dao, Daniel Dhumeaux, Amar Paul Dhillon, Je´roˆme Dumortier, Olivier Ernst, Dominique Franco, Fre´de´ric Gauthier, Jean Gugenheim, Emmanuel Jacquemin, Daniel Jaeck, Brigitte Le Bail, Se´- bastien Lepreux, Anne de Muret, Fre´de´ric Oberti, Danielle Pariente, Franc¸ois Paye, Franc¸ois-Rene´ Pruvost, Alberto Quaglia, Pierre Rousselot, Antonio Sa Cunha, Marie Christine Saint-Paul, Jean Saric, Pierre Rousselot, Anne Rullier, Janick Selves, Nathalie Sturm. We thank the technicians from the CEPH, Fondation Jean Dausset for their help in sequencing and all the clinicians that referred the patients., Zucman-Rossi, Jessica, CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Genomique Fonctionnelle des Tumeurs Solides, Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ) -IFR105-Université Paris Diderot - Paris 7 ( UPD7 ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), Université Paris-Sud - Paris 11 ( UP11 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Paul Brousse, Service de gastro-entérologie, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Trousseau [APHP], Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Diderot - Paris 7 ( UPD7 ) -Hôpital Beaujon, Centre Hospitalier Universitaire d'Angers ( CHU Angers ), PRES Université Nantes Angers Le Mans ( UNAM ), Centre de Recherche Saint-Antoine ( CR Saint-Antoine ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ), Université Paris-Sud - Paris 11 ( UP11 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Bicêtre, CHU Bordeaux [Bordeaux]-Hôpital Saint -André, Toxicologie Moleculaire, Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), and Université Bordeaux Segalen - Bordeaux 2-IFR66-Institut National de la Santé et de la Recherche Médicale ( INSERM )
Subjects: Male, Pathology, MESH : Liver Neoplasms, MESH : Retrospective Studies, MESH: beta Catenin, MESH : Aged, MESH : Genotype, Malignant transformation, MESH: Genotype, MESH: Adenoma, Liver Cell, 0302 clinical medicine, MESH: Liver Neoplasms, MESH : Female, Hepatocyte Nuclear Factor 1-alpha, MESH: Carcinoma, Hepatocellular, beta Catenin, MESH: Aged, MESH: Middle Aged, Liver Neoplasms, MESH : Adult, Middle Aged, 3. Good health, MESH : Phenotype, Phenotype, 030220 oncology & carcinogenesis, Hepatocellular carcinoma, MESH : Hepatocyte Nuclear Factor 1-alpha, [ SDV.MHEP.HEG ] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Female, 030211 gastroenterology & hepatology, MESH : Mutation, MESH : Carcinoma, Hepatocellular, Adult, medicine.medical_specialty, Carcinoma, Hepatocellular, MESH: Mutation, Adolescent, Genotype, Adenoma, MESH : Male, Biology, MESH: Phenotype, Adenoma, Liver Cell, 03 medical and health sciences, MESH : Adenoma, Liver Cell, MESH : Adolescent, medicine, Carcinoma, Humans, MESH : Middle Aged, MESH: Hepatocyte Nuclear Factor 1-alpha, Pathological, Aged, Retrospective Studies, MESH: Adolescent, MESH: Humans, Hepatology, MESH : Humans, MESH: Retrospective Studies, MESH: Adult, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Hepatocellular adenoma, MESH : beta Catenin, medicine.disease, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, digestive system diseases, MESH: Male, Mutation, Inflammatory Hepatocellular Adenoma, Steatosis, MESH: Female
Abstract: Hepatocellular adenomas are benign tumors that can be difficult to diagnose. To refine their classification, we performed a comprehensive analysis of their genetic, pathological, and clinical features. A multicentric series of 96 liver tumors with a firm or possible diagnosis of hepatocellular adenoma was reviewed by liver pathologists. In all cases, the genes coding for hepatocyte nuclear factor 1alpha (HNF1alpha) and beta-catenin were sequenced. No tumors were mutated in both HNF1alpha and beta-catenin enabling tumors to be classified into 3 groups, according to genotype. Tumors with HNF1alpha mutations formed the most important group of adenomas (44 cases). They were phenotypically characterized by marked steatosis (P < 10(-4)), lack of cytological abnormalities (P < 10(-6)), and no inflammatory infiltrates (P < 10(-4)). In contrast, the group of tumors defined by beta-catenin activation included 13 lesions with frequent cytological abnormalities and pseudo-glandular formation (P < 10(-5)). The third group of tumors without mutation was divided into two subgroups based on the presence of inflammatory infiltrates. The subgroup of tumors consisting of 17 inflammatory lesions, resembled telangiectatic focal nodular hyperplasias, with frequent cytological abnormalities (P = 10(-3)), ductular reaction (P < 10(-2)), and dystrophic vessels (P = .02). In this classification, hepatocellular carcinoma associated with adenoma or borderline lesions between carcinoma and adenoma is found in 46% of the beta-catenin-mutated tumors whereas they are never observed in inflammatory lesions and are rarely found in HNF1alpha mutated tumors (P = .004). In conclusion, the molecular and pathological classification of hepatocellular adenomas permits the identification of strong genotype-phenotype correlations and suggests that adenomas with beta-catenin activation have a higher risk of malignant transformation.
Published: 2006
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30 results on '"Nathalie Sturm"'

1. The microenvironment of DLBCL is characterized by noncanonical macrophages recruited by tumor-derived CCL5

2. Dysfunctional BTN3A together with deregulated immune checkpoints and type I/II IFN dictate defective interplay between pDCs and γδ T cells in melanoma patients, which impacts clinical outcomes

3. Multi-organ failure induced by Nivolumab in the context of allo-stem cell transplantation

4. Nanoparticles in foods? A multiscale physiopathological investigation of iron oxide nanoparticle effects on rats after an acute oral exposure: Trace element biodistribution and cognitive capacities

5. A proliferation‐inducing ligand–mediated anti‐inflammatory response of astrocytes in multiple sclerosis

6. Immunologic Features of Patients With Advanced Hepatocellular Carcinoma Before and During Sorafenib or Anti-programmed Death-1/Programmed Death-L1 Treatment

7. Combination of AKT inhibitor ARQ 092 and sorafenib potentiates inhibition of tumor progression in cirrhotic rat model of hepatocellular carcinoma

8. Influence of Progenitor-Derived Regeneration Markers on Hepatitis C Virus-Related Cirrhosis Outcome (ANRS CO12 CirVir Cohort)

9. Clinicopathological description of 43 oncocytic adrenocortical tumors: importance of Ki-67 in histoprognostic evaluation

10. Molecular Classification of Hepatocellular Adenoma Associates With Risk Factors, Bleeding, and Malignant Transformation

11. A Single Test Combining Blood Markers and Elastography is More Accurate Than Other Fibrosis Tests in the Main Causes of Chronic Liver Diseases

12. Progression of fibrosis in patients with chronic viral hepatitis is associated with IL-17 + neutrophils

13. Liver-infiltrating CD8+ lymphocytes as prognostic factor for tumour recurrence in hepatitis C virus-related hepatocellular carcinoma

14. Precise evaluation of liver histology by computerized morphometry shows that steatosis influences liver stiffness measured by transient elastography in chronic hepatitis C

15. ESM-1 expression in stromal cells is predictive of recurrence after radiofrequency ablation in early hepatocellular carcinoma

16. Determination of reliability criteria for liver stiffness evaluation by transient elastography

17. AST/ALT ratio is not an index of liver fibrosis in chronic hepatitis C when aminotransferase activities are determinate according to the international recommendations

18. Including osteoprotegerin and collagen IV in a score-based blood test for liver fibrosis increases diagnostic accuracy

19. Immunohistochemical markers on needle biopsies are helpful for the diagnosis of focal nodular hyperplasia and hepatocellular adenoma subtypes

20. Comparison of nine blood tests and transient elastography for liver fibrosis in chronic hepatitis C: the ANRS HCEP-23 study

21. A New Combination of Blood Test and Fibroscan for Accurate Non-Invasive Diagnosis of Liver Fibrosis Stages in Chronic Hepatitis C

22. Temozolomide treatment in aggressive pituitary tumors and pituitary carcinomas: a French multicenter experience

23. Systematic Analysis of G Protein-Coupled Receptor Gene Expression in Adrenocorticotropin-Independent Macronodular Adrenocortical Hyperplasia Identifies Novel Targets for Pharmacological Control of Adrenal Cushing’s Syndrome

24. Automation of the Hepascore and validation as a biochemical index of liver fibrosis in patients with chronic hepatitis C from the ANRS HC EP 23 Fibrostar cohort

25. Features and distribution of CD8 T cells with human leukocyte antigen class I-specific receptor expression in chronic hepatitis C

26. Prospective comparison of six non-invasive scores for the diagnosis of liver fibrosis in chronic hepatitis C

27. Association of CYP1B1 Germ Line Mutations with Hepatocyte Nuclear Factor 1{alpha}-Mutated Hepatocellular Adenoma

28. Inflammatory pseudotumour of the liver: a variant rich in giant atypical reactive dendritic cells

29. MacDuffie syndrome and primary sclerosing cholangitis: an exceptional association

30. Genotype-phenotype correlation in hepatocellular adenoma: new classification and relationship with HCC

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