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1,167 results on '"Laboratoire d'anatomie pathologique"'

51. cIMPACT-NOW update 5: recommended grading criteria and terminologies for IDH-mutant astrocytomas

Author: Caterina Giannini, Catriona McLean, Howard Colman, Chitra Sarkar, Dominique Figrarella-Branger, Arie Perry, Gregory N. Fuller, David N. Louis, Kenneth Aldape, Robert B. Jenkins, Andreas von Deimling, Martin J. van den Bent, Roger Stupp, Guido Reifenberger, Johan M. Kros, Bette K. Kleinschmidt-DeMasters, Eric C. Holland, Takashi Komori, Daniel J. Brat, Michael Weller, National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH), Institut de neurophysiopathologie (INP), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Anatomie Pathologique-Neuropathologique [AP-HM Hôpital La Timone], Hôpital de la Timone [CHU - APHM] (TIMONE), Departments of Applied Physics [New Haven], Yale University [New Haven], Mayo Clinic [Rochester], Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Brat D.J., Aldape K., Colman H., Figrarella-Branger D., Fuller G.N., Giannini C., Holland E.C., Jenkins R.B., Kleinschmidt-DeMasters B., Komori T., Kros J.M., Louis D.N., McLean C., Perry A., Reifenberger G., Sarkar C., Stupp R., van den Bent M.J., von Deimling A., Weller M., Pathology, and Neurology
Subjects: business.industry, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV]Life Sciences [q-bio], Mutant, [SDV.CAN]Life Sciences [q-bio]/Cancer, Bioinformatics, IDH mutant astrocytoma, Article, Pathology and Forensic Medicine, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, 030220 oncology & carcinogenesis, Medicine, Neurology (clinical), business, Grading (tumors), 030217 neurology & neurosurgery, ComputingMilieux_MISCELLANEOUS
Abstract: International audience
Published: 2020
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52. EB1-dependent long survival of glioblastoma-grafted mice with the oral tubulin-binder BAL101553 is associated with inhibition of tumor angiogenesis

Author: Raphael Berges, Dominique Figarella-Branger, Aurélie Tchoghandjian, Heidi Lane, Arnauld Sergé, Diane Braguer, Felix Bachmann, Stéphane Honoré, Institut de neurophysiopathologie (INP), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Anatomie Pathologique-Neuropathologique [AP-HM Hôpital La Timone], Hôpital de la Timone [CHU - APHM] (TIMONE), and Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)
Subjects: 0301 basic medicine, cancer stem cells, [SDV]Life Sciences [q-bio], experimental cancer therapeutics, 03 medical and health sciences, 0302 clinical medicine, Cancer stem cell, medicine, Secretion, microtubule-targeting agent, business.industry, glioblastoma, Cancer, medicine.disease, Phenotype, In vitro, 3. Good health, Endothelial stem cell, 030104 developmental biology, Oncology, Mechanism of action, 030220 oncology & carcinogenesis, Cancer research, medicine.symptom, Stem cell, business, Research Paper
Abstract: International audience; Glioblastoma (GBM) are aggressive brain tumors with limited treatment options. Cancer stem-like cells (CSLCs) contribute to GBM invasiveness, representing promising targets. BAL101553, a prodrug of BAL27862, is a novel small molecule tubulin-binding agent, promoting tumor cell death through spindle assembly checkpoint activation, which is currently in Phase 1/2a in advanced solid tumor patients including GBM. This study aimed to evaluate long-term daily oral BAL101553 treatment of mice orthotopically grafted with GBM CSLCs (GBM6) according to EB1 expression-level, and to decipher its mechanism of action on GBM stem cells. Oral treatment with BAL101553 for 100 days provoked a large EB1 expression level-dependent survival benefit, together with a decrease in tumor growth and brain invasion. Formation of vascular structures by the fluorescent GBM6-GFP-sh0 cells, mimicking endothelial vascular networks, was observed in the brains of control grafted mice. Following BAL101553 treatment, vessels were no longer detectable, suggesting inhibition of the endothelial trans-differentiation of GBM stem cells. In vitro, BAL27862 treatment resulted in a switch to the endothelial-like phenotype of GBM6 towards an astrocytic phenotype. Moreover, the drug inhibited secretion of VEGF, thus preventing normal endothelial cell migration activated by CSLCs. The decrease in VEGF secretion was confirmed in a human GBM explant following drug treatment. Altogether, our data first confirm the potential of EB1 expression as a response-predictive biomarker of BAL101553 in GBM we previously published and add new insights in BAL101553 long-term action by counteracting CSLCs mediated tumor angiogenesis. Our results strongly support BAL101553 clinical studies in GBM patients.
Published: 2020
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53. Reverse transcriptase multiplex ligation-dependent probe amplification in endomyocardial biopsies for the diagnosis of cardiac allograft rejection

Author: Philippe Ruminy, Romain Guillemain, Jean-Paul Duong Van Huyen, Jean-Luc Taupin, Pierre-Julien Viailly, Philippe Rouvier, Nicolas Adam, Sabine Pattier, Claire Toquet, Patrick Bruneval, Ahmad Abdel Sater, Guillaume Coutance, Fanny Drieux, Eric Epailly, Arnaud François, Marie-Pierre Chenard, Marion Rabant, Shaida Varnous, Alexandre Loupy, Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), 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), Laboratoire d'anatomie pathologique [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut de cardiologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Anatomie et Cytologie Pathologique [CHU Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Equipe Traitement de l'information en Biologie Santé (TIBS - LITIS), Laboratoire d'Informatique, de Traitement de l'Information et des Systèmes (LITIS), Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Université Le Havre Normandie (ULH), Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), NANTES (NANTES - Ana Path), Centre hospitalier universitaire de Nantes (CHU Nantes), Equipe de Recherche sur les Rationalités Philosophiques et les Savoirs (ERRAPHIS), Université Toulouse - Jean Jaurès (UT2J), Service d'Anatomie Pathologique Générale, CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], Service de Chirurgie Cardio-Vasculaire, CHU Strasbourg-Nouvel Hôpital Civil, Department of Chest Medicine, Mont-Godinne Hospital-Catholic University of Louvain de Mont-Godinne, Service de transplantation cardiaque [CHU Nantes], Service de virologie et d'immunologie biologique, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Transplantation Rénale, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Laboratoire de Recherche en Imagerie : Méthodes d'imagerie des Échanges transcapillaires (LRI - EA4062), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), CCSD, Accord Elsevier, 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), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de pathologie [CHU Strasbourg], CHU Strasbourg, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), and Hopital Saint-Louis [AP-HP] (AP-HP)
Subjects: Adult, Graft Rejection, Male, musculoskeletal diseases, Pulmonary and Respiratory Medicine, medicine.medical_specialty, Pathology, Biopsy, medicine.medical_treatment, [SDV]Life Sciences [q-bio], 030204 cardiovascular system & hematology, 030230 surgery, Allograft Rejection, 03 medical and health sciences, 0302 clinical medicine, GNLY, medicine, molecular biology, Humans, Multiplex, Multiplex ligation-dependent probe amplification, ComputingMilieux_MISCELLANEOUS, Retrospective Studies, Heart transplantation, class prediction analysis, Transplantation, business.industry, Myocardium, CCL18, Histology, Middle Aged, Allografts, Reverse transcriptase, 3. Good health, [SDV] Life Sciences [q-bio], Cross-Sectional Studies, endomyocardial biopsy, histopathology, Heart Transplantation, RNA, Female, Surgery, Histopathology, Cardiology and Cardiovascular Medicine, business, Multiplex Polymerase Chain Reaction
Abstract: International audience; Background: Molecular biology has emerged as a potential companion to histology for the diagnosis of rejection after heart transplantation. Reverse transcriptase multiplex ligation-dependent probe amplification (RT-MLPA) is a technique of targeted gene expression analysis suitable for formalin-fixed paraffin-embedded (FFPE) biopsies. Our aim was to assess RT-MLPA for the diagnosis of allograft rejection in heart transplantation.Methods: We performed a cross-sectional, case-control, multicenter study. After the selection of a 14-transcript panel (endothelial burden, Natural killer cells, interferon-γ pathway, effector T-cells, and antigen presentation), RT-MLPA was applied to 183 FFPE endomyocardial biopsies (EMB), randomized into a training (n = 113) and a validation (n = 70) series. A two-step class prediction analysis was developed (Linear prediction score-LPS1: rejection vs non-rejection; LPS2: antibody-mediated rejection [AMR] vs acute cellular rejection [ACR]). A study of the agreement between pathology and RT-MLPA was performed.Results: Overall, 48 ACR, 82 AMR, 5 mixed rejection, and 48 non-rejection EMBs were analyzed. Three molecular clusters were delineated by unsupervised hierarchical analysis (molecular non-rejection, ACR, and AMR). AMR was characterized by the high expression of CCL4, GNLY, FCGR3, CXCL11 and ACR by the high expression of CCL18 and ADAMdec. RT-MLPA and histopathology agreed in the final diagnosis in 82.2%, 67.7%, and 76.8% of the EMB in the test, validation, and overall cohort, respectively. Disagreement cases were more common in the case of histologic low-grade rejection and early post-transplant EMB.Conclusions: RT-MLPA is a suitable technique for targeted gene expression analysis on FFPE EMB with a good overall agreement with the histologic diagnosis of heart allograft rejection.
Published: 2020
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54. Medulloblastomas associated with an APC germline pathogenic variant share the good prognosis of CTNNB1-mutated medulloblastomas

Author: Marie-Bernadette Delisle, Anne-Isabelle Bertozzi-Salomon, Marc Polivka, Hélène Zattara, Aurore Surun, Laurence Brugières, Fabienne Prieur, Franck Bourdeaut, Alexandre Vasiljevic, Pierre Leblond, Pascale Varlet, Nicolas André, Françoise Desseigne, Dominique Figarella-Branger, Eric Sariban, Rosine Guimbaud, Christelle Dufour, Cécile Faure-Conter, Claire Alapetite, Florence Coulet, Léa Guerrini-Rousseau, Chrystelle Colas, François Doz, Sandra Raimbault, Claude-Alain Maurage, Brigitte Lacour, Claire Berger, Institut de neurophysiopathologie (INP), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Anatomie Pathologique-Neuropathologique [AP-HM Hôpital La Timone], and Hôpital de la Timone [CHU - APHM] (TIMONE)
Subjects: Adult, Male, Cancer Research, Adolescent, Adenomatous polyposis coli, [SDV]Life Sciences [q-bio], Adenomatous Polyposis Coli Protein, Context (language use), medulloblastoma, Germline, Thyroid carcinoma, WNT, 03 medical and health sciences, 0302 clinical medicine, Gardner Syndrome, Medicine, Humans, Cerebellar Neoplasms, Child, Gardner syndrome, Osteoma, neoplasms, Germ-Line Mutation, beta Catenin, 030304 developmental biology, Retrospective Studies, Medulloblastoma, 0303 health sciences, biology, business.industry, Wnt signaling pathway, Editorials, medicine.disease, familial adenomatosis polyposis, 3. Good health, nervous system diseases, APC, stomatognathic diseases, Oncology, Adenomatous Polyposis Coli, 030220 oncology & carcinogenesis, Cancer research, biology.protein, Female, Neurology (clinical), business
Abstract: Background Medulloblastomas may occur in a predisposition context, including familial adenomatosis polyposis. Medulloblastomas related to a germline pathogenic variant of adenomatous polyposis coli (APC) remain rare and poorly described. Their similarities with sporadic WNT medulloblastomas still require description. Methods We performed a multicentric retrospective review of 12 patients treated between 1988 and 2018 for medulloblastoma with an identified or highly suspected (personal or familial history) APC germline pathogenic variant. We report personal and familial history APC gene pathogenic variants whenever available: clinical and histologic characteristics of the medulloblastoma, treatments, and long-term outcome, including second tumor and late sequelae. Results Medulloblastomas associated with APC pathogenic variants are mainly classic (11/11 patients, 1 not available), nonmetastatic (10/12 patients) medulloblastomas, with nuclear immunoreactivity for ß-catenin (9/9 tested cases). Ten of 11 assessable patients are disease free with a median follow-up of 10.7 years (range, 1–28 y). Secondary tumors included desmoid tumors in 7 patients (9 tumors), 1 thyroid carcinoma, 2 pilomatricomas, 1 osteoma, 1 vertebral hemangioma, and 1 malignant triton in the radiation field, which caused the only cancer-related death in our series. Conclusions Medulloblastomas associated with an APC pathogenic variant have an overall favorable outcome, even for metastatic tumors. Yet, long-term survival is clouded by second tumor occurrence; treatment may play some role in some of these second malignancies. Our findings raise the question of applying a de-escalation therapeutic protocol to treat patients with APC germline pathogenic variants given the excellent outcome, and reduced intensity of craniospinal irradiation may be further evaluated.
Published: 2020
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55. WHO grade has no prognostic value in the pediatric high-grade glioma included in the HERBY trial

Author: Felice Giangaspero, Chris Jones, Christophe Deroulers, Dominique Figarella-Branger, Marie-Cécile Le Deley, Thomas S. Jacques, Gwénaël Le Teuff, Tim Jaspan, Torsten Pietsch, J. Grill, Pascale Varlet, Felipe Andreiuolo, Christine Haberler, Institut de neurophysiopathologie (INP), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Anatomie Pathologique-Neuropathologique [AP-HM Hôpital La Timone], Hôpital de la Timone [CHU - APHM] (TIMONE), Imagerie et Modélisation en Neurobiologie et Cancérologie (IMNC (UMR_8165)), and Université Paris-Sud - Paris 11 (UP11)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, Oncology, Cancer Research, [SDV]Life Sciences [q-bio], Datasets as Topic, MESH: Neoplasm Grading, Central Pathology Review, MESH: World Health Organization, MESH: Glioma, 0302 clinical medicine, MESH: Child, Multicenter Studies as Topic, MESH: Datasets as Topic, Child, Randomized Controlled Trials as Topic, MESH: Chemoradiotherapy, [PHYS]Physics [physics], biology, Brain Neoplasms, Chemoradiotherapy, Glioma, Prognosis, 3. Good health, Bevacizumab, Glioma grading, Child, Preschool, 030220 oncology & carcinogenesis, Ki-67, MESH: Brain Neoplasms, Female, MESH: Clinical Trials, Phase II as Topic, high-grade glioma, medicine.medical_specialty, Adolescent, Antineoplastic Agents, World Health Organization, World health, MESH: Prognosis, 03 medical and health sciences, Clinical Trials, Phase II as Topic, MESH: Bevacizumab, Internal medicine, grading criteria, pediatric, Temozolomide, medicine, Humans, Grading (tumors), MESH: Temozolomide, High-Grade Glioma, MESH: Adolescent, MESH: Humans, business.industry, MESH: Child, Preschool, Who grade, medicine.disease, MESH: Male, MESH: Randomized Controlled Trials as Topic, biology.protein, MESH: Multicenter Studies as Topic, MESH: Antineoplastic Agents, Neurology (clinical), Neoplasm Grading, business, Pediatric Neuro-Oncology, MESH: Female, 030217 neurology & neurosurgery
Abstract: Background The World Health Organization (WHO) adult glioma grading system is questionable in pediatric high-grade gliomas (pHGGs), which are biologically distinct from adult HGGs. We took advantage of the neuropathological review data obtained during one of the largest prospective randomized pHGG trials, namely HERBY (NCT01390948), to address this issue in children with newly diagnosed non-brainstem HGG. Methods HGG diagnosis was confirmed by pre-randomization, real-time central pathology review using WHO 2007 criteria, followed by a consensus review blinded to clinical factors and outcomes. We evaluated association between WHO 2007 grade and other clinical/radiological/biological characteristics and the prognostic value of WHO 2007 grade, midline location, and selected biomarkers (Ki-67 index/Olig2/CD34/EGFR/p53/H3F3A K27M mutation) on overall survival. Results Real-time central neuropathological review was feasible in a multicenter study, with a mean time of 2.4 days, and led to the rejection of HGG diagnosis in 20 of 163 cases (12.3%). The different grading criteria and resulting WHO grade were not significantly associated with overall survival in the entire population (n = 118) or in midline and non-midline subgroups. H3F3A K27M mutation was significantly associated with poor outcome. No significant prognostic value was observed for grade, even after regrading H3F3A K27M-mutated midline glioma as grade IV (WHO 2016). Midline location and a high Ki-67 index (≥20%) were associated with poor outcome (P = 0.004 and P = 0.04, respectively). A 10% increase in Ki-67 index was associated with a hazard ratio of 1.53 (95% CI: 1.27–1.83; P < 0.0001). Conclusion Our findings suggest that WHO grade III versus IV has no prognostic value in pediatric HGG.
Published: 2020
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56. Germline TIM-3 Mutations Characterize Sub-Cutaneous Panniculitis T-Cell Lymphomas with Hemophagocytic Lymphohistiocytic Syndrome

Author: Simon Gravel, Sylvie Fraitag, Janie Charlebois, Jacek Majewski, Catherine Thieblemont, Rachel Conyers, Brigitte Bader-Meunier, Patrick Nitschke, Tenzin Gayden, Nada Jabado, Fernando E. Sepulveda, Paul G Ekert, Andrea Bajic, Mikko Taipale, Geneviève de Saint Basile, Daniel Schramek, Benedicte Neven, Jean-Sebastien Diana, Dong-Anh Khuong-Quang, Alain Fischer, David Michonneau, David Mitchell, Dzana Dervovic, Frank Sicheri, Maxime Battistella, Elvis Terci Valera, Alexandrine Garrigue, Stéphane Blanche, Despina Moshous, Hamid Nikbakht, Christopher McCormack, Rola Dali, Marianne Besnard, Jonathan Pratt, Nancy Hamel, Sharon Abish, Susan Kelso, H. Miles Prince, Christine Bole-Feysot, Van-Hung Nguyen, Frédéric Guerin, Leonie G. Mikael, William D. Foulkes, The University of MelbourneParkville, VIC, Australia., McGill University = Université McGill [Montréal, Canada], Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Sao Paulo (Brazil), Developpement Normal et Pathologique du Système Immunitaire, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of Toronto [Canada], Canadian Centre for Computational Genomics, Montreal, Canada, Sinai Health System, Toronto, Canada, Géosciences Environnement Toulouse (GET), Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Observatoire Midi-Pyrénées (OMP), Météo France-Centre National d'Études Spatiales [Toulouse] (CNES)-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Météo France-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD), McGill University and Genome Quebec Innovation Centre, Centre de Référence Déficits Immunitaires Héréditaires (CEREDIH), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), McGill University Health Center [Montreal] (MUHC), Pediatric Hematology Oncology, Montreal Children's Hosp., Montreal, Canada, Nutrition, inflammation et dysfonctionnement de l'axe intestin-cerveau (ADEN), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service Immunologie et Hématologie, Space Sciences Laboratory [Berkeley] (SSL), University of California [Berkeley], University of California-University of California, Gvh et Gvl : Physiopathologie Chez l'Homme et Chez l'Animal, Incidence et Role Therapeutique, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Anatomie pathologique [CHU Saint-Louis], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], The Royal Children's Hospital, Melbourne, Australia, Urgences pédiatriques, Hôpital Necker Enfants Malades, Université Paris Descartes, Paris, France, parent, Peter MacCallum Cancer Centre [Melbourne, Australie], Department of Medicine, University of Melbourne, Melbourne, Australia, Centre Hospitalier de Polynésie Française, Service d'immuno-hématologie pédiatrique [CHU Necker], Murdoch Children's Research Institute (MCRI), Laboratoire d'anatomie pathologique [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Department of Human Genetics [Montréal], Chaire Médecine expérimentale (A. Fischer), Collège de France (CdF (institution)), Department of Human Genetics , Department of Experimental Medicine, Radboud University Medical Center [Nijmegen], Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Observatoire Midi-Pyrénées (OMP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Centre National d'Études Spatiales [Toulouse] (CNES), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), and McGill University
Subjects: T cell, Immunology, Biochemistry, Germline, 03 medical and health sciences, 0302 clinical medicine, Immune system, Medicine, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, Hemophagocytic lymphohistiocytosis, Innate immune system, biology, business.industry, Cell Biology, Hematology, medicine.disease, Immune checkpoint, 3. Good health, Lymphoma, medicine.anatomical_structure, biology.protein, [SDV.IMM]Life Sciences [q-bio]/Immunology, Antibody, business, 030215 immunology
Abstract: Introduction Sub-cutaneous panniculitis T-cell lymphomas (SPTCL), a rare non-Hodgkin lymphoma, can be associated with hemophagocytic lymphohistiocytosis (HLH), a life-threatening activation of the immune system which adversely impacts survival. T-cell immunoglobulin mucin 3 (TIM-3) is a modulator of immune responses expressed on subgroups of T- and innate immune cells. In this work we describe the first germline variants associated with SPTCL, which are in the TIM-3 gene. Methods We sequenced 27 SPTCL cases to identify gene variants. We performed TIM-3 functional analysis on immune cells from patients and HEK293 cells engineered to overexpress wild-type or mutant TIM-3. Results We identified homozygous, germline, loss-of-function, missense variants in highly conserved residues of TIM-3, namely p.Y82C and p.I97M in about 60% (16/27) of SPTCL cases. These samples were drawn from cases series across 3 continents. Patients with bi-allelic TIM-3 mutations were younger at diagnosis, and several had life-threatening HLH and severe disease course. TIM-3 mutations show specific geographic distribution. Y82C TIM-3 mutations occur on a founder chromosome in patients with East-Asian and Polynesian ancestry, while I97M TIM-3 is observed in Caucasians. Both variants induce protein misfolding and cytoplasmic retention of TIM-3. Loss of TIM-3 membrane expression in TIM-3 mutants abrogates the PD-1/PDL-1 checkpoint and prevents the termination of a Th1-immune response. In HEK293 cells, mutant TIM-3 was not expressed on the cell surface. Defective TIM-3 expression leads to persistent immune activation with increased production of inflammatory cytokines including TNF-alpha and IL-1beta by innate immune cells. Conclusion Our findings highlight HLH/SPTCL as a new genetic entity where loss of the TIM-3 immune checkpoint is associated with T-cell infiltration of adipose tissue and inflammasome activation. This is the first causative germline defect identified in SPTCL. While our findings indicate that TIM-3-mutant HLH/SPTCL benefit from immunomodulation, therapeutic repression of the TIM-3 checkpoint could have serious adverse consequences. Disclosures Prince: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees.
Published: 2019
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57. Characterization of two rat models of cystic fibrosis—KO and F508del CFTR—Generated by Crispr‐Cas9

Author: Marc Chanson, Louise Galmiche, Elise Dreano, Laurent Tesson, Juliette Lynn Simonin, Isabelle Sermet-Gaudelus, Marc Bacchetta, Claire Usal, Jérémy Sadoine, Lotfi Slimani, A. Hatton, Charles-Henry Cottart, Danielle Tondelier, Lucile Vignaud, Ignacio Anegon, Jean-Paul Concordet, Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Département de Pédiatrie, Gynécologie & Obstétrique [Genève, Switzerland] (UNIGE), Université de Genève (UNIGE), Département de Physiologie Cellulaire & Métabolisme [Genève, Switzerland] (UNIGE), Laboratoire d'anatomie pathologique [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Plate-forme de 'transgénèse immunophénomique du rat' (P2R - INSERM UMS016/CNRS UMS3556/UN FED4203), Structure fédérative de recherche François Bonamy (SFR François Bonamy), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche en Santé de l'Université de Nantes (IRS-UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche en Santé de l'Université de Nantes (IRS-UN), Pathologies, Imagerie et Biothérapies oro-faciales (EA 2496), Université Paris Descartes - Paris 5 (UPD5), Plateforme Imageries du vivant [Paris] (Faculté de chirurgie dentaire), Structure et Instabilité des Génomes (STRING), Muséum national d'Histoire naturelle (MNHN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre Maladie Rare Mucoviscidose et Maladies du CFTR (CHU Necker - Enfants Malades [AP-HP]), Université Paris Descartes - Faculté de Médecine (UPD5 Médecine), Université Paris Descartes - Faculté de Pharmacie de Paris (UPD5 Pharmacie), TEFOR, Grant/Award Number: RIIINSB-0014, France Life Imaging, Grant/Award Number: ANR-11-INBS-0006, Swiss Cystic Fibrosis Foundation CFCH, Fondation Maladies Rares, Infrastructures Biologie-Santé, IHU-CESTI, Grant/Award Number: ANR-10-IBHU-005, IRSR Pays de la Loire, Vaincre la Mucoviscidose, Swiss National Foundation, Grant/Award Number : 310030_172909., ANR-11-INBS-0006,FLI,France Life Imaging(2011), ANR-10-IBHU-0005,CESTI (TSI-IHU),Centre Européen des Sciences de la Transplantation et de l'Immunothérapie (TSI-IHU)(2010), Le Bihan, Sylvie, Infrastructures - France Life Imaging - - FLI2011 - ANR-11-INBS-0006 - INBS - VALID, Instituts Hospitalo-Universitaires B - Centre Européen des Sciences de la Transplantation et de l'Immunothérapie (TSI-IHU) - - CESTI (TSI-IHU)2010 - ANR-10-IBHU-0005 - IBHU - VALID, and Université de Genève = University of Geneva (UNIGE)
Subjects: Medicine (General), [SDV]Life Sciences [q-bio], Biology, Primary cultures, Cystic fibrosis, cystic fibrosis, primary cultures, 03 medical and health sciences, 0302 clinical medicine, R5-920, In vivo, CFTR channel activity, medicine, rat, ddc:612, 030304 developmental biology, Submucosal glands, 0303 health sciences, ddc:618, Vas deferens, Histology, Original Articles, General Medicine, respiratory system, medicine.disease, CFTR modulators, Molecular biology, animal models, Animal models, 3. Good health, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, 030228 respiratory system, Cell culture, Rat, Original Article, Pancreas, Ex vivo
Abstract: International audience; Background:Genetically engineered animals are essential for gaining a proper understanding of the disease mechanisms of cystic fibrosis (CF). The rat is a relevant laboratory model for CF because of its zootechnical capacity, size, and airway characteristics, including the presence of submucosal glands.Methods:We describe the generation of a CF rat model (F508del) homozygous for the p.Phe508del mutation in the transmembrane conductance regulator (Cftr) gene. This model was compared to new Cftr -/- rats (CFTR KO). Target organs in CF were examined by histological staining of tissue sections and tooth enamel was quantified by micro-computed tomography. The activity of CFTR was evaluated by nasal potential difference (NPD) and short-circuit current measurements. The effect of VX-809 and VX-770 was analyzed on nasal epithelial primary cell cultures from F508del rats.Results:Both newborn F508del and Knock out (KO) animals developed intestinal obstruction that could be partly compensated by special diet combined with an osmotic laxative. The two rat models exhibited CF phenotypic anomalies such as vas deferens agenesis and tooth enamel defects. Histology of the intestine, pancreas, liver, and lungs was normal. Absence of CFTR function in KO rats was confirmed ex vivo by short-circuit current measurements on colon mucosae and in vivo by NPD, whereas residual CFTR activity was observed in F508del rats. Exposure of F508del CFTR nasal primary cultures to a combination of VX-809 and VX-770 improved CFTR-mediated Cl- transport.Conclusions:The F508del rats reproduce the phenotypes observed in CFTR KO animals and represent a novel resource to advance the development of CF therapeutics.
Published: 2019
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58. Ovarian and peritoneal psammocarcinoma: Results of a multicenter study on 25 patients

Author: Jean-Baptiste Delhorme, Jordan Ohayon, Sébastien Gouy, Gerlinde Averous, Catherine Genestie, Léopold Gaichies, Olivier Glehen, Jean-Marc Guilloit, Denis Pezet, Francois Quenet, Gwenaël Ferron, Cécile Brigand, Philippe Morice, Charles Honoré, Julio Abba, Karine Abboud, Mohammad Alyami, Catherine Arvieux, Naoual Bakrin, Gisèle Balagué, Vincent Barrau, Houda Ben Rejeb, Jean-Marc Bereder, Isabelle Berton-Rigaud, Frédéric Bibeau, Isabelle Bonnefoy, Dominique Bouzard, Ivan Bricault, Sébastien Carrère, Cécile de Chaisemartin, Madleen Chassang, Anne Chevallier, Thomas Courvoisier, Peggy Dartigues, Anthony Dohan, Julien Dubreuil, Frédéric Dumont, Clarisse Eveno, Marie Faruch-Bilfeld, Juliette Fontaine, Laure Fournier, Johan Gagniere, Delphine Geffroy, Laurent Ghouti, François-Noël Gilly, Laurence Gladieff, Diane Goéré, Aymeric Guibal, Frédéric Guyon, Bruno Heyd, Christine Hoeffel, Constance Hordonneau, Sylvie Isaac, Peggy Jourdan-Enfer, Rachid Kaci, Reza Kianmanesh, Catherine Labbé-Devilliers, Joëlle Lacroix, Bernard Lelong, Agnès Leroux-Broussier, Yoann Lherm, Réa Lo Dico, Gérard Lorimier, Caroline Malhaire, Frédéric Marchal, Pascale Mariani, Emilie Mathiotte, Pierre Meeus, Eliane Mery, Simon Msika, Cédric Nadeau, Pablo Ortega-Deballon, Guillaume Passot, Olivier Pellet, Patrice Peyrat, Nicolas Pirro, Marc Pocard, Flora Poizat, Jack Porcheron, Anaïs Poulet, François Quenet, Patrick Rat, Pierre Rousselot, Pascal Rousset, Hélène Senellart, Martine Serrano, Vincent Servois, Olivia Sgabura, Andrea Skanjeti, Magali Svrcek, Raphaël Tetreau, Emilie Thibaudeau, Yann Touchefeu, Jean-Jacques Tuech, Séverine Valmary-Degano, Delphine Vaudoyer, Stéphane Velasco, Véronique Verriele-Beurrier, Laurent Villeneuve, Romuald Wernert, Franck Zinzindohoue, Département de chirurgie générale et digestive [CHU Strasbourg], Centre Hospitalier Universitaire de Strasbourg (CHU de Strasbourg ), Institut Gustave Roussy (IGR), Département de chirurgie gynécologique [Gustave Roussy], Service d'anatomie pathologique [CHU Pitié-Salpêtrière], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Université de Caen Normandie - UFR Santé (UNICAEN Santé), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU), Hôpital Nord, Hôpital nord, Service d'Oncologie Médicale [Centre hospitalier Lyon Sud - HCL], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), CHU Grenoble, Hôpitaux Universitaires de Strasbourg, Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), Laboratoire d'anatomo-pathologie, CRLCC Val d'Aurelle - Paul Lamarque, Département de chirurgie, Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA), Centre hospitalier universitaire de Poitiers (CHU Poitiers), Département de biologie et pathologie médicales [Gustave Roussy], Department of Body and Interventional Imaging, Hôpital Lariboisière, Paris, France., Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université de Lille, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Toulouse [Toulouse], Institut Claudius Regaud, 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), Chirurgie digestive et hépatobiliaire, CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Ciblage thérapeutique en Oncologie (EA3738), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Hospices Civils de Lyon (HCL), Département de chirurgie générale [Gustave Roussy], Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Service de chirurgie viscérale et digestive - Unité de transplantation hépatique, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Centre Hospitalier Universitaire de Reims (CHU Reims), Service de Radiologie, Service de pathologie, Service de Chirurgie Générale, Digestive et Endocrine [CHU Reims], Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, Service de Radiologie [CLCC Baclesse], Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Centre de recherches (CRT), Société Lafarge, Service de Chirurgie d'Oncologie Digestive [CHU Lariboisière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Paul Papin(Angers), 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), Centre de Recherche en Automatique de Nancy (CRAN), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Institut Curie [Paris], Centre Léon Bérard [Lyon], Institut Claudius Regaud. Department of pathology, Hôpital Louis Mourier - AP-HP [Colombes], Department of Gynecology and Obstetrics, Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Service de Chirurgie Digestive (AP-HM), Université de la Méditerranée - Aix-Marseille 2, Hôpital Lariboisière, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Service de Biopathologie [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Chirurgie digestive, Centre Hospitalier Universitaire de Saint-Etienne, Laboratoire Joliot Curie, École normale supérieure - Lyon (ENS Lyon)-Centre National de la Recherche Scientifique (CNRS), CRLC Val d'Aurelle-Paul Lamarque, Service de Chirurgie Digestive, Cancérologique, Générale, Endocrinienne et Urgences (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Laboratoire d'Anatomie Pathologique, CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Department of Radiology, Centre René Gauducheau, CRLCC René Gauducheau, Université de Lyon, (le programme) Cartes d'identité des tumeurs (CIT), Ligue Nationales Contre le Cancer (LNCC), Institut du Cancer de Montpellier (ICM), Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), Laboratoire d'éthique médicale et médecine légale (LEM), Université Paris Descartes - Paris 5 (UPD5), Service de Pathologie, Centro de Investigaciones Oceanograficas e Hidrograficas (CIOH), DIMAR, Ministerio de Defensa Nacional, Colombie, Unité de Méthodologie en Recherche Clinique, Université de Lyon-Université de Lyon-Hospices Civils de Lyon (HCL), Service de chirurgie digestive, générale et cancérologique [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), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), École normale supérieure de Lyon (ENS de Lyon)-Centre National de la Recherche Scientifique (CNRS), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL), and Université Paris Diderot - Paris 7 (UPD7)-Hôpital Lariboisière-Fernand-Widal [APHP]
Subjects: Hyperthermic Intraperitoneal Chemotherapy, Intraperitoneal chemotherapy, chemistry.chemical_compound, 0302 clinical medicine, Infusions, Parenteral, Peritoneal Neoplasms, Ovarian Neoplasms, Univariate analysis, 030219 obstetrics & reproductive medicine, General Medicine, Cytoreduction Surgical Procedures, Middle Aged, Neoadjuvant Therapy, Progression-Free Survival, 3. Good health, Survival Rate, medicine.anatomical_structure, Oncology, Chemotherapy, Adjuvant, 030220 oncology & carcinogenesis, Female, France, Peritoneum, Pancreas, Adult, medicine.medical_specialty, Adolescent, Ovary, Antineoplastic Agents, Psammocarcinoma, 03 medical and health sciences, Young Adult, medicine, Humans, Aged, business.industry, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Carboplatin, Surgery, chemistry, Multicenter study, Conventional PCI, Neoplasm Grading, business, Neoplasms, Cystic, Mucinous, and Serous, Rare disease
Abstract: International audience; Purpose: Psammocarcinoma (PK) is a rare disease of unknown origin. We aimed to report the characteristics, management and survival of patients operated on for PK within the French Network for Rare Peritoneal Malignancies (RENAPE) expert centers.Patients and methods: All consecutive cases of PK operated within all 26 RENAPE centers between 1997 and 2018 were retrospectively analyzed.Results: Twenty-five patients were identified. The median age was 53 years [range 17–78]. None of the patients had extra peritoneal metastases at diagnosis. A median of 6 cycles of carboplatin-based systemic chemotherapy was delivered in 52% preoperatively (n = 13) and 56% postoperatively (n = 14); associated with placlitaxel for 12 patients. All patients were operated on. The median PCI was 23 [0–33]. Eighty-four percent had a complete cytoreductive surgery through digestive (n = 7), spleen (n = 3), pancreas (n = 1) resections and/or multiple peritonectomies (n = 11). Five patients (20%) had intraperitoneal chemotherapy. Morbidity (Dindo-Clavien ≥3) was 12%. No postoperative death occurred. After a median follow-up of 42 months (range [2–194]), the median overall (OS) and progression-free (DFS) survival times were respectively 128 months and 31 months. Eighteen patients recurred (72%), mainly in the peritoneum (n = 16). Four of them (22%) were reoperated. The 5 and 10-year DFS rates were both 20.3%. The 5 and 10-year OS rates were 62% and 51.7%, respectively. A complete cytoreductive surgery was associated with a better OS and DFS in a univariate analysis.Conclusion: Complete cytoreductive surgery is the cornerstone of the PK's management as a primary treatment. Recurrence remains common and new adjuvant strategies seem needed.
Published: 2019
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59. Ki‐67 and MCM6 labeling indices are correlated with overall survival in anaplastic oligodendroglioma, IDH1‐mutant and 1p/19q‐codeleted: a multicenter study from the French POLA network

Author: Celso Pouget, Sébastien Hergalant, Emilie Lardenois, Stéphanie Lacomme, Rémi Houlgatte, Catherine Carpentier, Caroline Dehais, Fabien Rech, Luc Taillandier, Marc Sanson, Romain Appay, Carole Colin, Dominique Figarella‐Branger, Shyue‐Fang Battaglia‐Hsu, Guillaume Gauchotte, Christine Desenclos, H. Sevestre, Philippe Menei, A. Rousseau, T. Cruel, S. Lopez, M.I. Mihai, A. Petit, R. Seizeur, I. Quintin‐Roué, C. Adam, F. Parker, S. Eimer, H. Loiseau, L. Bekaert, F. Chapon, D. Ricard, C. Godfraind, T. Khallil, D. Cazals‐Hatem, T. Faillot, C. Gaultier, M. C Tortel, I. Carpiuc, P. Richard, W. Lahiani, H. Aubriot‐Lorton, F. Ghiringhelli, C‐A Maurage, E. Le Rhun, E. M. Gueye, F. Labrousse, F. Ducray, D. Meyronet, O. Chinot, L. Bauchet, V. Rigau, P. Beauchesne, M. Campone, D. Loussouarn, D. Fontaine, F. Vandenbos‐Burel, A. Le. Floch, P. Roger, C. Blechet, M. Fesneau, A. Carpentier, A. Idbaih, J. Y. Delattre, K. Mokhtari, F. Bielle, S. Hamdi, M. Polivka, S. Milin, P. Colin, M. D. Diebold, D. Chiforeanu, E. Vauleon, O. Langlois, A. Laquerriere, F. Forest, M. J. Motso‐Fotso, M. Andraud, G. Runavot, B. Lhermitte, G. Noel, S. Gaillard, C. Villa, N. Desse, C. Rousselot‐Denis, I. Zemmoura, E. Cohen‐Moyal, E. Uro‐Coste, F. Dhermain, Service de Pathologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Centre de Ressources Biologiques - [Nancy] (CRB Nancy), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Neurochirurgie [CHRU Nancy], Institut des Neurosciences de Montpellier (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Service de neurologie [CHRU Nancy], OncoNeuroTek [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Institut de neurophysiopathologie (INP), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Aix Marseille Université (AMU), Laboratoire d'Anatomie Pathologique-Neuropathologique [AP-HM Hôpital La Timone], Hôpital de la Timone [CHU - APHM] (TIMONE), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université - Département de neurologie 2 - Mazarin, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP]
Subjects: 0301 basic medicine, Male, Proliferation index, [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], 0302 clinical medicine, Research Articles, Aged, 80 and over, Brain Neoplasms, General Neuroscience, [SDV.BBM.MN]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular Networks [q-bio.MN], Middle Aged, Prognosis, Isocitrate Dehydrogenase, 3. Good health, Survival Rate, Microglial cell activation, Ki-67, Immunohistochemistry, Female, France, [STAT.ME]Statistics [stat]/Methodology [stat.ME], Adult, IDH1, Mitotic index, Oligodendroglioma, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Postsynaptic specialization, Pathology and Forensic Medicine, 03 medical and health sciences, Young Adult, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Glioma, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], [SDV.MHEP.AHA]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], medicine, Mitotic Index, Humans, Aged, [INFO.INFO-DB]Computer Science [cs]/Databases [cs.DB], Gene Expression Profiling, medicine.disease, Minichromosome Maintenance Complex Component 6, 030104 developmental biology, Ki-67 Antigen, Mutation, biology.protein, Cancer research, Neurology (clinical), [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], 030217 neurology & neurosurgery, Gene Deletion
Abstract: International audience; Anaplastic oligodendroglioma (AO), IDH‐mutant and 1p/19q codeleted (IDHmut+/1p19qcodel), is a high‐grade glioma with only limited prognostic markers. The primary objective of this study was to evaluate, by immunohistochemistry, the prognostic value of two proliferation markers, MCM6 and Ki‐67, in a large series of IDHmut+/1p19qcodel AO included in the POLA (“Prise en charge des Oligodendrogliomes Anaplasiques”) French national multicenter network. We additionally examined the transcriptome obtained from this series to understand the functional pathways dysregulated with the mRNA overexpression of these two markers. The labelling indices (LI) of MCM6 and Ki‐67 were obtained via computer‐assisted color image analyses on immunostained AO tissues of the cohort (n=220). Furthermore, a subgroup of AO (n=68/220) was used to perform transcriptomic analyses. A high LI of either MCM6 (≥50%) or Ki‐67 (≥ 15%) correlated with shorter overall survival, both in univariate (P=0.013 and P=0.004, respectively) and multivariate analyses (P=0.027; multivariate Cox model including age, mitotic index, MCM6 and Ki‐67). MCM6 and Ki‐67 LI also correlated with overall survival in an additional retrospective cohort of 30 grade II IDHmut+/1p19qcodel oligodendrogliomas. The prognostic value of MCM6 mRNA level was confirmed in The Cancer Genome Atlas (TCGA) IDHmut+/1p19qcodel gliomas. The transcriptomic approach revealed that high transcriptional expressions of MCM6 and MKI67 were both linked positively with cell cycle progression, DNA replication, mitosis, pro‐neural phenotype as well as neurogenesis, and negatively with microglial cell activation, immune response, positive regulation of myelination, oligodendrocyte development, beta‐amyloid binding, and postsynaptic specialization.In conclusion, the overexpression of MCM6 and/or Ki‐67 is independently associated to shorter overall survival in IDHmut+/1p19qcodel AO. These two easy‐to‐use and cost‐effective markers could thus be used concurrently in routine pathology practice. Additionally, the transcriptomic analyses showed that AO with high proliferation index have down‐regulated immune response and lower microglial cells activation, and bears pro‐neural phenotype.
Published: 2019
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60. Glycolipids Recognized by A2B5 Antibody Promote Proliferation, Migration, and Clonogenicity in Glioblastoma Cells

Author: Raphael Berges, Aurélie Tchoghandjian, Nathalie Baeza-Kallee, Carole Colin, Emilie Denicolai, Romain Appay, Dominique Figarella-Branger, Aurélie Soubéran, Institut de neurophysiopathologie (INP), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Anatomie Pathologique-Neuropathologique [AP-HM Hôpital La Timone], Hôpital de la Timone [CHU - APHM] (TIMONE), Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), and Assistance Publique - Hôpitaux de Marseille (APHM)
Subjects: 0301 basic medicine, Cancer Research, endocrine system, cancer stem cell, [SDV]Life Sciences [q-bio], [SDV.CAN]Life Sciences [q-bio]/Cancer, medicine.disease_cause, lcsh:RC254-282, Article, Epitope, 03 medical and health sciences, 0302 clinical medicine, Cancer stem cell, medicine, biology, Chemistry, Cell growth, glioblastoma, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, 3. Good health, 030104 developmental biology, Oncology, Cell culture, Apoptosis, 030220 oncology & carcinogenesis, biology.protein, Cancer research, tumorigenicity, Antibody, Carcinogenesis, ST8SIA3, Neuraminidase, A2B5
Abstract: A2B5+ cells isolated from human glioblastomas exhibit cancer stem cell properties. The A2B5 epitope belongs to the sialoganglioside family and is synthetized by the ST8 alpha-N-acetyl-neuraminidase &alpha, 2,8-sialyltransferase 3 (ST8SIA3) enzyme. Glycolipids represent attractive targets for solid tumors, therefore, the aim of this study was to decipher A2B5 function in glioblastomas. To this end, we developed cell lines expressing various levels of A2B5 either by genetically manipulating ST8SIA3 or by using neuraminidase. The overexpression of ST8SIA3 in low-A2B5-expressing cells resulted in a dramatic increase of A2B5 immunoreactivity. ST8SIA3 overexpression increased cell proliferation, migration, and clonogenicity in vitro and tumor growth when cells were intracranially grafted. Conversely, lentiviral ST8SIA3 inactivation in low-A2B5-expressing cells resulted in reduced proliferation, migration, and clonogenicity in vitro and extended mouse survival. Furthermore, in the shST8SIA3 cells, we found an active apoptotic phenotype. In high-A2B5-expressing cancer stem cells, lentiviral delivery of shST8SIA3 stopped cell growth. Neuraminidase treatment, which modifies the A2B5 epitope, impaired cell survival, proliferation, self-renewal, and migration. Our findings prove the crucial role of the A2B5 epitope in the promotion of proliferation, migration, clonogenicity, and tumorigenesis, pointing at A2B5 as an attractive therapeutic target for glioblastomas.
Published: 2019
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61. New sequential combinations of non-invasive fibrosis tests provide an accurate diagnosis of advanced fibrosis in NAFLD

Author: Theophile Gerster, Christophe Bureau, Jean-Marie Péron, Justine Barthelon, Isabelle Fouchard, Frédéric Oberti, Juliette Foucher, Maeva Guillaume, Brigitte Le Bail, Marie Irles, Paul Calès, Wassil Merrouche, Adrien Lannes, Floraine Zuberbuhler, Vincent Leroy, Gilles Hunault, Victor de Lédinghen, Laurence Pelade, Sophie Michalak, Jérôme Boursier, Jérémie Riou, Marine Roux, Jean-Baptiste Hiriart, Cyrielle Delabaudière, Hémodynamique, Interaction Fibrose et Invasivité tumorales Hépatiques (HIFIH), Université d'Angers (UA), Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES), Département d'hépatologie (CHU Angers), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), CHU Bordeaux [Bordeaux], Université Grenoble Alpes - UFR Médecine (UGA UFRM), Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), PRES Université Nantes Angers Le Mans (UNAM), Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Laboratoire d'anatomie pathologique, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Micro et Nanomédecines Translationnelles (MINT), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Service d'Hépato-Gastro-Entérologie, CHU Bordeaux [Bordeaux]-Hôpital Saint-André, Institut des sciences juridique et philosophique de la Sorbonne - UMR 8103 (ISJPS), Université Paris 1 Panthéon-Sorbonne (UP1)-Centre National de la Recherche Scientifique (CNRS), Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), and Hôpital Haut-Lévêque [CHU Bordeaux]
Subjects: 0301 basic medicine, Adult, Liver Cirrhosis, Male, medicine.medical_specialty, FIBROMETER, Biopsy, Gastroenterology, Cohort Studies, 03 medical and health sciences, Random Allocation, 0302 clinical medicine, Fibrosis, Non-alcoholic Fatty Liver Disease, Internal medicine, medicine, Blood test, Humans, ComputingMilieux_MISCELLANEOUS, Aged, Hematologic Tests, Hepatology, medicine.diagnostic_test, Receiver operating characteristic, business.industry, FibroTest, Fatty liver, Middle Aged, medicine.disease, Prognosis, 3. Good health, Data Accuracy, [STAT]Statistics [stat], 030104 developmental biology, Liver, Liver biopsy, Elasticity Imaging Techniques, 030211 gastroenterology & hepatology, Female, business, Transient elastography, Algorithms, Biomarkers
Abstract: Background & Aims Advanced liver fibrosis is an important diagnostic target in non-alcoholic fatty liver disease (NAFLD) as it defines the subgroup of patients with impaired prognosis. The non-invasive diagnosis of advanced fibrosis is currently limited by the suboptimal positive predictive value and the grey zone (representing indeterminate diagnosis) of fibrosis tests. Here, we aimed to determine the best combination of non-invasive tests for the diagnosis of advanced fibrosis in NAFLD. Methods A total of 938 patients with biopsy-proven NAFLD were randomized 2:1 into derivation and validation sets. All patients underwent liver stiffness measurement with vibration controlled transient elastography (VCTE) and blood fibrosis tests (NAFLD fibrosis score, Fibrosis-4 [FIB4], Fibrotest, Hepascore, FibroMeter). FibroMeterVCTE, which combines VCTE results and FibroMeter markers in a single test, was also calculated in all patients. Results For the diagnosis of advanced fibrosis, VCTE was significantly more accurate than the blood tests (area under the receiver operating characteristic curve [AUROC]: 0.840 ± 0.013, p ≤0.005). FibroMeter was the most accurate blood test (AUROC: 0.793 ± 0.015, p ≤0.017). The combinatory test FibroMeterVCTE outperformed VCTE and blood tests (AUROC: 0.866 ± 0.012, p ≤0.005). The sequential combination of FIB4 then FibroMeterVCTE (FIB4-FMVCTE algorithm) or VCTE then FibroMeterVCTE (VCTE-FMVCTE algorithm) provided an excellent diagnostic accuracy of 90% for advanced fibrosis, with liver biopsy only required to confirm the diagnosis in 20% of cases. The FIB4-FMVCTE and VCTE-FMVCTE algorithms were significantly more accurate than the pragmatic algorithms currently proposed. Conclusion The sequential combination of fibrosis tests in the FIB4-FMVCTE and VCTE-FMVCTE algorithms provides a highly accurate solution for the diagnosis of advanced fibrosis in NAFLD. These algorithms should now be validated for the diagnosis of advanced liver fibrosis in diabetology or primary care settings. Lay summary The evaluation of liver fibrosis is mandatory in non-alcoholic fatty liver disease (NAFLD), as advanced fibrosis identifies the subgroup of patients with impaired prognosis. FibroMeterVCTE is a new fibrosis test combining blood markers and the result of vibration controlled transient elastography (VCTE) into a single diagnostic test. Our results show that FibroMeterVCTE outperforms other blood fibrosis tests and VCTE alone for the diagnosis of advanced fibrosis in a large multi-centric cohort of 938 patients with biopsy-proven NAFLD. Sequential algorithms using a simple blood test or VCTE as a first-line procedure, then FibroMeterVCTE as a second-line test accurately classified 90% of patients.
Published: 2019
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62. Thyroid Incidentaloma on 18F-fluorocholine PET/CT and 68Ga-PSMA PET/CT Revealing a Medullary Thyroid Carcinoma

Author: Stéphane Bardet, Mathieu Gauthé, Agathe Edet-Sanson, Virginie Saguet-Rysanek, Renaud Ciappuccini, Unité de recherche interdisciplinaire pour la prévention et le traitement des cancers (ANTICIPE), 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)-Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Imagerie médicale - Médecine nucléaire [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), Laboratoire d'Anatomie Pathologique [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), Service de médecine nucléaire [CHU Tenon], CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Service de Médecine Nucléaire [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Bodescot, Myriam
Subjects: Male, Medullary cavity, Gallium Radioisotopes, [SDV.CAN]Life Sciences [q-bio]/Cancer, Choline, 030218 nuclear medicine & medical imaging, Thyroid carcinoma, 03 medical and health sciences, Prostate cancer, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Positron Emission Tomography Computed Tomography, medicine, Humans, Radiology, Nuclear Medicine and imaging, Thyroid Neoplasms, Edetic Acid, Gallium Isotopes, Aged, Incidental Findings, PET-CT, business.industry, Incidentaloma, Thyroid, Medullary thyroid cancer, General Medicine, medicine.disease, Carcinoma, Neuroendocrine, 3. Good health, medicine.anatomical_structure, Calcitonin, 030220 oncology & carcinogenesis, Radiopharmaceuticals, business, Nuclear medicine, Oligopeptides
Abstract: International audience; A 66-year-old man with prostate cancer underwent F-fluorocholine PET/CT and thereafter Ga-labeled prostate-specific membrane antigen PET/CT to explore a rising prostate-specific antigen level. Both PET/CT studies showed a thyroid incidentaloma of the right lobe. Neck ultrasound confirmed the presence of a 16-mm right thyroid nodule. The serum calcitonin level was moderately increased at 25 ng/mL (
Published: 2019
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63. Mycolactone as Analgesic: Subcutaneous Bioavailability Parameters

Author: David Guilet, Estelle Marion, Pascal Richomme, Jean-Paul Saint André, Laurent Marsollier, Anne Croué, Dimitri Bréard, Priscille Brodin, Jérémie Babonneau, Marie-Line Reynaert, ATOMycA (CRCINA-ÉQUIPE 6), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Substances d'Origine Naturelle et Analogues Structuraux (SONAS), Université d'Angers (UA), SFR UA 4207 QUAlité et SAnté du Végétal (QUASAV), Université d'Angers (UA)-Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN)-AGROCAMPUS OUEST, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Ecole supérieure d'Agricultures d'Angers (ESA), Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Laboratoire d’Anatomie Pathologique [ICO, Angers] (Site Paul Papin), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER-UNICANCER, This work was supported by the region Pays de la Loire (Kalmos project), the Agence Nationale de Recherche (ANR-17-CE18-0001), the Institut Pasteur of Lille (granted to PB and M-LR), the Inserm Program ATIP avenir (granted to LM), the region Pays de la Loire (Kalmos project) and Angers University., ANR-17-CE18-0001,AT2R-TRAAK-BIOANALGESICS,Caractérisations moléculaires et cellulaires de voies de signalisation de la douleur: contrôle de la douleur dans l'ulcère de buruli comme source d'inspiration pour la conception rationnelle de nouveaux analgésiques puissants(2017), Bernardo, Elizabeth, Caractérisations moléculaires et cellulaires de voies de signalisation de la douleur: contrôle de la douleur dans l'ulcère de buruli comme source d'inspiration pour la conception rationnelle de nouveaux analgésiques puissants - - AT2R-TRAAK-BIOANALGESICS2017 - ANR-17-CE18-0001 - AAPG2017 - VALID, Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Université d'Angers (UA)-Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN)-AGROCAMPUS OUEST-Ecole supérieure d'Agricultures d'Angers (ESA), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), ATIP AVENIR / ATOMycA (CRCINA - Département INCIT - Equipe 6), Centre de recherche de Cancérologie et d'Immunologie / Nantes - Angers (CRCINA), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Institut National de la Recherche Agronomique (INRA)-Ecole supérieure d'Agricultures d'Angers (ESA)-Université de Nantes (UN)-AGROCAMPUS OUEST-Université d'Angers (UA), Centre d’Infection et d’Immunité de Lille (CIIL) - U1019 - UMR 8204 (CIIL), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), and Institut de cancérologie de l'Ouest - Paul Papin (ICO - Paul Papin)
Subjects: 0301 basic medicine, Buruli ulcer, [SDV.CAN]Life Sciences [q-bio]/Cancer, mycolactone, Pharmacology, medicine.disease_cause, 03 medical and health sciences, chemistry.chemical_compound, Subcutaneous injection, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, biological action, medicine, Pharmacology (medical), Mycolactone, Original Research, Mycobacterium ulcerans, biology, Toxin, lcsh:RM1-950, analgesia, Hypoesthesia, biology.organism_classification, medicine.disease, 3. Good health, lcsh:Therapeutics. Pharmacology, 030104 developmental biology, Nociception, chemistry, 030220 oncology & carcinogenesis, medicine.symptom, bioavailability, Panniculitis
Abstract: Jérémie Babonneau, Dimitri Bréard and Marie-Line Reynaert have contributed equally to this work. Priscille Brodin, Pascal Richomme and Laurent Marsollier are co-senior authors.; International audience; Mycobacterium ulcerans is the bacillus responsible for Buruli ulcer, an infectious disease and the third most important mycobacterial disease worldwide, after tuberculosis and leprosy. M. ulcerans infection is a type of panniculitis beginning mostly with a nodule or an oedema, which can progress to large ulcerative lesions. The lesions are caused by mycolactone, the polyketide toxin of M. ulcerans. Mycolactone plays a central role for host colonization as it has immunomodulatory and analgesic effects. On one hand, mycolactone induces analgesia by targeting type-2 angiotensin II receptors (AT 2 R), causing cellular hyperpolarization and neuron desensitization. Indeed, a single subcutaneous injection of mycolactone into the mouse footpad induces a long-lasting hypoesthesia up to 48 h. It was suggested that the long-lasting hypoesthesia may result from the persistence of a significant amount of mycolactone locally following its injection, which could be probably due to its slow elimination from tissues. To verify this hypothesis, we investigated the correlation between hypoesthesia and mycolactone bioavailability directly at the tissue level. Various quantities of mycolactone were then injected in mouse tissue and hypoesthesia was recorded with nociception assays over a period of 48 h. The hypoesthesia was maximal 6 h after the injection of 4 µg mycolactone. The basal state was reached 48 h after injection, which demonstrated the absence of nerve damage. Surprisingly, mycolactone levels decreased strongly during the first hours with a reduction of 70 and 90% after 4 and 10 h, respectively. Also, mycolactone did not diffuse in neighboring skin tissue and only poorly into the bloodstream upon direct injection. Nevertheless, the remaining amount was sufficient to induce hypoesthesia during 24 h. Our results thus demonstrate that intact mycolactone is rapidly eliminated and that very small amounts of mycolactone are sufficient to induce hypoesthesia. Taken together, our study points out that mycolactone ought to be considered as a promising analgesic.
Published: 2019
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64. MSH2/BRCA1 expression as a DNA-repair signature predicting survival in early-stage lung cancer patients from the IFCT-0002 Phase 3 Trial

Author: Julien Mazieres, Elisabeth Brambilla, Françoise Galateau-Sallé, Didier Debieuvre, Olivier Molinier, Pierre Fouret, Solenn Brosseau, Fatéméh Dubois, Valérie Gounant, Denis Moro-Sibilot, Alexandra Langlais, Guénaëlle Levallet, Gérard Zalcman, Michèle Beau-Faller, Elisabeth Quoix, Virginie Westeel, Emmanuel Bergot, Franck Morin, Jean-Louis Pujol, Martine Antoine, Laboratoire d'Anatomie Pathologique [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), Unité de recherche interdisciplinaire pour la prévention et le traitement des cancers (ANTICIPE), 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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-UNICANCER, Service d'Anatomie et cytologie pathologiques [CHU Pitié-Salpêtrière] (ACP), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), 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), Service de pneumologie [CHU Caen], AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital de Hautepierre [Strasbourg], Service de Pneumologie - Oncologie Thoracique - Maladies Pulmonaires Rares [CHU Tenon], CHU Tenon [AP-HP], CHU Grenoble, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble, Centre Hospitalier Emile Muller [Mulhouse] (CH E.Muller Mulhouse), Groupe Hospitalier de Territoire Haute Alsace (GHTHA), Centre Hospitalier Le Mans (CH Le Mans), CHU Toulouse [Toulouse], Nouvel Hôpital Civil de Strasbourg, Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), 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), Intergroupe Francophone de Cancérologie Thoracique [Paris] (IFCT), Intergroupe Francophone de Cancérologie thoracique, Service de Pneumologie, oncologie thoracique et allergologie respiratoire [CHRU Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Brunaud, Carole, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN)-Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Anatomie et cytologie pathologiques = Service de Pathologie [CHU Pitié-Salpêtrière] (ACP), 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 Tenon], Service de Pneumologie = Pneumologie - Oncologie Thoracique - Maladies Pulmonaires Rares [CHU Tenon], and Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)
Subjects: Male, 0301 basic medicine, Lung Neoplasms, DNA Repair, neo-adjuvant chemotherapy, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Prospective evaluation, 0302 clinical medicine, Carcinoma, Non-Small-Cell Lung, Prospective Studies, Promoter Regions, Genetic, DNA Modification Methylases, BRCA1 Protein, Middle Aged, Prognosis, Neoadjuvant Therapy, 3. Good health, Gene Expression Regulation, Neoplastic, MutS Homolog 2 Protein, Oncology, 030220 oncology & carcinogenesis, Dna breaks, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Female, Non small cell, Risk of death, MGMT, Research Paper, Adult, medicine.medical_specialty, [SDV.CAN]Life Sciences [q-bio]/Cancer, Marie curie, 03 medical and health sciences, Drug Therapy, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], medicine, Overall survival, Humans, Lung cancer, Ku Autoantigen, non-small cell lung cancer, Aged, Neoplasm Staging, Gynecology, business.industry, Tumor Suppressor Proteins, DNA Methylation, BRCA1, medicine.disease, Survival Analysis, MSH2, DNA Repair Enzymes, 030104 developmental biology, [SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, business
Abstract: // Guenaelle Levallet 1 , Fatemeh Dubois 2 , Pierre Fouret 3 , Martine Antoine 4 , Solenn Brosseau 2,5,6 , Emmanuel Bergot 2,5 , Michele Beau-Faller 7 , Valerie Gounant 6,8 , Elisabeth Brambilla 9 , Didier Debieuvre 10 , Olivier Molinier 11 , Francoise Galateau-Salle 1 , Julien Mazieres 12 , Elisabeth Quoix 13 , Jean-Louis Pujol 14 , Denis Moro-Sibilot 15 , Alexandra Langlais 16 , Franck Morin 16 , Virginie Westeel 17 and Gerard Zalcman 5,6,18,19 1 Service d’Anatomie et Cytologie Pathologique, Centre Hospitalier Universitaire de Caen, Normandie Universite, Caen, France 2 Normandie Universite; UMR 1086 INSERM, Caen, France 3 Service d’Anatomie Pathologique, Pitie-Salpetriere, AP-HP, Universite Pierre et Marie Curie (UPMC), Paris, France 4 Service d’Anatomie Pathologique, Hopital Tenon, AP-HP, Universite Pierre et Marie Curie (UPMC), Paris, France 5 Service de Pneumologie et Oncologie Thoracique, Centre Hospitalier Universitaire de Caen, Normandie Universite, Caen, cedex, France 6 Service d’Oncologie Thoracique, Hopital Bichat-Claude Bernard, AP-HP, Universite Paris-Diderot, Paris, France 7 Laboratoire de Biochimie et Biologie moleculaire, Hopital de Hautepierre, Centre Hospitalier Universitaire de Strasbourg, Universite de Strasbourg, BP426 Strasbourg, Cedex, France 8 Service de Pneumologie, Hopital Tenon, AP-HP, Universite Pierre et Marie Curie (UPMC), Paris, France 9 Service d’Anatomie Pathologique, Hopital Albert Michallon, Centre Hospitalier Universitaire de Grenoble, La Tronche, France 10 Service de Pneumologie, GHRMSA-Centre Hospitalier Eric Muller, Mulhouse, France 11 Service de Pneumologie, Centre Hospitalier du Mans, Le Mans, France 12 Service de Pneumologie, Hopital Larrey, Centre Hospitalier Universitaire de Toulouse, Universite de Toulouse III, Toulouse, France 13 Service de Pneumologie, Nouvel Hopital Civil, Hospices Civils de Strasbourg, Universite de Strasbourg, BP426 Strasbourg, Cedex, France 14 Service de Pneumologie, Centre Hospitalier Universitaire Arnaud de Villeneuve, Universite de Montpellier, Montpellier, France 15 Unite d’Oncologie Thoracique–Pneumologie, CHU de Grenoble, INSERM U823, Grenoble, France 16 Intergroupe Francophone de Cancerologie Thoracique (IFCT), Paris, France 17 Service de Pneumologie, Hopital Jean-Minjoz, Centre Hospitalier Universitaire de Besancon, Universite de Franche-Comte, Besancon, France 18 CIC INSERM 1425-CLIP2 Paris-Nord, Hopital Bichat-Claude Bernard, AP-HP, Paris, France 19 On Behalf of the IFCT (Intergroupe Francophone de Cancerologie Thoracique) Correspondence to: Gerard Zalcman, email: // Keywords : non-small cell lung cancer; neo-adjuvant chemotherapy; MSH2; BRCA1; MGMT Received : August 08, 2016 Accepted : December 05, 2016 Published : December 19, 2016 Abstract Introduction: DNA repair is a double-edged sword in lung carcinogenesis. When defective, it promotes genetic instability and accumulated genetic alterations. Conversely these defects could sensitize cancer cells to therapeutic agents inducing DNA breaks. Methods: We used immunohistochemistry (IHC) to assess MSH2, XRCC5, and BRCA1 expression in 443 post-chemotherapy specimens from patients randomized in a Phase 3 trial, comparing two neoadjuvant regimens in 528 Stage I-II non-small cell lung cancer (NSCLC) patients (IFCT-0002). O 6 MGMT promoter gene methylation was analyzed in a subset of 208 patients of the same trial with available snap-frozen specimens. Results: Median follow-up was from 90 months onwards. Only high BRCA1 (n = 221, hazard ratio [HR] = 1.58, 95% confidence interval [CI] [ 1 . 07 - 2 . 34 ], p = 0.02) and low MSH2 expression (n = 356, HR = 1.52, 95% CI [ 1 . 11 - 2 . 08 ], p = 0.008) significantly predicted better overall survival (OS) in univariate and multivariate analysis. A bootstrap re-sampling strategy distinguished three patient groups at high ( n = 55, low BRCA1 and high MSH2, median OS >96 months, HR = 2.5, 95% CI [ 1 . 45 - 4 . 33 ], p = 0.001), intermediate (n = 82, median OS = 73.4 p = 0.0596), and low (high BRCA1 and low MSH2, n = 67, median OS = ND, HR = 0.51, 95% CI [ 0 . 31 - 0 . 83 ], p = 0.006) risk of death. Interpretation: DNA repair protein expression assessment identified three different groups of risk of death in early-stage lung cancer patients, according to their tumor MSH2 and BRCA1 expression levels. These results deserve prospective evaluation of MSH2/BRCA1 theranostic value in lung cancer patients treated with combinations of DNA-damaging chemotherapy and drugs targeting DNA repair, such as Poly(ADP-ribose) polymerase (PARP) inhibitors.
Published: 2016
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65. MYD88 Somatic Mutation Is a Diagnostic Criterion in Primary Cutaneous Large B-Cell Lymphoma

Author: Vanessa Szablewski, François Le Gall, Anne de Muret, Jean-Philippe Merlio, Nicolas Ortonne, Agnès Carlotti, Maxime Battistella, David Cappellen, Marie Beylot-Barry, Béatrice Vergier, Audrey Gros, F. Franck, François Comoz, Anne Pham-Ledard, Sarah Menguy, Anne Croue, Brigitte Balme, Marie-Hélène Lorton, Laurence Lamant, Physiopathologie du cancer du foie, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Bordeaux Segalen - Bordeaux 2, Service d'anatomo-pathologie [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Cancer et Transplantation : Physiopathologie et Réponse Thérapeutique (UMR 1165), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), INSERM U955, équipe 9, 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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Laboratoire d'Anatomie Pathologique [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), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service d'anatomie et cytologie pathologiques [Purpan], Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Service de Pathologie, Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), CHU Pontchaillou [Rennes], CHU Clermont-Ferrand, Département de Pathologie, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Département de biologie de la tumeur, CHU Bordeaux [Bordeaux], Service de pathologie [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Service Anatomie et cytologie pathologiques [CHU Toulouse], Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse], and Jonchère, Laurent
Subjects: PCFCL, [SDV.CAN]Life Sciences [q-bio]/Cancer, Primary cutaneous B-cell lymphoma, Dermatology, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Biochemistry, primary cutaneous follicle center lymphoma, 030207 dermatology & venereal diseases, 03 medical and health sciences, 0302 clinical medicine, Germline mutation, [SDV.CAN] Life Sciences [q-bio]/Cancer, medicine, primary cutaneous B-cell lymphoma, PCBCL, B-cell lymphoma, Molecular Biology, ComputingMilieux_MISCELLANEOUS, primary cutaneous marginal zone lymphoma, GC, business.industry, Germinal center, Cell Biology, [SDV.MHEP.DERM] Life Sciences [q-bio]/Human health and pathology/Dermatology, PCLBCL-LT, medicine.disease, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, germinal center, primary cutaneous large B-cell lymphoma-leg type, 030220 oncology & carcinogenesis, PCMZL, Immunology, Mutation (genetic algorithm), Cancer research, Myeloid Differentiation Factor 88, Primary cutaneous marginal zone lymphoma, Differential diagnosis, business, [SDV.MHEP.DERM]Life Sciences [q-bio]/Human health and pathology/Dermatology
Abstract: International audience; no abstract
Published: 2016
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66. Addition of high-dose cytarabine to immunochemotherapy before autologous stem-cell transplantation in patients aged 65 years or younger with mantle cell lymphoma (MCL Younger): a randomised, open-label, phase 3 trial of the European Mantle Cell Lymphoma Network

Author: Georg Maschmeyer, Bernd Metzner, Corinne Haioun, Richard Delarue, Thomas Fischer, Ulrich Dührsen, Michal Szymczyk, Jan Walewski, Mathias Hänel, Michael Unterhalt, Catherine Thieblemont, Norma Peter, Kamal Bouabdallah, Christiane Pott, Michael Hallek, Vincent Ribrag, Stephan Stilgenbauer, André Bosly, Catherine Sebban, Josef Birkmann, Christian Schmidt, Marie-Hélène Delfau-Larue, Jürgen Finke, Wolfgang Hiddemann, Nicole Brousse, Elizabeth Macintyre, Gilles Salles, Pierre Feugier, Wolfram Klapper, Roswitha Forstpointner, Eva Hoster, Michael Kneba, Rene-Olivier Casasnovas, Martin Dreyling, Lothar Kanz, Reda Bouabdallah, Olivier Hermine, Imagine - Institut des maladies génétiques ( IMAGINE - U1163 ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ), Department of Internal Medicine III, University of Munich, Institute of Oncology, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology ( MCMCC ), CHU Dinant-Godinne UCL Namur, Internal Medicine III, Universität Ulm, APHP Hôpital Saint Louis, Institut Charles Gerhardt Montpellier - Institut de Chimie Moléculaire et des Matériaux de Montpellier ( ICGM ICMMM ), Université Montpellier 1 ( UM1 ) -Université Montpellier 2 - Sciences et Techniques ( UM2 ) -Ecole Nationale Supérieure de Chimie de Montpellier ( ENSCM ) -Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), Département d'Hematologie, Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Second Medical Department, University Hospital Schleswig-Holstein, University of Cologne, Service d'hématologie [Hôpital Edouard Herriot - HCL], Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon ( HCL ) -Hospices Civils de Lyon ( HCL ), Nutrition-Génétique et Exposition aux Risques Environnementaux ( NGERE ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Lorraine ( UL ), Hématologie, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy ( IGR ) -Institut Gustave Roussy ( IGR ), Paracelsus Medical University, Ludwig-Maximilians University Hospital, Service d'hématologie clinique, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), Klinikum Chemnitz, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), University Hospital Freiburg, Carl Thiem Hospital Cottbus, Université Mohamed Boudiaf de M'sila, Centre Léon Bérard [Lyon], Agence départementale d’architecture et d’urbanisme du Haut-Rhin ( ADAUHR ), University Hospital Essen, Medizinische Klinik, Hämatologie und Onkologie, Klinikum Ernst von Bergmann, Department of Internal Medicine II (Oncology, Hematology, Immunology, Rheumatology, Pulmonology), University Hospital Tuebingen, Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Laboratoire d'anatomie pathologique [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Department of Pathology, Hematopathology Section and Lymph Node Registry, Universityhospital Schleswig-Holstein, Campus Kiel, 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'immunologie biologique, University Hospital Schleswig–Holstein, III. Medizinische Klinik, Technische Universität München [München] ( TUM ), Institut Imagine (UMR 1163), Laboratory of Cellular and Molecular Mechanisms of Hemathological Disorders and Therapeutic Implication, Maria Sklodowska-Curie Memorial Cancer Center, Institut Charles Gerhardt - Institut de Chimie Moléculaire et des Matériaux de Montpellier (ICG ICMMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM) - Université Montpellier 2 - Sciences et Techniques (UM2) - Université Montpellier 1 (UM1) - Centre National de la Recherche Scientifique (CNRS), Institut Paoli Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC) - Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Service de Radio-Oncologie [Lyon], Hospices Civils de Lyon - Centre Hospitalier Lyon Sud [Pierre Bénite], Hôpital Edouard Herriot, Hospices Civils de Lyon - Hôpital Edouard Herriot, Institut Gustave Roussy (IGR), Assistance publique - Hôpitaux de Paris (AP-HP) - Hôpital Henri Mondor - Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service d'Hématologie Clinique (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), University Medical Centre Freiburg, Centre Hospitalier Universitaire de Bordeaux, Agence départementale d’architecture et d’urbanisme du Haut-Rhin (ADAUHR), Laboratoire d'Informatique de l'Université du Maine (LIUM), Université du Maine (UM), Service d'hématologie biologique, Assistance publique - Hôpitaux de Paris (AP-HP) - Université Paris Descartes - Paris 5 (UPD5) - AP-HP Hôpital Necker - Enfants Malades [Paris], AP-HP Hôpital Necker - Enfants Malades [Paris], Service hématologie, Assistance publique - Hôpitaux de Paris (AP-HP) - Groupe Hospitalier Necker-Enfants Malades, 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), and Technische Universität München [München] (TUM)
Subjects: Adult, Male, medicine.medical_specialty, Vincristine, Transplantation Conditioning, Medizin, Lymphoma, Mantle-Cell, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, 03 medical and health sciences, 0302 clinical medicine, Autologous stem-cell transplantation, International Prognostic Index, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, Treatment Failure, Cyclophosphamide, ComputingMilieux_MISCELLANEOUS, business.industry, Cytarabine, Hematopoietic Stem Cell Transplantation, General Medicine, Middle Aged, medicine.disease, Combined Modality Therapy, Surgery, Transplantation, Doxorubicin, 030220 oncology & carcinogenesis, Prednisone, Female, Rituximab, Mantle cell lymphoma, Immunotherapy, business, Immunosuppressive Agents, Febrile neutropenia, 030215 immunology, medicine.drug
Abstract: Summary Background Mantle cell lymphoma is characterised by a poor long-term prognosis. The European Mantle Cell Lymphoma Network aimed to investigate whether the introduction of high-dose cytarabine to immunochemotherapy before autologous stem-cell transplantation (ASCT) improves outcome. Methods This randomised, open-label, parallel-group, phase 3 trial was done in 128 haemato-oncological hospital departments or private practices in Germany, France, Belgium, and Poland. Patients aged 65 years or younger with untreated stage II–IV mantle cell lymphoma were centrally randomised (1:1), with computer-assisted random block selection, to receive either six courses of R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) followed by myeloablative radiochemotherapy and ASCT (control group), or six courses of alternating R-CHOP or R-DHAP (rituximab plus dexamethasone, high-dose cytarabine, and cisplatin) followed by a high-dose cytarabine-containing conditioning regimen and ASCT (cytarabine group). Patients were stratified by study group and international prognostic index. The primary outcome was time to treatment failure from randomisation to stable disease after at least four induction cycles, progression, or death from any cause. Patients with stage II–IV mantle cell lymphoma were included in the primary analysis if treatment was started according to randomisation. For safety analyses, patients were assessed according to the treatment actually started. This study is registered with ClinicalTrials.gov, number NCT00209222. Findings Of 497 patients (median age 55 years [IQR 49–60]) randomised from July 20, 2004, to March 18, 2010, 234 of 249 in the control group and 232 of 248 in the cytarabine group were included in the primary analysis. After a median follow-up of 6·1 years (95% CI 5·4–6·4), time to treatment failure was significantly longer in the cytarabine group (median 9·1 years [95% CI 6·3–not reached], 5 year rate 65% [95% CI 57–71]) than in the control group (3·9 years [3·2–4·4], 40% [33–46]; hazard ratio 0·56; p=0·038). During induction immunochemotherapy, patients who received high-dose cytarabine had increased grade 3 or 4 haematological toxicity (haemoglobin 71 [29%] of 241m vs 19 [8%] of 227 controls; platelets 176 [73%] of 240 vs 21 [9%] of 225), grade 3 or 4 febrile neutropenia (39 [17%] of 230 vs 19 [8%] of 224), and grade 1 or 2 renal toxicity (creatinine 102 [43%] of 236 vs 22 [10%] of 224). The number of ASCT-related deaths was similar (eight [3·4%]) in both groups. Interpretation Immunochemotherapy containing high-dose cytarabine followed by ASCT should be considered standard of care in patients aged 65 years or younger with mantle cell lymphoma. Funding European Commission, Lymphoma Research Foundation, and Roche.
Published: 2016
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67. SCENITH: A Flow Cytometry-Based Method to Functionally Profile Energy Metabolism with Single-Cell Resolution

Author: Evelina Gatti, Julien-Paul Gigan, Sébastien Boissonneau, Alexis J. Combes, Peter Yan, Jessica Tsui, Rafael J. Argüello, Ania I. Baaziz, Remy Char, Matthew F. Krummel, Voahirana Camosseto, Evens Bousiquot, Bushra Samad, Emeline Tabouret, Dominique Figarella-Branger, Philippe Pierre, Institut de neurophysiopathologie (INP), Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Service d'Anatomie Pathologique et de Neuropathologie [Hôpital de la Timone - CHU - APHM], Hôpital de la Timone [CHU - APHM] (TIMONE)-Assistance Publique - Hôpitaux de Marseille (APHM), Neuro-Oncologie [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), 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), Institut National de la Santé et de la Recherche Médicale (INSERM), University of California [San Francisco] (UC San Francisco), University of California (UC), Department of Pathology, University of California, San Francisco, Aix-Marseille Université - Faculté de médecine (AMU MED), Aix Marseille Université (AMU), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Anatomie Pathologique-Neuropathologique [AP-HM Hôpital La Timone], Hôpital de la Timone [CHU - APHM] (TIMONE), Institute for Research in Biomedicine ( iBiMED), Universidade de Aveiro, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), University of California [San Francisco] (UCSF), University of California, and ARGUELLO, Rafael
Subjects: Male, protein synthesis and metabolism, 0301 basic medicine, Physiology, [SDV]Life Sciences [q-bio], Cell, metabolism analysis in samples from patients, Medical Biochemistry and Metabolomics, Inbred C57BL, Mice, 0302 clinical medicine, Neoplasms, 2.1 Biological and endogenous factors, Aetiology, Cells, Cultured, Cancer, Whole blood, Cultured, medicine.diagnostic_test, Hematology, Middle Aged, Phenotype, medicine.anatomical_structure, Metabolome, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Single-Cell Analysis, Reprogramming, Adult, Pediatric Research Initiative, Cell type, [SDV.IMM] Life Sciences [q-bio]/Immunology, metabolic profiling of blood samples, Cells, metabolic function by flow cytometry, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Computational biology, Biology, Article, Flow cytometry, Endocrinology & Metabolism, 03 medical and health sciences, Immune system, Clinical Research, Genetics, medicine, Animals, Humans, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Molecular Biology, tumor immunometabolism, Inflammatory and immune system, translation and metabolism, Cell Biology, Fibroblasts, Mice, Inbred C57BL, 030104 developmental biology, Biochemistry and Cell Biology, cell culture media and metabolism, metabolic gene signatures, Energy Metabolism, functional assay metabolism single cells, 030217 neurology & neurosurgery, Ex vivo
Abstract: International audience; Energetic metabolism reprogramming is critical for cancer and immune responses. Current methods to functionally profile the global metabolic capacities and dependencies of cells are performed in bulk. We designed a simple method for complex metabolic profiling called SCENITH, for single-cell energetic metabolism by profiling translation inhibition. SCENITH allows for the study of metabolic responses in multiple cell types in parallel by flow cytometry. SCENITH is designed to perform metabolic studies ex vivo, particularly for rare cells in whole blood samples, avoiding metabolic biases introduced by culture media. We analyzed myeloid cells in solid tumors from patients and identified variable metabolic profiles, in ways that are not linked to their lineage or their activation phenotype. SCENITH's ability to reveal global metabolic functions and determine complex and linked immune-phenotypes in rare cell subpopulations will contribute to the information needed for evaluating therapeutic responses or patient stratification.
Published: 2020
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68. Has adherence to treatment guidelines for mid/low rectal cancer affected the management of patients? A monocentric study of 604 consecutive patients

Author: Rémy Morello, Gil Lebreton, Y. Eid, Arnaud Alves, M.P. Galais, Céline Bazille, Audrey Fohlen, Alexandre Thobie, M. Finochi, J. Lubrano, B. Dupont, Véronique Bouvier, Olivier Dejardin, Benjamin Menahem, Service de Chirurgie Viscérale et Digestive [CHU Caen], CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Unité de recherche interdisciplinaire pour la prévention et le traitement des cancers (ANTICIPE), 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)-Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Caen Normandie - UFR Santé (UNICAEN Santé), Normandie Université (NU)-Normandie Université (NU), Registre des Tumeurs Digestives [CHU Caen], Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-UNICANCER, Laboratoire d'Anatomie Pathologique [CHU Caen], Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Service de Radiologie [CHU Caen], Hypoxie, physiopathologies cérébrovasculaire et tumorale (CERVOxy), Imagerie et Stratégies Thérapeutiques des pathologies Cérébrales et Tumorales (ISTCT), Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Service d'Hépato-Gastro-Enterologie et Nutrition [CHU Caen], Unité de Biostatistique et de Recherche Clinique (UBRC), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), and CCSD, Accord Elsevier
Subjects: Male, medicine.medical_specialty, [SDV.MHEP.CHI] Life Sciences [q-bio]/Human health and pathology/Surgery, Survival, Colorectal cancer, Anal Canal, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.MHEP.CHI]Life Sciences [q-bio]/Human health and pathology/Surgery, 03 medical and health sciences, 0302 clinical medicine, Low rectal cancer, Postoperative Complications, Sex Factors, [SDV.CAN] Life Sciences [q-bio]/Cancer, Disease severity, Recurrence, Chart review, Multidisciplinary management, medicine, Humans, Rectal cancer, Aged, Quality of Health Care, Patient Care Team, medicine.diagnostic_test, business.industry, Rectal Neoplasms, General surgery, Magnetic resonance imaging, General Medicine, medicine.disease, University hospital, Magnetic Resonance Imaging, Quality Improvement, 3. Good health, Clinical Practice, Recommendations for clinical practice, Treatment Outcome, 030220 oncology & carcinogenesis, Curative surgery, 030211 gastroenterology & hepatology, Surgery, Female, France, Guideline Adherence, business, Tomography, X-Ray Computed, Organ Sparing Treatments
Abstract: In 2006 under the supervision of the French health authorities (HAS), recommendations for clinical practice (RCP) in the management of rectal cancers were first published. The primary objective of this study was to assess the impact of these guidelines on multidisciplinary management in terms of therapeutic strategies based on disease staging and quality indicators for surgical excision. Secondarily, we assessed the impact of the RCPs on postoperative and oncological outcomes.All consecutive patients having undergone curative surgical excision for middle and low (subperitoneal) rectal cancer from 1995 to 2017 in the university hospital of Caen were included in accordance with the relevant French guidelines. They were divided into two groups: before (Gr1) and after (Gr2) 2006. For each group, a chart review was conducted on demographic variables, preoperative rectal tumor features, disease severity variables and quality of surgery variables. Postoperative and oncological outcomes were likewise assessed and compared between the two groups.Six hundred and four patients were included (Gr1, n=266; Gr2, n=338). Compliance with French guidelines significantly improved (i) use of magnetic resonance imaging (P0.0001) and CT-scan (P0.0001)]; (ii) organization of multidisciplinary tumor boards (P0.0001) leading to suitable neo-adjuvant treatment plan classification (P0.0001). Consequently, compliance improved widespread total mesorectal excision (P0.0001), sphincter-sparing surgery (P=0,0005), and completeness of curative resection in the specimen (P0.0001). Although postoperative 90-day mortality was similar, overall postoperative morbidity significantly increased in Gr2 (P0.0001). Overall (P=0.0005) and disease-free survival (P=0.0016) of patients in Gr2 were significantly prolonged and correlated with a significant reduction in local and distant recurrences.Compliance with the relevant French guidelines improved the quality of multidisciplinary management of patients undergoing curative surgery for subperitoneal rectal cancer. However, further progress is still needed to render accession to the recommendations more comprehensive.
Published: 2019
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69. Factors Associated with Relapse and Dependence to Glucocorticoids in Giant-Cell Arteritis

Author: Hubert de Boysson, Achille Aouba, Claire Delmas, A. Dumont, Nicolas Martin Silva, Jonathan Boutemy, G. Maigné, Jean-Jacques Parienti, Audrey Sultan, Gaétane Planchard, Service de médecine interne [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), Unité de Biostatistique et de Recherche Clinique (UBRC), Groupe de Recherche sur l'Adaptation Microbienne (GRAM 2.0), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Université de Caen Normandie (UNICAEN), Normandie Université (NU), Université de Caen Normandie - UFR Santé (UNICAEN Santé), Normandie Université (NU)-Normandie Université (NU), 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, Laboratoire d'Anatomie Pathologique [CHU Caen], Mzembaba, Sandy, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), and Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille
Subjects: Male, Computed Tomography Angiography, Comorbidity, Disease, 030204 cardiovascular system & hematology, Gastroenterology, Tertiary Care Centers, 0302 clinical medicine, Recurrence, Risk Factors, Positron Emission Tomography Computed Tomography, Immunology and Allergy, Prospective cohort study, Stroke, ComputingMilieux_MISCELLANEOUS, Aged, 80 and over, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Middle Aged, Prognosis, 3. Good health, Predictive factor, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Female, France, Vasculitis, Glucocorticoid, medicine.drug, medicine.medical_specialty, Substance-Related Disorders, Giant Cell Arteritis, Immunology, 03 medical and health sciences, Rheumatology, Internal medicine, medicine, Humans, In patient, Glucocorticoids, [SDV.MP] Life Sciences [q-bio]/Microbiology and Parasitology, Aged, Retrospective Studies, 030203 arthritis & rheumatology, business.industry, medicine.disease, Takayasu Arteritis, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Giant cell arteritis, [SDV.MP.BAC] Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, business, Follow-Up Studies
Abstract: Objective.To identify characteristics and factors associated with relapse and glucocorticoid (GC) dependence in patients with giant cell arteritis (GCA).Methods.We retrospectively analyzed 326 consecutive patients with GCA followed for at least 12 months. Factors associated with relapse and GC dependence were identified in multivariable analyses.Results.The 326 patients (73% women) were followed up for 62 (12–262) months. During followup, 171 (52%) patients relapsed, including 113 (35%) who developed GC dependence. Relapsing patients had less history of stroke (p = 0.01) and presented large-vessel vasculitis (LVV) more frequently on imaging (p = 0.01) than patients without relapse. During the first months, therapeutic strategy did not differ among relapsing and nonrelapsing patients. GC-dependent patients were less likely to have a history of stroke (p = 0.004) and presented LVV on imaging more frequently (p = 0.005) than patients without GC-dependent disease. In multivariable analyses, LVV was an independent predictive factor of relapse (HR 1.49, 95% CI 1.002–2.12; p = 0.04) and GC dependence (OR 2.19, 95% CI 1.19–4.05; p = 0.01). Conversely, stroke was a protective factor against relapse (HR 0.21, 95% CI 0.03–0.68; p = 0.005) and GC-dependent disease (OR 0.10, 95% CI 0.001–0.31; p = 0.0005). Patients with a GC-dependent disease who received a GC-sparing agent had a shorter GC treatment duration than those without (p = 0.008).Conclusion.In this study, LVV was an independent predictor of relapse and GC dependence. Further prospective studies are needed to confirm these findings and to determine whether patients with LVV require a different treatment approach.
Published: 2019
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70. Loss of ARHGEF1 causes a human primary antibody deficiency

Author: Anne Durandy, Sébastien Lofek, Hicham Lamrini, Eric Oksenhendler, Loic Chentout, Isabelle André-Schmutz, Elizabeth Macintyre, Sven Kracker, Marie-Céline Deau, Marc Bras, Lucie Heurtier, Amélie Trinquand, Marina Cavazzana, Amine Bouafia, Véronique Meignin, Olivier Alibeu, Alain Fischer, Julie Bruneau, Thierry Jo Molina, Capucine Picard, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Necker - Enfants Malades [AP-HP], Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Laboratoire d'Anatomie Pathologique, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Génétique Humaine des Maladies Infectieuses (Inserm U980), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Service hématologie, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Imagine - Institut des maladies génétiques (IMAGINE - U1163), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Plateforme de bioinformatique (UNIV Paris Descartes), Université Paris Descartes - Paris 5 (UPD5), Hôpital Hôtel Dieu, Département de Biothérapie [CHU Necker], CHU Necker - Enfants Malades [AP-HP]-Université Paris Descartes - Paris 5 (UPD5)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Developpement Normal et Pathologique du Système Immunitaire, Service d'Immunopathologie Clinique, ANR-15-CE15-0020,PIKimun,Caractérisation de la voie PI3K / AKT / mTOR - dans les lymphocytes humains(2015), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5), Chaire Médecine expérimentale (A. Fischer), and Collège de France (CdF (institution))
Subjects: 0301 basic medicine, Male, RHOA, Primary Immunodeficiency Diseases, T-Lymphocytes, [SDV]Life Sciences [q-bio], GTP-Binding Protein alpha Subunits, G12-G13, 03 medical and health sciences, Phosphatidylinositol 3-Kinases, 0302 clinical medicine, medicine, Humans, Lymphocytes, Protein kinase B, PI3K/AKT/mTOR pathway, B cell, ComputingMilieux_MISCELLANEOUS, B-Lymphocytes, rho-Associated Kinases, [SDV.GEN]Life Sciences [q-bio]/Genetics, biology, Chemistry, Siblings, Germinal center, General Medicine, Marginal zone, Actin cytoskeleton, Germinal Center, Molecular biology, 3. Good health, Haematopoiesis, 030104 developmental biology, medicine.anatomical_structure, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, 030220 oncology & carcinogenesis, biology.protein, Commentary, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, rhoA GTP-Binding Protein, Immunologic Memory, Proto-Oncogene Proteins c-akt, Rho Guanine Nucleotide Exchange Factors, Research Article, Signal Transduction
Abstract: ARHGEF1 is a RhoA-specific guanine nucleotide exchange factor expressed in hematopoietic cells. We used whole-exome sequencing to identify compound heterozygous mutations in ARHGEF1, resulting in the loss of ARHGEF1 protein expression in 2 primary antibody–deficient siblings presenting with recurrent severe respiratory tract infections and bronchiectasis. Both ARHGEF1-deficient patients showed an abnormal B cell immunophenotype, with a deficiency in marginal zone and memory B cells and an increased frequency of transitional B cells. Furthermore, the patients’ blood contained immature myeloid cells. Analysis of a mediastinal lymph node from one patient highlighted the small size of the germinal centers and an abnormally high plasma cell content. On the molecular level, T and B lymphocytes from both patients displayed low RhoA activity and low steady-state actin polymerization (even after stimulation of lysophospholipid receptors). As a consequence of disturbed regulation of the RhoA downstream target Rho-associated kinase I/II (ROCK), the patients’ lymphocytes failed to efficiently restrain AKT phosphorylation. Enforced ARHGEF1 expression or drug-induced activation of RhoA in the patients’ cells corrected the impaired actin polymerization and AKT regulation. Our results indicate that ARHGEF1 activity in human lymphocytes is involved in controlling actin cytoskeleton dynamics, restraining PI3K/AKT signaling, and confining B lymphocytes and myelocytes within their dedicated functional environment.
Published: 2019
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71. Detection of ALK and ROS1 rearrangements by immunocytochemistry on cytological samples

Author: Frankel, Diane, Bourlard, Donatienne, Garcia, Stephane, Robaglia-Schlupp, Andrée, Peker, Emel, Groliere, Adele, Kaspi, Elise, Roll, Patrice, Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Biologie Cellulaire [Hôpital de la Timone - APHM], Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Aix-Marseille Université - Faculté de médecine (AMU MED), Aix Marseille Université (AMU), Laboratoire d'anatomie pathologique - [Hôpital Nord - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital Nord [CHU - APHM], Aix-Marseille Université - Faculté de pharmacie (AMU PHARM), CCSD, Accord Elsevier, and Hôpital Nord [CHU - APHM]-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)
Subjects: Lung adenocarcinoma, [SDV.GEN]Life Sciences [q-bio]/Genetics, ALK, [SDV.GEN] Life Sciences [q-bio]/Genetics, Lung cancer, ROS1, Cytology, Immunocytochemistry
Abstract: International audience; The identification of ALK and ROS1 rearrangements has become essential for the theranostic management of patients with non-small cell lung cancer, especially in stage IV or inoperable patients. These testings are now performed by immunohistochemistry on histological samples and confirmed by fluorescent in situ hybridization in case of positive or doubtful results. The diagnosis of lung cancer is often performed at an advanced or metastatic stage and cytological sample could be the only material containing malignant cells available at these stages. Therefore, the detection of ALK and ROS1 rearrangement by immunocytochemical analysis on cytological specimens is needed. We performed this test on 27 cytological samples of lung adenocarcinomas, and we compared our results with several other techniques: on the same sample or on biopsy in another laboratory, on the same sample by fluorescent in situ hybridization and/or immunochemistry. We found a very good concordance between all these techniques, thus validating our immunocytochemical method on cytological samples according to the ISO 15189 norm. (C) 2018 Elsevier Masson SAS. All rights reserved.
Published: 2019
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72. Promoter hypermethylation of genes encoding for RASSF/Hippo pathway members reveals specific alteration pattern in diffuse gliomas

Author: Gaëtane Planchard, Sylvie Lecot-Cotigny, Guénaëlle Levallet, Gérard Zalcman, Jean-Sébastien Guillamo, Emmanuèle Lechapt-Zalcman, Lien Bekaert, Christian Creveuil, Evelyne Emery, Elodie A. Pérès, Imagerie et Stratégies Thérapeutiques des pathologies Cérébrales et Tumorales (ISTCT), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Unité de Biostatistique et de Recherche Clinique (UBRC), 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 Neurochirurgie [CHU Caen], Laboratoire d'Anatomie Pathologique [CHU Caen], CIC - CHU Bichat, Institut National de la Santé et de la Recherche Médicale (INSERM), Service d’oncologie thoracique et essais précoces [CHU Bichat], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and GHU Paris Psychiatrie et Neurosciences
Subjects: 0301 basic medicine, Adult, Male, Adolescent, [SDV]Life Sciences [q-bio], [SDV.CAN]Life Sciences [q-bio]/Cancer, Protein Serine-Threonine Kinases, Pathology and Forensic Medicine, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Recurrence, medicine, Gene silencing, Humans, Hippo Signaling Pathway, Gene Silencing, Promoter Regions, Genetic, Gene, Aged, Neoplasm Staging, Aged, 80 and over, Hippo signaling pathway, business.industry, Tumor Suppressor Proteins, Astrocytoma, Promoter, Methylation, Glioma, DNA Methylation, Middle Aged, medicine.disease, Prognosis, 030104 developmental biology, 030220 oncology & carcinogenesis, DNA methylation, Cancer research, Molecular Medicine, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Oligodendroglioma, Neoplasm Grading, business, Signal Transduction
Abstract: Ras association domain family (RASSF)/Hippo pathway alterations are poorly characterized in diffuse gliomas. We assayed promoter methylation of LATS1/2, MST1(STK4)/MST2(STK3), RASSF1, RASSF2, Nore1A/RASSF5, RASSF6, and RASSF10 genes in 133 diffuse gliomas. The RASSF/Hippo pathway was highly silenced in gliomas, particularly RASSF1A (79.4%) and LATS2 (35.9%). The most frequent combination of promoter hypermethylation of one RASSF gene and one Hippo pathway member's gene was RASSF1/LATS2-coupled hypermethylation [n = 44 (33.08%)]. Hypermethylated profiles were related to IDH mutation, yet not randomly in IDH-mutated gliomas, because LATS2 promoter hypermethylation was more frequent in oligodendroglioma than in astrocytoma. RASSF1 and LATS2 promoter hypermethylation predicted a longer overall survival (OS). Considering hypermethylation of these two promoters, Cox proportional hazard regression analysis categorized the patients into three prognostic groups: i) high risk of death (n = 24; both RASSF1 and LATS2 unmethylated promoters; median OS, 13 months); ii) intermediate risk of death (n = 65; RASSF1 or LATS2 hypermethylated promoter; median OS, 50.5 months; HR = 3.3; 95% CI, 1.6–6.4; P = 0.001); and iii) low risk of death (n = 44; both RASSF1 and LATS2 hypermethylated promoters; median OS, 119 months; HR = 75.1; 95% CI, 3.3–15.1; P = 0.001). We have thus highlighted a simple two-gene (RASSF1/LATS2) methylation signature as a tool to stratify different prognostic groups of patients with diffuse glioma, adding further prognostic information within the IDH-mutated group.
Published: 2019
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73. Epidemiology of intrahepatic, perihilar, and distal cholangiocarcinoma in the French population

Author: Aimen Al Mahjoub, Véronique Bouvier, Guy Launoy, Andrea Mulliri, Céline Bazille, Arnaud Alves, Audrey Fohlen, Benjamin Menahem, Jean Lubrano, Unité de recherche interdisciplinaire pour la prévention et le traitement des cancers (ANTICIPE), 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)-Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Chirurgie Viscérale et Digestive [CHU Caen], CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Registre des cancers digestifs du Calvados [CHU Caen], Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-UNICANCER, Laboratoire d'Anatomie Pathologique [CHU Caen], Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Service de Radiologie [CHU Caen], Hypoxie, physiopathologies cérébrovasculaire et tumorale (CERVOxy), Imagerie et Stratégies Thérapeutiques des pathologies Cérébrales et Tumorales (ISTCT), Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), 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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU), Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-UNICANCER, and Bodescot, Myriam
Subjects: Male, Pediatrics, medicine.medical_specialty, Population, MEDLINE, [SDV.CAN]Life Sciences [q-bio]/Cancer, Cholangiocarcinoma, 03 medical and health sciences, Age Distribution, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Bile Ducts, Extrahepatic, Epidemiology, medicine, Humans, Sex Distribution, education, Survival rate, Aged, Aged, 80 and over, education.field_of_study, Hepatology, business.industry, Incidence, Incidence (epidemiology), Gastroenterology, Middle Aged, 3. Good health, Survival Rate, Bile Ducts, Intrahepatic, Bile Duct Neoplasms, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, 030220 oncology & carcinogenesis, Female, 030211 gastroenterology & hepatology, Age distribution, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, France, Presentation (obstetrics), business, Klatskin Tumor
Abstract: The objective of this study was to investigate the differences between cholangiocarcinoma (CC) subtypes in terms of incidence rate, clinical presentation, management and survival by applying a stable anatomical classification in a population-based study.Cancer data for the period 2000-2012 were obtained from a specialized digestive cancer registry in the Department of Calvados, France. Patients' files were checked, and the diagnosis was verified by two hepatobiliary surgeons. This approach prevents classifying perihilar cholangiocarcinoma (PHCC) as intrahepatic cholangiocarcinoma (ICC), thereby allowing an accurate estimation of their respective epidemiological characteristics.A total of 320 patients with CC were included. ICC represented 41% (130), whereas PHCC and distal cholangiocarcinoma represented 36 (116) and 23% (74), respectively. The mean age at the time of diagnosis differed significantly between the three subtypes (P0.05). ICC was discovered accidently more frequently than PHCC, which was associated significantly with clinical symptoms. No change in the incidence or survival rates of CC subtypes were noticed, except for PHCC, in which female individuals had a significantly shorter median and 5-year survival rate of 0% (P0.05).The frequency of PHCC is overestimated in the literature. The anatomical reclassification of CC subtypes shows the stability of their incidence and survival rates. Considering ICC and PHCC as two different entities implies the need to assign a specific topographic code for PHCC.
Published: 2019
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74. Implications of reconstruction protocol for histo-biological characterisation of breast cancers using FDG-PET radiomics

Author: Nicolas Aide, Jean-Michel Grellard, Thibault Salomon, Cécile Blanc-Fournier, Charline Lasnon, Christelle Levy, Service de médecine nucléaire [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), Unité de recherche interdisciplinaire pour la prévention et le traitement des cancers (ANTICIPE), Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN)-Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'Anatomie Pathologique [CHU Caen], Unité de Biostatistique et de Recherche Clinique (UBRC), Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), and Bodescot, Myriam
Subjects: lcsh:Medical physics. Medical radiology. Nuclear medicine, lcsh:R895-920, [SDV.CAN]Life Sciences [q-bio]/Cancer, computer.software_genre, 030218 nuclear medicine & medical imaging, Correlation, 18F-FDG-PET, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, Radiomics, [SDV.CAN] Life Sciences [q-bio]/Cancer, Voxel, Interquartile range, medicine, Radiology, Nuclear Medicine and imaging, Prospective cohort study, Cardiac imaging, Original Research, business.industry, Reconstruction algorithm, medicine.disease, 3. Good health, 030220 oncology & carcinogenesis, Reconstruction, Heterogeneity, Nuclear medicine, business, computer
Abstract: Background The aim of this study is to determine if the choice of the 18F-FDG-PET protocol, especially matrix size and reconstruction algorithm, is of importance to discriminate between immunohistochemical subtypes (luminal versus non-luminal) in breast cancer with textural features (TFs). Procedures Forty-seven patients referred for breast cancer staging in the framework of a prospective study were reviewed as part of an ancillary study. In addition to standard PET imaging (PSFWholeBody), a high-resolution breast acquisition was performed and reconstructed with OSEM and PSF (OSEMbreast/PSFbreast). PET standard metrics and TFs were extracted. For each reconstruction protocol, a prediction model for tumour classification was built using a random forests method. Spearman coefficients were used to seek correlation between PET metrics. Results PSFWholeBody showed lower numbers of voxels within VOIs than OSEMbreast and PSFbreast with median (interquartile range) equal to 130 (43–271), 316 (167–1042), 367 (107–1221), respectively (p
Published: 2018
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75. In Vivo Feasibility of Arterial Embolization with Permanent and Absorbable Suture: The FAIR-Embo Concept

Author: Vincent Vidal, Pauline Brige, Jean-François Hak, Benjamin Guillet, Mickaël Bobot, A Haffner, Jean-Michel Bartoli, Guy Moulin, A Jacquier, Gilles Soulez, Farouk Tradi, P. Gach, Sophie Chopinet, Département de Radiologie [Hôpital de la Timone - APHM], Hôpital de la Timone [CHU - APHM] (TIMONE), Centre Européen de Recherche en Imagerie médicale (CERIMED), Centre National de la Recherche Scientifique (CNRS)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-École Centrale de Marseille (ECM)-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU), Laboratoire d'Imagerie Interventionnelle Expérimentale (LIIE), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de chirurgie générale et viscérale [Hôpital de la Timone - APHM], Centre recherche en CardioVasculaire et Nutrition (C2VN), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de néphrologie et transplantation rénale [Hôpital de la Conception - APHM], Assistance Publique - Hôpitaux de Marseille (APHM)-Hôpital de la Conception [CHU - APHM] (LA CONCEPTION ), Service d'Anatomie Pathologique et de Neuropathologie [Hôpital de la Timone - CHU - APHM], Hôpital de la Timone [CHU - APHM] (TIMONE)-Assistance Publique - Hôpitaux de Marseille (APHM), Dpt Radiologie [Montréal], Université de Montréal [Montréal], Centre de résonance magnétique biologique et médicale (CRMBM), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS), HOPITAL NORD MARSEILLE - APHM - SERV RADIOPHARM, Départment de Radiologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-École Centrale de Marseille (ECM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Centre National de la Recherche Scientifique (CNRS), Department of Digestive Surgery University Hospital Timone, AP-HM, Département de Néphrologie et transplantation [Hôpital Saint Louis - APHP], Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Laboratoire d'Anatomie Pathologique-Neuropathologique [AP-HM Hôpital La Timone], Department of Radiology, Centre Hospitalier de l’Universite´ de Montre´al, Department of Radiopharmacy, AP-HM, Brige, Pauline, Assistance Publique - Hôpitaux de Marseille (APHM)-Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), and Université de Montréal (UdeM)
Subjects: medicine.medical_specialty, [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, Swine, medicine.medical_treatment, Life-threatening bleeding, [SDV]Life Sciences [q-bio], Absorbable suture, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, Embolization, 0302 clinical medicine, Life-threatening bleeding Emerging countries, In vivo, Absorbable Implants, medicine, Animals, Radiology, Nuclear Medicine and imaging, Polyglactin 910, ComputingMilieux_MISCELLANEOUS, Kidney, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, medicine.diagnostic_test, Sutures, business.industry, Embolization Agent, Polyethylene Terephthalates, Arterial Embolization, Angiography, Digital Subtraction, Digital subtraction angiography, Arteries, Embolization, Therapeutic, 3. Good health, Surgery, Emerging countries, [SDV] Life Sciences [q-bio], Non-absorbable suture, medicine.anatomical_structure, [SDV.IB.IMA] Life Sciences [q-bio]/Bioengineering/Imaging, Treatment Outcome, Models, Animal, Feasibility Studies, Cardiology and Cardiovascular Medicine, business, Tomography, X-Ray Computed, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Follow-Up Studies
Abstract: International audience; Purpose Arterial embolization has been shown to be effective and safe for the management of bleeding, especially for postpartum and pelvic traumatic bleeding. We propose to evaluate the proof of concept of feasibility and effectiveness of arterial embolization with absorbable and non-absorbable sutures in a porcine model. Materials and Methods In the acute setting (n = 1), several different arteries (mesenteric, splenic, pharyngeal, kidney) were embolized using non-absorbable sutures (NAS): Mersutures braided sutures (polyethylene terephthalate). In the chronic setting (n = 3), only lower pole renal arteries were embolized. On the right side, NAS was used, whereas on the left side embolization was realized with absorbable suture (AS): Vicryl((R)) braided suture (polyglactin 910). The chronic group was followed for 3 months. The pigs received contrast-enhanced CT the day before embolization (D-1), after the embolization (D0), at 1 month and 3 months after embolization (M1 and M3); digital subtraction angiography (DSA) was done at D0 and M3 and histological analysis at M3. Results All vascular targets were effectively embolized without any pre- or postoperative complications. Both DSAs and CTs at M3 showed a 100% recanalization rate for the AS embolization and a partial reversal rate for the NAS embolization. A renal hypotrophy in the embolized region was observed during both the M1 and M3 scans for both sutures (AS and NAS) with a clear hypotrophy for the NAS embolized kidney. Conclusion Embolization by AS and NAS (FAIR-Embo) is a feasible and effective treatment which opens up the possibility of global use of this inexpensive and widely available embolization agent.
Published: 2018
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76. Optimization of a dedicated protocol using a small-voxel PSF reconstruction for head-and-neck 18FDG PET/CT imaging in differentiated thyroid cancer

Author: Nicolas Aide, Stéphane Bardet, Renaud Ciappuccini, Cédric Desmonts, Cécile Blanc-Fournier, Idlir Licaj, Unité de recherche interdisciplinaire pour la prévention et le traitement des cancers (ANTICIPE), 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)-Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), Service de médecine nucléaire [CHU Caen], Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Centre de recherche clinique [CHU Caen] (CRC), Normandie Université (NU)-Normandie Université (NU)-Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Laboratoire d'Anatomie Pathologique [CHU Caen], Bodescot, Myriam, 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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-UNICANCER, and Normandie Université (NU)
Subjects: lcsh:Medical physics. Medical radiology. Nuclear medicine, Focus (geometry), lcsh:R895-920, [SDV.CAN]Life Sciences [q-bio]/Cancer, Iterative reconstruction, computer.software_genre, Thyroid cancer, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Voxel, Medicine, List-mode acquisition, Radiology, Nuclear Medicine and imaging, Lymph node, Cardiac imaging, Original Research, business.industry, 18FDG PET/CT, Cancer, medicine.disease, Point spread function, 3. Good health, medicine.anatomical_structure, Cervical lymph nodes, 030220 oncology & carcinogenesis, business, Nuclear medicine, computer, Head and neck imaging
Abstract: International audience; BACKGROUND:18FDG PET/CT is crucial before neck surgery for nodal recurrence localization in iodine-refractory differentiated or poorly differentiated thyroid cancer (DTC/PDTC). A dedicated head-and-neck (HN) acquisition performed with a thin matrix and point-spread-function (PSF) modelling in addition to the whole-body PET study has been shown to improve the detection of small cancer deposits. Different protocols have been reported with various acquisition times of HN PET/CT. We aimed to compare two reconstruction algorithms for disease detection and to determine the optimal acquisition time per bed position using the Siemens Biograph6 with extended field-of-view.METHODS:Twenty-one consecutive and unselected patients with DTC/PDTC underwent HN PET/CT acquisition using list-mode. PET data were reconstructed, mimicking five different acquisition times per bed position from 2 to 10 min. Each PET data set was reconstructed using 3D-ordered subset expectation maximisation (3D-OSEM) or iterative reconstruction with PSF modelling with no post filtering (PSFallpass). These reconstructions resulted in 210 anonymized datasets that were randomly reviewed to assess 18FDG uptake in cervical lymph nodes or in the thyroid bed using a 5-point scale. Noise level, maximal standard uptake values (SUVmax), tumour/background ratios (TBRs) and dimensions of the corresponding lesion on the CT scan were recorded. In surgical patients, the largest tumoral size of each lymph node metastasis was measured by a pathologist.RESULTS:The 120 HN PET studies of the 12 patients with at least 1 18FDG focus scored malignant formed the study group. Noise level significantly decreased between 2 and 4 min for both 3D-OSEM and PSFallpass reconstructions (p
Published: 2018
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77. A recurrent point mutation in PRKCA is a hallmark of chordoid gliomas

Author: Shai Rosenberg, Franck Bielle, Iva Simeonova, Isabelle Le Roux, Vincent Gleize, Marine Giry, Marie-Hélène Aubriot-Lorton, Emmanuelle Huillard, Bertille Bance, Michel Kalamarides, Anna Lasorella, Sophie Paris, Marc Sanson, Chiara Villa, Alexandre Vasiljevic, Dominique Figarella-Branger, Mailys Daniau, Antonio Iavarone, Emmanuèle Lechapt-Zalcman, Stefano Maria Pagnotta, Ariane Sharif, Karima Mokhtari, Marc Polivka, Maite Verreault, Aravindan Arun Nadaradjane, Yannick Marie, Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Sharett Institute of Oncology [Jerusalem, Israel], Hadassah Medical Organization [Jerusalem, Israel], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), ONERA - The French Aerospace Lab [Châtillon], ONERA-Université Paris Saclay (COmUE), Biologie des Interactions Neurones / Glie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), OncoNeuroTek [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Hôpital Lariboisière, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Laboratoire d'Anatomie Pathologique-Neuropathologique [AP-HM Hôpital La Timone], Hôpital de la Timone [CHU - APHM] (TIMONE), Institut de neurophysiopathologie (INP), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Cognition, Action, et Plasticité Sensorimotrice [Dijon - U1093] (CAPS), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Foch [Suresnes], Service Maladies Héréditaires du Métabolisme et Dépistage Néonatal [CHU Lyon] (Centre de Biologie et Pathologie Est), Hospices Civils de Lyon (HCL)-Groupement Hospitalier Est, Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Herbert Irving Comprehensive Cancer Center, Columbia University [New York], Departments of Pathology and Laboratory Medicine (Neuropathology) and Neurology, UCLA Medical Center-David Geffen School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), University of California (UC)-University of California (UC)-University of California [Los Angeles] (UCLA), University of California (UC)-University of California (UC), ANR-10-IAHU-0006,IHU-A-ICM,Institut de Neurosciences Translationnelles de Paris(2010), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Neuropathologie Raymond Escourolle, Assistance publique - Hôpitaux de Paris (AP-HP) (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)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Université Paris Diderot - Paris 7 (UPD7)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Service de Neurochirurgie [CHU Pitié-Salpêtrière], 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, University of California-University of California-University of California [Los Angeles] (UCLA), University of California-University of California, Service de neurologie 2 [CHU Pitié-Salpêtrière], Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP]-Sorbonne Université (SU), ONERA, Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Lariboisière-Université Paris Diderot - Paris 7 (UPD7), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], 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, and program 'Investissements d'avenir' ANR-10-IAIHU-06,program 'Investissements d'avenir' ANR-10-IAIHU-06
Subjects: 0301 basic medicine, Adult, Male, Protein Kinase C-alpha, Science, [SDV]Life Sciences [q-bio], Mutant, function predictions, General Physics and Astronomy, medicine.disease_cause, Isozyme, General Biochemistry, Genetics and Molecular Biology, Cell membrane, 03 medical and health sciences, medicine, Humans, Point Mutation, lcsh:Science, Cancer genetics, Protein kinase C, Cells, Cultured, Aged, Cell Proliferation, eIF2, Multidisciplinary, Chemistry, Cell growth, Point mutation, General Chemistry, Glioma, Middle Aged, Molecular biology, 3. Good health, 030104 developmental biology, medicine.anatomical_structure, OncogenesProtein, Female, lcsh:Q, Carcinogenesis, Cerebral Ventricle Neoplasms
Abstract: Chordoid glioma (ChG) is a characteristic, slow growing, and well-circumscribed diencephalic tumor, whose mutational landscape is unknown. Here we report the analysis of 16 ChG by whole-exome and RNA-sequencing. We found that 15 ChG harbor the same PRKCA D463H mutation. PRKCA encodes the Protein kinase C (PKC) isozyme alpha (PKCα) and is mutated in a wide range of human cancers. However the hot spot PRKCA D463H mutation was not described in other tumors. PRKCA D463H is strongly associated with the activation of protein translation initiation (EIF2) pathway. PKCαD463H mRNA levels are more abundant than wild-type PKCα transcripts, while PKCαD463H is less stable than the PCKαWT protein. Compared to PCKαWT, the PKCαD463H protein is depleted from the cell membrane. The PKCαD463H mutant enhances proliferation of astrocytes and tanycytes, the cells of origin of ChG. In conclusion, our study identifies the hallmark mutation for chordoid gliomas and provides mechanistic insights on ChG oncogenesis.
Published: 2018
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78. Germline HAVCR2 mutations altering TIM-3 characterize subcutaneous panniculitis-like T cell lymphomas with hemophagocytic lymphohistiocytic syndrome

Author: Fernando E. Sepulveda, Geneviève de Saint Basile, Patrick Nitschke, Stéphane Blanche, Maxime Battistella, David Michonneau, Nada Jabado, Shriya Deshmukh, David Mitchell, Christine Bole-Feysot, Janie Charlebois, Bénédicte Neven, Hamid Nikbakht, Mikko Taipale, Paul G Ekert, Christopher McCormack, William D. Foulkes, Leonie G. Mikael, Alexandrine Garrigue, Dzana Dervovic, Nancy Hamel, Andrea Bajic, Simon Gravel, Despina Moshous, Sharon Abish, Frank Sicheri, Rachel Conyers, Van-Hung Nguyen, Frédéric Guerin, Susan Kelso, Sylvie Fraitag, H. Miles Prince, Jean-Sebastien Diana, Rola Dali, Marianne Besnard, Jonathan Pratt, Elvis Terci Valera, Dong-Anh Khuong-Quang, Catherine Thieblemont, Alain Fischer, Tenzin Gayden, Jacek Majewski, Brigitte Bader-Meunier, Daniel Schramek, Department of Human Genetics [Montréal], McGill University = Université McGill [Montréal, Canada], Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Children’s Cancer Center, The Royal Children’s Hospital and Murdoch Children’s Research Institute, Parkville, Victoria, Australia, Department of Pediatrics, University of Melbourne, Parkville, Victoria, Australia, Department of Pediatrics, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil, Developpement Normal et Pathologique du Système Immunitaire, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Molecular Genetics [Toronto], University of Toronto, Cancer Research Program, Research Institute of the McGill University Health Center, Montreal, Quebec, Canada, Canadian Centre for Computational Genomics, Montreal, Canada, Division of Experimental Medicine [Montréal, QC, Canada] (Department of Medicine), McGill University Health Center [Montreal] (MUHC), Lunenfeld-Tanenbaum Research Institute [Toronto, Canada], Géosciences Environnement Toulouse (GET), Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Observatoire Midi-Pyrénées (OMP), Météo France-Centre National d'Études Spatiales [Toulouse] (CNES)-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Météo France-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD), McGill University and Genome Quebec Innovation Centre, Centre de Référence Déficits Immunitaires Héréditaires (CEREDIH), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Pediatric Hematology Oncology, Montreal Children's Hosp., Montreal, Canada, Nutrition, inflammation et dysfonctionnement de l'axe intestin-cerveau (ADEN), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service Immunologie et Hématologie, Space Sciences Laboratory [Berkeley] (SSL), University of California [Berkeley], University of California-University of California, Gvh et Gvl : Physiopathologie Chez l'Homme et Chez l'Animal, Incidence et Role Therapeutique, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Anatomie pathologique [CHU Saint-Louis], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Department of Pathology, Montreal Children’s Hospital, McGill University Health Centre, Montreal, Quebec, Canada, Département d'Immunologie, hématologie et rhumatologie pédiatriques [Hôpital Necker-Enfants malades - APHP], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Department of Dermatology, St. Vincent’s Hospital, Fitzroy, Victoria, Australia, Department of Oncology [Melbourne, Australie], Peter MacCallum Cancer Centre [Melbourne, Australie], Department of Neonatology, Centre Hospitalier de Polynésie Française, Papeete, French Polynesia, Service d'immuno-hématologie pédiatrique [CHU Necker], epartment of Pediatrics, University of Melbourne, Parkville, Victoria, Australia, Laboratoire d'anatomie pathologique [CHU Necker], Chaire Médecine expérimentale (A. Fischer), Collège de France (CdF (institution)), Department of Human Genetics , Department of Experimental Medicine, Radboud University Medical Center [Nijmegen], Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Observatoire Midi-Pyrénées (OMP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Centre National d'Études Spatiales [Toulouse] (CNES), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), and McGill University
Subjects: 0301 basic medicine, Adult, Male, Panniculitis, Adolescent, T cell, [SDV]Life Sciences [q-bio], Biology, HAVCR2, Lymphoma, T-Cell, Lymphohistiocytosis, Hemophagocytic, Diagnosis, Differential, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Immune system, Germline mutation, Subcutaneous Panniculitis-Like T-Cell Lymphoma, Exome Sequencing, Genetics, medicine, T-cell lymphoma, Humans, Genetic Predisposition to Disease, Child, Hepatitis A Virus Cellular Receptor 2, Germ-Line Mutation, ComputingMilieux_MISCELLANEOUS, Aged, Aged, 80 and over, Hemophagocytic lymphohistiocytosis, [SDV.GEN]Life Sciences [q-bio]/Genetics, Innate immune system, Infant, Middle Aged, medicine.disease, 3. Good health, Pedigree, 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Immunology, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female
Abstract: Subcutaneous panniculitis-like T cell lymphoma (SPTCL), a non-Hodgkin lymphoma, can be associated with hemophagocytic lymphohistiocytosis (HLH), a life-threatening immune activation that adversely affects survival1,2. T cell immunoglobulin mucin 3 (TIM-3) is a modulator of immune responses expressed on subgroups of T and innate immune cells. We identify in ~60% of SPTCL cases germline, loss-of-function, missense variants altering highly conserved residues of TIM-3, c.245A>G (p.Tyr82Cys) and c.291A>G (p.Ile97Met), each with specific geographic distribution. The variant encoding p.Tyr82Cys TIM-3 occurs on a potential founder chromosome in patients with East Asian and Polynesian ancestry, while p.Ile97Met TIM-3 occurs in patients with European ancestry. Both variants induce protein misfolding and abrogate TIM-3’s plasma membrane expression, leading to persistent immune activation and increased production of inflammatory cytokines, including tumor necrosis factor-α and interleukin-1β, promoting HLH and SPTCL. Our findings highlight HLH–SPTCL as a new genetic entity and identify mutations causing TIM-3 alterations as a causative genetic defect in SPTCL. While HLH–SPTCL patients with mutant TIM-3 benefit from immunomodulation, therapeutic repression of the TIM-3 checkpoint may have adverse consequences.
Published: 2018
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79. Prostate cancer heterogeneity: texture analysis score based on multiple magnetic resonance imaging sequences for detection, stratification and selection of lesions at time of biopsy

Author: Arnauld Villers, Audrey Fohlen, Francesco Giganti, Myriam Bernaudin, Céline Bazille, Henry Rusinek, Mark Emberton, Artem Mikheev, Vincent Lepennec, Clement Orczyk, Samuel Valable, Imagerie et Stratégies Thérapeutiques des pathologies Cérébrales et Tumorales (ISTCT), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), University College London Hospitals (UCLH), Service d'Urologie [CHU Caen], Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Division of Surgery and Interventional Science [London, UK], University College of London [London] (UCL), Service d'Urologie, andrologie et transplantation rénale [CHRU Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service de Radiologie [CHU Caen], Laboratoire d'Anatomie Pathologique [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), Department of Radiology, New York University Langone Medical Center, New York, NY, New York University [New York] (NYU), NYU System (NYU)-NYU System (NYU), Department of Urology [London, UK] (Charing Cross Hospital), Imperial College NHS Trust [London, UK] -Charing Cross Hospital [London, UK], and Imperial College London-Charing Cross Hospital [London, UK]
Subjects: Male, Urology, Proof of Concept Study, 030218 nuclear medicine & medical imaging, Correlation, Cohort Studies, 03 medical and health sciences, Prostate cancer, 0302 clinical medicine, McNemar's test, stratification, Predictive Value of Tests, Biopsy, medicine, Image Processing, Computer-Assisted, Humans, biopsy, Multiparametric Magnetic Resonance Imaging, Aged, PCSM, medicine.diagnostic_test, Receiver operating characteristic, business.industry, Prostate Cancer, [SCCO.NEUR]Cognitive science/Neuroscience, Area under the curve, Prostatic Neoplasms, Magnetic resonance imaging, Middle Aged, medicine.disease, Confidence interval, Detection, MRI image, ROC Curve, radiomics, 030220 oncology & carcinogenesis, processing, Neoplasm Grading, Nuclear medicine, business
Abstract: OBJECTIVE To undertake an early proof-of-concept study on a novel, semi-automated texture-based scoring system in order to enhance the association between magnetic resonance imaging (MRI) lesions and clinically significant prostate cancer (SPCa). PATIENTS AND METHODS With ethics approval, 536 imaging volumes were generated from 20 consecutive patients who underwent multiparametric MRI (mpMRI) at time of biopsy. Volumes of interest (VOIs) included zonal anatomy segmentation and suspicious MRI lesions for cancer (Likert Scale score >2). Entropy (E), measuring heterogeneity, was computed from VOIs and plotted as a multiparametric score defined as the entropy score (ES) = E ADC + E Ktrans + E Ve + E T2WI. The reference test that was used to define the ground truth comprised systematic saturation biopsies coupled with MRI-targeted sampling. This generated 422 cores in all that were individually labelled and oriented in three-dimensions. Diagnostic accuracy for detection of SPCa, defined as Gleason score ≥3 + 4 or >3 mm of any grade of cancer on a single core, was assessed using receiver operating characteristics, correlation, and descriptive statistics. The proportion of cancerous lesions detected by ES and visual scoring (VS) were statistically compared using the paired McNemar test. RESULTS Any cancer (Gleason score 6-8) was found in 12 of the 20 (60%) patients, with a median PSA level of 8.22 ng/mL. SPCa (mean [95% confidence interval, CI] ES = 17.96 [0.72] NATural information unit [NAT]) had a significantly higher ES than non-SPCa (mean [95% CI] ES = 15.33 [0.76] NAT). The ES correlated with Gleason score (rs = 0.568, P = 0.033) and maximum cancer core length (ρ = 0.781; P < 0.001). The area under the curve for the ES (0.89) and VS (0.91) were not significantly different (P = 0.75) for the detection of SPCa amongst MRI lesions. Best ES estimated numerical threshold of 16.61 NAT led to a sensitivity of 100% and negative predictive value of 100%. The proportion of MRI lesions that were found to be positive for SPCa using this ES threshold (54%) was significantly higher (P < 0.001) than using the VS (24% of score 3, 4, 5) in a paired analysis using the McNemar test. In all, 53% of MRI lesions would have avoided biopsy sampling without missing significant disease. CONCLUSION Capturing heterogeneity of prostate cancer across multiple MRI sequences with the ES yielded high performances for the detection and stratification of SPCa. The ES outperformed the VS in predicting positivity of lesions, holding promise in the selection of targets for biopsy and calling for further understanding of this association.
Published: 2018
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80. A role for RASSF1A in tunneling nanotube formation between cells through GEFH1/Rab11 pathway control

Author: Dubois, Fatéméh, Jean-Jacques, Bastien, Roberge, Hélène, Bénard, Magalie, Galas, Ludovic, Schapman, Damien, Elie, Nicolas, Goux, Didier, Keller, Maureen, Maille, Elodie, Bergot, Emmanuel, Zalcman, Gérard, Levallet, Guénaëlle, Hypoxie, physiopathologies cérébrovasculaire et tumorale (CERVOxy), Imagerie et Stratégies Thérapeutiques des pathologies Cérébrales et Tumorales (ISTCT), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Anatomie Pathologique [CHU Caen], Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Plate-Forme de Recherche en Imagerie Cellulaire de Haute-Normandie (PRIMACEN), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Normandie Université (NU)-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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-High-tech Research Infrastructures for Life Sciences (HeRacLeS), Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Interactions Cellules Organismes Environnement (ICORE), Œstrogènes, reproduction, cancer (OeReCa), Normandie Université (NU)-Normandie Université (NU), Cancers et préventions, Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de pneumologie [CHU Caen], Unité de génétique et biologie des cancers (U830), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d’oncologie thoracique et essais précoces [CHU Bichat], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Couteau, Florence, Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Normandie Université (NU)-Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rouen Normandie (UNIROUEN), and Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: lcsh:Cytology, Research, Tumor Suppressor Proteins, [SCCO.NEUR]Cognitive science/Neuroscience, Cell Membrane, lcsh:R, [SCCO.NEUR] Cognitive science/Neuroscience, lcsh:Medicine, Actomyosin, RASSF1A, Exosomes, Cell Line, Pleural and lung cancer, Intercellular communication, rab GTP-Binding Proteins, Gene Knockdown Techniques, Rab11, Humans, Vimentin, Gene Silencing, lcsh:QH573-671, GEF-H1, Extracellular Space, Tunneling nanotubes, Rho Guanine Nucleotide Exchange Factors
Abstract: Background By allowing intercellular communication between cells, tunneling nanotubes (TNTs) could play critical role in cancer progression. If TNT formation is known to require cytoskeleton remodeling, key mechanism controlling their formation remains poorly understood. Methods The cells of human bronchial (HBEC-3, A549) or mesothelial (H2452, H28) lines are transfected with different siRNAs (inactive, anti-RASSF1A, anti-GEFH1 and / or anti-Rab11). At 48 h post-transfection, i) the number and length of the nanotubes per cell are quantified, ii) the organelles, previously labeled with specific tracers, exchanged via these structures are monitored in real time between cells cultured in 2D or 3D and in normoxia, hypoxia or in serum deprivation condition. Results We report that RASSF1A, a key-regulator of cytoskeleton encoded by a tumor-suppressor gene on 3p chromosome, is involved in TNTs formation in bronchial and pleural cells since controlling proper activity of RhoB guanine nucleotide exchange factor, GEF-H1. Indeed, the GEF-H1 inactivation induced by RASSF1A silencing, leads to Rab11 accumulation and subsequent exosome releasing, which in turn contribute to TNTs formation. Finally, we provide evidence involving TNT formation in bronchial carcinogenesis, by reporting that hypoxia or nutriment privation, two almost universal conditions in human cancers, fail to prevent TNTs induced by the oncogenic RASSF1A loss of expression. Conclusions This finding suggests for the first time that loss of RASSF1A expression could be a potential biomarker for TNTs formation, such TNTs facilitating intercellular communication favoring multistep progression of bronchial epithelial cells toward overt malignancy. Electronic supplementary material The online version of this article (10.1186/s12964-018-0276-4) contains supplementary material, which is available to authorized users.
Published: 2018
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81. Identification of novel recurrent ETV6-IgH fusions in primary central nervous system lymphoma

Author: Dominique Figarella-Branger, Franck Bielle, Clovis Adam, Louis Royer-Perron, Guillaume Gauchotte, David Meyronet, Aurélie Bruno, Chiara Villa, Amithys Rahimian, Blandine Boisselier, Carole Soussain, Fabrice Chrétien, Khê Hoang-Xuan, Caroline Houillier, Sandrine Eimer, Mailys Daniau, Frederic Davi, Karima Mokhtari, Karim Labreche, Justine Guegan, Pierre de la Grange, Agusti Alentorn, Marc Polivka, Audrey Rousseau, Frédéric Lemoine, Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), OncoNeuroTek [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], GenoSplice, Ltd, GenoSplice technology, GenoSplice [Paris], iCONICS, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d’Anatomopathologie [Le Kremlin-Bicêtre], AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Hospices civils de Lyon, hôpital neurologique Pierre-Wertheimer, Laboratoire d'Anatomie Pathologique-Neuropathologique [AP-HM Hôpital La Timone], Hôpital de la Timone [CHU - APHM] (TIMONE), Service de Pathologie [Hôpital Foch], Hôpital Foch [Suresnes], Centre Hospitalier Sainte Anne [Paris], Centre Hospitalier Universitaire de Bordeaux (CHU de Bordeaux), Département de Pathologie Cellulaire et Tissulaire [CHU Angers] (Laboratoire d’Histopathologie-Cytopathologie), Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Hôpital René HUGUENIN (Saint-Cloud), This work is part of the national program Cartes d’Identité des Tumeurs (CIT) funded and developed by the Ligue nationale contre le cancer, the Institut National du Cancer, Association pour la recherche sur les tumeurs cérébrales (ARTC), Cancéropôle Île-de-France 'Emergence 2015-1' (2015-1-EMERG-05-INSERM 6-1), Ligue nationale contre le cancer (Comité du Val d’Oise, R14044DD), Ligue Nationale contre le cancer 'Recherche épidemiologique' (N° PRE2015.LNCC), Fondation pour la Recherche Médicale (FDT20140930968), and the program 'Investissements d’avenir' ANR-10-IAIHU-06, and the Institut National du Cancer (INCa) (Réseau Expert National LOC, Lymphomes Oculo-Cérébraux). This study was supported by the Lymphomes Oculo-Cérébraux (LOC) study group network (Réseau national de centres experts des lymphomes primitifs du système nerveux central), We would like to thank the French LOC Network investigators. Specimens from Marseille were retrieved from the AP-HM tumor bank AC 2013-1786, ANR-10-IAHU-0006,IHU-A-ICM,Institut de Neurosciences Translationnelles de Paris(2010), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Incubateur et Pépinière d'Entreprises Paris-Salpêtrière (iPEPS-ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'Hématologie clinique [CHU Pitié-Salpêtrière], Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de neurologie 1 [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)
Subjects: 0301 basic medicine, Male, Cancer Research, Oncogene Proteins, Fusion, MESH: Central Nervous System Neoplasms, Fusion gene, Central Nervous System Neoplasms, 0302 clinical medicine, hemic and lymphatic diseases, MESH: Middle Aged, medicine.diagnostic_test, Primary central nervous system lymphoma, RNA sequencing, ETV6-IgH, MESH: Follow-Up Studies, Middle Aged, Prognosis, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], 3. Good health, Survival Rate, Oncology, fusion gene, MESH: Repressor Proteins, 030220 oncology & carcinogenesis, Basic and Translational Investigations, Female, Lymphoma, Large B-Cell, Diffuse, MESH: Biomarkers, Tumor, Haploinsufficiency, Immunoglobulin Heavy Chains, MESH: Immunoglobulin Heavy Chains, MESH: Proto-Oncogene Proteins c-ets, MESH: Survival Rate, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, MESH: Prognosis, 03 medical and health sciences, primary CNS lymphoma, medicine, Biomarkers, Tumor, Humans, Survival rate, MESH: Humans, Proto-Oncogene Proteins c-ets, medicine.disease, MESH: Male, Lymphoma, haploinsufficiency, Repressor Proteins, ETV6, 030104 developmental biology, Cancer research, Immunoglobulin heavy chain, MESH: Lymphoma, Large B-Cell, Diffuse, Neurology (clinical), MESH: Female, Fluorescence in situ hybridization, Follow-Up Studies, MESH: Oncogene Proteins, Fusion
Abstract: International audience; Background: Primary central nervous system lymphoma (PCNSL) represents a particular entity within non-Hodgkin lymphomas and is associated with poor outcome. The present study addresses the potential clinical relevance of chimeric transcripts in PCNSL discovered by using RNA sequencing (RNA-seq).Methods: Seventy-two immunocompetent and newly diagnosed PCNSL cases were included in the present study. Among them, 6 were analyzed by RNA-seq to detect new potential fusion transcripts. We confirmed the results in the remaining 66 PCNSL. The gene fusion was validated by fluorescence in situ hybridization (FISH) using formalin-fixed paraffin-embedded (FFPE) samples. We assessed the biological and clinical impact of one new gene fusion.Results: We identified a novel recurrent gene fusion, E26 transformation-specific translocation variant 6-immunoglobulin heavy chain (ETV6-IgH). Overall, ETV6-IgH was found in 13 out of 72 PCNSL (18%). No fusion conserved an intact functional domain of ETV6, and ETV6 was significantly underexpressed at gene level, suggesting an ETV6 haploinsufficiency mechanism. The presence of the gene fusion was also validated by FISH in FFPE samples. Finally, PCNSL samples harboring ETV6-IgH showed a better prognosis in multivariate analysis, P = 0.03, hazard ratio = 0.33, 95% CI = 0.12-0.88. The overall survival at 5 years was 69% for PCNSL harboring ETV6-IgH versus 29% for samples without this gene fusion.Conclusions: ETV6-IgH is a new potential surrogate marker of PCNSL with favorable prognosis with ETV6 haploinsufficiency as a possible mechanism. The potential clinical impact of ETV6-IgH should be validated in larger prospective studies.
Published: 2018
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82. New insights into diagnosis and therapeutic options for proliferative hepatoblastoma

Author: Christophe Grosset, Benoit Rousseau, Thérèse Commes, Katarzyna B. Hooks, Tony Ernault, Nathalie Dugot-Senant, Anne Rullier, Anne-Aurélie Raymond, Marie-Annick Buendia, Jérôme Audoux, Sophie Branchereau, Laurence Brugières, Monique Fabre, Coralie Danet, Sarah Lesjean, Martin Hagedorn, Helena Fazli, Thierry Leste-Lasserre, Sophie Taque, Catherine Guettier, Biothérapies des maladies génétiques et cancers, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), SeqOne [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-CHU Saint-Eloi, Physiopathologie du cancer du foie, Physiopathologie et traitement des maladies du foie, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AP-HP Hôpital Paul Brousse, Pathologies infectieuses et cancers : aspects biologiques et thérapeutiques (PICABT), Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Institut Bergonié - CRLCC Bordeaux-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U1215, Institut National de la Santé et de la Recherche Médicale (INSERM), Mécanismes moléculaires de l'angiogénèse, Animalerie A2, Université Bordeaux Segalen - Bordeaux 2, Département de chirurgie pédiatrique, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Bicêtre, Département de cancérologie de l'enfant et de l'adolescent [Gustave Roussy], Institut Gustave Roussy (IGR), Service d'Hématologie et d'Oncologie pédiatrique, CHU Pontchaillou [Rennes], Departement de Pathologie, Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Paul Brousse, Hôpital Bicêtre, Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Bicêtre, Service de pathologie [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Cellules souches normales et cancéreuses, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), Fibrose hépatique et cancer du foie, Université Bordeaux Segalen - Bordeaux 2-IFR66-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de pharmacologie et de biologie structurale (IPBS), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Hooks, Katarzyna, Initiative d'excellence de l'Université de Bordeaux - - IDEX BORDEAUX2010 - ANR-10-IDEX-0003 - IDEX - VALID, Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Neurocentre Magendie : Physiopathologie de la Plasticité Neuronale (U1215 Inserm - UB), Université de Bordeaux (UB)-Institut François Magendie-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Bordeaux Ségalen [Bordeaux 2], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Service de médecine de l'enfant et de l'adolescent [CHU Rennes], Virus Hépatotropes et Cancers, Université Paris-Sud - Paris 11 (UP11)-IFR89-EA 3541, Laboratoire départemental de la Côte d'Or, Conseil General, Laboratoire d'anatomie pathologique, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), ANR-10-IDEX-0003,IDEX BORDEAUX,Initiative d'excellence de l'Université de Bordeaux(2010), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), INSERM, Neurocentre Magendie, U1215, Physiopathologie de la Plasticité Neuronale, F-33000 Bordeaux, France, Service de médecine de l'enfant et de l'adolescent, 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)-Hôpital Paul Brousse-Université Paris-Sud - Paris 11 (UP11), Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Institut Bergonié [Bordeaux], UNICANCER-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse, Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, and Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)
Subjects: 0301 basic medicine, Hepatoblastoma, DNA Repair, [SDV]Life Sciences [q-bio], Antineoplastic Agents, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, liver cancer, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Fanconi anemia, medicine, cancer stratification, Humans, Poly-ADP-Ribose Binding Proteins, ComputingMilieux_MISCELLANEOUS, Hepatology, Sequence Analysis, RNA, Bortezomib, Gene Expression Profiling, Liver Neoplasms, bortezomib, Hep G2 Cells, hepatoblastoma, medicine.disease, Fanconi Anemia Complementation Group Proteins, 3. Good health, Gene expression profiling, [SDV] Life Sciences [q-bio], DNA Topoisomerases, Type II, 030104 developmental biology, Fanconi Anemia, Immunology, Cancer research, Proteasome inhibitor, Immunohistochemistry, Liver cancer, ITGA6, Biomarkers, medicine.drug
Abstract: Surgery and cisplatin-based treatment of hepatoblastoma (HB) currently guarantee the survival of 70%-80% of patients. However, some important challenges remain in diagnosing high-risk tumors and identifying relevant targetable pathways offering new therapeutic avenues. Previously, two molecular subclasses of HB tumors have been described, C1 and C2, with C2 being the subgroup with the poorest prognosis, a more advanced tumor stage, and the worst overall survival rate. An associated 16-gene signature to discriminate the two tumoral subgroups was proposed, but it has not been transferred into clinical routine. To address these issues, we performed RNA sequencing of 25 tumors and matched normal liver samples from patients. The transcript profiling separated HB into three distinct subgroups named C1, C2A, and C2B, identifiable by a concise four-gene signature: hydroxysteroid 17-beta dehydrogenase 6, integrin alpha 6, topoisomerase 2-alpha, and vimentin, with topoisomerase 2-alpha being characteristic for the proliferative C2A tumors. Differential expression of these genes was confirmed by quantitative RT-PCR on an expanded cohort and by immunohistochemistry. We also revealed significant overexpression of genes involved in the Fanconi anemia (FA) pathway in the C2A subgroup. We then investigated the ability of several described FA inhibitors to block growth of HB cells in vitro and in vivo. We demonstrated that bortezomib, a Food and Drug Administration-approved proteasome inhibitor, strongly impairs the proliferation and survival of HB cell lines in vitro, blocks FA pathway-associated double-strand DNA repair, and significantly impedes HB growth in vivo.The highly proliferating C2A subtype is characterized by topoisomerase 2-alpha gene up-regulation and FA pathway activation, and the HB therapeutic arsenal could include bortezomib for the treatment of patients with the most aggressive tumors. (Hepatology 2018;68:89-102).
Published: 2018
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83. Genetic analyses of undifferentiated small round cell sarcoma identifies a novel sarcoma subtype with a recurrent CRTC1-SS18 gene fusion

Author: Alholle, Abdullah, Karanian, Marie, Brini, Anna T., Morris, Mark R., Kannappan, Vinodh, Niada, Stefania, Niblett, Angela, Ranchère-Vince, Dominique, Daniel PISSALOUX, Delfour, Christophe, Maran-Gonzalez, Aurelie, Antonescu, Cristina R., Sumathi, Vaiyapuri, Tirode, Franck, Latif, Farida, University of Birmingham [Birmingham], 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-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Léon Bérard [Lyon], University of Milan, Istituto Ortopedico Galeazzi-IRCCS, University of Wolverhampton, Robert Aitken Institute of Clinical Research [Birmingham], Laboratoire d’Anatomie Pathologique [CHU Gui de Chauliac], Centre Hospitalier Universitaire de Montpellier (CHU Montpellier ), Institut du Cancer de Montpellier (ICM), Memorial Sloane Kettering Cancer Center [New York], TIRODE, Franck, Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Università degli Studi di Milano = University of Milan (UNIMI)
Subjects: Adult, Male, undifferentiated small round cell sarcoma, Soft Tissue Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Article, [SDV.CAN] Life Sciences [q-bio]/Cancer, Cell Movement, Proto-Oncogene Proteins, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Biomarkers, Tumor, Humans, Genetic Predisposition to Disease, Neoplasm Invasiveness, Cell Proliferation, gene fusion, Cell Differentiation, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Repressor Proteins, HEK293 Cells, Phenotype, Molecular Diagnostic Techniques, Sarcoma, Small Cell, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Female, RNA-seq, Ewing sarcoma, Transcription Factors
Abstract: In recent years, undifferentiated small round cell sarcomas (USRCSs) have been divided into a variety of new, rare, sarcoma subtypes, including the group of Ewing-like sarcomas, which have the morphological appearance of Ewing sarcomas, but carry CIC-DUX4, BCOR-CCNB3 and other gene fusions different from the classic EWSR1-ETS gene fusion. Using high-throughput RNA-sequencing (RNA-seq) analyses, we identified a novel recurrent gene fusion, CRTC1-SS18, in two cases of USRCS that lacked any known translocation. RNA-seq results were confirmed by reverse transcription polymerase chain reaction, long-range polymerase chain reaction, and fluorescence in situ hybridization. In vitro, we showed that the cells expressing the gene fusion were morphologically distinct and had enhanced oncogenic potential as compared with control cells. Expression profile comparisons with tumours of other sarcoma subtypes demonstrated that both cases clustered close to EWSR1-CREB1-positive tumours. Moreover, these analyses indicated enhanced NTRK1 expression in CRTC1-SS18-positive tumours. We conclude that the novel gene fusion identified in this study adds a new subtype to the USRCSs with unique gene signatures, and may be of therapeutic relevance. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John WileySons, Ltd.
Published: 2018
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84. A Collet–Sicard syndrome due to internal carotid artery dissection associated with cerebral amyloid angiopathy–related inflammation

Author: Pascale Marcorelles, François Rouhart, Dewi Guellec, Douraied Ben Salem, Vanessa Saliou, Serge Timsit, Fabien Zagnoli, Julien Ognard, CHRU Brest - Service d'Imagerie médicale (CHU - Brest - HM), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), CHRU Brest - Service de Rhumatologie (CHU - BREST - Rhumato), CIC Brest, Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital de la Cavale Blanche, Laboratoire d'Anatomie Pathologique, Hôpital Morvan Brest-Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Service de Neurologie [Brest], Hôpital d'Instruction des Armées Clermont Tonnerre, and Service de Santé des Armées
Subjects: Pathology, medicine.medical_specialty, Amyloid, [SDV]Life Sciences [q-bio], 050801 communication & media studies, Inflammation, Case Report, Dissection (medical), vasculitis, Collet-Sicard syndrome, 03 medical and health sciences, 0508 media and communications, 0302 clinical medicine, medicine, Cerebral amyloid angiopathy, ComputingMilieux_MISCELLANEOUS, Internal carotid artery dissection, lcsh:R5-920, cerebral amyloid angiopathy–related inflammation, business.industry, 05 social sciences, General Medicine, Collet–Sicard syndrome, medicine.disease, 3. Good health, dissection, Presentation (obstetrics), medicine.symptom, business, Vasculitis, lcsh:Medicine (General), 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Background: Cerebral amyloid angiopathy–related inflammation is a rare condition with approximately 100 reported cases. Its clinical manifestations are varied. We report here a novel presentation of this disease. Case presentation: A 61-year-old Caucasian man presented with rapidly progressive paralysis of the IX, X, XI and XII right cranial nerves associated with right central facial nerve palsy. Brain computed tomography angiography and cerebral catheter angiography found a focal fusiform enlargement of the distal cervical portion of the right internal carotid artery, related to a pseudo-aneurysm suggesting an evolution of a dissection and intra-cranial vessel dysplasia. Brain magnetic resonance imaging showed multiple asymmetrical subcortical regions of hyperintensity on T2 fluid-attenuated inversion recovery sequences. Punctiform cortical hyposignals on T2-weighted gradient echo magnetic resonance imaging sequences were mostly congruent with the white matter hyperintensities. There was a decreased cerebral perfusion at the frontal hyperintense fluid-attenuated inversion recovery region. Spectrometry identified a lactate–lipid peak. A brain biopsy showed intravascular amyloid deposits. Corticosteroid therapy was initiated, leading to a dramatic improvement of both clinical condition and magnetic resonance imaging brain lesions. Conclusion: This case report suggests that extra-cranial vasculitis and dysplasia can exceptionally be found in patients satisfying cerebral amyloid angiopathy–related inflammation criteria.
Published: 2018
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85. [PD-L1 testing in non-small cell lung carcinoma: Guidelines from the PATTERN group of thoracic pathologists]

Author: Sylvie, Lantuejoul, Julien, Adam, Nicolas, Girard, Mickael, Duruisseaux, Audrey, Mansuet-Lupo, Aurélie, Cazes, Isabelle, Rouquette, Laure, Gibault, Stéphane, Garcia, Martine, Antoine, Jean Michael, Vignaud, Françoise, Galateau-Sallé, Christine, Sagan, Cécile, Badoual, Frédérique, Penault-Llorca, Diane, Damotte, 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), Pathology, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Normandie Université (NU), Service de Pathologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôtel-Dieu, Pathologie vasculaire et endocrinologie rénale - Chaire de médecine expérimentale (INSERM U36), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), Centre de Recherche en Cancérologie de Marseille (CRCM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), Interactions cellulaires tumorales et leur environnement et réponse aux agents anti-cancéreux, Université Pierre et Marie Curie - Paris 6 (UPMC), Laboratoire d'Anatomie Pathologique [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), Anatomy-Pathology Hôpital Nord Laënnec, Hôpital Guillaume-et-René-Laennec [Saint-Herblain], Service d'anatomo-pathologie [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), Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Service de chirurgie thoracique et d'anatomopathologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Hôtel Dieu, 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), 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: PD-L1, Lung Neoplasms, Organoplatinum Compounds, Quality Assurance, Health Care, Recommandations, [SDV.CAN]Life Sciences [q-bio]/Cancer, Guidelines, B7-H1 Antigen, Specimen Handling, Antineoplastic Agents, Immunological, Carcinoma, Non-Small-Cell Lung, Antineoplastic Combined Chemotherapy Protocols, Biomarkers, Tumor, Humans, Molecular Targeted Therapy, Randomized Controlled Trials as Topic, Cancer, Patient Selection, Immunohistochimie, Immunohistochemistry, Neoplasm Proteins, Poumon, Clinical Trials, Phase III as Topic, Reagent Kits, Diagnostic, Lung cancer, Algorithms
Abstract: International audience; Lung cancer is the leading cause of cancer death in France with low response rates to conventional chemotherapy. Nevertheless, new therapies have emerged recently, among which PD1 immune checkpoint inhibitors (ICI), such as nivolumab (OPDIVO®, Bristol-Myers Squibb) and pembrolizumab (KEYTRUDA®, Merck & Co), or PD-L1 ICI, such as atezolizumab (TECENTRIQ®, Genentech), durvalumab (IMFINZI®, Astra-Zeneca), and avelumab (BAVENCIO®, EMD Serono). The prescription of pembrolizumab for advanced stage non-small cell lung carcinoma (NSCLC) patients requires the demonstration of PD-L1 expression by tumor cells by immunohistochemistry (IHC) (minimum of 50% of positive tumor cells is required for first-line setting, and of 1% for second-line and beyond) and PD-L1 assay is now considered as a companion diagnostic tool for this drug. Numerous standardized PD-L1 assays performed on dedicated platforms have been validated in clinical trials, each antibody being associated to one specific PD1 or PD-L1 inhibitor. However, not all pathologists have access to the dedicated platforms and the high cost of these assays is still a limitation to their implementation; in addition, the small size of the NSCLC tumor samples does not allow to perform at the same time multiple assays for multiple drugs. The use of laboratory-developed tests seems feasible but their validation must guarantee the same sensitivities and specificities as standardized tests. In this context, the French group of thoracic pathologists PATTERN has teamed up with thoracic oncologists to provide recommendations on the indication, the critical technical steps and the interpretation of the PD-L1 IHC test to help pathologists to implement quickly and in the best conditions this new theranostic test.
Published: 2018
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86. Merkel Cells Sense Cooling with TRPM8 Channels

Author: Virginie Penalba, Jean-Marc Aimonetti, Nancy Osorio, Yann Roudaut, Laurent Misery, Marcel Crest, Thierry Merrot, Edith Ribot-Ciscar, Nicolas Lebonvallet, Patrick Delmas, Christelle Le Gall-Ianotto, Valentine Bouvier, 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), Neurobiologie intégrative et adaptative (NIA), Université de Provence - Aix-Marseille 1-Centre National de la Recherche Scientifique (CNRS), Neurosciences sensorielles et cognitives (NSC), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), UMR 6578 : Anthropologie Bio-Culturelle (UAABC), Université de la Méditerranée - Aix-Marseille 2-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Neurosciences de Brest (LNB), Université de Brest (UBO), Laboratoire d'Anatomie Pathologique, Hôpital Morvan Brest-Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Laboratoire de neurophysiologie cellulaire (LNPC), Aimonetti, Jean-Marc, Laboratoire sur les interactions Epithéliums Neurones (LIEN), and Centre Hospitalier Régional Universitaire de Brest (CHRU Brest)
Subjects: 0301 basic medicine, Keratinocytes, TRPV3, [SDV]Life Sciences [q-bio], TRPV1, TRPM Cation Channels, Dermatology, Biochemistry, Merkel Cells, 03 medical and health sciences, Transient receptor potential channel, Mice, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], medicine, TRPM8, Animals, Humans, RNA, Messenger, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Receptor, Molecular Biology, Ion channel, Cells, Cultured, ComputingMilieux_MISCELLANEOUS, Mice, Knockout, integumentary system, Chemistry, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Cell Biology, Mechanoreceptor, Cold Temperature, 030104 developmental biology, medicine.anatomical_structure, Gene Expression Regulation, Models, Animal, Biophysics, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Merkel cell, Mechanoreceptors, [SDV.MHEP.DERM]Life Sciences [q-bio]/Human health and pathology/Dermatology
Abstract: International audience; In the skin, Merkel cells connect with keratinocytes and Ab nerve fibers to form a touch receptor that functions as a slow adapting mechanoreceptor (slow adapting type 1). In human and mouse Merkel cells, we observed an increased concentration of intracellular Ca 2þ ions in response to cold temperature and transient receptor potential melastatine 8 (TRPM8) ion channel agonists. A reduction in the response to cooling and TRPM8 ag-onists occurred after the addition of TRPM8 antagonists, as well as in TRPM8 knockout mice. Cold temperature and TRPM8 agonists also induced a current that was inhibited by a TRPM8 antagonist. Our results indicate that Merkel cells sense cooling through TRPM8 channels. We hypothesized that cooling modulates the slow adapting type 1 receptor response. Cooling mouse skin to 22 C reduced the slow adapting type 1 receptor discharge frequency. Interestingly, we observed no such reduction in TRPM8 knockout mice. Similarly, in human skin, a temperature of 22 C applied to the slow adapting type 1 receptive field reduced the spiking discharge. Altogether, our results indicate that Merkel cells are polymodal sensory cells that respond to mild cold stimuli through the activation of TRPM8 channels. Thermal activation of Merkel cells, and possibly other TRPM8-expressing non-neuronal cells, such as keratinocytes, potentially adapts the discharge of slow adapting type 1 receptors during cooling.
Published: 2018
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87. [Augmented pathology, future or present ?]

Author: Frédéric Bibeau, Cécile Badoual, Service d'anatomo-pathologie [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), Laboratoire d'Anatomie Pathologique [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), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), and CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)
Subjects: 0303 health sciences, 03 medical and health sciences, 0302 clinical medicine, 030220 oncology & carcinogenesis, ComputingMilieux_MISCELLANEOUS, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030304 developmental biology, Pathology and Forensic Medicine
Abstract: International audience
Published: 2019
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88. Constitutive autophagy contributes to resistance to TP53-mediated apoptosis in Epstein-Barr virus-positive latency III B-cell lymphoproliferations

Author: Sonia Chelouah, Martine Raphael, Guillaume Meurice, Philippe Gaulard, Catherine Pioche-Durieu, Aude Robert, Patrice Codogno, Joëlle Wiels, Lyubomir T. Vassilev, Catherine Guettier, Anaïs Pujals, Nadine Martin-Garcia, Marc Lipinski, Marion Le Gentil, Loëtitia Favre, Eric Le Cam, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, Institut des Matériaux, de Microélectronique et des Nanosciences de Provence (IM2NP), Université de Toulon (UTLN)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Institut Gustave Roussy (IGR), Signalisation, noyaux et innovations en cancérologie (UMR8126), Centre National de la Recherche Scientifique (CNRS)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Plateforme de Bioinformatique [Gustave Roussy], Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse (AMMICa), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Plateforme de Génomique [Gustave Roussy], Laboratoire d'Anatomie Pathologique [AP-HP - Le Kremlin-Bicêtre], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital de Bicêtre, Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Aix Marseille Université (AMU)-Université de Toulon (UTLN)-Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), and Le Cam, Eric
Subjects: 0301 basic medicine, Herpesvirus 4, Human, Lymphoma, [SDV]Life Sciences [q-bio], Gene Expression, Apoptosis, Biology, Piperazines, 03 medical and health sciences, 0302 clinical medicine, Downregulation and upregulation, Cell Line, Tumor, hemic and lymphatic diseases, Autophagy, medicine, Humans, NFKB Signaling Pathway, Molecular Biology, ComputingMilieux_MISCELLANEOUS, PI3K/AKT/mTOR pathway, B cell, Cell Proliferation, B-Lymphocytes, Cell growth, Imidazoles, Cell Biology, BECN1, Basic Research Paper, 3. Good health, [SDV] Life Sciences [q-bio], 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Cancer research, Tumor Suppressor Protein p53
Abstract: The Epstein-Barr virus (EBV) is associated with various lymphoproliferative disorders and lymphomas. We have previously demonstrated that treating wild-type TP53-expressing B cell lines with the TP53 pathway activator nutlin-3 induced apoptosis in EBV-negative and EBV-positive latency I cells whereas EBV-positive latency III cells remained much more apoptosis-resistant. Here, we report a constitutively high level of autophagy in these resistant cells which express high levels of the proautophagic protein BECN1/Beclin 1 based, at least in part, on the activation of the NFKB signaling pathway by the viral protein LMP1. Following treatment with nutlin-3, several autophagy-stimulating genes were upregulated both in EBV-negative and EBV-positive latency III cells. However the process of autophagy was only triggered in the latter and was associated with an upregulation of SESN1/sestrin 1 and inhibition of MTOR more rapid than in EBV-negative cells. A treatment with chloroquine, an inhibitor of autophagy, potentiated the apoptotic effect of nutlin-3, particularly in those EBV-positive cells which were resistant to apoptosis induced by nutlin-3 alone, thereby showing that autophagy participates in this resistant phenotype. Finally, using immunohistochemical staining, clinical samples from various B cell lymphoproliferations with the EBV-positive latency II or III phenotype were found to harbor a constitutively active autophagy.
Published: 2015
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89. Prevalence and distribution of HPV genotypes and cervical-associated lesions in sexually active young French women following HPV vaccine

Author: V. Jooste, C. Mougin, C.H. Bretagne, David Guenat, A.M. Bouvier, Séverine Valmary-Degano, Didier Riethmuller, J L Prétet, I. Bedgedjian, Service d'Anatomie pathologique [CHRU Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Registre Bourguignon des Cancers Digestifs, Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Equipe EPICAD (LNC - U1231), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC (UR 3181) (CEF2P / CARCINO), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Laboratoire d'Excellence : Lipoprotéines et Santé : prévention et Traitement des maladies Inflammatoires et du Cancer (LabEx LipSTIC), Institut National de la Recherche Agronomique (INRA)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Paris-Sud - Paris 11 (UP11)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Gustave Roussy (IGR)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM)-Fédération Francophone de la Cancérologie Digestive, FFCD-Université de Montpellier (UM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Centre National de Référence des Papillomavirus (CNRP), Service de Gynécologie Obstétrique [CHRU Besançon], Laboratoire d'anatomie pathologique [Besancon], Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Hôpital Jean Minjoz-Université de Franche-Comté (UFC), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC (EA 3181) (CEF2P / CARCINO), Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université de Franche-Comté (UFC), Institut National de la Recherche Agronomique (INRA)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Paris-Sud - Paris 11 (UP11)-École pratique des hautes études (EPHE)-Institut Gustave Roussy (IGR)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc (CRLCC - CGFL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Fédération Francophone de la Cancérologie Digestive, FFCD-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-France-Comté] (EFS [Bourgogne-France-Comté])-Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Université de Franche-Comté (UFC)-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon), Service de gynécologie-obstétrique [CHRU Besançon], Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Gustave Roussy (IGR)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM)-Fédération Francophone de la Cancérologie Digestive, FFCD-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), and Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université de Montpellier (UM)
Subjects: Hpv genotypes, Adult, medicine.medical_specialty, Human papillomavirus, HPV 16, Uterine Cervical Neoplasms, HPV vaccines, [SDV.MHEP.GEO]Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, 03 medical and health sciences, Sexually active, Young Adult, 0302 clinical medicine, Internal medicine, Cytology, Genotype, medicine, Prevalence, Humans, 030212 general & internal medicine, Papillomavirus Vaccines, HPV vaccine, Cervical cancer, Human papillomavirus 16, Human papillomavirus 18, business.industry, Human papillomavirus 11, HPV prevalence, Prevention, Papillomavirus Infections, Obstetrics and Gynecology, virus diseases, University hospital, medicine.disease, Human papillomavirus 6, female genital diseases and pregnancy complications, 3. Good health, Hpv testing, Reproductive Medicine, 030220 oncology & carcinogenesis, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Female, France, business
Abstract: Background Despite the availability of safe and effective HPV vaccines in France, more than 80% of girls remain unvaccinated. Setting A regional university hospital referral center in France. Objective To estimate the overall prevalence and distribution of HPV in vaccinated, sexually active young French women who were screened for cervical cancer by cytology and HPV testing. Methods High-risk HPV (HR-HPV) prevalence, genotype-specific prevalence and extent of multiple infections were assessed in 125 cervical samples from females with available vaccine data using hc2 assay and INNO-LiPA assay. HPV status was analyzed in accordance with cytological data. Results In our series, mean age was 23 years, overall prevalence of HR-HPV was 52% and was correlated with the lesion grade. The diversity of HPV genotypes was broad. Single HR-HPV infections were identified in 11%, 21% and 47% of women with NILM, ASC-US/-H and LSIL respectively. Multiple infections with HR-HPV were detected in 28% of the specimens. Only 24.5% of women with NILM presented infections with 2 genotypes or more, vs 28% of women with ASC-US/-H and 35% of women with LSIL. The overall prevalence of genotypes covered by the quadrivalent vaccine was low (5.9%); with 4.2%, 0%, 0.8% and 0.8% for HPV 16, HPV 18, HPV 6 and HPV 11 respectively. Conclusion Among HPV-vaccinated young women, HR-HPV are detected at a high rate, and an association with the grade of cytological abnormalities was observed. However, HPV 16 and 18, both targeted by the vaccines, are remarkably rare among young French women since program implementation.
Published: 2018
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90. Insertion/deletion polymorphisms are convenient and reliable markers to assess chromosomal instability in human tumors

Author: Agnès Marchio, Benoit Terris, Pascal Pineau, Anne Dejean, Abdellah Akil, Organisation Nucléaire et Oncogenèse / Nuclear Organization and Oncogenesis, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire des Hépatites Virales [Casablanca, Maroc] (LHV), Institut Pasteur du Maroc, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Laboratoire d'anatomie pathologique, Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), This work was supported by the French Na- tional League Against Cancer (LNCC) and the Pasteur Institutes International Network (RIIP)., and Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0301 basic medicine, Cancer Research, Carcinoma, Hepatocellular, Clinical Biochemistry, Alu element, Loss of Heterozygosity, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Genome, High Resolution Melt, Pathology and Forensic Medicine, Loss of heterozygosity, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Chromosome instability, Chromosomal Instability, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Insertion deletion, Humans, Indel, Alleles, ComputingMilieux_MISCELLANEOUS, Retrospective Studies, Genetics, Polymorphism, Genetic, Liver Neoplasms, 3. Good health, 030104 developmental biology, Oncology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, 030217 neurology & neurosurgery, Allelic loss, Microsatellite Repeats
Abstract: Chromosomal instability (CIN) is frequently associated with a poor outcome in human carcinomas. The genomes of the main human malignancies are well defined as hundreds of tumors have been characterized by arrays. Targeting the appropriate chromosomes with set of markers appears as a realistic approach for CIN assessment. We decided to test the reliability of different insertion/deletion (InDel) polymorphisms to detect allelic loss in a subset of previously characterized hepatocellular carcinomas (HCC). To this aim 3 kinds of markers, L1 insertion (n=1), Alu insertions (n=4) and Marshfield InDel (MID, n=8) markers, were tested on a series of 68 paired HCC/non-tumor liver samples that were previously characterized for loss of heterozygosity (LOH). All markers were analyzed on agarose gels and some were tested with the high resolution melting (HRM) technique. Heterozygosity of the tested markers was high with a mean of 0.489 and a range of 0.265–0.525. Using 6 markers for chromosome 8p, the sensitivity of the method was high. LOH was detected in all samples known to be affected (n=34) whereas retention was found in 29/30 samples (specificity of 96.6%). Finally, the HRM analysis applied to 2 MID markers provided consistent profiles enabling closed-tube determination of chromosomes 17p and 18q status. Overall, our work suggests that different types of InDel markers are suitable for CIN detection in human tumors and may provide convenient and useful information for basic or translational research as well as for future applications in clinical practice.
Published: 2018
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91. Basal ganglia involvement in ARX patients: The reason for ARX patients very specific grasping?

Author: Curie, Aurore, Friocourt, Gaëlle, Des Portes, Vincent, Roy, Alice, Nazir, Tatjana, Brun, Amandine, Cheylus, Anne, Marcorelles, Pascale, Retzepi, Kalliroi, Maleki, Nasim, Bussy, Gérald, Paulignan, Yves, Reboul, Anne, Ibarrola, Danielle, Kong, Jian, Hadjikhani, Nouchine, Laquerrière, Annie, Gollub, Randy, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital [Boston]-Harvard Medical School [Boston] (HMS), centre de référence 'Déficiences intellectuelles de causes rares' (CRDI), Hospices Civils de Lyon (HCL)-Ministère de la santé-Hôpital Femme-Mère Enfant (HFME), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Psychiatric Neuroimaging Program, Department of Psychiatry, Harvard Medical School [Boston] (HMS)-Massachusetts General Hospital [Boston], Gillberg Neuropsychiatry Centre [Göteborg, Sueden], Institute of Neuroscience and Physiology [Göteborg]-University of Gothenburg (GU), Institut des Sciences cognitives Marc Jeannerod - Laboratoire sur le langage, le cerveau et la cognition (L2C2), École normale supérieure - Lyon (ENS Lyon)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Laboratoire d'Anatomie Pathologique, Centre Hospitalier Régional Universitaire de Brest (CHRU Brest)-Hôpital Morvan Brest, Laboratoire de Neurosciences de Brest (LNB), Université de Brest (UBO), Centre d'Etude et de Recherche Multimodal Et Pluridisciplinaire en imagerie du vivant (CERMEP - imagerie du vivant), Université de Lyon-Université de Lyon-CHU Grenoble-Hospices Civils de Lyon (HCL)-CHU Saint-Etienne-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Hôpital Morvan Brest-Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-CHU Grenoble-Hospices Civils de Lyon (HCL)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)
Subjects: Doublecortin Protein, CP, cortical plate, ROI, region of interest, Intellectual disability, SVZ, subventricular zone, ICV, intracranial volume, lcsh:Computer applications to medicine. Medical informatics, Limb, MGE, medial ganglionic eminence, Basal Ganglia, lcsh:RC346-429, VZ, ventricular zone, WG, weeks of gestation, Interneurons, Pregnancy, Humans, Human brain development, CGE, caudal ganglionic eminence, LGE, lateral ganglionic eminence, SGL, subpial granular layer, gamma-Aminobutyric Acid, lcsh:Neurology. Diseases of the nervous system, Homeodomain Proteins, Neurons, IZ, intermediate zone, Hand Strength, Morphometric MRI, Genes, Homeobox, Apraxia, Ideomotor, [SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, Regular Article, Kinematic, DS, down syndrome, IQ, intelligence quotient, [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, Mutation, Limb Kinetic Apraxia, lcsh:R858-859.7, Female, ARX, MZ, marginal zone, ID, Intellectual Disability, LKA, Limb Kinetic Apraxia, MRI, magnetic resonance imaging, GE, ganglionic eminences, XLAG, X-linked lissencephaly with abnormal genitalia, ARX, Aristaless-Related homeoboX gene (according to the genetic convention, ARX was written in italics when it refers to the gene, in plain-text characters when it refers to the protein, in capital letters when it refers to the human gene, and in lowercase when it refers to the mouse gene), Transcription Factors
Abstract: The ARX (Aristaless Related homeoboX) gene was identified in 2002 as responsible for XLAG syndrome, a lissencephaly characterized by an almost complete absence of cortical GABAergic interneurons, and for milder forms of X-linked Intellectual Disability (ID) without apparent brain abnormalities. The most frequent mutation found in the ARX gene, a duplication of 24 base pairs (c.429_452dup24) in exon 2, results in a recognizable syndrome in which patients present ID without primary motor impairment, but with a very specific upper limb distal motor apraxia associated with a pathognomonic hand-grip, described as developmental Limb Kinetic Apraxia (LKA). In this study, we first present ARX expression during human fetal brain development showing that it is strongly expressed in GABAergic neuronal progenitors during the second and third trimester of pregnancy. We show that although ARX expression strongly decreases towards the end of gestation, it is still present after birth in some neurons of the basal ganglia, thalamus and cerebral cortex, suggesting that ARX also plays a role in more mature neuron functioning. Then, using morphometric brain MRI in 13 ARX patients carrying c.429_452dup24 mutation and in 13 sex- and age-matched healthy controls, we show that ARX patients have a significantly decreased volume of several brain structures including the striatum (and more specifically the caudate nucleus), hippocampus and thalamus as well as decreased precentral gyrus cortical thickness. We observe a significant correlation between caudate nucleus volume reduction and motor impairment severity quantified by kinematic parameter of precision grip. As basal ganglia are known to regulate sensorimotor processing and are involved in the control of precision gripping, the combined decrease in cortical thickness of primary motor cortex and basal ganglia volume in ARX dup24 patients is very likely the anatomical substrate of this developmental form of LKA., Highlights • c.429_452dup24 in ARX is responsible for ID with Limb Kinetic Apraxia. • During human brain development, ARX is expressed in GABAergic neuronal progenitors. • ARX patients have a significantly decreased caudate nucleus volume by MRI. • This caudate nucleus volume reduction is correlated with motor impairment severity. • These anatomic findings may explain this developmental form of Limb Kinetic Apraxia.
Published: 2018
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92. Néphropathies secondaires à un déficit en cobalamine C : première étude histopathologique comparative

Author: Lemoine, Mathilde, A, Francois, S, Grange, Rabant, M, D, Cassiman, Cassuto, Elisabeth, Le Meur, Yannick, JF, Benoist, Guerrot, Dominique, Service de Néphrologie, Rouen, Service d'Anatomie et Cytologie Pathologique [CHU Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Service de réanimation médicale [CHU Rouen], Hôpital Charles Nicolle [Rouen]-CHU Rouen, Laboratoire d'anatomie pathologique [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Center for Metabolic Bone Diseases, Catholic University of Leuven, Service de Néphrologie, CHU Nice, CHRU Brest - Service de Nephrologie (CHU - BREST - Nephrologie), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Lymphocyte B et Auto-immunité (LBAI), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Laboratoire de biochimie [CHU Debré], AP-HP Hôpital universitaire Robert-Debré [Paris], and Service de Néphrologie [Rouen]
Subjects: [SDV]Life Sciences [q-bio], ComputingMilieux_MISCELLANEOUS
Abstract: International audience
Published: 2017

93. Protective Effect of Argan and Olive Oils against LPS-Induced Oxidative Stress and Inflammation in Mice Livers

Author: Kamouni, Soufiane, Kebbaj, Riad, Andreoletti, Pierre, El Ktaibi, Abderrahim, Rharrassi, Issam, Essamadi, Abdelkhalid, El Kebbaj, M’hammed Saïd, Mandard, Stéphane, Latruffe, Norbert, Vamecq, Joseph, Nasser, Boubker, Cherkaoui-Malki, Mustapha, Laboratoire de Biochimie et Neurosciences [Settat, Maroc], Faculté des Sciences et Techniques de Settat-Université Hassan I [Maroc], Laboratoire des Sciences et Technologies de la Santé [Settat, Maroc], Institut Supérieur des Sciences de la Santé [Settat, Maroc] ( ISSS ) -Université Hassan I [Settat, Maroc], Laboratoire Bio-PeroxIL. Biochimie du Peroxysome, Inflammation et Métabolisme Lipidique ( Bio-PeroxIL ), Université de Bourgogne ( UB ), Laboratoire d’Anatomie Pathologique [Marrakech, Maroc], Hôpital Militaire Avicenne [Marrakech, Maroc], Laboratoire de Biochimie [Casablanca, Maroc], Université Hassan II Ain Chock, Casablanca.-Faculté des Sciences Ain Chock Casablanca, Equipe LIPNESS (LNC - U1231) ( LIPNESS ), Lipides - Nutrition - Cancer [Dijon - U1231] ( LNC ), Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Maladies RAres du DEveloppement embryonnaire et du MEtabolisme : du Phénotype au Génotype et à la Fonction ( RADEME ), Hôpital Jeanne de Flandre [Lille]-Université de Lille-Centre Hospitalier Régional Universitaire de Lille ( CHRU de Lille ) -Clinique de Génétique médicale Guy Fontaine [CHRU LIlle]-Centre de référence maladies rares Anomalies du développement [CHRU Lille], Laboratoire d'Hormonologie, Métabolisme-Nutrition & Oncologie ( HMNO ), Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ) -Département de Biochimie et Biologie Moléculaire-Centre de Biologie et Pathologie (CBP) Pierre-Marie Degand-INSERM Structures Partenaires, This work was supported by the Ministère de l’enseignement et de la Recherche, Morocco. The Projet PPR from the Centre National Pour la Recherche Scientifique et Technique (CNRST)-Morocco. The followship 'bourse Jeunes chercheurs' from Lafarge, Andzoa and Agrotech. The Action Intégrée of the Comité Mixte Inter-universitaire Franco-Marocain (CMIFM, AIMA/14/310, Campus France N° 30293PA) from the PHC Volubulis program, Ministère des Affaires Etrangères, the Conseil Régional de Bourgogne and the Ministère de l’enseignement et de la Recherche. The authors would like to acknowledge networking support by the COST Action CA 16112 NutRedOx (Personalized Nutrition in aging society: redox control of major age-related diseases), supported by COST (European Cooperation in Science and Technology)., Faculté des Sciences et Techniques [Settat] (FSTS), Université Hassan 1er [Settat]-Université Hassan 1er [Settat], Université Hassan 1er [Settat]-Institut Supérieur des Sciences de la Santé [Settat, Maroc] (ISSS), Laboratoire Bio-PeroxIL. Biochimie du Peroxysome, Inflammation et Métabolisme Lipidique (Bio-PeroxIL), Université de Bourgogne (UB), Faculté des Sciences Aïn Chock [Casablanca] (FSAC), Université Hassan II [Casablanca] (UH2MC)-Université Hassan II [Casablanca] (UH2MC), Equipe LIPNESS (LNC - U1231) (LIPNESS), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Maladies RAres du DEveloppement embryonnaire et du MEtabolisme : du Phénotype au Génotype et à la Fonction - ULR 7364 (RADEME), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Laboratoire d'Hormonologie, Métabolisme-Nutrition & Oncologie (HMNO), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Département de Biochimie et Biologie Moléculaire-Centre de Biologie et Pathologie (CBP) Pierre-Marie Degand-INSERM Structures Partenaires, INSERM Structures Partenaires-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre de Biologie et Pathologie (CBP) Pierre-Marie Degand-Département de Biochimie et Biologie Moléculaire, and Mandard, Stéphane
Subjects: argan oil, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Liver Diseases, Anti-Inflammatory Agents, lipopolysaccharides, Antioxidants, Article, cytokines, sepsis, lcsh:Chemistry, Mice, Liver, lcsh:Biology (General), lcsh:QD1-999, antioxidant enzymes, inflammation, [ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology, Dietary Supplements, Animals, Plant Oils, oxidative stress, Olive Oil, lcsh:QH301-705.5, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; Sepsis causes severe dysregulation of organ functions, via the development of oxidative stress and inflammation. These pathophysiological mechanisms are mimicked in mice injected with bacterial lipopolysaccharide (LPS). Here, protective properties of argan oil against LPS-induced oxidative stress and inflammation are explored in the murine model. Mice received standard chow, supplemented with argan oil (AO) or olive oil (OO) for 25 days, before septic shock was provoked with a single intraperitoneal injection of LPS, 16 hours prior to animal sacrifice. In addition to a rise in oxidative stress and inflammatory markers, injected LPS also caused hepatotoxicity, accompanied by hyperglycemia, hypercholesterolemia and hyperuremia. These LPS-associated toxic effects were blunted by AO pretreatment, as corroborated by normal plasma parameters and cell stress markers (glutathione: GSH) and antioxidant enzymology (catalase, CAT; superoxide dismutase, SOD and glutathione peroxidase, GPx). Hematoxylin–eosin staining revealed that AO can protect against acute liver injury, maintaining a normal status, which is pointed out by absent or reduced LPS-induced hepatic damage markers (i.e., alanine aminotransferase (ALT) and aspartate transaminase (AST)). Our work also indicated that AO displayed anti-inflammatory activity, due to down-regulations of genes encoding pro-inflammatory cytokines Interleukin-6 (IL-6) and Tumor Necrosis Factor-α (TNF-α) and in up-regulations of the expression of anti-inflammatory genes encoding Interleukin-4 (IL-4) and Interleukin-10 (IL-10). OO provided animals with similar, though less extensive, protective changes. Collectively our work adds compelling evidence to the protective mechanisms of AO against LPS-induced liver injury and hence therapeutic potentialities, in regard to the management of human sepsis. Activations of IL-4/Peroxisome Proliferator-Activated Receptors (IL-4/PPARs) signaling and, under LPS, an anti-inflammatory IL-10/Liver X Receptor (IL-10/LXR) route, obviously indicated the high potency and plasticity of the anti-inflammatory properties of argan oil.
Published: 2017
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94. Solid papillary carcinoma with reverse polarity of the breast harbors specific morphologic, immunohistochemical and molecular profile in comparison with other benign or malignant papillary lesions of the breast: a comparative study of 9 additional cases

Author: Magali Lacroix-Triki, Nadjla Alsadoun, Michel Parent, Pascal Wuithier, Marie-Hélène Koeb, Laurent Arnould, Romain Boidot, Isabelle Bedgedjian, Elsy El Alam, Gaëtan MacGrogan, Caroline Truntzer, Dan Medioni, Isabelle Robert, Département de Biologie et pathologie des tumeurs [Centre Georges-François Leclerc], Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER, Département de Biopathologie (Institut Bergonié - CRLCC Bordeaux), Institut Bergonié [Bordeaux], Département de biologie et pathologie médicales [Gustave Roussy], Institut Gustave Roussy (IGR), Service d'Anatomie pathologique [CHRU Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Cypath (Lyon), Département de Biopathologie [Institut Curie, Paris], Institut Curie [Paris], Pathologie Nord Unilabs, Centre de Pathologie (Tarbes), Atalante Pathologie (Rennes), Laboratoire d'anatomie pathologique [Besancon], Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Hôpital Jean Minjoz-Université de Franche-Comté (UFC), and Medipath Cannes-Antibes-Grasse
Subjects: 0301 basic medicine, Pathology, medicine.medical_specialty, Proliferative index, [SDV.CAN]Life Sciences [q-bio]/Cancer, Breast Neoplasms, Pathology and Forensic Medicine, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, Intraductal papilloma, medicine, Carcinoma, Biomarkers, Tumor, Humans, Breast, Solid papillary carcinoma, Aged, Cell Proliferation, business.industry, Gene Expression Profiling, Myoepithelial cell, Papillary tumor, Hyperplasia, Middle Aged, medicine.disease, Immunohistochemistry, Carcinoma, Papillary, Isocitrate Dehydrogenase, 3. Good health, 030104 developmental biology, 030220 oncology & carcinogenesis, Mutation, Breast cancer, Solid papillary carcinoma, Female, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; Solid papillary carcinoma with reverse polarity is a rare breast cancer of favorable prognosis that can be difficult to diagnose. We report here nine additional cases of this tumor, and we describe its morphologic, immunohistochemical and molecular profile in comparison to other types of papillary and micropapillary lesions of the breast that are intraductal papilloma with usual ductal hyperplasia, encapsulated papillary carcinoma, solid papillary carcinoma and invasive micropapillary carcinoma. We studied nine cases of this special papillary tumor and six of each other types mentioned above. We found that solid papillary carcinoma with reverse polarity harbor specific morphologic features as cuboid or tall cells with abundant eosinophilic cytoplasms located at the basal pole giving the impression of reverse nuclear polarity. Nuclei were sometimes grooved. Immunohistochemistry demonstrated the lack of myoepithelial cells, as in encapsulated papillary carcinoma and solid papillary carcinoma, questioning their invasive nature. Seven of nine solid papillary carcinoma with reverse polarity showed a low Ki67 proliferative index (Ki67
Published: 2017
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95. Impact of Cytomegalovirus infection on the outcome of patients with cirrhosis: a preliminary study

Author: Jean-Baptiste Bour, Laurent Andreoletti, Vanessa Cottet, Jean-Louis Jouve, J.-J. Raabe, Elisabeth Monnet, Gérard Thiéfin, Samira Fafi-Kremer, Morgan Faivre, Séverine Valmary-Degano, Georges Herbein, François Habersetzer, Michel Doffoel, Brice Malve, Hélène Barraud, V. Di Martino, Evelyne Schvoerer, Jean-Pierre Bronowicki, Christine Binquet, C. Richou, Patrick Hillon, Service d'Hépatologie, Hôpital Jean Minjoz, Centre Hospitalier Universitaire de Besançon, Université de Franche Comté, Centre Hospitalier Régional Universitaire Hôpital Jean Minjoz [Besançon], Centre d'Investigation Clinique 1432 (Dijon) - Epidemiologie Clinique/Essais Cliniques ( CIC-EC ), Université de Bourgogne ( UB ) -Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Laboratoire de sérologie-virologie (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Laboratoire d'anatomie pathologique [Besancon], Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Hôpital Jean Minjoz-Université de Franche-Comté ( UFC ), Unité de virologie médicale [Reims], Hôpital Robert Debré, Service d'Hépato-gastro-entérologie [CHR Metz-Thionville], Centre hospitalier régional Metz-Thionville ( CHR Metz-Thionville ), Service de Virologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ), Laboratoire de Virologie [Strasbourg], Service d'Ophtalmologie (CHU de Dijon), Centre d'Investigation Clinique 1432 (Dijon) - Module Plurithématique : Périnatalité Cancérologie Handicap et Ophtalmologie ( CIC-P803 ), Université de Bourgogne ( UB ) -Direction Générale de l'Organisation des Soins (DGOS)-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service d'Hépato-Gastro-Entérologie (CHU de Dijon), Service d'hépato-gastroentérologie, CHU Strasbourg-Hopital Civil, Centre d'Investigation Clinique de Besançon ( CICB ), Etablissement Français du Sang Bourgogne Franche-Comté-Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Franche-Comté ( UFC ), Service d'hépatogastroentérologie (CHU Reims), Centre Hospitalier Universitaire de Reims ( CHU Reims ), Service d'Hépatologie [CHRU Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Centre d'Investigation Clinique 1432 (Dijon) - Epidemiologie Clinique/Essais Cliniques (CIC-EC), Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Service d'Anatomie pathologique [CHRU Besançon], Centre hospitalier régional Metz-Thionville (CHR Metz-Thionville), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre d'Investigation Clinique 1432 (Dijon) - Module Plurithématique : Périnatalité Cancérologie Handicap et Ophtalmologie (CIC-P803), Institut National de la Santé et de la Recherche Médicale (INSERM)-Direction Générale de l'Organisation des Soins (DGOS)-Université de Bourgogne (UB), Centre d'Investigation Clinique de Besançon (Inserm CIC 1431), Université de Franche-Comté (UFC), and Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])
Subjects: Clinical aspects, Cirrhosis and its complications, 0303 health sciences, medicine.medical_specialty, Cirrhosis, Hepatology, business.industry, Clinical aspects, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, medicine.disease, Gastroenterology, Outcome (game theory), 3. Good health, Cytomegalovirus infection, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, 030211 gastroenterology & hepatology, [ SDV.MHEP.HEG ] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Cirrhosis and its complications, business, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology
Abstract: International audience
Published: 2017
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96. Expression of Toll-like Receptor 9 Increases with Progression of Cervical Neoplasia in Tunisian Women - A Comparative Analysis of Condyloma, Cervical Intraepithelial Neoplasia and Invasive Carcinoma

Author: Thalja Laassili, Samir Boubaker, Emna Fehri, Ikram Guizani, Rahima Bel Haj Rhouma, Kaouther Ouerhani, Emna Ennaifer, Monia Ardhaoui, Laboratoire d’Anatomie Pathologique Humaine et Expérimentale, Institut Pasteur de Tunis, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Laboratoire d'Epidémiologie Moléculaire et de Pathologie Expérimentale Appliquée aux Maladies Infectieuses (LR11IPT04), and Université de Tunis El Manar (UTM)-Institut Pasteur de Tunis
Subjects: Cancer Research, Pathology, medicine.medical_specialty, cervical cancer, Epidemiology, [SDV]Life Sciences [q-bio], Uterine Cervical Neoplasms, Cervix Uteri, Biology, Cervical intraepithelial neoplasia, Malignant transformation, Immunoenzyme Techniques, TLR9, 03 medical and health sciences, 0302 clinical medicine, Immune system, Biomarkers, Tumor, medicine, Humans, Neoplasm Invasiveness, Toll, Neoplasm Staging, 030304 developmental biology, Cervical cancer, 0303 health sciences, Public Health, Environmental and Occupational Health, like receptors, Prognosis, Uterine Cervical Dysplasia, medicine.disease, 3. Good health, Oncology, Condylomata Acuminata, Toll-Like Receptor 9, 030220 oncology & carcinogenesis, immunohistochemistry, Carcinoma, Squamous Cell, Immunohistochemistry, Biomarker (medicine), Female, Immunostaining, Follow-Up Studies
Abstract: International audience; Toll-like receptors (TLRs) are expressed in immune and tumor cells and recognize pathogen-associated molecular patterns. Cervical cancer (CC) is directly linked to a persistent infection with high risk human papillomaviruses (HR-HPVs) and could be associated with alteration of TLRs expression. TLR9 plays a key role in the recognition of DNA viruses and better understanding of this signaling pathway in CC could lead to the development of novel immunotherapeutic approaches. The present study was undertaken to determine the level of TLR9 expression in cervical neoplasias from Tunisian women with 53 formalin-fixed and paraffin-embedded specimens, including 22 samples of invasive cervical carcinoma (ICC), 18 of cervical intraepithelial neoplasia (CIN), 7 of condyloma and 6 normal cervical tissues as control cases. Quantification of TLR9 expression was based on scoring four degrees of extent and intensity of immunostaining in squamous epithelial cells. TLR9 expression gradually increased from CIN1 (80% weak intensity) to CIN2 (83.3% moderate), CIN3 (57.1% strong) and ICC (100% very strong). It was absent in normal cervical tissue and weak in 71.4% of condyloma. The mean scores of TLR9 expression were compared using the Kruskall-Wallis test and there was a statistical significance between normal tissue and condyloma as well as between condyloma, CINs and ICC. These results suggest that TLR9 may play a role in progression of cervical neoplasia in Tunisian patients and could represent a useful biomarker for malignant transformation of cervical squamous cells.
Published: 2014
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97. Quantification of portal–bridging fibrosis area more accurately reflects fibrosis stage and liver stiffness than whole fibrosis or perisinusoidal fibrosis areas in chronic hepatitis C

Author: Jean-Pierre Zarski, Jérôme Boursier, Victor de Lédinghen, Brigitte Le Bail, Jeremy Sandrini, Paul Calès, Marie-Christine Rousselet, Julien Chaigneau, Nathalie Sturm, Hémodynamique, Interaction Fibrose et Invasivité tumorales Hépatiques (HIFIH), Université d'Angers (UA), Département d'anatomie et cythologie pathologique, CHU Grenoble-Hôpital Michallon, Département de Gastroentérologie et hépatologie, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-Hôpital Michallon, 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), Laboratoire d'anatomie pathologique, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Département d'hépatologie et de gastroentérologie [CHU Bordeaux], Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], BaRITOn - Bordeaux Research in Translational Oncology, and Université de Bordeaux Ségalen [Bordeaux 2]
Subjects: Adult, Liver Cirrhosis, Male, Pathology, medicine.medical_specialty, Cirrhosis, [SDV]Life Sciences [q-bio], Gastroenterology, Pathology and Forensic Medicine, 03 medical and health sciences, 0302 clinical medicine, image analysis, Fibrosis, Internal medicine, medicine, Humans, automated segmentation, Stage (cooking), liver biopsy, medicine.diagnostic_test, business.industry, Hepatitis C, Hepatitis C, Chronic, Middle Aged, medicine.disease, 3. Good health, Fatty Liver, Fibroscan, Liver, 030220 oncology & carcinogenesis, Portal fibrosis, Liver biopsy, Disease Progression, Elasticity Imaging Techniques, Female, 030211 gastroenterology & hepatology, Elastography, Steatosis, business, Algorithms, morphometry
Abstract: International audience; Morphometry provides an objective evaluation of fibrosis in liver diseases. We developed an image analysis algorithm using automated thresholding and segmentation to separately quantify the areas and the fractal dimensions of portal–bridging fibrosis and perisinusoidal fibrosis in chronic hepatitis C liver biopsies. We studied 427 digitized liver biopsies and compared the automated measures of the different fibrosis compartments with (1) the Metavir F (fibrosis) and A (activity) histological scores, (2) the digitally assessed area of steatosis, and (3) the liver stiffness measured by elastography (Fibroscan). The perisinusoidal fibrosis area was higher than that of portal fibrosis in stages ≤F2; it reached its highest value in F2 stage and stabilized thereafter. The F3 stage was characterized by equal proportions of portal–bridging and perisinusoidal fibrosis, whereas portal–bridging area was predominant in cirrhosis. Measurement of portal–bridging fibrosis showed highly significantly different values between contiguous F stages; the ratio of portal–bridging fibrosis/perisinusoidal fibrosis displayed less overlap between Metavir stages than did the whole fibrosis area values. Fractal dimension showed that portal–bridging fibrosis tended to display a homogeneous surface-like spatial organization, whereas perisinusoidal fibrosis appeared more heterogeneous according to stage and curvilinear. The portal–bridging fibrosis area was low in cases with low Metavir activity and little steatosis, and became predominant with increasing activity and steatosis. Using stepwise multiple linear regression analysis, the liver stiffness was independently correlated to the portal–bridging fibrosis area (first step, P
Published: 2014
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98. Signature patterns of human papillomavirus type 16 in invasive anal carcinoma

Author: Bernadette Kantelip, Jean-Luc Prétet, Francine Arbez-Gindre, Marie Joly, Christiane Mougin, Benoit Girardo, Jean-François Bosset, Elise Jacquin, Franck Monnien, Séverine Valmary-Degano, Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC ( CEF2P / CARCINO ), Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Université Bourgogne Franche-Comté ( UBFC ) -Université de Franche-Comté ( UFC ), Laboratoire d'anatomie pathologique [Besancon], Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Hôpital Jean Minjoz-Université de Franche-Comté ( UFC ), Service d'oncologie Médicale, Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Hôpital Jean Minjoz, Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC (EA 3181) (CEF2P / CARCINO), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Service d'Anatomie pathologique [CHRU Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), and Service d'Oncologie Médicale [CHRU Besançon]
Subjects: Adult, Male, Proliferative index, Anal Carcinoma, viruses, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Real-Time Polymerase Chain Reaction, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Pathology and Forensic Medicine, law.invention, 03 medical and health sciences, 0302 clinical medicine, law, Genotype, Prevalence, Humans, DNA Integration, Gene, Polymerase chain reaction, Aged, Neoplasm Staging, 030304 developmental biology, Aged, 80 and over, Human papillomavirus 16, 0303 health sciences, Carcinoma, Papillomavirus Infections, virus diseases, Middle Aged, Viral Load, Anus Neoplasms, Immunohistochemistry, Virology, 3. Good health, Real-time polymerase chain reaction, 030220 oncology & carcinogenesis, DNA, Viral, Cancer research, Female, Viral load
Abstract: International audience; Many studies have reported that most invasive anal carcinomas contain high-risk human papillomaviruses (HPVs), HPV16 being the most prevalent type. This study aimed to investigate HPV status and cellular biomarkers in invasive anal cancers. HPV genotype distribution was determined in 76 anal cancers by the INNO-LiPA assay (Innogenetics, Gent, Belgium). HPV16-positive samples were then tested for viral load and physical state with type-specific real-time polymerase chain reaction targeting E6, E2, and albumin genes. Samples were also subjected to immunohistochemical analysis of p16, Ki-67, p53, and p21. Of the analyzable tumors, 98.6% were positive for α-HPV DNA. HPV16 was the most prevalent genotype (89.0%), followed by HPV39 (4.1%) and HPV33 (2.7%). HPV16 viral load was high, ranging from 2.1 × 10(3) to 1.5 × 10(7) copies/10(3) cells. Integration of HPV16 estimated by the E2/E6 ratio was detected in 77.8% of cases, among which 70.4% were mixed integrated and episomal DNA cases and 7.4% were fully integrated DNA cases. The latter cases were associated with a low HPV16 load compared with cases containing either episomes or mixed integrated and episomal DNA. As expected, most HPV16-positive tumors expressed p16 (92.6%) with a high proliferative index, whereas a minority of them overexpressed p53 (10.3%). p21 expression did not appear to correlate with p53 expression. Although HPV16 was almost exclusively detected, high viral load and differences in DNA integration have been identified in the present series of anal cancers. HPV features assessed in conjunction with expression of cell-cycle regulators could be helpful, as joint biomarkers, in predicting clinical outcome.
Published: 2013
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99. Subcutaneous Panniculitis-like T-cell Lymphoma: Immunosuppressive Drugs Induce Better Response than Polychemotherapy

Author: Christine Bodemer, Saskia Ingen-Housz-Oro, Tony Petrella, Olivier Hermine, Nathalie Franck, Sylvie Fraitag, Martine Bagot, David Michonneau, Maxime Battistella, Marie Beylot-Barry, Béatrice Vergier, Stéphane Barete, Nicole Brousse, Nicolas Ortonne, Marc Maynadié, Laboratoire d'anatomie pathologique [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Maisonneuve-Rosemont Hospital Research Center, University of Montreal, CHU Henri Mondor [Créteil], Service de Dermatologie [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Université Pierre et Marie Curie - Paris 6 (UPMC), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service d'Anatomie pathologique [CHU Saint-Louis], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Service de dermatologie [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], Dpt anatomie pathologique [CHU Bordeaux], Université de Bourgogne (UB), Service de dermatologie [CHU Necker], Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Dermatologie [Saint-Louis], Immunologie, dermatologie, oncologie, Oncodermatologie, immunologie et cellules souches cutanées (IDO (U976 / UMR_S 976)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Hématologie Clinique Adulte [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], CHU Henri Mondor, Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Cochin [AP-HP], Université Pierre et Marie Curie - Paris 6 ( UPMC ), Dpt Dermatologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [APHP], Assistance publique - Hôpitaux de Paris (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Université de Bourgogne ( UB ), Service de dermatologie [CHU Necker-Enfants malades], Imagine - Institut des maladies génétiques ( IMAGINE - U1163 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Oncodermatologie, immunologie et cellules souches cutanées ( DIO U976 ), Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), and Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Male, Panniculitis, Time Factors, Biopsy, medicine.medical_treatment, Gastroenterology, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, 030207 dermatology & venereal diseases, 0302 clinical medicine, Subcutaneous Panniculitis-Like T-Cell Lymphoma, Antineoplastic Combined Chemotherapy Protocols, Child, medicine.diagnostic_test, Remission Induction, General Medicine, Middle Aged, 3. Good health, Treatment Outcome, Immunosuppressive drug, Child, Preschool, 030220 oncology & carcinogenesis, Disease Progression, Female, France, Immunosuppressive Agents, Adult, medicine.medical_specialty, Adolescent, [ SDV.IMM.IMM ] Life Sciences [q-bio]/Immunology/Immunotherapy, [SDV.CAN]Life Sciences [q-bio]/Cancer, Dermatology, Lymphoma, T-Cell, Young Adult, 03 medical and health sciences, Internal medicine, medicine, Humans, Medical history, Pathological, Proportional Hazards Models, Retrospective Studies, business.industry, Autoantibody, Infant, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, medicine.disease, Lymphoma, business, [ SDV.MHEP.DERM ] Life Sciences [q-bio]/Human health and pathology/Dermatology, [SDV.MHEP.DERM]Life Sciences [q-bio]/Human health and pathology/Dermatology
Abstract: International audience; Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a rare condition usually considered to have a favourable prognosis. However, it is not known whether polychemotherapy or immunosuppressive-based therapy is the best approach for treating SPTCL. Using data collected between 2000 and 2012 in France, we analysed clinical, biological and pathological data of 27 patients with SPTCL. Medical history revealed that 40% of patients had been previously diagnosed with an autoimmune disorder and 22% with inflammatory panniculitis. Haemophagocytic syndrome was present in 37% of cases. Autoantibodies were positive in 65% of cases. Complete remission (CR) was reached in 74% of cases. Immunosuppressive drug treatment was given in 69.5% of patients (group 1) and polychemotherapy in 30.5% (group 2). CR was 81.2% and 28.5% (p?=?0.025), respectively. Progression rate was 6.2% and 42.8% (p?=?0.067), respectively. This study suggests that immunosuppressive drugs should be considered as the first-line treatment for SPTCL.
Published: 2017
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100. Un numéro thématique sur l’immuno-oncologie

Author: Bibeau, Frédéric, Badoual, Cécile, Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Laboratoire d'Anatomie Pathologique [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), Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), 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), Service de pathologie [CHU HEGP], Hôpital Européen Georges Pompidou [APHP] (HEGP), CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), 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), and 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)
Subjects: Neoplasms, Biomarkers, Tumor, Pathology, Humans, MESH: Immunohistochemistry, Biomarkers, Immunotherapy, Tumor, [SDV.CAN]Life Sciences [q-bio]/Cancer, Medical Oncology, Immunohistochemistry
Abstract: International audience; Le but de ce numéro thématique des Annales de Pathologie est de sensibiliser notre communauté à cette nouvelle discipline, séduisante dans son concept et dans les résultats qu’elle obtient. Pour ce faire, nous vous proposons quelques articles de synthèse sur l’immuno-oncologie, ses principes et une approche par organe, illustrant les stratégies d’aujourd’hui et de demain ainsi que les challenges que nous devrons relever. Cela va entraîner inévitablement quelques superpositions entre les domaines couverts, mais qui sont le reflet de la transversalité de cette discipline, et qui permettront au lecteur d’aborder ce numéro thématique en toute liberté, en retrouvant les prérequis de l’immuno-oncologie à chaque article. La morphologie sera-t-elle oubliée dans ce grand débat? Certainement pas ! L’histoire rebondit et gageons que les nouvelles approches en oncologie permettront d’isoler de nouvelles entités en pathologie… ou inversement. N’oublions pas que Jeremy Jass, pathologiste anglais, avait il y a déjà 30 ans, souligné l’importance de l’infiltrat immun dans les cancers colorectaux [1]. L’histoire n’est qu’un éternel recommencement…
Published: 2017
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