21 results on '"Nicole Brousse"'
Search Results
2. Gastrointestinal Disorder Associated with Olmesartan Mimics Autoimmune Enteropathy.
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Sophie Scialom, Georgia Malamut, Bertrand Meresse, Nicolas Guegan, Nicole Brousse, Virginie Verkarre, Coralie Derrieux, Elizabeth Macintyre, Philippe Seksik, Guillaume Savoye, Guillaume Cadiot, Lucine Vuitton, Lysiane Marthey, Franck Carbonnel, Nadine Cerf-Bensussan, and Christophe Cellier
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Medicine ,Science - Abstract
Background and objectivesAnti-hypertensive treatment with the angiotensin II receptor antagonist olmesartan is a rare cause of severe Sprue-like enteropathy. To substantiate the hypothesis that olmesartan interferes with gut immune homeostasis, clinical, histopathological and immune features were compared in olmesartan-induced-enteropathy (OIE) and in autoimmune enteropathy (AIE).MethodsMedical files of seven patients with OIE and 4 patients with AIE enrolled during the same period were retrospectively reviewed. Intestinal biopsies were collected for central histopathological review, T cell Receptor clonality and flow cytometric analysis of isolated intestinal lymphocytes.ResultsAmong seven olmesartan-treated patients who developed villous atrophy refractory to a gluten free diet, three had extra-intestinal autoimmune diseases, two had antibodies reacting with the 75 kilodalton antigen characteristic of AIE and one had serum anti-goblet cell antibodies. Small intestinal lesions and signs of intestinal lymphocyte activation were thus reminiscent of the four cases of AIE diagnosed during the same period. Before olmesartan discontinuation, remission was induced in all patients (7/7) by immunosuppressive drugs. After interruption of both olmesartan and immunosuppressive drugs in six patients, remission was maintained in 4 but anti-TNF-α therapy was needed in two.ConclusionThis case-series shows that olmesartan can induce intestinal damage mimicking AIE. OIE usually resolved after olmesartan interruption but immunosuppressive drugs may be necessary to achieve remission. Our data sustain the hypothesis that olmesartan interferes with intestinal immuno regulation in predisposed individuals.
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- 2015
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3. NKp46 is a diagnostic biomarker and may be a therapeutic target in gastrointestinal T-cell lymphoproliferative diseases: A CELAC study
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Nicolas Guegan, Florence Lhospice, Sascha Cording, Amélie Trinquand, Julie Bruneau, Olivier Hermine, Virginie Verkarre, Nicole Brousse, Christophe Cellier, Georgia Malamut, Elizabeth Macintyre, Felipe Suarez, Laurent Frenzel, Vahid Asnafi, Morgane Cheminant, Sherine Khater, Bertrand Meresse, Ambroise Marçais, Nadine Cerf-Bensussan, Tom van Gils, Chris J. J. Mulder, Thierry Jo Molina, Ludovic Lhermitte, C. cile Bonnafous, David Sibon, Anne-Sophie Jannot, Richard Delarue, Laurent Pouyet, Gastroenterology and hepatology, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Laboratory of molecular mechanisms of hematologic disorders and therapeutic implications (ERL 8254 - Equipe Inserm U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Département de Pathologie [CHU Necker], Université Sorbonne Paris Cité (USPC)-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 de Paris (UP), 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), VU University Medical Center [Amsterdam], Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Université Paris Descartes - Faculté de Médecine (UPD5 Médecine), Université Paris Descartes - Paris 5 (UPD5), 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 Paris Descartes Sorbonne Paris Cité, Imagine Institute, Paris, Mi-mAbs (C/O CIML), Centre d'Immunologie de Marseille - Luminy (CIML), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Innate Pharma, Service de gastroenterologie [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), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Mécanismes cellulaires et moléculaires des désordres hématologiques et implications thérapeutiques = Molecular mechanisms of hematological disorders and therapeutic implications (ERL 8254), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Cité (UPCité), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), and Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
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0301 basic medicine ,Male ,MESH: Biopsy / methods ,Enteropathy-Associated T-Cell Lymphoma / diagnosis ,Entropathy-Associated T-Cell Lymphoma / etiology ,Enteropathy-Associated T-Cell Lymphoma / immunology ,T cell ,Biopsy ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Coeliac Disease ,Coeliac disease ,03 medical and health sciences ,0302 clinical medicine ,Enteropathy-Associated T-Cell Lymphoma ,Intestinal mucosa ,Intestine, Small ,medicine ,Cytotoxic T cell ,Humans ,Intestinal Mucosa ,MESH: Enteropathy-Associated T-Cell Lymphoma / pathology ,Intestinal Mucosa / immunology ,Intestinal Mucosa / pathology ,Killer Cells, Natural / immunology ,Antibody Targeted Therapy ,Cells, Cultured ,business.industry ,Natural Cytotoxicity Triggering Receptor 1 ,Gastroenterology ,MESH: Natural Cytotoxicity Triggering Receptor 1 / immunology ,Antibodies, Monoclonal ,[SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology ,Middle Aged ,medicine.disease ,NKG2D ,Prognosis ,3. Good health ,Killer Cells, Natural ,Celiac Disease ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Cancer research ,Intraepithelial lymphocyte ,Enteropathy-associated T-cell lymphoma ,Female ,France ,Gastrointestinal Lymphoma ,business ,Ex vivo ,Biomarkers ,Tumour markers - Abstract
ObjectivesPrimary GI T-cell lymphoproliferative diseases (T-LPD) are heterogeneous entities, which raise difficult diagnosis and therapeutic challenges. We have recently provided evidences that lymphomas complicating coeliac disease (CD) arise from innate-like lymphocytes, which may carry NK receptors (NKRs).DesignNKRs expression was compared by flow cytometry in intraepithelial lymphocytes (IEL) from CD, type I or type II refractory CD (RCD). NKp46 was next assessed by immunohistochemistry in paraffin-embedded biopsies from 204 patients with CD, RCDI, RCDII or GI T-cell lymphomas and from a validation cohort of 61 patients. The cytotoxic properties of an anti-NKp46 monoclonal antibody conjugated to pyrrolobenzodiazepine (PBD) was tested ex vivo in human primary tumour cells isolated from fresh duodenal biopsies.ResultsNKp46 (but not CD94, NKG2A, NKG2C, NKG2D) was significantly more expressed by malignant RCDII IEL than by normal IEL in CD and RCDI. In paraffin biopsies, detection of >25 NKp46+ IEL per 100 epithelial cells discriminated RCDII from CD and RCDI. NKp46 was also detected in enteropathy-associated T-cell lymphomas (EATL, 24/29) and in monomorphic epitheliotropic intestinal T-cell lymphomas (MEITL, 4/4) but not in indolent T-LPD (0/15). Treatment with anti-NKp46-PBD could efficiently and selectively kill human NKp46+ primary IEL ex vivo.ConclusionNKp46 is a novel biomarker useful for diagnosis and therapeutic stratification of GI T-LPD. Strong preclinical rationale identifies anti-NKp46-PBD as a promising therapy for RCDII, EATL and MEITL.
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- 2019
4. 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
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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)
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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.
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- 2016
5. The localisation of the apical Par/Cdc42 polarity module is specifically affected in microvillus inclusion disease
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André Le Bivic, Ophélie Nicolle, Marion Rabant, Dominique Massey-Harroche, Nicole Brousse, Olivier Goulet, Grégoire Michaux, and Frank M. Ruemmele
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0301 basic medicine ,Enterocyte ,Polarity (physics) ,Cell Biology ,General Medicine ,Anatomy ,Apical membrane ,Biology ,Microvillus ,Intestinal absorption ,Syntaxin 3 ,3. Good health ,Cell biology ,03 medical and health sciences ,030104 developmental biology ,medicine.anatomical_structure ,Cell polarity ,medicine ,Epithelial polarity - Abstract
BACKGROUND INFORMATION: . Microvillus inclusion disease (MVID) is a genetic disorder affecting intestinal absorption. It is caused by mutations in MYO5B or syntaxin 3 (STX3) affecting apical membrane trafficking. Morphologically MVID is characterised by a depletion of apical microvilli and the formation of microvillus inclusions inside the cells, suggesting a loss of polarity. To investigate this hypothesis we examined the location of essential apical polarity determinants in five MVID patients. RESULTS: We found that the polarity determinants Cdc42, Par6B, PKCζ/ι and the structural proteins ezrin and phospho-ezrin were lost from the apical membrane and accumulated either in the cytoplasm or on the basal side of enterocytes in patients which suggests an inversion of cell polarity. Moreover microvilli-like structures were observed at the basal side in electron microscopy. We next performed Myo5B depletion in 3D-grown human Caco2 cells forming cysts and we found a direct link between the loss of Myo5B and the mislocalisation of the same apical proteins; furthermore we observed that a majority of cyst displayed an inverted polarity phenotype as seen in some patients. Finally we found that this loss of polarity was specific for MVID: tissue samples of patients with Myo5B independent absorption disorders showed normal polarity but we identified Cdc42 as a potentially essential biomarker for tricho-hepato-enteric syndrome. CONCLUSION: Our findings indicate that the loss of Myo5B induces a strong loss of enterocyte polarity, potentially leading to polarity inversion. SIGNIFICANCE: Our results show that polarity determinants could be useful markers to help establishing a diagnosis in patients. Furthermore they could be used to characterise other rare intestinal absorption diseases.
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- 2015
6. A Single-Tube, EuroClonality-Inspired, TRG Clonality Multiplex PCR Aids Management of Patients with Enteropathic Diseases, including from Formaldehyde-Fixed, Paraffin-Embedded Tissues
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Olivier Hermine, Nadine Cerf-Bensussan, Virginie Verkarre, Bertrand Meresse, Thierry Jo Molina, Nicole Brousse, Amélie Trinquand, Coralie Derrieux, Julie Bruneau, Georgia Malamut, Christophe Cellier, Elizabeth Macintyre, Patrick Villarese, David Sibon, Marion Alcantara, and Ludovic Lhermitte
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0301 basic medicine ,Pathology ,medicine.medical_specialty ,Tissue Fixation ,Lymphoproliferative disorders ,Lymphoma, T-Cell ,Pathology and Forensic Medicine ,03 medical and health sciences ,0302 clinical medicine ,Immunophenotyping ,Formaldehyde ,Multiplex polymerase chain reaction ,medicine ,Humans ,Multiplex ,Prospective Studies ,Gene Rearrangement ,Paraffin Embedding ,business.industry ,Gene rearrangement ,medicine.disease ,Lymphoma ,Celiac Disease ,030104 developmental biology ,030220 oncology & carcinogenesis ,Molecular Medicine ,Immunohistochemistry ,Intraepithelial lymphocyte ,business ,Multiplex Polymerase Chain Reaction - Abstract
Celiac disease is a chronic inflammation of the small intestine with villous atrophy that can become refractory to a gluten-free diet. Two categories of refractory celiac disease can be distinguished by the phenotype of intraepithelial lymphocytes and the status of TRG genes. Their distinction is important because 30% to 50% of type II but only 0% to 14% of type I evolve to an aggressive enteropathy-associated T-cell lymphoma and therefore require intensive treatment. Currently, differential diagnosis integrates immunohistochemistry, immunophenotyping, and TRG clonality analyses, but each has limitations. A single-tube multiplex TRG PCR (ECN) was prospectively compared to an in-house two-tube TRG PCR (N2T) in 73 samples, including 67 cryopreserved intestine tissues. Thirteen formalin-fixed, paraffin-embedded (FFPE) samples were also analyzed retrospectively. The ECN PCR had comparable efficiency to detect major clonal rearrangements in highly infiltrated tissues from T-cell lymphoproliferative disorders and type II refractory celiac disease and to detect the persistence of minor clones in type II refractory celiac disease follow-up samples. The ECN PCR abolished the risk of amplification of false-positive weak clonal rearrangements in cryopreserved specimens and allowed improved detection of clonal rearrangements in DNA from FFPE samples. The ECN PCR allows robust assessment of cryopreserved and FFPE digestive tissues at diagnosis and follow-up of enteropathies with villous atrophy, thus guiding therapeutic management.
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- 2018
7. Incidence, Presentation, and Prognosis of Malignancies in Ataxia-Telangiectasia: A Report From the French National Registry of Primary Immune Deficiencies
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Nicole Brousse, Felipe Suarez, Alain Fischer, Danielle Canioni, Jean-Philippe Jais, Olivier Hermine, Nizar Mahlaoui, Catherine Dubois d'Enghien, Chantal Andriamanga, and Dominique Stoppa-Lyonnet
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Adult ,Male ,Oncology ,Cancer Research ,medicine.medical_specialty ,Lymphoma ,Population ,Ataxia Telangiectasia ,Neoplasms ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Carcinoma ,Humans ,Registries ,Prolymphocytic leukemia ,education ,Aged ,Retrospective Studies ,education.field_of_study ,Leukemia ,business.industry ,Incidence ,Lymphoma, Non-Hodgkin ,Incidence (epidemiology) ,Age Factors ,Immunologic Deficiency Syndromes ,Cancer ,Retrospective cohort study ,Middle Aged ,Prognosis ,medicine.disease ,Hodgkin Disease ,Acute Disease ,Mutation ,Ataxia-telangiectasia ,Immunology ,Female ,France ,business - Abstract
Purpose Biallelic mutations in ATM cause ataxia-telangiectasia (AT), a rare inherited disease with a high incidence of cancer. Precise estimates of the risk, presentation, and outcomes of cancer in patients with AT need to be addressed in large series. Patients and Methods In this large retrospective cohort, 69 patients with cancers (24.5%) were identified among 279 patients with AT. Centralized review was performed on 60% of the lymphomas. Incidence rates were compared with the French population, and risk factors were analyzed. Results Eight patients developed acute leukemias (including four T-cell acute lymphoblastic leukemias), 12 developed Hodgkin lymphoma (HL), 38 developed non-Hodgkin lymphoma (NHL), three developed T-cell prolymphocytic leukemia (T-PLL), and eight developed carcinoma at a median age of 8.3, 10.6, 9.7, 24.2, and 31.4 years, respectively (P < .001). The majority of NHLs were aggressive B-cell NHL. Epstein-Barr virus was associated with all of the HLs and 50% of the NHLs. Overall survival was shorter in patients with AT who developed cancer compared with those who did not develop cancer (15 v 24 years, respectively; P < .001). Survival was improved in patients who achieved a major response to treatment (3.46 v 0.87 years for major v minor responses, respectively; P = .011). Immunodeficiency was associated with increased risk of cancer. ATM mutation type was associated with a difference in survival in the entire cohort but not with cancer incidence or cancer survival. Conclusion B-cell NHL, HL, and acute lymphoblastic leukemia occur at a high rate and earlier age than carcinomas in AT. T-PLLs are rarer than initially reported. Prognosis is poor, but patients may benefit from treatment with an improved survival.
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- 2015
8. Actinomyces in Chronic Granulomatous Disease: An Emerging and Unanticipated Pathogen
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Nizar Mahlaoui, Steven M. Holland, Uri Lopatin, Ulrich Siler, Nicole Brousse, Bojana Beović, Reinhard Zbinden, Janine Reichenbach, Louise Galmiche, Tayfun Güngör, Stéphane Blanche, Samer Kayal, Reinhard Seger, University of Zurich, and Reichenbach, J
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Male ,Sulfamethoxazole ,Antibiotics ,Disease ,Azithromycin ,Granulomatous Disease, Chronic ,Actinomycosis ,Communicable Diseases, Emerging ,Polymerase Chain Reaction ,2726 Microbiology (medical) ,Trimethoprim ,Chronic granulomatous disease ,Child ,Bone Marrow Transplantation ,biology ,10179 Institute of Medical Microbiology ,Clindamycin ,Ceftriaxone ,Penicillin G ,Anti-Bacterial Agents ,Infectious Diseases ,Penicillin V ,Female ,medicine.drug ,Adult ,Microbiology (medical) ,Adolescent ,medicine.drug_class ,610 Medicine & health ,DNA, Ribosomal ,Article ,Microbiology ,Young Adult ,medicine ,Actinomyces ,Humans ,business.industry ,Amoxicillin ,2725 Infectious Diseases ,Meropenem ,medicine.disease ,biology.organism_classification ,10036 Medical Clinic ,Immunology ,570 Life sciences ,Thienamycins ,business - Abstract
Background. Chronic granulomatous disease (CGD) is a rare inherited disease of the phagocyte NADPH oxidase system that causes defective production of toxic oxygen metabolites, impaired bacterial and fungal killing, and recurrent life-threatening infections, mostly by catalase-producing organisms. We report for the first time, to our knowledge, chronic infections with Actinomyces species in 10 patients with CGD. Actinomycosis is a chronic granulomatous condition that commonly manifests as cervicofacial, pulmonary, or abdominal disease, caused by slowly progressive infection with oral and gastrointestinal commensal Actinomyces species. Treatment of actinomycosis is usually simple in immunocompetent individuals, requiring long-term, high-dose intravenous penicillin, but is more complicated in those with CGD because of delayed diagnosis and an increased risk of chronic invasive or debilitating disease. Methods. Actinomyces was identified by culture, staining, 16S ribosomal DNA polymerase chain reaction, and/ or a complement fixation test in 10 patients with CGD. Results. All 10 patients presented with a history of fever and elevated inflammatory signs without evident focus. Diagnosis was delayed and clinical course severe and protracted despite high-dose intravenous antibiotic therapy and/or surgery. These results suggest an unrecognized and unanticipated susceptibility to weakly pathogenic Actinomyces species in patients with CGD because these are catalase-negative organisms previously thought to be nonpathogenic in CGD. Conclusions. Actinomycosis should be vigorously sought and promptly treated in patients with CGD presenting with uncommon and prolonged clinical signs of infection. Actinomycosis is a catalase-negative infection important to consider in CGD.
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- 2017
9. Impact of Expert Pathologic Review of Lymphoma Diagnosis: Study of Patients From the French Lymphopath Network
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Mylène Dandoit, Catherine Chassagne-Clément, Alexandra Traverse-Glehen, Gilles Salles, Marie Parrens, Peggy Dartigues, Marie-Pierre Chenard-Neu, Marc Maynadié, B. Fabiani, Pierre Brousset, Françoise Berger, Laurent Martin, Jean-François Michiels, Claire Bastien, Josette Brière, Michel Peoc'h, Patrick Tas, Diane Damotte, Philippe Gaulard, Martine Patey, Nadia Amara, Manuela Delage, Anne Moreau, Isabelle Quintin-Roue, Céline Bossard, Antoine de Mascarel, Marie-Christine Copin, Pierre Déchelotte, Henri Sevestre, Isabelle Soubeyran, Sylvie Thiebault, Luc Xerri, Camille Laurent, Jean-Michel Picquenot, Christiane Copie-Bergman, Antoine Martin, Frédéric Charlotte, Blandine Fabre, Béatrice Vergier, Georges Delsol, Flavie Arbion, Corinne Haioun, Tony Petrella, Marine Baron, Marie-Christine Rousselet, Thomas Filleron, Cécile Le Naoures, Thérèse Rousset, Nicole Brousse, and Thierry Jo Molina
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Cancer Research ,Pathology ,medicine.medical_specialty ,Myeloid ,Lymphoma ,Newly diagnosed ,03 medical and health sciences ,0302 clinical medicine ,hemic and lymphatic diseases ,Medicine ,Humans ,Lymphoid neoplasms ,Prospective Studies ,Prospective cohort study ,Referral and Consultation ,Neoplasm Grading ,Potential impact ,Pathology, Clinical ,business.industry ,Lymphoma diagnosis ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,Clinical Competence ,France ,business ,Who classification ,030215 immunology - Abstract
Purpose To prospectively assess the clinical impact of expert review of lymphoma diagnosis in France. Materials and Methods From January 2010 to December 2013, 42,145 samples from patients with newly diagnosed or suspected lymphomas were reviewed, according to the 2008 WHO classification, in real time by experts through the Lymphopath Network. Changes in diagnosis between referral and expert review were classified as major or minor according to their potential impact on patient care. Results The 42,145 reviewed samples comprised 36,920 newly diagnosed mature lymphomas, 321 precursor lymphoid neoplasms, 314 myeloid disorders, and 200 nonhematopoietic neoplasms, with 4,390 benign lesions. There were 4,352 cutaneous and 32,568 noncutaneous lymphomas. The most common mature noncutaneous lymphomas were diffuse large B-cell lymphomas (32.4%), follicular lymphomas (15.3%), classic Hodgkin lymphomas (13%), peripheral T-cell lymphomas (6.3%) of which angioimmunoblastic T-cell lymphomas (2.3%) were the most frequent, and mucosa-associated lymphoid tissue lymphomas (5.8%). A diagnostic change between referral and expert review occurred in 19.7% of patients, with an estimated impact on patient care for 17.4% of patients. This rate was significantly higher for patients sent with a provisional diagnosis seeking expert second opinion (37.8%) than for patients sent with a formal diagnosis (3.7%). The most frequent discrepancies were misclassifications in lymphoma subtype (41.3%), with 12.3% being misclassifications among small B-cell lymphoma entities. Fewer than 2% of changes were between benign and malignant lymphoid conditions. Minor changes (2.3%) mostly consisted of follicular lymphoma misgrading and diffuse large B-cell lymphoma subtype misclassification. Conclusion To our knowledge, this study provides the largest ever description of the distribution of lymphoma entities in a western country and highlights how expert review significantly contributes to a precise lymphoma diagnosis and optimal clinical management in a proportion of patients.
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- 2017
10. Subcutaneous Panniculitis-like T-cell Lymphoma: Immunosuppressive Drugs Induce Better Response than Polychemotherapy
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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)
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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.
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- 2017
11. Prognostic Value of Ki-67 Index, Cytology, and Growth Pattern in Mantle-Cell Lymphoma: Results From Randomized Trials of the European Mantle Cell Lymphoma Network
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Stephan Stilgenbauer, Andreas Rosenwald, Christoph Loddenkemper, Olivier Hermine, Bertrand Coiffier, Catherine Thieblemont, Johanna Kluin-Nelemans, Wolfgang Hiddemann, Christian Schmidt, Michael Hallek, Michael Pfreundschuh, Françoise Berger, Heinz-Wolfram Bernd, Roswitha Forstpointner, Reda Bouabdallah, Wolfram Klapper, Eva Hoster, Roman Kodet, Lothar Kanz, Nicole Brousse, Martin Dreyling, Thomas F. E. Barth, Sylvia Hartmann, Ursula Vehling-Kaiser, Michael Unterhalt, Vincent Ribrag, Stefano Pileri, Grzegorz Rymkiewicz, Damage and Repair in Cancer Development and Cancer Treatment (DARE), and Stem Cell Aging Leukemia and Lymphoma (SALL)
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Oncology ,Male ,Cancer Research ,Pathology ,Time Factors ,Biopsy ,Kaplan-Meier Estimate ,Lymphoma, Mantle-Cell ,IMPROVES RESPONSE ,0302 clinical medicine ,International Prognostic Index ,Risk Factors ,Cytology ,CYCLOPHOSPHAMIDE ,Medicine ,Randomized Controlled Trials as Topic ,Aged, 80 and over ,biology ,PROLIFERATION ,Discriminant Analysis ,Middle Aged ,Prognosis ,Immunohistochemistry ,Tumor Burden ,Europe ,030220 oncology & carcinogenesis ,Ki-67 ,SURVIVAL ,Female ,Adult ,medicine.medical_specialty ,DOXORUBICIN ,MCL-NETWORK ,Malignancy ,IMMUNOCHEMOTHERAPY ,Risk Assessment ,VALIDATION ,03 medical and health sciences ,Predictive Value of Tests ,Internal medicine ,Humans ,VINCRISTINE ,Aged ,Cell Proliferation ,Proportional Hazards Models ,Retrospective Studies ,business.industry ,Proportional hazards model ,MIPI ,Retrospective cohort study ,medicine.disease ,Lymphoma ,Ki-67 Antigen ,Multivariate Analysis ,biology.protein ,Mantle cell lymphoma ,business ,030215 immunology - Abstract
Purpose Mantle-cell lymphoma (MCL) is a rather aggressive B-cell malignancy whose considerable variability of individual outcome is associated with clinical characteristics (Mantle Cell Lymphoma International Prognostic Index [MIPI]). The Ki-67 index is a strong independent prognostic factor; however, the biologic MIPI (MIPI-b) distinguishes only two groups, which does not appropriately depict the clinical heterogeneity. By using the cohort from the European MCL Younger and MCL Elderly trials, we aimed to evaluate the additional prognostic impact of cytology and growth pattern and to improve risk stratification with the Ki-67 index and MIPI. Patients and Methods Diagnostic tumor biopsies were reviewed by the European Mantle Cell Lymphoma Pathology Panel to determine Ki-67 index by using published guidelines, cytology, and growth pattern. We evaluated prognostic effects for overall survival (OS) by Cox regression. For the cohort used for MIPI-b development (German Low-Grade Lymphoma Study Group [GLSG] 1996 and GLSG2000), we checked whether the equally weighted combination of Ki-67 index (dichotomized at the validated 30% cutoff) and MIPI risk groups was adequate and compared the prognostic power of this modified combination to MIPI and MIPI-b for the MCL Younger/MCL Elderly cohort. Results The Ki-67 index was assessed in 508 of 832 patients (median age, 62 years). Blastoid cytology was associated with inferior OS independently of MIPI but not independently of the Ki-67 index. Growth pattern was not independently prognostic. The modified combination of the Ki-67 index and MIPI separated four groups with 5-year OS: 85%, 72%, 43%, and 17% (P < .001) and was more discriminative than MIPI and MIPI-b. Conclusion Using the Ki-67 index is superior to using cytology and growth pattern as prognostic factors in MCL. The modified combination of the Ki-67 index and MIPI showed a refined risk stratification, reflecting their strong complementary prognostic effects while integrating the most relevant prognostic factors available in clinical routine.
- Published
- 2016
12. Gastrointestinal Disorder Associated with Olmesartan Mimics Autoimmune Enteropathy
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Nicolas Guegan, Sophie Scialom, Nadine Cerf-Bensussan, Coralie Derrieux, Lysiane Marthey, Nicole Brousse, Georgia Malamut, Lucine Vuitton, Philippe Seksik, Virginie Verkarre, Guillaume Cadiot, Franck Carbonnel, Christophe Cellier, Bertrand Meresse, Elizabeth Macintyre, Guillaume Savoye, 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), Service d'hépato-gastro-entérologie, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Interactions de l'épithelium intestinal et du système immunitaire (UMR_S 793), Institut National de la Recherche Agronomique (INRA)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), CHU Necker - Enfants Malades [AP-HP], Service d'Anatomie et de Cytologie Pathologiques, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], PremUp Foundation, Institut de Recherche pour le Développement (IRD)-Université Paris-Sud - Paris 11 (UP11)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-CHI Créteil-Université Paris Descartes - Paris 5 (UPD5)-Sorbonne Universités-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'immuno-hématologie pédiatrique [CHU Necker], Service hématologie, French group of faecal microbotia transplantation (FGFT), CHU Saint-Antoine [APHP], Service d'Hépato-Gastroentérologie [Rouen], Hôpital Charles Nicolle [Rouen]-CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), 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), Institute for Research and Innovation in Biomedicine (IRIB), UNIROUEN - UFR Santé (UNIROUEN UFR Santé), Normandie Université (NU)-Normandie Université (NU), Université de Reims Champagne-Ardenne (URCA), Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon), Hôpital Bicêtre, Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Bicêtre, Hépatogastroentérologie, CHU de Bicêtre, Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Interactions de l'épithelium intestinal et du système immunitaire ( UMR_S 793 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Recherche Agronomique ( INRA ), 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 ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Sorbonne Universités-Université Paris Descartes - Paris 5 ( UPD5 ) -CHI Créteil-Institut de Recherche pour le Développement ( IRD ) -Université Paris-Sud - Paris 11 ( UP11 ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Diderot - Paris 7 ( UPD7 ), French group of faecal microbotia transplantation ( FGFT ), Gastroenterology and nutrition department, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -CHU Saint-Antoine [APHP], Département des maladies de l'appareil digestif, CHU Rouen, Université de Reims Champagne-Ardenne ( URCA ), Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ), Université Paris-Sud - Paris 11 ( UP11 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Bicêtre, 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)-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), 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), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Descartes - Paris 5 (UPD5)-CHI Créteil-Institut de Recherche pour le Développement (IRD)-Université Paris-Sud - Paris 11 (UP11)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service d'Hépato-Gastroentérologie [CHU Rouen], Hôpital Charles Nicolle [Rouen]-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Institut de Recherche pour le Développement (IRD)-Université Paris-Sud - Paris 11 (UP11)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-CHI Créteil-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Charles Nicolle [Rouen], Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and HAL-UPMC, Gestionnaire
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Adult ,Male ,Adolescent ,Gastrointestinal Diseases ,Science ,Tetrazoles ,Angiotensin II receptor antagonist ,Autoimmune enteropathy ,Diagnosis, Differential ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Antigen ,medicine ,Humans ,Enteropathy ,Polyendocrinopathies, Autoimmune ,Aged ,Multidisciplinary ,business.industry ,[ SDV.SP.MED ] Life Sciences [q-bio]/Pharmaceutical sciences/Medication ,Imidazoles ,[SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology ,Middle Aged ,medicine.disease ,[SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology ,3. Good health ,Gastrointestinal disorder ,030220 oncology & carcinogenesis ,Immunology ,Medicine ,Female ,[ SDV.MHEP.HEG ] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology ,030211 gastroenterology & hepatology ,Gluten free ,Olmesartan ,business ,Angiotensin II Type 1 Receptor Blockers ,Research Article ,medicine.drug - Abstract
International audience; Background and Objectives : Anti-hypertensive treatment with the angiotensin II receptor antagonist olmesartan is a rare cause of severe Sprue-like enteropathy. To substantiate the hypothesis that olmesartan interferes with gut immune homeostasis, clinical, histopathological and immune features were compared in olmesartan-induced-enteropathy (OIE) and in autoimmune enteropathy (AIE).Methods : Medical files of seven patients with OIE and 4 patients with AIE enrolled during the same period were retrospectively reviewed. Intestinal biopsies were collected for central histopathological review, T cell Receptor clonality and flow cytometric analysis of isolated intestinal lymphocytes. Results : Among seven olmesartan-treated patients who developed villous atrophy refractory to a gluten free diet, three had extra-intestinal autoimmune diseases, two had antibodies reacting with the 75 kilodalton antigen characteristic of AIE and one had serum anti-goblet cell antibodies. Small intestinal lesions and signs of intestinal lymphocyte activation were thus reminiscent of the four cases of AIE diagnosed during the same period. Before olmesartan discontinuation, remission was induced in all patients (7/7) by immunosuppressive drugs. After interruption of both olmesartan and immunosuppressive drugs in six patients, remission was maintained in 4 but anti-TNF-α therapy was needed in two.Conclusion : This case-series shows that olmesartan can induce intestinal damage mimicking AIE. OIE usually resolved after olmesartan interruption but immunosuppressive drugs may be necessary to achieve remission. Our data sustain the hypothesis that olmesartan interferes with intestinal immuno regulation in predisposed individuals.
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- 2015
13. Cells Associated with the Malignant Clone in Non-Hodgkin�s Lymphomas
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Nicole Brousse, L. Nonnenmacher, Georges Delsol, Françoise Rigal-Huguet, T. Al Saati, E. Kuhlein, and P. Caveriviere
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Hodgkin s ,Clone (cell biology) ,Biology ,Virology - Published
- 2015
14. Azathioprine induction of tumors with microsatellite instability: risk evaluation using a mouse model
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Sahra, Bodo, Magali, Svrcek, Isabelle, Sourrouille, Peggy, Cuillières-Dartigues, Tatiana, Ledent, Sylvie, Dumont, Laetitia, Dinard, Philippe, Lafitte, Camille, Capel, Ada, Collura, Olivier, Buhard, Kristell, Wanherdrick, Alexandra, Chalastanis, Virginie, Penard-Lacronique, Bettina, Fabiani, Jean-François, Fléjou, Nicole, Brousse, Laurent, Beaugerie, Alex, Duval, and Martine, Muleris
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Adult ,Male ,congenital, hereditary, and neonatal diseases and abnormalities ,Time Factors ,Lymphoma ,Kaplan-Meier Estimate ,DNA Mismatch Repair ,Risk Assessment ,Young Adult ,thiopurine tolerance ,Risk Factors ,Azathioprine ,Animals ,Humans ,neoplasms ,Aged ,pharmacogenetics ,Mice, Knockout ,Dose-Response Relationship, Drug ,Middle Aged ,Inflammatory Bowel Diseases ,iatrogenic cancer ,Immunohistochemistry ,digestive system diseases ,Disease Models, Animal ,MutS Homolog 2 Protein ,Phenotype ,Female ,microsatellite instability ,Immunosuppressive Agents ,Research Paper - Abstract
Mismatch-repair (MMR)-deficient cells show increased in vitro tolerance to thiopurines because they escape apoptosis resulting from MMR-dependent signaling of drug-induced DNA damage. Prolonged treatment with immunosuppressants including azathioprine (Aza), a thiopurine prodrug, has been suggested as a risk factor for the development of late onset leukemias/lymphomas displaying a microsatellite instability (MSI) phenotype, the hallmark of a defective MMR system. We performed a dose effect study in mice to investigate the development of MSI lymphomas associated with long term Aza treatment. Over two years, Aza was administered to mice that were wild type, null or heterozygous for the MMR gene Msh2. Ciclosporin A, an immunosuppressant with an MMR-independent signaling, was also administered to Msh2(wt) mice as controls. Survival, lymphoma incidence and MSI tumor phenotype were investigated. Msh2(+/-) mice were found more tolerant than Msh2(wt) mice to the cytotoxicity of Aza. In Msh2(+/-) mice, Aza induced a high incidence of MSI lymphomas in a dose-dependent manner. In Msh2(wt) mice, a substantial lifespan was only observed at the lowest Aza dose. It was associated with the development of lymphomas, one of which displayed the MSI phenotype, unlike the CsA-induced lymphomas. Our findings define Aza as a risk factor for an MSI-driven lymphomagenesis process.
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- 2015
15. Histological Characteristics of Ataxia Telangiectasia Associated Lymphoproliferative Diseases. Results of the French Registry of Primary Immune Deficiencies
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Dominique Stoppa-Lyonnet, Catherine Dubois d'Enghien, Jean-Philippe Jais, Danielle Canioni, Alain Fischer, Nizar Mahlaoui, Nicole Brousse, Chantal Andriamanga, Olivier Hermine, and Felipe Suarez
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medicine.medical_specialty ,Pathology ,business.industry ,Immunology ,Lymphoproliferative disorders ,Germinal center ,Cancer ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Lymphoma ,hemic and lymphatic diseases ,Ataxia-telangiectasia ,medicine ,Carcinoma ,Histopathology ,business ,Diffuse large B-cell lymphoma - Abstract
Introduction Ataxia-telangiectasia (A-T) is a rare autosomal recessive disorder associated with mutations in the ATMgene and characterized by cerebellar ataxia, telangiectasia, immune defect, and a high incidence of lymphoid and solid cancers. We conducted a retrospective study of the patients with AT enrolled in the registry of the French National Reference Center for Primary Immune Deficiencies, in order to describe the incidence, subtypes, and outcomes of cancer and mainly of lymphoproliferative diseases (LPD) occurring in AT. Most of the LPD of this study were centrally reviewed by 2 expert hematopathologists. Patients & Results Sixty nine patients with cancers were identified among the 279 patients with AT of our cohort. Eight patients developed carcinomas, 8 acute leukemias, 3 T-cell prolymphocytic leukemias and 50 developed lymphomas. Among the lymphomas, 12 were classical Hodgkin's lymphomas (cHL), and 38 high-grade non-Hodgkin lymphomas (NHL, 26 of B-cell type, 4 of T-cell type, and 8 not phenotyped). We obtained a centralized histopathology review in 31 cases classified by pathology reports as cHL (n=6) and high-grade NHL (n=25). Cases were reviewed according to the WHO classification by H&E staining and immunohistochemistry. The presence of EBV was analyzed using antibodies to LMP and in situ hybridization for EBER. Concordance between the diagnosis established on pathology reports and the centralized review was excellent. All 6 cases of cHL were confirmed by the pathology review. The 25 cases initially diagnosed as high-grade NHL based on pathology reports fell into several WHO classification categories. Six corresponded to Burkitt's lymphomas (BL) and 12 to diffuse large B-cell lymphomas (DLBCL). Among the latter, 10 could be further classified according to cell-of-origin by the Hans algorithm as germinal center (GC, 2) and non-GC (8). Seven cases displayed polymorphic histological features reminiscent of post-transplant lymphoproliferative disorders (LPD), 5 polymorphic B cell LPD (pLPD), 1 with features of infectious mononucleosis (IM), another with features of plasmacytic hyperplasia LPD. EBV could be evaluated in 28 cases. All 6 cHL, 4 out of 11 DLBCL, all 5 pLPD, and the case of IM-like LPD were EBV positive by LMP and/or EBER staining. The 5 cases of BL that were evaluated were all EBV negative. Median age at diagnosis was 7.8 years [range 3 – 24], 14.9 [5.8 – 17.1], 12.2 [5.4 – 29] and 11 [6.3 – 17.7] for pLPD, cHL, BL and DLBCL respectively (p=ns). Median survival after diagnosis of lymphoma was 35, 8.6, 6 and 8 months for pLPD, cHL, BL and DLBCL respectively (p=ns). ATM mutation analysis was available for 20 cases (8 hypomorphic mutations, 12 loss-of-function mutations). There were no differences in age at diagnosis of lymphoma or survival according to the ATM mutation class or the EBV status. Conclusion B-cell malignancies including cHL and B-cell NHL are the most frequent malignancies in A-T and can be further classified as DLBCL, BL and cases with polymorphic features resembling post-transplant LPD. EBV seems to be associated with all cHL, approximately 50% of DLBCL and polymorphic LPD, but not with BL. The majority of DLBCL are non-GC type by immunohistochemistry. On this series of 31 patients, ATM mutation type was not associated with differences in type of lymphoma or outcome. Disclosures No relevant conflicts of interest to declare.
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- 2014
16. Tumor Cell Proliferation (Ki-67 Index) Overcomes Cytology and Growth Pattern As Prognostic Factor in Mantle-Cell Lymphoma – Results from Randomized Trials of the European MCL Network
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Grzegorz Rymkiewicz, Martin Dreyling, Christoph Loddenkemper, Michael Unterhalt, Heinz-Wolfram Bernd, Françoise Berger, Johanna Kluin-Nelemans, Nicole Brousse, Sylvia Hartmann, Stefano Pileri, Andreas Rosenwald, Thomas F. E. Barth, Roman Kodet, Eva Hoster, Wolfram Klapper, Olivier Hermine, and Wolfgang Hiddemann
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Oncology ,medicine.medical_specialty ,Pathology ,biology ,business.industry ,Immunology ,Hazard ratio ,Cell Biology ,Hematology ,medicine.disease ,Blastoid ,biology.organism_classification ,Biochemistry ,Lymphoma ,hemic and lymphatic diseases ,Internal medicine ,Cytology ,Ki-67 ,biology.protein ,Medicine ,Mantle cell lymphoma ,Rituximab ,business ,Diffuse large B-cell lymphoma ,medicine.drug - Abstract
On Behalf of the European MCL Pathology Panel Introduction: Mantle-cell lymphoma (MCL) is an aggressive B-cell lymphoma with a median overall survival (OS) of 5 years, but clinical course varies considerably. This variability has been partly explained by clinical characteristics forming the MIPI (Hoster et al., JCO 2014), but also biological and histological features such as tumor cell proliferation (Ki-67 index), cytology, or growth pattern (Tiemann et al., BJH 2005). Immuno-chemotherapy induction represents the current standard of care, in younger patients including high-dose cytarabine and followed by autologous stem cell transplantation, whereas older patients benefit from rituximab maintenance (Dreyling et al., Ann Oncol 2013). In 2004, the European MCL Network started two large randomized trials, MCL Younger and MCL Elderly, for previously untreated MCL patients. Histopathological features of diagnostic samples were centrally assessed by the European MCL Pathology Panel. Since MCL is relatively rare, evaluations of prognostic factors were mostly based on smaller, retrospectively collected patient cohorts. We now aimed to comparatively evaluate the prognostic value of Ki-67 index, cytology, and growth pattern using the data of these trials. Methods: The Ki-67 index was counted according to published guidelines (Klapper et al., J Hematopathol 2009). MCL cytology was classified as classic, small-cell (B-CLL-like), pleomorphic (DLBCL-like), or blastic (LB-like) (Vogt and Klapper, Histopathology 2013). MCLs with pleomorphic or blastic cytology were combined to blastoid MCL. The growth pattern was classified as diffuse (≤50% nodular) or non-diffuse (>50% nodular or predominantly mantle-zone pattern). The prognostic relevance of these markers was evaluated with respect to OS, adjusting for MIPI score. Results: Of 1012 trial patients with MCL, Ki-67 index, cytology, or growth pattern were available in 50%, 61%, and 47%, respectively. Reasons for missing information were mainly insufficient material or staining. Median Ki-67 index was 20% (2%-97%). 88% had classic MCL, 2% small-cell, 7% pleomorphic and 3% blastic cytology, summing up to 10% with blastoid MCL. 63% of patients had a diffuse growth pattern. Higher Ki-67 index, blastoid MCL, and diffuse growth were each associated with higher MIPI score. Growth pattern was not clearly associated with Ki-67 index or cytology, whereas pleomorphic (median Ki-67 index 39%, range 7%-90%) or blastic MCL (median 80%, 29%-97%) displayed a substantially higher Ki-67 index compared non-blastoid MCL (median 19%, 2%-95%). In univariable analyses, the adjusted OS hazard ratios for higher Ki-67 index (10% increase), blastoid MCL, or diffuse growth were 1.16 (95% CI 1.09-1.24, p Conclusions: In a large cohort of MCL patients treated in randomized trials according to current guidelines, tumor cell proliferation (Ki-67 index) was a powerful prognostic marker, superior to cytology and growth pattern, and independent of clinical prognostic factors. The Ki-67 index further stratified patients with non-blastoid as well as patients with blastoid MCL into groups with substantially different survival. Thus, standardized assessment of the Ki-67 index (Klapper et al. J Hematopathol 2009) should be routinely performed in clinical practice to allow a more comprehensive individual risk estimation of MCL patients. Further analyses will aim at the biological basis of this prognostic effect. Figure 1: Overall survival according to Ki-67 index (< vs. ≥ 30% from Determann et al., Blood 2008) in patients with non-blastoid (left) or blastoid (right) mantle-cell lymphoma (MCL) Figure 1:. Overall survival according to Ki-67 index (< vs. ≥ 30% from Determann et al., Blood 2008) in patients with non-blastoid (left) or blastoid (right) mantle-cell lymphoma (MCL) Figure 2 Figure 2. Disclosures Dreyling: Roche: Honoraria, Research Funding. Klapper:Roche: Research Funding.
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- 2014
17. Formes graves de dermatomyosites juvéniles en réanimation : présentation, prise en charge et évolution
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Brigitte Bader-Meunier, Laurent Dupic, Nicole Brousse, Alix Besançon, Christine Bodemer, Rémi Salomon, Pierre Quartier, K. Brochard, Cyril Gitiaux, M. Ferneiny, and Olivier Goulet
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Dermatology - Abstract
Introduction Les formes graves de dermatomyosites (DM) qui necessitent une admission en reanimation ou en unite de soins intensifs (rea/USI) sont rares chez l’enfant. Nous rapportons 11 cas de DM juveniles (DMJ) afin de determiner les motifs de prise en charge en reanimation, les signes d’alerte precoces de gravite et leur evolution. Materiel et methodes Il s’agit d’une etude retrospective des DMJ ayant necessite une hospitalisation en reanimation ou unite de soins intensifs entre 2005 et 2013 dans 2 centres (Necker-Enfants–Malades, Toulouse). L’anamnese, les caracteristiques cliniques et biologiques au diagnostic et a leur admission ont ete recueillies pour chaque patient. Observations Parmi les DMJ, 11/118 (8 filles et 3 garcons, âge median au diagnostic : 9,0 ± 3,1 ans) ont ete admises en rea/USI (9,3 %) pour les motifs suivants : 4 atteintes digestives (dont 2 avec des perforations digestives multiples, survenues au decours de bolus de corticoides), 2 cardiaques (1 arret cardiorespiratoire), 1 pneumopathie hypoxemiante, 1 PRES syndrome (sous ciclosporine), 2 micro-angiopathies thrombotiques (MAT) renales et 1 choc anaphylactique au rituximab. Resultats Des anomalies clinico-biologiques inhabituelles des DMJ et prodromiques de complications severes ont ete observees : hyponatremie (9) et hypoalbuminemie (9) et/ou formes œdemateuses generalisees (6), anemie (8), douleurs abdominales (7), thrombopenie (7). Parmi les 107 autres cas, aucun n’avait d’œdeme generalise, de thrombopenie ni d’hypoalbuminemie. Les traitements ont comporte : corticotherapie (11/11) dont bolus (5), immunoglobulines IV (7), echanges plasmatiques (EP) (7), rituximab (4) et cyclophosphamide (2). Evolution : un deces par pneumocystose pulmonaire ; 10 remissions partielles au decours du passage en reanimation. Actuellement, 5 sont en remission complete (dont 1 sous traitement) et 5 en remission partielle sous traitement. Discussion Certains signes semblent associes aux poussees severes de DMJ : les formes œdemateuses generalisees, de probables syndromes de fuite capillaire, l’atteinte digestive, les signes de MAT (thrombopenie), l’hyponatremie et l’hypoalbuminemie. Un diagnostic des complications et leur prise en charge precoces permettent d’obtenir une remission malgre la severite de certaines formes. Conclusion Cette etude suggere que des EP eventuellement associes au rituximab doivent etre rapidement discutes dans les formes tres severes. Les bolus de corticoides semblent favoriser la survenue de perforations digestives chez des patients ayant une atteinte digestive specifique prealable.
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- 2014
18. Immune deficiency-related enteropathy-lymphocytopenia-alopecia syndrome results from tetratricopeptide repeat domain 7A deficiency
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Fernando E. Sepulveda, Geneviève de Saint Basile, Pascal Cathébras, Marianne Debré, Henner F. Farin, Frank M. Ruemmele, Alain Fischer, Patrick Nitschke, Jana Pachlopnik-Schmid, Nicole Brousse, Hans Clevers, Stéphane Blanche, Amélie Bigorgne, A. Morali, Capucine Picard, Cécile Talbotec, Julie Lemale, Christine Bole-Feysot, Frédéric Rieux-Laucat, Roxane Lemoine, Sébastien Héritier, Hubrecht Institute for Developmental Biology and Stem Cell Research, University of Zurich, and de Saint Basile, Geneviève
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Adult ,Male ,Candidate gene ,RHOA ,Adolescent ,Colon ,Duodenum ,Immunology ,Mutation, Missense ,610 Medicine & health ,medicine.disease_cause ,Autoimmunity ,Pathogenesis ,Young Adult ,Immune system ,Lymphopenia ,medicine ,Pyloric Antrum ,Immunology and Allergy ,Humans ,Child ,Preschool ,2403 Immunology ,rho-Associated Kinases ,biology ,Infant ,Proteins ,Alopecia ,Middle Aged ,Actin cytoskeleton ,medicine.disease ,Inflammatory Bowel Diseases ,10036 Medical Clinic ,Child, Preschool ,Mutation ,2723 Immunology and Allergy ,biology.protein ,Cancer research ,Female ,Lymphocytopenia ,Signal transduction ,Missense ,rhoA GTP-Binding Protein - Abstract
Background Inflammatory bowel disease (IBD) is one of the most common chronic gastrointestinal diseases, but the underlying molecular mechanisms remain largely unknown. Studies of monogenic diseases can provide insight into the pathogenesis of IBD. Objective We thought to determine the underlying molecular causes of IBD occurring in 2 unrelated families in association with an immune deficiency. Methods We performed genetic linkage analysis and candidate gene sequencing on 13 patients from a large consanguineous family affected by early-onset IBD, progressive immune deficiency, and, in some cases, autoimmunity and alopecia, a condition we named enteropathy-lymphocytopenia-alopecia. The candidate gene was also sequenced in an unrelated patient with a similar phenotype. We performed histologic analysis of patients' intestinal biopsy specimens and carried out functional assays on PBMCs. Gut organoids derived from a patient's biopsy specimen were analyzed. Results We identified biallelic missense mutations in tetratricopeptide repeat domain 7A (TTC7A) in all patients from both families. The resulting TTC7A depletion modified the proliferation, adhesion, and migratory capacities of lymphocytes through inappropriate activation of the RhoA signaling pathway. Normal function was restored by wild-type TTC7A expression or addition of a RhoA kinase inhibitor. The growth and polarity of gut epithelial organoids were also found to be dependent on the RhoA signaling pathway. Conclusions We show that TTC7A regulates the actin cytoskeleton dynamics in lymphocytes through the RhoA signaling pathway and is required in both lymphocytes and epithelial cells for maintaining equilibrium between cell proliferation, migration, polarization, and cell death. Our study highlights variability in the phenotypic expression resulting from TTC7A deficiency and outlines that impairment of both epithelial cells and lymphocytes cooperatively causes IBD.
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- 2014
19. Impact of Expert Pathologic Review of Lymphoma Diagnosis: Study of Patients From the French Lymphopath Network.
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Laurent C, Baron M, Amara N, Haioun C, Dandoit M, Maynadié M, Parrens M, Vergier B, Copie-Bergman C, Fabiani B, Traverse-Glehen A, Brousse N, Copin MC, Tas P, Petrella T, Rousselet MC, Brière J, Charlotte F, Chassagne-Clement C, Rousset T, Xerri L, Moreau A, Martin A, Damotte D, Dartigues P, Soubeyran I, Peoch M, Dechelotte P, Michiels JF, de Mascarel A, Berger F, Bossard C, Arbion F, Quintin-Roué I, Picquenot JM, Patey M, Fabre B, Sevestre H, Le Naoures C, Chenard-Neu MP, Bastien C, Thiebault S, Martin L, Delage M, Filleron T, Salles G, Molina TJ, Delsol G, Brousset P, and Gaulard P
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- France, Humans, Lymphoma classification, Lymphoma therapy, Neoplasm Grading, Prospective Studies, Referral and Consultation, Clinical Competence, Lymphoma diagnosis, Lymphoma pathology, Pathology, Clinical
- Abstract
Purpose To prospectively assess the clinical impact of expert review of lymphoma diagnosis in France. Materials and Methods From January 2010 to December 2013, 42,145 samples from patients with newly diagnosed or suspected lymphomas were reviewed, according to the 2008 WHO classification, in real time by experts through the Lymphopath Network. Changes in diagnosis between referral and expert review were classified as major or minor according to their potential impact on patient care. Results The 42,145 reviewed samples comprised 36,920 newly diagnosed mature lymphomas, 321 precursor lymphoid neoplasms, 314 myeloid disorders, and 200 nonhematopoietic neoplasms, with 4,390 benign lesions. There were 4,352 cutaneous and 32,568 noncutaneous lymphomas. The most common mature noncutaneous lymphomas were diffuse large B-cell lymphomas (32.4%), follicular lymphomas (15.3%), classic Hodgkin lymphomas (13%), peripheral T-cell lymphomas (6.3%) of which angioimmunoblastic T-cell lymphomas (2.3%) were the most frequent, and mucosa-associated lymphoid tissue lymphomas (5.8%). A diagnostic change between referral and expert review occurred in 19.7% of patients, with an estimated impact on patient care for 17.4% of patients. This rate was significantly higher for patients sent with a provisional diagnosis seeking expert second opinion (37.8%) than for patients sent with a formal diagnosis (3.7%). The most frequent discrepancies were misclassifications in lymphoma subtype (41.3%), with 12.3% being misclassifications among small B-cell lymphoma entities. Fewer than 2% of changes were between benign and malignant lymphoid conditions. Minor changes (2.3%) mostly consisted of follicular lymphoma misgrading and diffuse large B-cell lymphoma subtype misclassification. Conclusion To our knowledge, this study provides the largest ever description of the distribution of lymphoma entities in a western country and highlights how expert review significantly contributes to a precise lymphoma diagnosis and optimal clinical management in a proportion of patients.
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- 2017
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20. Prognostic Value of Ki-67 Index, Cytology, and Growth Pattern in Mantle-Cell Lymphoma: Results From Randomized Trials of the European Mantle Cell Lymphoma Network.
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Hoster E, Rosenwald A, Berger F, Bernd HW, Hartmann S, Loddenkemper C, Barth TF, Brousse N, Pileri S, Rymkiewicz G, Kodet R, Stilgenbauer S, Forstpointner R, Thieblemont C, Hallek M, Coiffier B, Vehling-Kaiser U, Bouabdallah R, Kanz L, Pfreundschuh M, Schmidt C, Ribrag V, Hiddemann W, Unterhalt M, Kluin-Nelemans JC, Hermine O, Dreyling MH, and Klapper W
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- Adult, Aged, Aged, 80 and over, Biopsy, Discriminant Analysis, Europe, Female, Humans, Kaplan-Meier Estimate, Lymphoma, Mantle-Cell mortality, Lymphoma, Mantle-Cell therapy, Male, Middle Aged, Multivariate Analysis, Predictive Value of Tests, Prognosis, Proportional Hazards Models, Randomized Controlled Trials as Topic, Retrospective Studies, Risk Assessment, Risk Factors, Time Factors, Tumor Burden, Cell Proliferation, Immunohistochemistry, Ki-67 Antigen analysis, Lymphoma, Mantle-Cell chemistry, Lymphoma, Mantle-Cell pathology
- Abstract
Purpose: Mantle-cell lymphoma (MCL) is a rather aggressive B-cell malignancy whose considerable variability of individual outcome is associated with clinical characteristics (Mantle Cell Lymphoma International Prognostic Index [MIPI]). The Ki-67 index is a strong independent prognostic factor; however, the biologic MIPI (MIPI-b) distinguishes only two groups, which does not appropriately depict the clinical heterogeneity. By using the cohort from the European MCL Younger and MCL Elderly trials, we aimed to evaluate the additional prognostic impact of cytology and growth pattern and to improve risk stratification with the Ki-67 index and MIPI., Patients and Methods: Diagnostic tumor biopsies were reviewed by the European Mantle Cell Lymphoma Pathology Panel to determine Ki-67 index by using published guidelines, cytology, and growth pattern. We evaluated prognostic effects for overall survival (OS) by Cox regression. For the cohort used for MIPI-b development (German Low-Grade Lymphoma Study Group [GLSG] 1996 and GLSG2000), we checked whether the equally weighted combination of Ki-67 index (dichotomized at the validated 30% cutoff) and MIPI risk groups was adequate and compared the prognostic power of this modified combination to MIPI and MIPI-b for the MCL Younger/MCL Elderly cohort., Results: The Ki-67 index was assessed in 508 of 832 patients (median age, 62 years). Blastoid cytology was associated with inferior OS independently of MIPI but not independently of the Ki-67 index. Growth pattern was not independently prognostic. The modified combination of the Ki-67 index and MIPI separated four groups with 5-year OS: 85%, 72%, 43%, and 17% (P < .001) and was more discriminative than MIPI and MIPI-b., Conclusion: Using the Ki-67 index is superior to using cytology and growth pattern as prognostic factors in MCL. The modified combination of the Ki-67 index and MIPI showed a refined risk stratification, reflecting their strong complementary prognostic effects while integrating the most relevant prognostic factors available in clinical routine., (© 2016 by American Society of Clinical Oncology.)
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- 2016
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21. Incidence, presentation, and prognosis of malignancies in ataxia-telangiectasia: a report from the French national registry of primary immune deficiencies.
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Suarez F, Mahlaoui N, Canioni D, Andriamanga C, Dubois d'Enghien C, Brousse N, Jais JP, Fischer A, Hermine O, and Stoppa-Lyonnet D
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- Acute Disease, Adult, Age Factors, Aged, Female, France epidemiology, Hodgkin Disease epidemiology, Humans, Immunologic Deficiency Syndromes, Incidence, Lymphoma, Non-Hodgkin epidemiology, Male, Middle Aged, Mutation, Neoplasms genetics, Neoplasms mortality, Neoplasms therapy, Prognosis, Registries, Retrospective Studies, Ataxia Telangiectasia complications, Ataxia Telangiectasia mortality, Leukemia epidemiology, Lymphoma epidemiology, Neoplasms diagnosis, Neoplasms epidemiology
- Abstract
Purpose: Biallelic mutations in ATM cause ataxia-telangiectasia (AT), a rare inherited disease with a high incidence of cancer. Precise estimates of the risk, presentation, and outcomes of cancer in patients with AT need to be addressed in large series., Patients and Methods: In this large retrospective cohort, 69 patients with cancers (24.5%) were identified among 279 patients with AT. Centralized review was performed on 60% of the lymphomas. Incidence rates were compared with the French population, and risk factors were analyzed., Results: Eight patients developed acute leukemias (including four T-cell acute lymphoblastic leukemias), 12 developed Hodgkin lymphoma (HL), 38 developed non-Hodgkin lymphoma (NHL), three developed T-cell prolymphocytic leukemia (T-PLL), and eight developed carcinoma at a median age of 8.3, 10.6, 9.7, 24.2, and 31.4 years, respectively (P < .001). The majority of NHLs were aggressive B-cell NHL. Epstein-Barr virus was associated with all of the HLs and 50% of the NHLs. Overall survival was shorter in patients with AT who developed cancer compared with those who did not develop cancer (15 v 24 years, respectively; P < .001). Survival was improved in patients who achieved a major response to treatment (3.46 v 0.87 years for major v minor responses, respectively; P = .011). Immunodeficiency was associated with increased risk of cancer. ATM mutation type was associated with a difference in survival in the entire cohort but not with cancer incidence or cancer survival., Conclusion: B-cell NHL, HL, and acute lymphoblastic leukemia occur at a high rate and earlier age than carcinomas in AT. T-PLLs are rarer than initially reported. Prognosis is poor, but patients may benefit from treatment with an improved survival., (© 2014 by American Society of Clinical Oncology.)
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- 2015
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