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1. Ipilimumab 10 mg/kg versus ipilimumab 3 mg/kg in patients with unresectable or metastatic melanoma: a randomised, double-blind, multicentre, phase 3 trial

Author

Piotr Rutkowski, Lars Bastholt, Ralf Gutzmer, Claus Garbe, Virginia Ferraresi, Marta Nyakas, Omid Hamid, Joanna Pikiel, Jean-Jacques Grob, Paolo A. Ascierto, Céleste Lebbé, Caroline Robert, Delphine Hennicken, Vanna Chiarion-Sileni, Michael Smylie, Gabriella Liszkay, Florent Grange, Catriona M. McNeil, Luc Thomas, Dirk Schadendorf, Andrzej Mackiewicz, Michele Del Vecchio, Christoph Hoeller, Carmen Loquai, Michele Maio, Inge Marie Svane, Anila Qureshi, Brigitte Dréno, Ana Arance, Laurent Mortier, Istituto Nazionale Tumori Fondazione Pascale [Naples, Italy], Medical Oncology, National Cancer Institute [Milan, Italy], Institut Gustave Roussy ( IGR ), Department of Diagnostics and Cancer Immunology [Poznan, Poland], Greater Poland Cancer Centre [Poznan, Poland]-Poznan Medical University [Poland], Melanoma Oncology Unit [Padova, Italy], Veneto Institute of Oncology IOV-IRCCS [Padua, Italy], Institut d'Investigacions Biomèdiques August Pi I Sunyer [Barcelona, Spain] ( Hospital Clinic ), Immunologie, dermatologie, oncologie, 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 ), Odense University Hospital [Odense, Denmark], The Angeles Clinic and Research Institute [Los Angeles, CA, USA], Maria Sklodowska-Curie Memorial Cancer Center [Warsaw, Poland], Royal Prince Alfred Hospital ( RPAH - SYDNEY ), Melanoma Institute Australia [Sydney, NSW, Australia], Eberhard Karls University [Tübingen, Germany], University Medical Center [Mainz, Germany], Centre de Recherche en Cancérologie / Nantes - Angers ( CRCNA ), CHU Angers-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 ), Département de Dermatologie [CH Lyon-Sud, Pierre-Bénite], Centre Hospitalier Lyon Sud [CHU - HCL] ( CHLS ), Hospices Civils de Lyon ( HCL ) -Hospices Civils de Lyon ( HCL ), Hôpital de la Timone [CHU - APHM] ( TIMONE ), National Institute of Oncology [Budapest, Hungary], Oslo University Hospital [Oslo, Norway], Medizinische Hochschule Hannover [Hannover, Germany], Wojewodzkie Centrum Oncologii [Gdańsk, Poland], Département de Dermatologie [CHU de Reims], Centre Hospitalier Universitaire de Reims ( CHU Reims ), Medical University of Vienna [Austria], Istituti Fisioterapici Ospitalieri [Rome, Italy], Cross Cancer Institute [Edmonton, AB, Canada], University Hospital [Essen, Germany], Hôspital Claude Huriez [Lille, France], Herlev Hospital [Herlev, Denmark], University of Copenhagen ( KU ), Bristol-Myers Squibb [Princeton, NJ, USA], Istituto Toscano Tumori [Siena, Italy], University Hospital of Siena [Italy], Bristol-Myers Squibb., Institut Gustave Roussy (IGR), Institut d'Investigacions Biomèdiques August Pi I Sunyer [Barcelona, Spain] (Hospital Clinic ), 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), Cedars-Sinai Medical Center, Royal Prince Alfred Hospital (RPAH - SYDNEY), Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen, 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), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Hôpital de la Timone [CHU - APHM] (TIMONE), Oslo University Hospital [Oslo], Centre Hospitalier Universitaire de Reims (CHU Reims), Medizinische Universität Wien = Medical University of Vienna, Hôpital Claude Huriez [Lille], CHU Lille, Herlev and Gentofte Hospital, Bristol-Myers Squibb [Princeton], and Bernardo, Elizabeth

Subjects
Male, 0301 basic medicine, Medizin, Gastroenterology, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, law.invention, 0302 clinical medicine, Randomized controlled trial, law, Clinical endpoint, Melanoma, education.field_of_study, Hazard ratio, Antibodies, Monoclonal, Alanine Transaminase, Middle Aged, Colitis, Intention to Treat Analysis, 3. Good health, Survival Rate, Treatment Outcome, Oncology, 030220 oncology & carcinogenesis, Female, medicine.drug, Diarrhea, medicine.medical_specialty, Population, [SDV.CAN]Life Sciences [q-bio]/Cancer, Antineoplastic Agents, Ipilimumab, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Double-Blind Method, Internal medicine, Journal Article, medicine, Humans, Hypophysitis, Adverse effect, education, Survival rate, Aged, Intention-to-treat analysis, business.industry, Surgery, 030104 developmental biology, business, Follow-Up Studies
Abstract

BACKGROUND: A phase 2 trial suggested increased overall survival and increased incidence of treatment-related grade 3-4 adverse events with ipilimumab 10 mg/kg compared with ipilimumab 3 mg/kg in patients with advanced melanoma. We report a phase 3 trial comparing the benefit-risk profile of ipilimumab 10 mg/kg versus 3 mg/kg.METHODS: This randomised, double-blind, multicentre, phase 3 trial was done in 87 centres in 21 countries worldwide. Patients with untreated or previously treated unresectable stage III or IV melanoma, without previous treatment with BRAF inhibitors or immune checkpoint inhibitors, were randomly assigned (1:1) with an interactive voice response system by the permuted block method using block size 4 to ipilimumab 10 mg/kg or 3 mg/kg, administered by intravenous infusion for 90 min every 3 weeks for four doses. Patients were stratified by metastasis stage, previous treatment for metastatic melanoma, and Eastern Cooperative Oncology Group performance status. The patients, investigators, and site staff were masked to treatment assignment. The primary endpoint was overall survival in the intention-to-treat population and safety was assessed in all patients who received at least one dose of study treatment. This study is completed and was registered with ClinicalTrials.gov, number NCT01515189.FINDINGS: Between Feb 29, and July 9, 2012, 727 patients were enrolled and randomly assigned to ipilimumab 10 mg/kg (365 patients; 364 treated) or ipilimumab 3 mg/kg (362 patients; all treated). Median follow-up was 14·5 months (IQR 4·6-42·3) for the ipilimumab 10 mg/kg group and 11·2 months (4·9-29·4) for the ipilimumab 3 mg/kg group. Median overall survival was 15·7 months (95% CI 11·6-17·8) for ipilimumab 10 mg/kg compared with 11·5 months (9·9-13·3) for ipilimumab 3 mg/kg (hazard ratio 0·84, 95% CI 0·70-0·99; p=0·04). The most common grade 3-4 treatment-related adverse events were diarrhoea (37 [10%] of 364 patients in the 10 mg/kg group vs 21 [6%] of 362 patients in the 3 mg/kg group), colitis (19 [5%] vs nine [2%]), increased alanine aminotransferase (12 [3%] vs two [1%]), and hypophysitis (ten [3%] vs seven [2%]). Treatment-related serious adverse events were reported in 133 (37%) patients in the 10 mg/kg group and 66 (18%) patients in the 3 mg/kg group; four (1%) versus two (INTERPRETATION: In patients with advanced melanoma, ipilimumab 10 mg/kg resulted in significantly longer overall survival than did ipilimumab 3 mg/kg, but with increased treatment-related adverse events. Although the treatment landscape for advanced melanoma has changed since this study was initiated, the clinical use of ipilimumab in refractory patients with unmet medical needs could warrant further assessment.FUNDING: Bristol-Myers Squibb.

Published
2017
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2. Reply to 'Comment on ‘Association of subungual melanoma and subungual squamous cell carcinoma: A case series’'

Author

Brigitte Chouvet, L. Depaepe, Amélie Boespflug, Stéphane Dalle, Sébastien Debarbieux, Delphine Maucort-Boulch, Brigitte Balme, Luc Thomas, 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), Service de Dermatologie, Centre Hospitalier Sud, Hospices Civils, Lyon, Département de Dermatologie [CH Lyon-Sud, Pierre-Bénite], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Biostatistiques santé, Département biostatistiques et modélisation pour la santé et l'environnement [LBBE], Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Hospices Civils de Lyon (HCL), and Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
medicine.medical_specialty, business.industry, Melanoma, Dermatology, medicine.disease, [STAT]Statistics [stat], 030207 dermatology & venereal diseases, 03 medical and health sciences, 0302 clinical medicine, 030220 oncology & carcinogenesis, Carcinoma, Squamous Cell, Carcinoma, Humans, Medicine, Basal cell, Subungual melanoma, business, ComputingMilieux_MISCELLANEOUS
Abstract

International audience

Published
2019
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3. The Ectodysplasin receptor EDAR acts as a tumor suppressor in melanoma by conditionally inducing cell death

Author

Sophie Léon, Patrick Mehlen, Amélie Royet, Vincent Laudet, Jonathan Vial, Marie Castets, Sarah Dinvaut, Sophie Pantalacci, Garance Tondeur, Arnaud de la Fouchardière, Olivier Micheau, Denis Maillet, Marion Creveaux, Stéphane Dalle, Lise Gratadou-Hupon, L. Depaepe, Philippe A. Cassier, Alexa Sadier, Antonin Tortereau, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Ecole Nationale Vétérinaire de Lyon (ENVL), Interactions Cellules Environnement - UR (ICE), VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS), Laboratoire de biologie et modélisation de la cellule (LBMC UMR 5239), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Département de Dermatologie [CH Lyon-Sud, Pierre-Bénite], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Centre Léon Bérard [Lyon], 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, Observatoire océanologique de Banyuls (OOB), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-École normale supérieure - Lyon (ENS Lyon)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), and 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)

Subjects
0301 basic medicine, Programmed cell death, Mice, Nude, Dependence receptor, Biology, Article, law.invention, 03 medical and health sciences, Mice, 0302 clinical medicine, stomatognathic system, law, Cell Line, Tumor, medicine, Ectodysplasin A receptor, Animals, Humans, Tumor Necrosis Factor receptor (TNFR), Receptor, Molecular Biology, Melanoma, Mice, Knockout, Cell Death, integumentary system, Kinase, Edar Receptor, HEK 293 cells, Ectodysplasin receptor EDAR, Cell Biology, Ectodysplasins, medicine.disease, Mice, Inbred C57BL, 030104 developmental biology, HEK293 Cells, 030220 oncology & carcinogenesis, Mutation, Cancer research, Suppressor, Female, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; Ectodysplasin receptor EDAR is seen as a typical Tumor Necrosis Factor receptor (TNFR) family member known to interact with its ligand Eda-A1, and signaling mainly through the nuclear factor-kappaB (NF-κB) and c-jun N-terminal kinases pathways. Mutations in genes that encode proteins involved in EDAR transduction cascade cause anhidrotic ectodermal dysplasia. Here, we report an unexpected pro-apoptotic activity of EDAR when unbound to its ligand Eda-A1, which is independent of NF-κB pathway. Contrarily to other death receptors, EDAR does recruit caspase-8 to trigger apoptosis but solely upon ligand withdrawal, thereby behaving as the so-called dependence receptors. We propose that pro-apoptotic activity of unbound EDAR confers it a tumor suppressive activity. Along this line, we identified loss-of-pro-apoptotic function mutations in EDAR gene in human melanoma. Moreover, we show that the invalidation of EDAR in mice promotes melanoma progression in a B-Raf mutant background. Together, these data support the view that EDAR constrains melanoma progression by acting as a dependence receptor.

Published
2019
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4. Ineffective anti PD-1 therapy after BRAF inhibitor failure in advanced melanoma

Author

Stéphane Dalle, Gérard Duru, Luc Thomas, Mona Amini-Adle, M. Le-Bouar, N. Khanafer, Département de Dermatologie [CH Lyon-Sud, Pierre-Bénite], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Laboratoire des pathogènes émergents -- Emerging Pathogens Laboratory (LPE-Fondation Mérieux), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Biostatistique des Hospices Civils de Lyon, Hospices Civils de Lyon (HCL), Centre International de Recherche en Infectiologie - UMR (CIRI), Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS 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)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Oncology, Male, Cancer Research, medicine.medical_treatment, Programmed Cell Death 1 Receptor, 0302 clinical medicine, Surgical oncology, Treatment Failure, Melanoma, Hazard ratio, Middle Aged, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, 3. Good health, 030220 oncology & carcinogenesis, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Immunotherapy, medicine.drug, Cohort study, Research Article, Adult, Proto-Oncogene Proteins B-raf, BRAF inhibitor, medicine.medical_specialty, Treatment sequence, Ipilimumab, lcsh:RC254-282, 03 medical and health sciences, Internal medicine, Genetics, medicine, Humans, neoplasms, Aged, Retrospective Studies, Chemotherapy, business.industry, medicine.disease, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Discontinuation, Anti PD-1, 030104 developmental biology, Mutation, business
Abstract

International audience; BACKGROUND: Anti-PD-1 and BRAF-inhibitors (BRAFi) have been approved as first-line treatments in advanced melanoma. To date, no prospective data are available to give the best sequence of treatment. The objective of this study was to evaluate in real-life the efficacy of anti-PD-1 after BRAFi, ipilimumab, or chemotherapy failure. METHODS: This was a single institution cohort analysis in patients treated with anti-PD-1 right after BRAFi, ipilimumab, or chemotherapy failure. Melanoma evolution after anti-PD-1 initiation was analyzed in BRAF-mutated and BRAF wild-type patients. The efficacy of treatment was evaluated by Objective Response Rate (ORR), Disease Control Rate (DCR), Progression-Free Survival (PFS), and Overall Survival (OS). RESULTS: Seventy-four patients were included: 33 wild-type and 41 BRAF-mutated melanoma. ORR to anti-PD-1 was significantly lower in BRAF-mutated patients (12.2% vs. 45.5%, p = 0.002). After anti-PD-1 initiation, the median PFS and OS was significantly shorter in the BRAF mutated group (2 vs. 5~months and 7 vs. 20~months, p = 0.001). The hazard ratio for disease progression was of 2.3 (95%CI:1.3-3.9; p = 0.003) and 2.5 (95%CI:1.3-4.5; p = 0.005) for death. Thirty-nine percent of BRAF-mutated-patients died within 3~months after anti-PD-1 initiation. Rapid death (

Published
2018
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5. Epidermolysis bullosa simplex generalized severe induces a Th17 response and is improved by Apremilast treatment

Author

E. Castela, Christine Chiaverini, Frédéric Bérard, Fanny Morice-Picard, J.-P. Lacour, Didier Bessis, Jean-François Nicolas, Aurore Rozières, Meri K. Tulic, D. Baty, Jean Kanitakis, Pierre Vabres, J. Mazereeuw, Thierry Passeron, Emmanuelle Bourrat, Service de Dermatologie [Nice], Hôpital Archet 2 [Nice] (CHU), Immunologie de l'allergie cutanée et vaccination – Immunology of skin allergy and vaccination, Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Inserm U1065, Centre Méditerranéen de Médecine Moléculaire, Centre de référence national des Maladies Génétiques à Expression Cutanée - National Reference Center for Genodermatoses and Rare Skin Diseases (MAGEC), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Département d'allergie et d'immunologie clinique [CHU Lyon Sud], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Département de Dermatologie [CH Lyon-Sud, Pierre-Bénite], Infections Virales et Pathologie Comparée - UMR 754 (IVPC), Institut National de la Recherche Agronomique (INRA)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Service de Dermatologie (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Département de dermatologie [CHU de Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), CHU Bordeaux [Bordeaux], Ninewells Hospital and Medical School [Dundee], Centre de Référence des Epidermolyses Bulleuses Héréditaires [Nice] (CREBHN), Centre Hospitalier Universitaire de Nice (CHU Nice), Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de référence national des Maladies Génétiques à Expression Cutanée (MAGEC), CHU Necker - Enfants Malades [AP-HP]-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Institut National de la Recherche Agronomique (INRA)-École pratique des hautes études (EPHE)-Université Claude Bernard Lyon 1 (UCBL), Centre Hospitalier Universitaire de Montpellier (CHU Montpellier ), CHU Toulouse [Toulouse], Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], and Institut National de la Recherche Agronomique (INRA)-École pratique des hautes études (EPHE)

Subjects
Adult, Male, Pathology, medicine.medical_specialty, Inflammation, Pilot Projects, Dermatology, Pathogenesis, 030207 dermatology & venereal diseases, 03 medical and health sciences, Epidermolysis bullosa simplex, Young Adult, 0302 clinical medicine, medicine, CXCL10, Humans, Child, Retrospective Studies, Skin, integumentary system, business.industry, Anti-Inflammatory Agents, Non-Steroidal, Infant, Newborn, Keratin-14, Infant, Middle Aged, medicine.disease, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, 3. Good health, Thalidomide, Treatment Outcome, Child, Preschool, Epidermolysis Bullosa Simplex, Mutation, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, CXCL9, Keratin-5, Th17 Cells, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Apremilast, medicine.symptom, business, Infiltration (medical), Immunostaining, medicine.drug
Abstract

International audience; BACKGROUND: Epidermolysis bullosa simplex generalized severe is a genetic disorder caused by mutation in KRT5 or KRT14 genes. Usually considered as a mechanical disease, recent data argue for additional inflammatory mechanisms. OBJECTIVES: The aim of this study was to assess the inflammation in the skin of patients with EBS. METHODS: A first immunohistochemical retrospective study was performed on frozen skin samples from 17 EBS-gen sev patients. A second multicenter prospective study was conducted on 10 patients with severe EBS-gen sev. Blister fluid and epidermis were processed for immunochemistry analysis and quantitative real time PCR. Cytokine expression was analyzed in blister fluid and compared with controls. RESULTS: Histological analysis showed a constant dermal perivascular CD4+ lymphocytes infiltrate in skin biopsies of blister (n=17) as well as in rubbed skin (n=5), an epidermal infiltration of neutrophils and eosinophils in 70% of cases and an increased immunostaining for CXCL9 and CXCL10 in blistering skin. High levels of Th17 cytokines were detected in lesional skin. Three adult patients with EBS-gen sev were treated with apremilast with a dramatic improvement of skin blistering and good tolerance. CONCLUSION: Our study demonstrates the importance of inflammation in EBS-gen sev patients and underlines the key role for Th17 cells in its pathogenesis. In addition, this study provides promising new therapeutic approaches for this disabling disorder. This article is protected by copyright. All rights reserved.

Published
2018
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6. Wells' syndrome-like reaction following Argas reflexus bites

Author

Aurore Rozières, Clemmie Martin, Sébastien Debarbieux, Frédéric Bérard, Christiane Hilger, Département de Dermatologie [CH Lyon-Sud, Pierre-Bénite], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Autophagie infection et immunité - Autophagy Infection Immunity (APY), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Infection and Immunity [Luxembourg City], Luxembourg Institute of Health (LIH), Immunologie de l'allergie cutanée et vaccination – Immunology of skin allergy and vaccination, Département d'allergie et d'immunologie clinique [CHU Lyon Sud], Centre International de Recherche en Infectiologie - UMR (CIRI), Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS 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)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)

Subjects
Adult, 0301 basic medicine, medicine.medical_specialty, Argas, Dermatology, 03 medical and health sciences, Rare Diseases, 0302 clinical medicine, Eosinophilia, medicine, Animals, Humans, ComputingMilieux_MISCELLANEOUS, Tick Bites, business.industry, Biopsy, Needle, Cellulitis, Argas reflexus, Immunohistochemistry, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, 030104 developmental biology, 030228 respiratory system, Wells syndrome, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, business
Abstract

International audience

Published
2018
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7. Methotrexate Versus Cyclosporine in Adults with Moderate-to-Severe Atopic Dermatitis: A Phase III Randomized Noninferiority Trial

Author

Frédéric Bérard, Sophie Grande, Catherine Goujon, Muriel Rabilloud, Marie-Christine Ferrier le Bouedec, M. Lahfa, Jean-François Nicolas, Catherine Mercier, Gérard Guillet, F. Cambazard, Manuelle Viguier, Claire Bernier, Karima Dahel, Delphine Staumont-Sallé, David Bottigioli, Service d'immunologie [Centre Hospitalier Lyon Sud - HCL], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Service de Dermatologie [AP-HP Hôpital Saint-Louis], 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), Service de Dermatologie, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service de dermatologie [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Laboratoire Inflammation, Tissus épithéliaux et Cytokines (LITEC), Université de Poitiers, Service Dermatologie [CHU Toulouse], Pôle Clinique des Voies respiratoires [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), CHU Clermont-Ferrand, Service de Dermatologie [CHU Saint-Etienne], Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E)-Université Jean Monnet - Saint-Étienne (UJM), Hospices Civils de Lyon (HCL), Département de Dermatologie [CH Lyon-Sud, Pierre-Bénite], Biostatistiques santé, Département biostatistiques et modélisation pour la santé et l'environnement [LBBE], Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Immunologie de l'allergie cutanée et vaccination – Immunology of skin allergy and vaccination, Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de dermatologie (CHU de Toulouse), CHU Toulouse [Toulouse], University Hospital of St-Etienne, Department of Dermatology, Centre International de Recherche en Infectiologie - UMR (CIRI), Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS 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)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)

Subjects
Adult, Male, Moderate to severe, medicine.medical_specialty, Dose, Severity of Illness Index, Gastroenterology, Trial, Dermatitis, Atopic, Young Adult, 030207 dermatology & venereal diseases, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Clinical endpoint, Humans, Immunology and Allergy, Medicine, Single-Blind Method, In patient, 030212 general & internal medicine, SCORAD, Adverse effect, Atopic dermatitis, medicine.diagnostic_test, business.industry, medicine.disease, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, 3. Good health, Surgery, Treatment Outcome, Methotrexate, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Cyclosporine, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Dermatologic Agents, business, medicine.drug
Abstract

International audience; BACKGROUND: Methotrexate is currently used to treat atopic dermatitis but has never been assessed versus cyclosporine in adults. OBJECTIVE: This study evaluated the efficacy and safety of methotrexate versus cyclosporine in patients with moderate-to-severe atopic dermatitis. METHODS: Patients were randomized to receive either oral methotrexate (15 mg/wk) or cyclosporine (2.5 mg/kg/d) for 8~weeks. The primary end point was a patient achieving 50% improvement in the SCORing Atopic Dermatitis index (SCORAD 50) at week 8. When the primary end point was not achieved, methotrexate was increased to 25 mg and cyclosporine to 5 mg during the next 16 weeks. The secondary end points were a patient achieving a 50% reduction in the Eczema Area Severity Intensity index (EASI 50) and SCORAD 50 at each visit (ClinicalTrials.gov no. NCT00809172). RESULTS: A total of 97 patients received methotrexate 15 mg (n~= 50) or cyclosporine 2.5 mg (n~= 47). Regarding the primary end point at week 8, methotrexate was inferior to cyclosporine because the proportion of patients with SCORAD 50 was 8% (4 of 50) in the methotrexate arm versus 42% (18 of 43) in the cyclosporine arm. The difference in percentages for the 2 treatment groups (2-sided 90% CI) was~-34% (-48% to~-20%). At week 8, methotrexate and cyclosporine dosages were increased in 56% and 49% of the patients, respectively. Regarding EASI 50, the noninferiority end point was reached at week 20 in 92% (22 of 24) of patients in the methotrexate arm and 87% (26 of 30) of patients in the cyclosporine arm. The treatment-related adverse events were more frequent with cyclosporine (P \textless .0001). CONCLUSIONS: Methotrexate 15 mg/wk was inferior to cyclosporine 2.5 mg/kg/d at week 8. Increasing the doses of methotrexate to 25 mg/wk induced a significant improvement versus cyclosporine at week~20.

Published
2018
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8. Clinicopathological Findings of Chronic Rejection in a Face Grafted Patient

Author

Fanny Buron, Emmanuel Morelon, Jean Baptiste Pialat, Palmina Petruzzo, Sylvie Testelin, Lionel Badet, Olivier Thaunat, Bernard Devauchelle, Jean Kanitakis, Service de Transplantation, Néphrologie et Immunologie Clinique [Hôpital Edouard Herriot, HCL], Hospices Civils de Lyon (HCL)-Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL), Department of Medical Sciences, Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Département de Dermatologie [CH Lyon-Sud, Pierre-Bénite], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Département de chirurgie maxillofaciale et stomatologie [CHU d'Amiens-Picardie], CHU Amiens-Picardie, Service de Radiologie, Lymphocytes B effecteurs et à mémoire – Effector and memory B cells, Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Adult, Graft Rejection, Male, Pathology, medicine.medical_specialty, Erythema, Biopsy, medicine.medical_treatment, Asymptomatic, Vascularized Composite Allotransplantation, medicine, Humans, Hypopigmentation, Transplantation, Facial Transplantation, business.industry, Graft Survival, Immunosuppression, Allografts, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Tacrolimus, 3. Good health, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Chronic Disease, [SDV.IMM]Life Sciences [q-bio]/Immunology, medicine.symptom, business, Immunosuppressive Agents
Abstract

International audience; BACKGROUND: Skin chronic rejection (CR) in vascularized composite allotransplantation has not been included in the Banff classification yet. We report a face-transplant patient who developed cutaneous clinicopathologic changes suggestive of CR. METHODS: The recipient was a 27-year-old man with severe disfigurement of the lower face due to a pyrotechnic explosion. He received a facial allograft, including mandible, cheeks, lips, and chin, in November 2009. Immunosuppression included antithymocyte globulins and bone-marrow infusion then steroids, tacrolimus, and mycophenolate mofetil. RESULTS: During the first posttransplant year the acute rejection episodes were characterized by reversible oedema and erythema of the graft. Subsequently, the patient developed primary asymptomatic Epstein-Barr virus (EBV) infection, followed by EBV+ B-cell lymphoma and hepatic EBV-associated posttransplant smooth muscle tumors; therefore, the immunosuppressive treatment was greatly reduced. Since the second posttransplant year, the allografted facial skin became progressively sclerotic and presented pigmented macules on a background of hypopigmentation and teleangiectasias, resulting in a poikilodermatous aspect. Skin biopsies showed epidermal atrophy, basal cell vacuolization, and diffuse dermal sclerosis in the absence of significant dermal cell infiltration. The dermal capillaries showed thickened walls and narrowed lumina, whereas the large vessels did not show significant alterations. Neither donor-specific antibodies nor vascular Cd4 deposits were detected.A dysfunction of the graft functions occurred. It was evidenced by a decrease in mouth opening and modification of some phonemes although lip closure was still possible allowing food intake. CONCLUSIONS: This is the first report suggestive of CR in a face allotransplantation after immunosuppression minimization.

Published
2015
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9. Deciphering the Role of Oncogenic MITFE318K in Senescence Delay and Melanoma Progression

Author

Jean-François Ottavi, Brigitte Bressac-de Paillerets, Karine Bille, Gian Marco De Donatis, Guillaume Bossis, Thomas Strub, Mickaël Ohanna, Stéphane Rocchi, Jean-Philippe Lacour, Véronique Hofman, Irwin Davidson, Sandrine Marchetti, Yann Cheli, Marie-Christine Birling, Paul Hofman, Thomas Luc, Jean-Christophe Marine, Frederic Luciano, Fanélie-Marie Jouenne, Marina Boncompagni, Corine Bertolotto, Flavie Luciani, Marie-Françoise Avril, Caroline Bonet, Justine Leclerc, N. Poulalhon, Robert Ballotti, Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Régulations cellulaires et oncogenèse (RCO), Institut Curie [Paris]-Centre National de la Recherche Scientifique (CNRS), Réponses cellulaires au microenvironnement et cancer, Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Gustave Roussy (IGR), Biologie et pathologies des cellules mélanocytaires : de la pigmentation cutanée aux mélanomes, COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-IFR50-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), Institut de Recherche sur le Cancer et le Vieillissement (IRCAN), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), AxesSim, Physiopathologie de la survie et de la mort cellulaire et infection virale, French National Infrastructure for Mouse Phenogenomics (PHENOMIN), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Département de Dermatologie [CH Lyon-Sud, Pierre-Bénite], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), ERI-21/EA 4319, Laboratoire de Pathologie Clinique et Expérimentale et CRB INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Louis Pasteur [Chartres]-Université de Nice Sophia-Antipolis (UNSA), Service de Dermatologie [Nice], Hôpital Archet 2 [Nice] (CHU), Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Immunologie intégrative des tumeurs (UMR 1186), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), This work was funded by la Société Française de Dermatologie, Melanoma Research Alliance (MRA Team Science Award #269626), ANR-13-BSV1-0025-01 to RB, Fondation pour la Recherche Médicale, La Ville de Nice, Cancéropôle PACA to CB, INCa grant 2013-1-MELA-05 to BBdP, Grant Fondation Gustave Roussy 2009, No. PRI-2010-18 to BBdP, Grant 2011 ITMO-Plan Cancer to BBdP, ICGC No. 201102 to BBdP., ANR-13-BSV1-0025,MITF-SUMOcode,Role de la SUMOylation de MITF (Microphthalmia associated Transcription Factor) dans la pigmentation cutanée, et le développement des nævus.(2013), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), BERTOLOTTO-BALLOTTI, BERTOLOTTO-BALLOTTI, and Blanc 2013 - Role de la SUMOylation de MITF (Microphthalmia associated Transcription Factor) dans la pigmentation cutanée, et le développement des nævus. - - MITF-SUMOcode2013 - ANR-13-BSV1-0025 - Blanc 2013 - VALID

Subjects
0301 basic medicine, Senescence, Adult, Proto-Oncogene Proteins B-raf, Cancer Research, Skin Neoplasms, Primary Cell Culture, Endogeny, [SDV.CAN]Life Sciences [q-bio]/Cancer, Proximity ligation assay, Biology, Melanin, 03 medical and health sciences, Mice, Germline mutation, [SDV.CAN] Life Sciences [q-bio]/Cancer, Cell Line, Tumor, medicine, Nevus, Animals, Humans, Melanoma, Cellular Senescence, Germ-Line Mutation, Aged, Microphthalmia-Associated Transcription Factor, integumentary system, PTEN Phosphohydrolase, Sumoylation, Middle Aged, medicine.disease, Microphthalmia-associated transcription factor, 3. Good health, body regions, Disease Models, Animal, 030104 developmental biology, Oncology, Cancer research, Melanocytes, Transcriptome
Abstract

International audience; BACKGROUND:MITF encodes an oncogenic lineage-specific transcription factor in which a germline mutation ( MITFE318K ) was identified in human patients predisposed to both nevus formation and, among other tumor types, melanoma. The molecular mechanisms underlying the oncogenic activity of MITF E318K remained uncharacterized.METHODS:Here, we compared the SUMOylation status of endogenous MITF by proximity ligation assay in melanocytes isolated from wild-type (n = 3) or E318K (n = 4) MITF donors. We also used a newly generated Mitf E318K knock-in (KI) mouse model to assess the role of Mitf E318K (n = 7 to 13 mice per group) in tumor development in vivo and performed transcriptomic analysis of the tumors to identify the molecular mechanisms. Finally, using immortalized or normal melanocytes (wild-type or E318K MITF, n = 2 per group), we assessed the role of MITF E318K on the induction of senescence mediated by BRAF V600E . All statistical tests were two-sided.RESULTS:We demonstrated a decrease in endogenous MITF SUMOylation in melanocytes from MITF E318K patients (mean of cells with hypoSUMOylated MITF, MITF E318K vs MITF WT , 94% vs 44%, difference = 50%, 95% CI = 21.8% to 67.2%, P = .004). The Mitf E318K mice were slightly hypopigmented (mean melanin content Mitf WT vs Mitf E318K/+ , 0.54 arbitrary units [AU] vs 0.36 AU, difference = -0.18, 95% CI = -0.36 to -0.007, P = .04). We provided genetic evidence that Mitf E318K enhances BRaf V600E -induced nevus formation in vivo (mean nevus number for Mitf E318K , BRaf V600E vs Mitf WT , BRaf V600E , 68 vs 44, difference = 24, 95% CI = 9.1 to 38.9, P = .006). Importantly, although Mitf E318K was not sufficient to cooperate with BRaf V600E alone in promoting metastatic melanoma, it accelerated tumor formation on a BRaf V600E , Pten-deficient background (median survival, Mitf E318K/+ = 42 days, 95% CI = 31 to 46 vs Mitf WT = 51 days, 95% CI = 50 to 55, P

Published
2017
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10. Comparative histological analysis of drug-induced maculopapular exanthema and DRESS

Author

Sylvia H. Kardaun, Audrey Nosbaum, B. Balme, Delphine Maucort-Boulch, B. Bensaid, L. Depaepe, J.-F. Nicolas, Michel D'Incan, François Skowron, Jean Kanitakis, Frédéric Bérard, Centre hospitalier de Valence, Département d'allergie et d'immunologie clinique [CHU Lyon Sud], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Département de Dermatologie [CH Lyon-Sud, Pierre-Bénite], Department of Dermatology, Hôpital Edouard Herriot [CHU - HCL], Immunologie de l'allergie cutanée et vaccination – Immunology of skin allergy and vaccination, Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Biostatistiques santé, Département biostatistiques et modélisation pour la santé et l'environnement [LBBE], Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand, University Medical Center, University of Groningen, Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Biostatistiques [Lyon], and Hospices Civils de Lyon (HCL)

Subjects
0301 basic medicine, Drug, Male, medicine.medical_specialty, Pathology, Drug-Related Side Effects and Adverse Reactions, media_common.quotation_subject, Dermatology, 030207 dermatology & venereal diseases, 03 medical and health sciences, 0302 clinical medicine, Maculopapular exanthema, medicine, 80 and over, Eosinophilia, Humans, SYSTEMIC SYMPTOMS DRESS, media_common, Retrospective Studies, Aged, Aged, 80 and over, Atypical Lymphocyte, Dermal Involvement, EOSINOPHILIA, integumentary system, business.industry, Exanthema, Middle Aged, medicine.disease, equipment and supplies, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, 3. Good health, 030104 developmental biology, Infectious Diseases, ERUPTIONS, Initial phase, Drug Hypersensitivity Syndrome, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.IMM]Life Sciences [q-bio]/Immunology, Histopathology, Female, medicine.symptom, business, human activities, Spongiosis
Abstract

BackgroundCutaneous adverse drug reactions frequently present as a benign maculopapular exanthema (MPE) with a rapid healing. Sometimes systemic signs are present, which could represent a more severe or systemic MPE (sMPE) or even be the initial phase of a drug reaction with eosinophilia and systemic symptoms (DRESS). Histopathology associated with MPE, sMPE and DRESS has not been well characterized.ObjectivesTo study the cutaneous histopathological changes associated with MPE, sMPE and DRESS.MethodsA retrospective clinicopathological analysis of 13 cases of MPE, 13 of sMPE and 45 of DRESS, collected in one centre from 2005 to 2013.ResultsThe number of histopathological changes per section increased gradually from MPE to sMPE and DRESS. Prevalence of spongiosis, dermal lymphocytes, eosinophils and neutrophils did not differ between MPE, sMPE and DRESS. Keratinocyte damage, rare in MPE, was regularly found in sMPE and frequent in DRESS. The density of the inflammatory infiltrate increased progressively from MPE to sMPE and DRESS. Atypical lymphocytes were absent in MPE, present in sMPE and more frequent in DRESS. Deep dermal involvement and leukocytoclastic vasculitis were only observed in DRESS.LimitationsThis was a retrospective study.ConclusionsNumerous histopathological changes per section in drug-induced exanthema should alert for a more severe form of cutaneous adverse drug reactions, i.e. DRESS.

Published
2016
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11. An integrated view of immune monitoring in vascularized composite allotransplantation

Author

Jean Kanitakis, Antoine Sicard, Valérie Dubois, Lionel Badet, Emmanuel Morelon, Olivier Thaunat, Palmina Petruzzo, Service de Transplantation, Néphrologie et Immunologie Clinique [Hôpital Edouard Herriot, HCL], Hospices Civils de Lyon (HCL)-Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL), Lymphocytes B effecteurs et à mémoire – Effector and memory B cells, Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Département de Dermatologie [CH Lyon-Sud, Pierre-Bénite], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Etablissement français du sang- Rhône-Alpes [Lyon], Department of Medical Sciences, Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Service d'Urologie et Chirurgie de la Transplantation, Hôpital Edouard Herriot [CHU - HCL], Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA)

Subjects
medicine.medical_specialty, Monitoring, 030232 urology & nephrology, 030230 surgery, Immune monitoring, Vascularized Composite Allotransplantation, Organ transplantation, 03 medical and health sciences, 0302 clinical medicine, Immune system, Antigen, Monitoring, Immunologic, Immunologic, Immunology and Allergy, Medicine, Humans, Transplantation, Immune status, business.industry, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, 3. Good health, Allograft rejection, Immunology, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.IMM]Life Sciences [q-bio]/Immunology, business
Abstract

International audience; PURPOSE OF REVIEW: Vascularized composite allotransplantation (VCA) has several immunological peculiarities that imply a specific immune monitoring. Here, we provide an integrated view of current procedures of immune monitoring in VCA and potential complementary approaches learned from organ transplantation. RECENT FINDINGS: Because the skin is highly immunogenic and is the main target of the alloimmune response, immune monitoring in VCA essentially relies on visual inspection and pathological examination of for-causes and protocol skin biopsies. Light microscopical and immunohistochemical analyses enable us to identify skin lesions that are characteristic, but not specific, of allograft rejection. Complementary approaches of immunological assessment may assist in reinforcing the diagnosis of rejection and preventing over-immunosuppression or under-immunosuppression. Such approaches can inform either on the patient's global immune status or more specifically on the B-cell-mediated or T-cell-mediated immune responses against donor antigens. SUMMARY: Strategies that integrate both the current 'gold standards' of monitoring in VCA and a complementary multilayer immunological assessment are likely to provide the highest precision for the personalized determination of the recipients' immunological status. The objective is a tailored adaptation of immunosuppressive treatment.

Published
2016
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12. Immunopathology of rejection: do the rules of solid organ apply to vascularized composite allotransplantation?

Author

Lionel Badet, Palmina Petruzzo, Valérie Dubois, Jean Kanitakis, Emmanuel Morelon, Olivier Thaunat, Lymphocytes B effecteurs et à mémoire – Effector and memory B cells, Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Transplantation, Néphrologie et Immunologie Clinique [Hôpital Edouard Herriot, HCL], Hospices Civils de Lyon (HCL)-Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL), Service d'Urologie et Chirurgie de la Transplantation, Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Etablissement français du sang- Rhône-Alpes [Lyon], Département de Dermatologie [CH Lyon-Sud, Pierre-Bénite], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Department of Medical Sciences, Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), Centre International de Recherche en Infectiologie - UMR (CIRI), Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS 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)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), and Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome]

Subjects
Graft Rejection, medicine.medical_specialty, Allosensitization, T cell, medicine.medical_treatment, T-Lymphocytes, Vascularized Composite Allotransplantation, Organ transplantation, Antibodies, Bone Marrow, Immunopathology, otorhinolaryngologic diseases, medicine, Immunology and Allergy, Animals, Humans, Transplantation, business.industry, Immunosuppression, Organ Transplantation, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, 3. Good health, stomatognathic diseases, medicine.anatomical_structure, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Immunology, [SDV.IMM]Life Sciences [q-bio]/Immunology, Bone marrow, Solid organ, business
Abstract

International audience; PURPOSE OF REVIEW: As both the number of vascularized composite allotransplants (VCAs) recipients and the duration of their follow-up are limited, immunopathology of VCA rejection remains incompletely understood. VCAs have several immunological peculiarities, which make inaccurate a direct extrapolation of all rules established for solid organs. RECENT FINDINGS: Despite their bone marrow content, VCA do not induce chimerism in recipient and are therefore not spontaneously tolerated. Skin compartment of VCA contains a high density of antigen-presenting cells (APCs), some with self-renewal capacity. Donor APCs are responsible for continuous direct allosensitization of recipient's T cells that explains the high incidence of skin T-cell-mediated rejection and their occurrence beyond 1 year.Regenerative capability of the skin prevents the development of chronic rejection of this compartment as long as immunosuppression is maintained. In contrast, VCA can develop graft arteriosclerosis, which could be because of T cell and/or chronic antibody-mediated rejection (AMR). VCA recipients can indeed develop donor-specific antibodies (DSA). Whether DSA can also trigger acute AMR of VCA remains to be clarified. SUMMARY: A better understanding of the specificities of the immunopathology of VCA rejection should pave the way for the rationalization of immunosuppressive strategies aiming at optimizing long-term outcome.

Published
2015
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13. Drug reaction with eosinophilia and systemic symptoms (DRESS): clinicopathological study of 45 cases

Author

Audrey Nosbaum, Jean Kanitakis, François Skowron, Michel D'Incan, L. Depaepe, B. Balme, Jean-François Nicolas, Sylvia H. Kardaun, Delphine Maucort-Boulch, Frédérique Bérard, B. Bensaid, Centre hospitalier de Valence, Département d'allergie et d'immunologie clinique [CHU Lyon Sud], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Département de Dermatologie [CH Lyon-Sud, Pierre-Bénite], Department of Dermatology, Hôpital Edouard Herriot [CHU - HCL], Biostatistiques santé, Département biostatistiques et modélisation pour la santé et l'environnement [LBBE], Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Immunologie de l'allergie cutanée et vaccination – Immunology of skin allergy and vaccination, Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand, University Medical Center, University of Groningen, Service de Biostatistiques [Lyon], Hospices Civils de Lyon (HCL), Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, Keratinocytes, Pathology, FEATURES, Severity of Illness Index, Perivascular Lymphocytic Infiltrate, 80 and over, Eosinophilia, Edema, Lymphocytes, Child, Aged, 80 and over, integumentary system, Middle Aged, Rash, 3. Good health, Lymphatic disease, Infectious Diseases, Child, Preschool, RASH, Drug Hypersensitivity Syndrome, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, medicine.symptom, Adult, medicine.medical_specialty, Adolescent, Fever, Dermatology, Necrosis, Young Adult, Severity of illness, medicine, Humans, Preschool, Lymphatic Diseases, Aged, Retrospective Studies, Atypical Lymphocyte, business.industry, medicine.disease, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Face, Epidermis, business, human activities, Spongiosis
Abstract

International audience; BACKGROUND: Drug reaction with eosinophilia and systemic symptoms (DRESS) is a rare and severe adverse drug reaction. Large detailed studies of histopathological features of DRESS are sparse and suggest an association between keratinocyte damage and the severity of visceral involvement. OBJECTIVES: To describe the dermatopathological features in a large series of DRESS and their possible association with clinical features and the severity of the disease. METHODS: A retrospective analysis of the clinicobiological and dermatopathological features in a monocentric cohort of patients with DRESS. RESULTS: From January 2005 to January 2013, 45 patients were validated as probable or definite cases of DRESS. The median age was 64~years (range 3-87). The most frequent clinical and biological features included: fever >=38.5°C (95%), facial oedema (72%), enlarged lymph nodes (51%), visceral involvement (75%), blood eosinophilia (97%) and atypical lymphocytes (82%). Severe DRESS occurred in 24% and a fatal outcome in 6% of patients. Histopathological analysis showed that no specific histopathological pattern was characteristic for DRESS. However, several changes in different cutaneous compartments were observed in 2 of 3 of cases. Spongiosis (55%) and keratinocyte damage (53%) were the most common epidermal changes. Spongiosis was associated with non-severe DRESS (P~=~0.041) whereas confluent keratinocyte necrosis correlated with severe DRESS (P~=~0.011). Vascular changes were frequent (88%). A moderate dermal perivascular lymphocytic infiltrate was invariably present, containing eosinophils, neutrophils and/or atypical lymphocytes in 57% of cases. CONCLUSIONS: Epidermal changes are indicative for the severity of DRESS.

Published
2015
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