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1. Langerhans cell histiocytosis: therapeutic strategy and outcome in a 30-year nationwide cohort of 1478 patients under 18 years of age

Author: Abdellatif Tazi, Jean-François Emile, Yves Reguerre, Jean Donadieu, Khê Hoang-Xuan, Charlotte Rigaud, Yves Bertrand, Jean Miron, Caroline Thomas, Patrick Lutz, Mohamed Barkaoui, Claire Galambrun, Despina Moshous, Aurore Coulomb, Nathalie Aladjidi, Ludovic Mansuy, Virginie Gandemer, Corinne Armari-Alla, Anne Lambilliotte, Anne Deville, Geneviève Plat, Sébastien Héritier, Eric Jeziorski, Sylvie Fraitag, Nicolas Leboulanger, CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hématologie et immunologie pédiatrique, Hospices Civils de Lyon (HCL)-CHU Lyon-Institut d'hématologie et d'oncologie pédiatrique [CHU - HCL] (IHOPe), Hospices Civils de Lyon (HCL)-Hôpital Femme-Mère-Enfant (HFME), Service d'hématologie pédiatrique-oncologie, Hôpital Jeanne de Flandre [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service d'Hémato-oncologie Pédiatrique, CHU Bordeaux [Bordeaux]-Hôpital Pellegrin, CIC - Bordeaux, Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU de Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service d'Hématologie pédiatrique, Hôpital de la Timone, Marseille, Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Service d'Hématologie et d'Oncologie Pédiatrique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Hôpital de la Tronche, Centre hospitalier Félix-Guyon [Saint-Denis, La Réunion], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'Anatomie et cytologie pathologiques [CHU Pitié-Salpêtrière] (ACP), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut de Génétique et Développement de Rennes (IGDR), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), CHU Pontchaillou [Rennes], 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), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], OncoNeuroTek [Paris], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Service de pneumologie [Saint-Louis], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Pathology, Groupe hospitalier Ambroise Paré, Registre français des neutropénies chroniques sévères, Institut National de la Santé et de la Recherche Médicale, Association Histiocytose France, Association la Petite Maison dans la Prairie, PHRC 2001 CHU Nantes, French Ministry of Health, RMHE, GARDRAT family, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP], Service d'anatomie pathologique [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP]-Sorbonne Université (SU), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Centre National de la Recherche Scientifique (CNRS), Service de neurologie Mazarin, CHU Pitié-Salpêtrière [APHP], Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Diderot - Paris 7 (UPD7), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Trousseau [APHP], Hospices Civils de Lyon ( HCL ) -CHU Lyon-Institut d'hématologie et d'oncologie pédiatrique [CHU - HCL] ( IHOPe ), Hospices Civils de Lyon ( HCL ) -Hôpital Femme-Mère-Enfant (HFME), Hôpital Jeanne de Flandre [Lille]-Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ), Assistance Publique - Hôpitaux de Marseille ( APHM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ), Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ), CHU Félix Guyon, Service d'anatomie pathologique, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Trousseau [APHP], Institut de Génétique et Développement de Rennes ( IGDR ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Centre National de la Recherche Scientifique ( CNRS ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), 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 ), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute ( ICM ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -CHU Pitié-Salpêtrière [APHP], Hôpital de la Salpétrière, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -CHU Pitié-Salpêtrière [APHP]-Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -CHU Pitié-Salpêtrière [APHP], Assistance publique - Hôpitaux de Paris (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris]-Université Paris Diderot - Paris 7 ( UPD7 ), Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité ( CRESS (U1153 / UMR_A 1125) ), Université Sorbonne Paris Cité ( USPC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut National de la Recherche Agronomique ( INRA ), Service d'Anatomie et cytologie pathologiques = Service de Pathologie [CHU Pitié-Salpêtrière] (ACP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Service de neurologie 1 [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], and Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA)
Subjects: 0301 basic medicine, Male, medicine.medical_specialty, Adolescent, [SDV]Life Sciences [q-bio], Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Refractory, Langerhans cell histiocytosis, Internal medicine, medicine, Humans, Cladribine, Child, [ SDV ] Life Sciences [q-bio], business.industry, historical comparisons, Age Factors, Infant, Newborn, Infant, Standard of Care, Hematology, medicine.disease, Combined Modality Therapy, Survival Analysis, Confidence interval, 3. Good health, Vinblastine, Surgery, Histiocytosis, Langerhans-Cell, 030104 developmental biology, Treatment Outcome, 030220 oncology & carcinogenesis, Child, Preschool, Population Surveillance, Cohort, Cytarabine, Female, France, business, Cohort study, medicine.drug, Follow-Up Studies
Abstract: International audience; The French national cohort of children with Langerhans cell histiocytosis (LCH) has included 1478 patients since it was established in 1983. LCH therapeutic strategies substantially changed in 1998, so we have divided the cohort into two 15-year periods. Starting in 1998, therapy duration increased from 6 to 12 months, repeated induction therapy was performed in cases showing a poor response to the first induction with vinblastine and steroids, and refractory disease in a risk organ (RO+) was treated with cladribine and cytarabine. A total of 483 (33%) patients were enrolled before 1998, and 995 (67%) after 1998. Five-year survival was 96·6% (95% confidence interval: 95·4–97·5%) overall, improving from 92% pre-1998 to 99% post-1998 (P \textless 0·001 adjusted to disease extent). This change was supported by an increase in 5-year survival from 60% to 92% in the RO+ group. Survival was particularly associated with cladribine and cytarabine among refractory RO+ patients. Disease reactivation was slightly less frequent after 1998, due to better enrolment of single-system patients, extended therapy duration, and more efficient second-line therapy. The crude rates of endocrine and neurological sequelae (the most frequent sequelae) appeared to improve over time, but this difference was not observed when the analysis was stratified by disease extent
Published: 2016
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2. Indications and outcomes of antifungal therapy in French patients with haematological conditions or recipients of haematopoietic stem cell transplantation

Author: Raoul Herbrecht, Anne Auvrignon, Catherine Cordonnier, Mauricette Michallet, Yves Bertrand, Paul Preziosi, Nizar Mahlaoui, Jean-Pierre Gangneux, Fabrice Ruiz, Norbert-Claude Gorin, Denis Caillot, Anne Thiebaut, Benoit Brethon, Service d'Hématologie, CHU Strasbourg, Hôpital du Bocage, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Service d'hématologie clinique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service d'hématologie [Hôpital Edouard Herriot - HCL], Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), IFR Necker-Enfants Malades (IRNEM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hématologie et immunologie pédiatrique, Hospices Civils de Lyon (HCL)-CHU Lyon-Institut d'hématologie et d'oncologie pédiatrique [CHU - HCL] (IHOPe), Hospices Civils de Lyon (HCL)-Hôpital Femme-Mère-Enfant (HFME), Service d'hématologie clinique et de thérapie cellulaire [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Saint-Antoine [AP-HP], Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), Hospices Civils de Lyon ( HCL ) -Hospices Civils de Lyon ( HCL ), IFR Necker-Enfants Malades ( IRNEM ), Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Hospices Civils de Lyon ( HCL ) -CHU Lyon-Institut d'hématologie et d'oncologie pédiatrique [CHU - HCL] ( IHOPe ), Hospices Civils de Lyon ( HCL ) -Hôpital Femme-Mère-Enfant (HFME), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Saint-Antoine [APHP], Institut de recherche, santé, environnement et travail ( Irset ), Université d'Angers ( UA ) -Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -École des Hautes Études en Santé Publique [EHESP] ( EHESP ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ) -Université des Antilles ( UA ), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Saint-Antoine [APHP]
Subjects: Male, medicine.medical_treatment, MESH : Prospective Studies, MESH : Aged, Hematopoietic stem cell transplantation, Aspergillosis, 0302 clinical medicine, MESH : Child, MESH: Child, MESH: Immunocompromised Host, Pharmacology (medical), Prospective Studies, Child, MESH: Treatment Outcome, Aged, 80 and over, 0303 health sciences, MESH: Middle Aged, MESH : Infant, invasive candidiasis, MESH: Infant, 3. Good health, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, MESH: Young Adult, Child, Preschool, Hematologic Neoplasms, MESH : Hematologic Neoplasms, Microbiology (medical), medicine.medical_specialty, MESH : Young Adult, MESH : Stem Cell Transplantation, 03 medical and health sciences, MESH : Adolescent, Humans, MESH : Middle Aged, MESH : Aged, 80 and over, Intensive care medicine, Aged, MESH : Mycoses, Pharmacology, MESH: Adolescent, MESH: Humans, 030306 microbiology, MESH : Humans, MESH: Child, Preschool, Infant, MESH: Adult, medicine.disease, MESH: Antifungal Agents, Survival Analysis, mortality, invasive fungal disease, Mycoses, chemistry, MESH: Female, Antifungal Agents, haematopoietic stem cell transplantation, MESH : Child, Preschool, chemistry.chemical_compound, MESH: Aged, 80 and over, [ SDV.MP ] Life Sciences [q-bio]/Microbiology and Parasitology, MESH : Female, 030212 general & internal medicine, Prospective cohort study, MESH: Aged, Mortality rate, MESH : Immunocompromised Host, Middle Aged, MESH : Adult, Treatment Outcome, Infectious Diseases, MESH: Survival Analysis, haematology, Female, France, MESH: Stem Cell Transplantation, Adult, Adolescent, MESH : Male, MESH : Antifungal Agents, MESH : Treatment Outcome, Neutropenia, Immunocompromised Host, Young Adult, MESH: Mycoses, Internal medicine, medicine, MESH : France, invasive aspergillosis, business.industry, MESH: Male, MESH: Prospective Studies, Transplantation, MESH: France, MESH : Survival Analysis, Caspofungin, business, Febrile neutropenia, Stem Cell Transplantation, MESH: Hematologic Neoplasms
Abstract: International audience; OBJECTIVES: Invasive fungal disease (IFD) remains a major concern in patients with haematological conditions. We describe diagnoses, therapeutic management and outcomes in unselected consecutive patients from haematological facilities treated for suspected or documented IFD. METHODS: In this observational prospective study, children/adults with haematological conditions or haematopoietic stem cell transplantation (HSCT) were recruited upon start of non-prophylactic systemic antifungal treatment in 37 French haematological facilities (December 2007 to December 2008). IFD episodes were classified according to the 2008 EORTC/MSG criteria. RESULTS: The cohort included 419 patients (298 adults and 121 children): 88% haematological malignancies, 28% HSCT recipients and 68% neutropenic. Patients had 423 IFD episodes: 21% mycologically documented (59% probable/proven aspergillosis, 32% proven candidiasis and 9% probable/proven other IFD) and 20% classified as possible IFD. The remaining cases were assigned to two groups: febrile neutropenia (34%) and unclassified (25%), 9% of which were classified as possible/probable/proven IFD by day 7. Treatment was thus initiated early in 59% of patients; liposomal amphotericin B and caspofungin were the most common single-agent therapies. The 12 week mortality was 18% for probable/proven aspergillosis, 15% for proven candidiasis, 10% for probable/proven other IFD, 9% for possible IFD, 3% for febrile neutropenia and 12% for unclassified episodes (log rank P = 0.016); it was dependent on age, complete remission of underlying haematological disease and mechanical ventilation. CONCLUSIONS: In this comprehensive sample of haematological patients receiving antifungal treatment, we observe a widespread resort to early therapy and a low mortality rate, including in patients with probable or proven IFD.
Published: 2012
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3. Long-term event-free survival, chimerism and fertility outcomes in 234 patients with sickle-cell anemia younger than 30 years after myeloablative conditioning and matched-sibling transplantation in France

Author: Eliane Gluckman, Yves Bertrand, Karima Yakouben, Isabelle Thuret, Charlotte Jubert, Bénédicte Neven, Felipe Suarez, F. Bernaudin, Sébastien Maury, Catherine Paillard, Patrick Lutz, Société Française de Greffe de Moelle et de Thérapie Cellulaire, Jacques-Olivier Bay, Catherine Poirot, M. Kuentz, Claire Galambrun, Dominique Bories, Marie Robin, Jean-Paul Vernant, Pierre Rohrlich, Gérard Socié, Nicole Raus, Corinne Pondarré, Jean-Hugues Dalle, Régis Peffault de Latour, Jean-Pierre Vannier, Nathalie Dhedin, Centre Hospitalier Intercommunal de Créteil (CHIC), Unité d'Hémato-Immunologie pédiatrique [Hôpital Robert Debré, Paris], Service d'Immuno-hématologie pédiatrique [Hôpital Robert Debré, Paris], Hôpital Robert Debré-Hôpital Robert Debré, Hôpital Henri Mondor, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hospices Civils de Lyon (HCL), CHI Créteil, Micro-Environnement et Régulation Cellulaire Intégrée (MERCI), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Physiopathologie, Autoimmunité, maladies Neuromusculaires et THErapies Régénératrices (PANTHER), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Service d'hématologie clinique, Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Université Pierre et Marie Curie - Paris 6 - UFR de Médecine Pierre et Marie Curie (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC), Service d'hématologie et immunologie pédiatrique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Service de pédiatrie, d'hématologie et d'oncologie [Hôpital de La Timone - APHM], Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Hôpital de la Timone [CHU - APHM] (TIMONE), CHU Bordeaux [Bordeaux], Centre Hospitalier Universitaire de Nice (CHU Nice), Role of intra-Clonal Heterogeneity and Leukemic environment in ThErapy Resistance of chronic leukemias (CHELTER), Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Service d'hématologie [Hôpital Edouard Herriot - HCL], Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hématologie moléculaire [CHU Mondor], CHU Henri Mondor, Service d'hématologie greffe [Saint-Louis], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Hématologie et immunologie pédiatrique, Hospices Civils de Lyon (HCL)-CHU Lyon-Institut d'hématologie et d'oncologie pédiatrique [CHU - HCL] (IHOPe), Hospices Civils de Lyon (HCL)-Hôpital Femme-Mère-Enfant (HFME), Hôpital Civil, Hopital Civil, Service d'Hématologie pédiatrique, Hôpital de la Timone, Marseille, Service de Greffe de Moelle - Unité AJA, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Service d'Hématologie clinique [CHU Pitié-Salpêtrière], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Clinical Research Unit, Biology of Reproduction Unit, Paris, France, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Role of intra-Clonal Heterogeneity and Leukemic environment in ThErapy Resistance of chronic leukemias - Clermont Auvergne (CHELTER), Université Clermont Auvergne (UCA), Service d'Hématologie Clinique [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: Hemolytic anemia, medicine.medical_specialty, Transplantation Conditioning, Anemia, [SDV]Life Sciences [q-bio], Graft vs Host Disease, Anemia, Sickle Cell, Gastroenterology, Chimerism, Article, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Humans, Progression-free survival, Red Cell Biology & its Disorders, ComputingMilieux_MISCELLANEOUS, Aged, business.industry, Siblings, Hazard ratio, Hematopoietic Stem Cell Transplantation, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Hematology, medicine.disease, Sickle cell anemia, Progression-Free Survival, 3. Good health, Transplantation, Fertility, 030220 oncology & carcinogenesis, France, business, Busulfan, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030215 immunology, medicine.drug
Abstract: Allogeneic stem cell transplantation remains the only curative treatment for sickle cell anemia (SCA), but the place of myeloablative conditioning in the procedure remains to be defined. The aim of the present study was to analyze long-term outcomes, including chimerism, SCA-related events and biological data (hemoglobin, reticulocytes, HbS%), and fertility in a French series of 234 SCA patients under 30 years of age who, from 1988 to 2012, received a matched-sibling-donor stem cell transplantation following standardized myeloablative conditioning [busulfan, cyclophosphamide and rabbit antithymocyte globulin (ATG)]. Since the first report of the series (1988-2004), 151 new consecutive patients with SCA have been similarly transplanted. Considering death, non-engraftment or rejection (donor cells 15 years (hazard ratio=4.37; P=0.002) and lower (5-15 vs. 20 mg/kg) ATG dose (hazard ratio=4.55; P=0.001). At one year, 44% of patients had mixed chimerism (5-95% donor cells), but those prepared with ATG had no graft rejection. No events related to SCA occurred in patients with mixed chimerism, even those with 15-20% donor cells, but hemolytic anemia stigmata were observed with donor cells
Published: 2020
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4. Lymphoid differentiation of hematopoietic stem cells requires efficient Cxcr4 desensitization

Author: Ali Dalloul, Yves Bertrand, Christine Bellanné-Chantelot, Julie Nguyen, Françoise Bachelerie, Sarah Beaussant-Cohen, Jean Donadieu, Marie-Laure Aknin, Fawzia Louache, Monika Wittner, Vincent Biajoux, Marion Espéli, Karl Balabanian, Françoise Gaudin, Vincent Rondeau, Christelle Freitas, Cytokines, chimiokines et immunopathologie, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hématopoïèse normale et pathologique (U1170 Inserm), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Inflammation, chimiokines et immunopathologie, Institut Paris-Saclay d’Innovation Thérapeutique (IPSIT), Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon), Hématologie et immunologie pédiatrique, Hospices Civils de Lyon (HCL)-CHU Lyon-Institut d'hématologie et d'oncologie pédiatrique [CHU - HCL] (IHOPe), Hospices Civils de Lyon (HCL)-Hôpital Femme-Mère-Enfant (HFME), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Service d'Hématologie et Oncologie pédiatriques, Hôpital Trousseau [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP], Institut Gustave Roussy (IGR), Institut Paris Saclay d’Innovation Thérapeutique (IPSIT), Université Paris-Sud - Paris 11 (UP11)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'hématologie-immunologie-oncologie pédiatrique [CHU Trousseau], CHU Trousseau [APHP], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Sud - Paris 11 (UP11), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR), Service d’Hémato-Oncologie Pédiatrique, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Hospices Civils de Lyon (HCL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Registre français des neutropénies chroniques sévères, Centre de référence des déficits Immunitaires Héréditaires, Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Balabanian, Karl, Université de Franche-Comté (UFC), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: [SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, 0301 basic medicine, medicine.medical_treatment, Cellular differentiation, [SDV]Life Sciences [q-bio], Gene Expression, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], CXCR4, 0302 clinical medicine, Homologous desensitization, Immunology and Allergy, Lymphocytes, Child, Research Articles, ComputingMilieux_MISCELLANEOUS, Bone Marrow Transplantation, Desensitization (medicine), Reverse Transcriptase Polymerase Chain Reaction, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Cell Differentiation, Flow Cytometry, 3. Good health, Cell biology, Haematopoiesis, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Warts, Stem cell, Signal Transduction, Adult, Receptors, CXCR4, Cell Survival, Primary Immunodeficiency Diseases, Immunology, Bone Marrow Cells, Mice, Transgenic, Biology, Article, 03 medical and health sciences, medicine, Animals, Humans, Lymphocyte Count, Progenitor cell, Immunologic Deficiency Syndromes, Hematopoietic Stem Cells, 030104 developmental biology, Mutation, Bone marrow, Spleen
Abstract: Using a mouse model harboring a naturally occurring WHIM syndrome–linked gain-of-function Cxcr4 mutation, Freitas et al. show that Cxcr4 desensitization is critical for quiescence/cycling balance of murine short-term hematopoietic stem cells and their differentiation into multipotent and downstream lymphoid-biased progenitors., The CXCL12/CXCR4 signaling exerts a dominant role in promoting hematopoietic stem and progenitor cell (HSPC) retention and quiescence in bone marrow. Gain-of-function CXCR4 mutations that affect homologous desensitization of the receptor have been reported in the WHIM Syndrome (WS), a rare immunodeficiency characterized by lymphopenia. The mechanisms underpinning this remain obscure. Using a mouse model with a naturally occurring WS-linked gain-of-function Cxcr4 mutation, we explored the possibility that the lymphopenia in WS arises from defects at the HSPC level. We reported that Cxcr4 desensitization is required for quiescence/cycling balance of murine short-term hematopoietic stem cells and their differentiation into multipotent and downstream lymphoid-biased progenitors. Alteration in Cxcr4 desensitization resulted in decrease of circulating HSPCs in five patients with WS. This was also evidenced in WS mice and mirrored by accumulation of HSPCs in the spleen, where we observed enhanced extramedullary hematopoiesis. Therefore, efficient Cxcr4 desensitization is critical for lymphoid differentiation of HSPCs, and its impairment is a key mechanism underpinning the lymphopenia observed in mice and likely in WS patients.
Published: 2017
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5. Employment in French young adult survivors of childhood leukemia: an LEA study (for Leucemies de l'Enfant et de l'Adolescent-childhood and adolescent leukemia)

Author: André Baruchel, Marie-Dominique Tabone, Justyna Kanold, Marie-Pascale Lehucher-Michel, Pascal Chastagner, Dominique Plantaz, Floriane Garnier, Nicolas Sirvent, Julie Berbis, Gérard Michel, Yves Bertrand, Pascal Auquier, Celine Reggio, Santé Publique et maladies Chroniques : Qualité de vie Concepts, Usages et Limites, Déterminants (SPMC), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM), Pédiatrie et oncologie pédiatrique [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Hématologie et immunologie pédiatrique, Hospices Civils de Lyon (HCL)-CHU Lyon-Institut d'hématologie et d'oncologie pédiatrique [CHU - HCL] (IHOPe), Hospices Civils de Lyon (HCL)-Hôpital Femme-Mère-Enfant (HFME), Service d'hématologie pédiatrique, CHU Clermont-Ferrand-CIC Inserm 501, Université de Montpellier (UM), Service Hématologie Infantile, CHU Grenoble, Service d'hématologie et immunologie pédiatrique, Université Paris Diderot - Paris 7 (UPD7)-Hôpital Robert Debré-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Service d'hématologie-immunologie-oncologie pédiatrique [CHU Trousseau], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP], Hôpital de la Timone [CHU - APHM] (TIMONE), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)
Subjects: Adult, Employment, Male, medicine.medical_specialty, Childhood leukemia, Adolescent, Population, [SHS.PSY]Humanities and Social Sciences/Psychology, Logistic regression, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Risk Factors, medicine, Humans, 030212 general & internal medicine, Survivors, Young adult, education, Psychiatry, Response rate (survey), education.field_of_study, Leukemia, Oncology (nursing), business.industry, Public health, medicine.disease, [SHS.ECO]Humanities and Social Sciences/Economics and Finance, 3. Good health, Oncology, quality, 030220 oncology & carcinogenesis, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, 8. Economic growth, Cohort, Female, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, Demography, Follow-Up Studies
Abstract: International audience; Our principal aim was to assess the occupational outcomes of French ă survivors of childhood leukemia, compared to national population. The ă secondary objective was to identify determinants linked with employment ă stability after childhood leukemia. ă All survivors aged 15 and over enrolled in the French LEA Cohort ă (Childhood and Adolescent Leukemia) were included. Occupational data ă were self-reported. The occupational distributions expected in the ă cohort for each age range were established based on the distribution in ă France as reference, and comparisons between observed and expected ă distributions were performed. Logistic regression model was used to ă explore determinants of stability of survivors' employment. ă The questionnaire was completed by 845 eligible survivors (response rate ă 87.8 %), with a mean age of 22.3 +/- 5.4 years and a mean follow-up ă duration of 14.3 +/- 6.3 years. Among the 361 survivors currently in the ă labor market, 36 (10.0 %) were seeking a job, which is significantly ă lower than expected (19.3 %) compared to French population. Conversely, ă among those currently employed, the number of survivors in unstable ă employment (43.9 %) was significantly higher than expected (33.5 %). ă Younger age and higher number of late effects were risk factors for ă unstable employment. ă While the employment rate of the young French adult population of ă childhood leukemia survivors seems rather positive, access to a steady ă job appears to be compromised for some survivors. ă A strategy to better identify particular subgroups of survivors at ă greatest risk for difficulties in their professional achievement will ă help ensure the development of specific intervention strategies and ă support procedures.
Published: 2016
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6. Metabolic syndrome in long-term survivors of childhood acute leukemia ă treated without hematopoietic stem cell transplantation: an LEA study

Author: Yves Bertrand, Paul Saultier, André Baruchel, Gérard Michel, Virginie Gandemer, Camille Vercasson, Patrick Lutz, Justyna Kanold, Audrey Contet, Guy Leverger, Stéphane Ducassou, Jean-Hugues Dalle, Marie-Dominique Tabone, Hervé Chambost, Sandrine Thouvenin, Marilyne Poirée, Nicolas Sirvent, Dominique Plantaz, Pascal Auquier, Julie Berbis, Claire Oudin, Service d'hématologie-immunologie-oncologie pédiatrique [CHU Trousseau], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Hôpital Robert Debré Paris, Hôpital Robert Debré, Service de pédiatrie, CHU Grenoble, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble, Institut de Génétique et Développement de Rennes (IGDR), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), CHU Pontchaillou [Rennes], Santé Publique et maladies Chroniques : Qualité de vie Concepts, Usages et Limites, Déterminants (SPMC), Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU), Service d'Hématologie pédiatrique, Hôpital de la Timone, Marseille, Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Service d'hématologie et immunologie pédiatrique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Hôpital Trousseau, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Pédiatrie et oncologie pédiatrique [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Nutrition, obésité et risque thrombotique (NORT), Aix Marseille Université (AMU)-Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hématologie et immunologie pédiatrique, Hospices Civils de Lyon (HCL)-CHU Lyon-Institut d'hématologie et d'oncologie pédiatrique [CHU - HCL] (IHOPe), Hospices Civils de Lyon (HCL)-Hôpital Femme-Mère-Enfant (HFME), Service d'hématologie pédiatrique, Université de la Méditerranée - Aix-Marseille 2-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Unité de Transplantation Médullaire, Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Hôpital d'enfants, Service Hématologie Infantile, Hôpital Pellegrin Tripode, CHU Clermont-Ferrand-CIC Inserm 501, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Université Paris Diderot - Paris 7 (UPD7)-Hôpital Robert Debré-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )
Subjects: Male, medicine.medical_treatment, [SHS.PSY]Humanities and Social Sciences/Psychology, Hematopoietic stem cell transplantation, 030204 cardiovascular system & hematology, Biochemistry, Gastroenterology, Cohort Studies, 0302 clinical medicine, Risk Factors, Antineoplastic Combined Chemotherapy Protocols, Prevalence, Survivors, Child, Abdominal obesity, Metabolic Syndrome, 2. Zero hunger, education.field_of_study, Acute leukemia, Leukemia, Remission Induction, Age Factors, Articles, Hematology, [SHS.ECO]Humanities and Social Sciences/Economics and Finance, Combined Modality Therapy, 3. Good health, quality, Child, Preschool, 030220 oncology & carcinogenesis, Cohort, Female, 030211 gastroenterology & hepatology, medicine.symptom, Cohort study, Adult, medicine.medical_specialty, Adolescent, Immunology, Population, Lower risk, Young Adult, 03 medical and health sciences, Internal medicine, medicine, Humans, Risk factor, education, National Cholesterol Education Program, Radiotherapy, business.industry, Cell Biology, medicine.disease, Surgery, Endocrinology, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Metabolic syndrome, business, Body mass index, Follow-Up Studies
Abstract: INTRODUCTION Acute leukemia (AL) accounts for one third of childhood cancers. Cardiovascular conditions are serious long-term complications of childhood AL. However, few studies have investigated the risk of metabolic syndrome (MetS), a known predictor of cardiovascular disease, in patients treated without hematopoietic stem cell transplantation (HSCT). We describe the overall and age-specific prevalence, and risk factors for MetS and its components in the L.E.A. French cohort of childhood AL survivors treated without HSCT. METHODS L.E.A. is a long-term follow-up program involving all childhood AL survivors treated in the French participating centers since 1980 (clinicaltrials.gov identifier: NCT 01756599). MetS was defined according to the National Cholesterol Education Program - Adult Treatment Panel III (NCEP-ATPIII) criteria revised in 2005. RESULTS The study included 650 adult patients. The mean age at evaluation was 24.2 years and the mean follow-up after leukemia diagnosis was 16.0 years. Central nervous system (CNS) irradiation was performed in 18.0% of patients (n=117). The prevalence of MetS was 6.9% (95% CI 5.1-9.2). The age-specific cumulative prevalence at 20, 25, 30 and 35 years of age was 1.3%, 6.1%, 10.8% and 22.4%, respectively, as shown in the Figure. The prevalence of decreased HDL-cholesterol, increased triglycerides, increased fasting glucose, increased blood pressure and increased abdominal circumference was 26.8%, 11.7%, 5.8%, 36.7% and 16.7%, respectively. The risk factors significantly associated with metabolic syndrome in the multivariate analysis were male gender, older age at last evaluation and higher body mass index at diagnosis, as shown in the Table. Cumulative steroid dose was not a significant risk factor. CNS-irradiated and non-irradiated patients exhibited different patterns of metabolic abnormalities, with more frequent abdominal obesity in irradiated patients and more frequent hypertension in non-irradiated patients. DISCUSSION Our study aimed to precisely describe the overall and age-specific prevalence, and risk factors of MetS in a large cohort of childhood AL survivors treated without HSCT. Notably, the subgroup treated with chemotherapy alone is one of the largest ever published, which is of particular interest as current protocols include very limited CNS irradiation indications. The prevalence of MetS was approximately two-fold higher than that observed in the adult French general population under 40 years of age. Moreover, the prevalence of MetS was found to increase markedly with age. An increased BMI at diagnosis was a risk factor for MetS. Children with an elevated BMI at diagnosis may have a genetic predisposition to metabolic disturbances or a socio-familial environment that renders them more vulnerable to metabolic complications. CNS irradiation was not found to be a risk factor for MetS. In the literature however, brain irradiation has been frequently reported as a risk factor for MetS. This variation with our study can probably be explained in part by the observation that our irradiated patients displayed a lower risk of elevated blood pressure along with a greater risk of increased abdominal circumference. The irradiated patients may therefore have a different metabolic risk profile compared with the non-irradiated patients, thereby suggesting varying mechanisms of pathogenesis. The results of our study confirm the need for early and prolonged follow-up of adult survivors of childhood AL even when treated without HSCT and without CNS irradiation. This prerequisite could enable both early detection of metabolic abnormalities and implementation of appropriate therapeutic procedures to reduce the morbidity and mortality associated with cardiovascular complications in such patients. Table. Multivariate analysis of potential risk factors for the metabolic syndrome OR: odds ratio; CI: confidence interval; BMI: body mass index; CNS: central nervous system; † OR per each additional year of follow-up; ‡ OR per each additional z-score unit; *significant values (p < 0.05) Table. Multivariate analysis of potential risk factors for the metabolic syndrome. / OR: odds ratio; CI: confidence interval; BMI: body mass index; CNS: central nervous system; † OR per each additional year of follow-up; ‡ OR per each additional z-score unit; *significant values (p < 0.05) Figure. Age-specific cumulative prevalence of the metabolic syndrome Figure. Age-specific cumulative prevalence of the metabolic syndrome Disclosures No relevant conflicts of interest to declare.
Published: 2016
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7. The Impact of Donor Type on Long-Term Health Status and Quality of Life after Allogeneic Hematopoietic Stem Cell Transplantation for Childhood Acute Leukemia: A Leucemie de l'Enfant et de L'Adolescent Study

Author: André Baruchel, Gérard Michel, Guy Leverger, Geneviève Plat, Charlotte Jubert, Marie-Dominique Tabone, Hervé Chambost, Justyna Kanold, Catherine Paillard, Jean-Hugues Dalle, Claire Galambrun, Virginie Gandemer, Yves Bertrand, Jacinthe Bonneau, Maryline Poiree, Claire Freycon, Virginie Villes, Isabelle Pellier, Sandrine Visentin, Julie Berbis, Claire Oudin, Cécile Pochon, Anne Sirvent, Pascal Auquier, Service de pédiatrie multidisciplinaire [Hôpital de la Timone Enfants - APHM], Hôpital de la Timone [CHU - APHM] (TIMONE), Santé Publique et maladies Chroniques : Qualité de vie Concepts, Usages et Limites, Déterminants (SPMC), Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU), Hématologie et immunologie pédiatrique, Hospices Civils de Lyon (HCL)-CHU Lyon-Institut d'hématologie et d'oncologie pédiatrique [CHU - HCL] (IHOPe), Hospices Civils de Lyon (HCL)-Hôpital Femme-Mère-Enfant (HFME), Service d'hématologie et immunologie pédiatrique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Service d'hématologie-immunologie-oncologie pédiatrique [CHU Trousseau], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Centre de référence des maladies héréditaires du métabolisme (MaMEA Nancy-Brabois), Groupe hospitalier Pellegrin, Service de Pédiatrie, Unité d'Oncologie et Hématologie Pédiatrique, Centre Hospitalier Universitaire de Nice (CHU Nice), Institut de Génétique et Développement de Rennes (IGDR), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), CHU Pontchaillou [Rennes], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Hématogoie pédiatrique, hôpital Sud, Service d'oncologie médicale [CHU Strasbourg], CHU Strasbourg, Service d'hématologie pédiatrique, CHU Clermont-Ferrand-CIC Inserm 501, Université de la Méditerranée - Aix-Marseille 2-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Service d'Hématologie pédiatrique, Hôpital de la Timone, Marseille, Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), CHU Toulouse [Toulouse], Hôpital Robert Debré Paris, Hôpital Robert Debré, Pédiatrie et oncologie pédiatrique [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), the French National Clinical Research Program (grant no. PHRC10-24-02), French National Cancer Institute (InCA), French National Research Agency (ANR) [2011-043], Canceropole PACA [2016-03], Regional Council PACA [2016-03], Herault and the Bouches-du-Rhone departmental comities of the Ligue Contre le Cancer, French Institute for Public Health Research (IRESP), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), and Jonchère, Laurent
Subjects: [SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, Male, Pediatrics, Cord blood transplantation, MESH: Late effects, medicine.medical_treatment, Health Status, MESH: Quality of life, Hematopoietic stem cell transplantation, Childhood leukemia, 0302 clinical medicine, Quality of life, Child, MESH: Cord blood transplantation, Acute leukemia, Late effect, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Hematology, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Tissue Donors, 3. Good health, Leukemia, 030220 oncology & carcinogenesis, Child, Preschool, Female, Cord Blood Stem Cell Transplantation, medicine.symptom, Unrelated Donors, medicine.medical_specialty, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH: Hematopoietic stem cell transplantation, 03 medical and health sciences, [SDV.MHEP.PED] Life Sciences [q-bio]/Human health and pathology/Pediatrics, MESH: Childhood leukemia, [SDV.CAN] Life Sciences [q-bio]/Cancer, medicine, Humans, Transplantation, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, business.industry, Late effects, Infant, Odds ratio, medicine.disease, Surgery, business, 030215 immunology
Abstract: International audience; We compared the long-term impact of donor type (sibling donor [SD] versus matched unrelated donor [MUD] or umbilical cord blood [UCB]) on late side effects and quality of life (QoL) in childhood acute leukemia survivors treated with hematopoietic stem cell transplantation. We included 314 patients who underwent transplantation from 1997 to 2012 and were enrolled in the multicenter French Leucemie de l'Enfant et de L'Adolescent ("Leukemia in Children and Adolescents") cohort. More than one-third of the patients were adults at last visit; mean follow-up duration was 6.2 years. At least 1 late effect was observed in 284 of 314 patients (90.4%). The average number of adverse late effects was 2.1 +/- 1, 2.4 +/- 2, and 2.4 +/- 2 after SD, MUD, and UCB transplantation, respectively. In a multivariate analysis, considering the SD group as the reference, we did not detect an impact of donor type for most sequelae, with the exception of increased risk of major growth failure after MUD transplantation (odds ratio [OR], 2.42) and elevated risk of osteonecrosis after UCB transplantation (OR, 4.15). The adults and children's parents reported comparable QoL among the 3 groups. Adult patient QoL scores were lower than age- and sex-matched French reference scores for almost all dimensions. We conclude that although these patients are heavily burdened by long-term complications, donor type had a very limited impact on their long-term health status and QoL.
Published: 2016
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8. Late thyroid complications in survivors of childhood acute leukemia. An LEA study

Author: Gérard Michel, Marie-Dominique Tabone, Jean-Hugues Dalle, Dominique Plantaz, P Chastagner, Vincent Barlogis, Patrick Lutz, Pascal Auquier, Julie Berbis, Claire Oudin, Maryline Poiree, André Baruchel, Sandrine Thouvenin, Justyna Kanold, Yves Bertrand, Stéphane Ducassou, Virginie Villes, Guy Leverger, Anne Sirvent, Virginie Gandemer, Service d'hématologie pédiatrique, Université de la Méditerranée - Aix-Marseille 2-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Santé Publique et maladies Chroniques : Qualité de vie Concepts, Usages et Limites, Déterminants (SPMC), Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU), Hématologie et immunologie pédiatrique, Hospices Civils de Lyon (HCL)-CHU Lyon-Institut d'hématologie et d'oncologie pédiatrique [CHU - HCL] (IHOPe), Hospices Civils de Lyon (HCL)-Hôpital Femme-Mère-Enfant (HFME), CHU Clermont-Ferrand-CIC Inserm 501, Service de Pédiatrie, Unité d'Oncologie et Hématologie Pédiatrique, Centre Hospitalier Universitaire de Nice (CHU Nice), Hôpital Pellegrin Tripode, Service Hématologie Infantile, CHU Grenoble, Service d'hématologie-immunologie-oncologie pédiatrique [CHU Trousseau], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Hôpital Robert Debré Paris, Hôpital Robert Debré, Institut de Génétique et Développement de Rennes (IGDR), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), CHU Pontchaillou [Rennes], Service de pédiatrie, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble, Pédiatrie et oncologie pédiatrique [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Service d'hématologie et immunologie pédiatrique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Hôpital Trousseau, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), French National Clinical Research Program, French National Cancer Institute (InCA), French National Research Agency (ANR), Canceropole PACA, Regional Council PACA, Herault Departmental Comity of the Ligue Contre le Cancer, French Institute for Public Health Research (IRESP), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université Paris Diderot - Paris 7 (UPD7)-Hôpital Robert Debré-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )
Subjects: Male, MESH: Therapy/adverse effects, [SHS.PSY]Humanities and Social Sciences/Psychology, Gastroenterology, 0302 clinical medicine, Risk Factors, MESH: Risk Factors, MESH: Child, Prevalence, Cumulative incidence, Survivors, MESH: Incidence, Child, Thyroid cancer, MESH: Combined Modality, MESH: Survivors, Acute leukemia, Leukemia, MESH: Thyroid Diseases/diagnosis, MESH: France/epidemiology, Incidence, Thyroid, Hematology, MESH: Follow-Up Studies, Total body irradiation, [SHS.ECO]Humanities and Social Sciences/Economics and Finance, Combined Modality Therapy, MESH: Leukemia/complications, 3. Good health, medicine.anatomical_structure, Child, Preschool, 030220 oncology & carcinogenesis, Acute Disease, MESH: Acute Disease, Female, France, Thyroid function, medicine.medical_specialty, MESH: Leukemia/epidemiology, MESH: Combined Modality Therapy/methods, MESH: Leukemia/therapy, MESH: Thyroid Diseases/epidemiology, Article, MESH: Multivariate Analysis, 03 medical and health sciences, Internal medicine, MESH: Thyroid Diseases/etiology, medicine, Humans, MESH: Prevalence, MESH: Humans, business.industry, MESH: Child, Preschool, medicine.disease, Thyroid Diseases, MESH: Male, Surgery, Transplantation, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Multivariate Analysis, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Prophylactic cranial irradiation, business, MESH: Female, Follow-Up Studies, 030215 immunology
Abstract: International audience; Thyroid complications are known side effects of irradiation. However, the risk of such complications in childhood acute leukemia survivors who received either central nervous system irradiation or hematopoietic stem cell transplantation is less described. We prospectively evaluated the incidence and risk factors for thyroid dysfunction and tumors in survivors of childhood acute myeloid or lymphoid leukemia. A total of 588 patients were evaluated for thyroid function, and 502 individuals were assessed for thyroid tumors (median follow-up duration: 12.6 and 12.5 years, respectively). The cumulative incidence of hypothyroidism was 17.3% (95% CI: 14.1-21.1) and 24.6% (95% CI: 20.4-29.6) at 10 and 20 years from leukemia diagnosis, respectively. Patients who received total body irradiation (with or without prior central nervous system irradiation) were at higher risk of hypothyroidism (adjusted HR: 2.87; P=0.04 and 2.79, P=0.01, respectively) as compared with transplanted patients who never received any irradiation. Patients transplanted without total body irradiation who received central nervous system irradiation were also at higher risk (adjusted HR: 3.39; P=0.02). Patients irradiated or transplanted at older than 10 years of age had a lower risk (adjusted HR: 0.61; P=0.02). Thyroid malignancy was found in 26 patients (5.2%). Among them, two patients had never received any type of irradiation: alkylating agents could also promote thyroid cancer. The cumulative incidence of thyroid malignancy was 9.6% (95% CI: 6.0-15.0) at 20 years. Women were at higher risk than men (adjusted HR: 4.74; P=0.002). In conclusion, thyroid complications are frequent among patients who undergo transplantation after total body irradiation and those who received prior central nervous system irradiation. Close monitoring is thus warranted for these patients. Clinicaltrials.gov identifier: NCT 01756599.
Published: 2016
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9. Pharmacokinetic and Pharmacodynamic Characterization of Graspa Versus Native L-Asparaginase in Combination with Cooprall Chemotherapy in a Phase 3 Randomized Trial for the Treatment of Patients with Relapsed Acute Lymphoblastic Leukemia (NCT01 51851 7)

Author: Thomas, Xavier, Bertrand, Yves, Baruchel, Andre, Blin, Nicolas, Tavernier, Emmanuelle, Ducassou, Stephane, Norbert Vey, Gandemer, Virginie, Cacheux, Victoria, Mazingue, Francoise, Raffoux, Emmanuel, Plat, Genevieve, Fernandes, Jose, Poiree, Maryline, Fornecker, Luc, Stephan, Jean-Louis, Hunault, Mathilde, Auvrignon, Anne, Leguay, Thibault, Lepretre, Stephane, Ferster, Alina, Pellier, Isabelle, Plouvier, Emmanuel, Schmitt, Claudine, Bonin, Cecile, Godfrin, Yann, El Hariry, Iman, 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), Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL), Hématologie et immunologie pédiatrique, Hospices Civils de Lyon (HCL)-CHU Lyon-Institut d'hématologie et d'oncologie pédiatrique [CHU - HCL] (IHOPe), Hospices Civils de Lyon (HCL)-Hôpital Femme-Mère-Enfant (HFME), Service d'hématologie et immunologie pédiatrique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Hôpital Pellegrin Tripode, Centre de Recherche en Cancérologie de Marseille (CRCM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), Pediatric Onco-Hematology Unit, CHU Pontchaillou [Rennes], Institut de Génétique et Développement de Rennes (IGDR), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), CHU Clermont-Ferrand, Service d'hématologie biologique, 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), Service de Pédiatrie, Unité d'Oncologie et Hématologie Pédiatrique, Centre Hospitalier Universitaire de Nice (CHU Nice), Service d'hématologie pédiatrique, CHU Saint-Etienne, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Trousseau [APHP], Groupe d'étude des proliférations lymphoïdes (GPL), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de pédiatrie, CHU Grenoble, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Service d'Hématologie Pédiatrique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )
Subjects: [SDV]Life Sciences [q-bio]
Abstract: WOS:000368020102004; International audience; Conference: 57th Annual Meeting of the American-Society-of-Hematology - Orlando, FL - DEC 05-08, 2015
Published: 2015

10. Updated Clinical Activity of Graspa Versus Native l-Asparaginase in Combination with Cooprall Regimen in Phase 3 Randomized Trial in Patients with Relapsed Acute Lymphoblastic Leukemia (NCT01518517)

Author: José Fernandes, Thibault Leguay, Norbert Vey, Stéphane Ducassou, Stéphane Leprêtre, Jean-Louis Stephan, Emmanuelle Tavernier, Iman El Hariry, Emmanuel Plouvier, Geneviève Plat, Poiree Maryline, Dominique Plantaz, Cecile Bonin, Anne Auvrignon, Xavier Thomas, Yves Bertrand, Claudine Schmitt, Françoise Mazingue, Alina Ferster, Luc Fornecker, Mathilde Hunault, Victoria Cacheux, Nicolas Blin, Emmanuel Raffoux, André Baruchel, Isabelle Pellier, Virginie Gandemer, Service d'hématologie et immunologie pédiatrique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Hématologie et immunologie pédiatrique, Hospices Civils de Lyon (HCL)-CHU Lyon-Institut d'hématologie et d'oncologie pédiatrique [CHU - HCL] (IHOPe), Hospices Civils de Lyon (HCL)-Hôpital Femme-Mère-Enfant (HFME), 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), Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL), Hôpital Pellegrin Tripode, Centre de Recherche en Cancérologie de Marseille (CRCM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), Pediatric Onco-Hematology Unit, CHU Pontchaillou [Rennes], Institut de Génétique et Développement de Rennes (IGDR), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), CHU Clermont-Ferrand, Service d'hématologie biologique, 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), Service d'hématologie pédiatrique, CHU Saint-Etienne, CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service Hématologie Infantile, CHU Grenoble, Groupe d'étude des proliférations lymphoïdes (GPL), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de pédiatrie, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Service d'Hématologie Pédiatrique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Université Paris Diderot - Paris 7 (UPD7)-Hôpital Robert Debré-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Centre de Recherche en Cancérologie de Lyon (CRCL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E)
Subjects: Oncology, medicine.medical_specialty, Pediatrics, Asparaginase, [SDV]Life Sciences [q-bio], Immunology, 02 engineering and technology, Biochemistry, law.invention, 03 medical and health sciences, chemistry.chemical_compound, Randomized controlled trial, law, Internal medicine, Acute lymphocytic leukemia, medicine, In patient, Adverse effect, 030304 developmental biology, 0303 health sciences, Surrogate endpoint, business.industry, Cell Biology, Hematology, 021001 nanoscience & nanotechnology, medicine.disease, Chemotherapy regimen, 3. Good health, Regimen, chemistry, 0210 nano-technology, business
Abstract: Background Asparaginase is a cornerstone in the treatment of ALL, but its utility is limited by toxicities including hypersensitivity. Clinical allergy is associated with inactivation of asparaginase by antibodies, which can also neutralize asparaginase without any clinical signs of hypersensitivity (silent inactivation). GRASPA (proposed eryaspase, E-Coli L-Asparaginase encapsulated into red blood cells) improves pharmacokinetics, tolerability and maintain circulating asparaginase (ASPA) activity due to the protective barrier of the erythrocyte membrane. In a recent Phase III trial, it has shown to prolong the asparaginase activity and significantly reduce the incidence of allergic reactions in pts with relapsed ALL. In the non-allergic pts, GRASPA significantly reduced the incidence of hypersensitivity (0% vs 46%; p100 IU/l was 21 ± 5 vs 9 ± 7 days in GRASPA and L-ASP, respectively (p Methods This open, randomized international Phase 3 study enrolled pts with relapsed ALL. The co-primary endpoints were the duration of ASPA activity > 100IU/L and the incidence of hypersensitivity during induction. Key secondary endpoints were complete remission, minimal residual disease, relapse rate, event free survival (EFS) and overall survival (OS). Pts (n=80), aged 1-55 years without prior hypersensitivity were randomized to GRASPA (150 IU/kg, n=26, Arm A) or native L-asparaginase (L-ASP, 10,000 IU/m², n= 28, Arm B). Additionally, 26 pts with prior hypersensitivity were treated with GRASPA in a single stratum (Arm C). All pts received COOPRALL protocol as a backbone chemotherapy. Results A total of 80 pts with relapsed and or refractory ALL were enrolled into the trial. There were a greater proportion of pts who completed the induction treatment in GRASPA arm (65%) than in the L-ASP arm (46%). The main reasons for treatment discontinuation were: target levels of asparagine depletion not reached (64%) in GRASPA arm, and adverse events (58%) in the L-ASP arm. In addition, in the L-ASP arm, 5 (19%) pts prematurely discontinued treatment due to disease progression. As of the cut-off date (28th August 2014), the majority of pts (63%) still continued in the study and followed-up for survival. The relapse rate at 6 and 12 mo was low, and accounted for 3 (13%; 95% CI: 2.6; 32.4) and 5 (26%; 95% CI: 9.1; 51.2) in the GRASPA arm, compared to 1 pt (5%) and 3 (17%; 95% CI: 3.6; 41.4) in the L-ASP arm, respectively. Except for L-ASP, and adult patients, the median EFS and OS were not reached for GRASPA in the entire set or in children, either at 12 months. Overall, there was a trend across all groups with lower EFS and OS event rates with GRASPA compared to L-ASP, as presented in table below. The 2-year follow up will be additionally provided at the meeting Table 1. GRASPA vs L-ASP All patients GRASPA = 26 L-ASP = 28 Children GRASPA = 21 L-ASP = 21 Adults GRASPA = 5 L-ASP = 7 12 mo EFS Median (mo) NR vs 11.6 NR 4.6 vs 1.6 Events 30.8% vs 50.0% 19.1% vs 38.1% 80% vs 85.7% HR 0.54 0.47 0.69 95% CI 0.23; 1.26 0.15; 1.47 0.20; 2.44 P Value* 0.153 0.196 0.569 12 mo OS Median (mo) NR NR 10 vs 8.2 Events 23.1% vs 32.1% 4.8% vs 14.3% 20% vs 42.8% HR 0.63 0.34 0.39 95% CI 023; 1.74 0.05; 2.42 0.05; 2.81 P Value* 0.377 0.424 0.705 *P value in all subsets is not statistically significant Conclusion GRASPA has demonstrated both safety and activity in pts with relapsed ALL, and provides an alternative treatment option for those patients. Disclosures Bertrand: ERYTECH Pharma: Consultancy. Thomas:ERYTECH Pharma: Consultancy. Vey:Roche: Honoraria; Janssen: Honoraria; Celgene: Honoraria. Bonin:ERYTECH Pharma: Employment. El Hariry:ERYTECH Pharma: Employment.
Published: 2015

11. Evaluation of the Impact of the Presence of Neutralizing L-Asparaginase Antibodies on the Efficacy and Safety of Graspa in Phase 3 Randomized Trial Versus Native L-Asparaginase in Patients with Relapsed Acute Lymphoblastic Leukemia (NCT01518517)

Author: Yves Bertrand, Françoise Mazingue, Cecile Bonin, Mathilde Hunault, Yann Godfrin, Anne Auvrignon, Claudine Schmitt, Jean-Louis Stephan, Dominique Plantaz, Emmanuel Raffoux, José Fernandes, Nicolas Blin, Geneviève Plat, Thibault Leguay, Maryline Poiree, Emmanuel Plouvier, Alina Ferster, Emmanuelle Tavernier, Xavier Thomas, André Baruchel, Stéphane Ducassou, Luc Fornecker, Victoria Cacheux, Stéphane Leprêtre, Iman El Hariry, Norbert Vey, Isabelle Pellier, Virginie Gandemer, Hématologie et immunologie pédiatrique, Hospices Civils de Lyon (HCL)-CHU Lyon-Institut d'hématologie et d'oncologie pédiatrique [CHU - HCL] (IHOPe), Hospices Civils de Lyon (HCL)-Hôpital Femme-Mère-Enfant (HFME), Service d'hématologie et immunologie pédiatrique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), 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), Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL), Hôpital Pellegrin Tripode, Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Pediatric Onco-Hematology Unit, CHU Pontchaillou [Rennes], Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Clermont-Ferrand, Service d'hématologie biologique, 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), Service de Pédiatrie, Unité d'Oncologie et Hématologie Pédiatrique, Centre Hospitalier Universitaire de Nice (CHU Nice), Service d'hématologie pédiatrique, CHU Saint-Etienne, CHU Pitié-Salpêtrière [AP-HP], CHU Trousseau [APHP], Service Hématologie Infantile, CHU Grenoble, Groupe d'étude des proliférations lymphoïdes (GPL), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de pédiatrie, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Service d'Hématologie Pédiatrique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E)
Subjects: Oncology, Asparaginase, medicine.medical_specialty, Lymphoblastic Leukemia, [SDV]Life Sciences [q-bio], Immunology, 02 engineering and technology, 030226 pharmacology & pharmacy, Biochemistry, law.invention, L asparaginase, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Randomized controlled trial, law, Acute lymphocytic leukemia, Internal medicine, medicine, In patient, biology, business.industry, Cell Biology, Hematology, 021001 nanoscience & nanotechnology, medicine.disease, Chemotherapy regimen, 3. Good health, chemistry, biology.protein, Antibody, 0210 nano-technology, business
Abstract: Background Asparaginase is a cornerstone in the treatment of ALL, but its utility is limited by toxicities including hypersensitivity. Clinical allergy is associated with inactivation of asparaginase by antibodies, which can also neutralize asparaginase without any clinical signs of hypersensitivity (silent inactivation). GRASPA (eryaspase - proposed INN) is an L-asparaginase encapsulated into the red blood cells. In a recent Phase III trial, it has shown to prolong the asparaginase activity and significantly reduce the incidence of allergic reactions in pts with relapsed ALL. Methods This open, randomized international Phase 3 study enrolled pts with relapsed ALL. The co-primary endpoints were the mean duration of asparaginase (ASPA) activity > 100 IU/L and incidence of hypersensitivity reactions during induction phase. Key secondary endpoints were safety, tolerability, complete remission and minimal residual disease rate, PK, and anti-ASPA antibodies (A-Abs) at baseline. Pts (n=80), aged 1-55 years without prior hypersensitivity were randomized to GRASPA (150 IU/kg, n=26, Arm A) or native L-asparaginase (L-ASP, 10,000 IU/m², n=28, Arm B). Additionally, 26 pts with prior hypersensitivity were treated with GRASPA in a single stratum (Arm C). All pts received COOPRALL protocol as a backbone chemotherapy. Here we report the impact of A-Abs on safety and efficacy of GRASPA. Assessments were performed at Day 4, 13, 18, and 27 (F1/F2 block), Day 6, 15, and 27 (VANDA block), and Day 6, 12 (R2/R1 block). Results At baseline, 23%, 25%, and 58% of pts had +ve A-Abs status in Arms A, B, and C, respectively. The mean duration of total ASPA activity (Days) adjusted for baseline antibody status is presented below, and shows that activity slightly differed with positive status; however, GRASPA maintained higher activity compared to L-ASP: Table 1. GRASPA L-ASP GRASPA L-ASP GRASPA (Arm C) Antibody status Negative Positive Negative Positive N 20 21 6 7 11 15 Mean (SD) 22.4 (3.6) 10.31 (8.1) 14.17 (5.1) 6.5 (4.0) 18.9 (6.8) 18.4 (6.2) Median 22.4 8.3 12.2 7.0 21.8 21.7 Min; Max 10.2; 30.7 0.0; 25.0 9.8; 21.8 1.9; 14.0 9.1; 27.9 6.9; 25.0 The incidence of hypersensitivity reactions were 0%, 7/21 (33%), and 2/11 (18%) in pts with negative A-Abs, compared to 0%, 6/7 (85.7%), and 1/15 (7%) in pts with positive A-Abs, in arms A, B and C, respectively. The CR rate during induction was 75%, 48%, and 64% in pts with negative A-Abs, compared to 33%, 14% and 48% in pts with positive A-Abs, in arms A, B and C, respectively. Conclusion These results show that about one third of pts without evidence of prior hypersensitivity have silent A-Abs activation. Positive A-Abs appeared to attenuate the clinical activity in all treatments arms. GRASPA consistently demonstrated activity and improved hypersensitivity regardless of A-Abs status, and therefore, GRASPA is a suitable option for patients with relapsed ALL. Disclosures Bertrand: ERYTECH Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees. Thomas:ERYTECH Pharma: Consultancy. Vey:Celgene: Honoraria; Roche: Honoraria; Janssen: Honoraria. Bonin:ERYTECH Pharma: Employment. Godfrin:ERYTECH Pharma: Employment. El Hariry:ERYTECH Pharma: Employment.
Published: 2015

12. Different outcome of T cell acute lymphoblastic leukemia with translocation t(11;14) treated in two consecutive children leukemia group EORTC trials

Author: Simon, Pauline, Suciu, Stefan, Clappier, Emmanuelle, Cavé, Hélène, Sirvent, Nicolas, Plat, Genevieve, Thyss, Antoine, Méchinaud, Françoise, Costa, Vitor M., Ferster, Alina, Lutz, Patrick, Mazingue, Françoise, Plantaz, Dominique, Plouvier, Emmanuel, Bertrand, Yves, Benoit, Yves, Dastugue, Nicole, Rohrlich, Pierre S., Europea, Childrens Leukemia Grp CLG, Département de génétique [Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Pédiatrie, Unité d'Oncologie et Hématologie Pédiatrique, Centre Hospitalier Universitaire de Nice (CHU Nice), CHU Toulouse [Toulouse], Haematology, Children's Cancer Center, The Royal Children's Hospital, Hôpital Universitaire des Enfants Reine Fabiola [Bruxelles, Belgique] (HUDERF), Service de pédiatrie, CHU Grenoble, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service Hématologie Infantile, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Hématologie et immunologie pédiatrique, Hospices Civils de Lyon (HCL)-CHU Lyon-Institut d'hématologie et d'oncologie pédiatrique [CHU - HCL] (IHOPe), Hospices Civils de Lyon (HCL)-Hôpital Femme-Mère-Enfant (HFME), and Laboratoire d'Hématologie
Subjects: Male, Pediatrics, medicine.medical_specialty, Adolescent, T cell, [SHS.PSY]Humanities and Social Sciences/Psychology, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, Translocation, Genetic, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Humans, Prospective Studies, Prospective cohort study, Child, Survival rate, Retrospective Studies, Chromosomes, Human, Pair 14, business.industry, Chromosomes, Human, Pair 11, Cancer, Retrospective cohort study, Hematology, General Medicine, [SHS.ECO]Humanities and Social Sciences/Economics and Finance, medicine.disease, 3. Good health, Survival Rate, Leukemia, medicine.anatomical_structure, Treatment Outcome, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, 030220 oncology & carcinogenesis, Child, Preschool, Quality of Life, Prednisolone, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Female, business, 030215 immunology, medicine.drug, Cohort study
Abstract: International audience; Acute lymphoblastic leukemia of T cell lineage (T-ALL) is an aggressive ă malignant disease which accounts for 15 % of childhood ALL. T(11;14) is ă the more frequent chromosomal abnormality in childhood T-ALL, but its ă prognostic value remained controversial. Our aim was to analyze the ă outcome of childhood T-ALL with t(11;14) to know if the presence of this ă translocation is associated with a poor prognosis. We conducted a ă retrospective study from a series of 20 patients with t(11;14), treated ă in two consecutive trials from the European Organization for Research ă and Treatment of Cancer Children Leukemia Group over a 19-year period ă from 1989 to 2008. There were no significant differences between the 2 ă consecutive groups of patients with t(11;14) regarding the clinical and ă biological features at diagnosis. Among 19 patients who reached complete ă remission, 9 patients relapsed. We noticed 7 deaths all relapse- or ă failure-related. In the 58881 study, a presence of t(11;14) was ă associated with a poor outcome with an event-free survival at 5 years at ă 22.2 % versus 65.1 % for the non-t(11;14) T-ALL (p = 0.0004). In the ă more recent protocol, the outcome of T-ALL with t(11;14) reached that of ă non-t(11;14) T-ALL with an event-free survival at 5 years at 65.5 versus ă 74.9 % (p = 0.93). The presence of t(11;14) appeared as a poor ă prognostic feature in the 58881 trial whereas this abnormality no longer ă affected the outcome in the 58951 study. This difference is probably ă explained by the more intensive chemotherapy in the latest trial.
Published: 2015
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13. Treatment of Childhood T-Cell Lymphoblastic Lymphoma-Long-Term Results of the SFOP LMT96 Trial

Author: Bergeron, Christophe, Coze, Carole, Segura, Céline, Pacquement, Hélène, Gandemer, Virginie, Ducassou, Stéphane, Patte, Catherine, Hématologie et immunologie pédiatrique, Hospices Civils de Lyon (HCL)-CHU Lyon-Institut d'hématologie et d'oncologie pédiatrique [CHU - HCL] (IHOPe), Hospices Civils de Lyon (HCL)-Hôpital Femme-Mère-Enfant (HFME), Pédiatrie et oncologie pédiatrique [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Institut Curie [Paris], Pediatric Onco-Hematology Unit, CHU Pontchaillou [Rennes], Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Hôpital Pellegrin, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Département de cancérologie de l'enfant et de l'adolescent [Gustave Roussy], Institut Gustave Roussy (IGR), Rhône 'Ligue Contre le Cancer' Association, Association Léon Bérard Enfant Cancéreux (ALBEC), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Jonchère, Laurent
Subjects: Male, Time Factors, Adolescent, [SDV]Life Sciences [q-bio], Infant, Lymphoma, T-Cell, Disease-Free Survival, [SDV] Life Sciences [q-bio], Survival Rate, Methotrexate, lymphoblastic malignancies, Child, Preschool, Antineoplastic Combined Chemotherapy Protocols, Humans, non-Hodgkin's lymphomas, Female, Prospective Studies, Child, Cyclophosphamide, Follow-Up Studies, Neoplasm Staging, childhood
Abstract: International audience; PURPOSE: Outcome of T-cell lymphoblastic lymphoma (T-LBL) in children is around 75-85% of event-free survival. The role of early intensification to improve outcome while using short infusions of high dose methotrexate (HDMTX) and shorter maintenance treatment was addressed by the French Society of Pediatric Oncology (SFOP) group. METHODS: From 1997 through 2003, 79 children (52 males; median age 10.5 years) were prospectively registered into the SFOP LMT 96 trial. The LMT96 protocol, with elements from the protocol of the Berlin-Frankfurt-Münster (BFM) Group included four main modifications: (a) 10 courses of HD-MTX (3 g/m(2) ) delivered over the first 44 weeks; (b) early intensification with cyclophosphamide together with the first course of HD-MTX; (c) a maintenance phase that included 6 monthly intensified chemotherapy pulses; and (d) treatment duration of 18 months for stages I-III. RESULTS: Eighty-nine percent of patients had an initial mediastinal involvement. With a median follow-up of 87 months, the 5-year event-free survival was 85% and overall survival 89%. Nine patients relapsed, eight during treatment. The early intensification did not change the pattern of relapses. Only 58% of patients experienced grade 3-4 neutropenia during the induction phase, 13% patients experienced grade 3 and 4 mucositis, and 5% patients experienced diabetes. The early intensification did not delay phases of chemotherapy. CONCLUSIONS: Early intensification in treatment for T-LBL in children is manageable. Three-hour infusion of HD-MTX did not jeopardize patient outcome. Our results are comparable with those of other international protocols in spite of shorter maintenance treatment for stages I-III. Pediatr Blood Cancer © 2015 Wiley Periodicals, Inc
Published: 2015
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14. Abstract CT113: A phase III, multicenter, randomized study evaluating the efficacy and safety and efficacy of erythrocyte encapsulated l-asparaginase (Ery001) versus native l-asparaginase (L-asp) in combination with COOPRALL regimen in patients with first relapse of acut

Author: Virginie Gandemer, André Baruchel, Emmanuelle Tavernier, Nicolas Blin, Yves Perel, Yves Bertrand, Norbert Vey, Iman El-Hariry, Xavier Thomas, Yann Godfrin, Hématologie et immunologie pédiatrique, Hospices Civils de Lyon (HCL)-CHU Lyon-Institut d'hématologie et d'oncologie pédiatrique [CHU - HCL] (IHOPe), Hospices Civils de Lyon (HCL)-Hôpital Femme-Mère-Enfant (HFME), Service d'hématologie et immunologie pédiatrique, Université Paris Diderot - Paris 7 (UPD7)-Hôpital Robert Debré-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Centre de Recherche en Cancérologie de Lyon (CRCL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL), Service d'Hémato-oncologie Pédiatrique, CHU Bordeaux [Bordeaux]-Hôpital Pellegrin, Centre de Recherche en Cancérologie de Marseille (CRCM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), Pediatric Onco-Hematology Unit, CHU Pontchaillou [Rennes], Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), 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), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )
Subjects: Cancer Research, medicine.medical_specialty, Asparaginase, business.industry, Incidence (epidemiology), [SDV]Life Sciences [q-bio], Gastroenterology, 3. Good health, Surgery, law.invention, Regimen, chemistry.chemical_compound, Oncology, Pharmacokinetics, chemistry, Tolerability, Randomized controlled trial, Refractory, law, Internal medicine, medicine, business, Adverse effect
Abstract: Asparaginases are a cornerstone in the treatment of ALL, but their utility is limited by toxicities including hypersensitivity. ERY001 improves pharmacokinetics and tolerability, while maintaining circulating asparaginase (ASPA) activity due to the protective barrier of the erythrocyte membrane. This phase III study enrolled pts with primary relapsed/refractory Ph- ALL. The co-primary endpoints were the duration of ASPA activity equal or greater than 100IU/L and the incidence of ASPA hypersensitivity during induction. Patients, aged 1-55 years, without prior ASPA hypersensitivity were randomized to ERY001 (150 IU/kg) or L-ASP(10.000IU/m2) in combination with COOPRALL. The patients with prior ASPA hypersensitivity received ERY001. ERY001 significantly reduced the incidence of ASPA hypersensitivity (0% vs 43%; p100IU/l significantly longer than L-ASP (20.5±5.2 vs 9.2±7.5 days; p These highly encouraging results show that ERY001 is a suitable option for patients with relapsed ALL maintaining ASPA efficacy with improved tolerability. Citation Format: Yves Bertrand, Andre Baruchel, Xavier Thomas, Nicolas Blin, Emmanuelle Tavernier, Yves Perel, Norbert Vey, Virginie Gandemer, Iman ElHariry, Yann Godfrin. A phase III, multicenter, randomized study evaluating the efficacy and safety and efficacy of erythrocyte encapsulated l-asparaginase (Ery001) versus native l-asparaginase (L-asp) in combination with COOPRALL regimen in patients with first relapse of acut [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT113. doi:10.1158/1538-7445.AM2015-CT113
Published: 2015
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15. A Phase I Study of Clofarabine With Multiagent Chemotherapy in Childhood High Risk Relapse of Acute Lymphoblastic Leukemia (VANDEVOL Study of the French SFCE Acute Leukemia Committee)

Author: Nelken, Brigitte, Cavé, Hélène, Leverger, Guy, Galambrun, Claire, Plat, Genevieve, Schmitt, Claudine, Thomas, Caroline, Vérité, Cecile, Brethon, Benoit, Gandemer, Virginie, Bertrand, Yves, Baruchel, André, Rohrlich, Pierre, Pôle Enfant, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Université Lille Nord (France), Département de génétique [Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service d'Hématologie pédiatrique, Hôpital de la Timone, Marseille, Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Service d'Hématologie Pédiatrique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre hospitalier universitaire de Nantes (CHU Nantes), Hôpital Pellegrin Tripode, Pediatric Onco-Hematology Unit, CHU Pontchaillou [Rennes], Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Hématologie et immunologie pédiatrique, Hospices Civils de Lyon (HCL)-CHU Lyon-Institut d'hématologie et d'oncologie pédiatrique [CHU - HCL] (IHOPe), Hospices Civils de Lyon (HCL)-Hôpital Femme-Mère-Enfant (HFME), Service d'hématologie et immunologie pédiatrique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Service d'hématologie, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Direction de la Recherche Clinique du CHRU de Lille, Service d'hématologie-immunologie-oncologie pédiatrique [CHU Trousseau], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-AP-HP Hôpital universitaire Robert-Debré [Paris], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Hôpital Jean Minjoz, and Jonchère, Laurent
Subjects: Male, Salvage Therapy, Adolescent, Dose-Response Relationship, Drug, Maximum Tolerated Dose, Adenine Nucleotides, [SDV]Life Sciences [q-bio], acute lymphoblastic leukemia, phase I, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Dexamethasone, [SDV] Life Sciences [q-bio], Young Adult, resistant disease, Child, Preschool, Antineoplastic Combined Chemotherapy Protocols, Asparaginase, Humans, Female, Arabinonucleosides, Mitoxantrone, Neoplasm Recurrence, Local, Child, Clofarabine, Etoposide
Abstract: International audience; BACKGROUND: Current outcome of very early relapse of acute lymphoblastic leukemia (ALL) in children remains poor. As a single agent, clofarabine provided a response rate of 26% in childhood ALL second relapse and, in combination with cyclophosphamide and etoposide, a 44% complete remission and complete remission without platelet recovery (CR+CRp) rate. Further multi-drug combinations need to be investigated. We used the VANDA regimen as a template, cytarabine being replaced by clofarabine. PATIENTS AND METHODS: A phase I study combining escalating doses of clofarabine (25% increments from 20 to 40 mg/m(2) /d) with fixed doses of mitoxantrone, etoposide, asparaginase, and dexamethasone was undertaken in children presenting with very early or second or post-transplant ALL relapse. RESULTS: Twenty patients were enrolled, 19 were evaluable. Four patients had previously been allografted. Dose-limiting toxicity (DLT) appeared at dose level 3 (32 mg/m(2) ), one out of six patients experienced a liver DLT. At dose level 4 (40 mg/m(2) ), four DLT occurred (two fungal infection and two liver DLT). The maximum tolerated dose (MTD) of clofarabine was thus determined to be 32 mg/m(2) . There was no toxic death. Eleven (57.9%) patients achieved a CR. Six patients proceeded to allogeneic stem cell transplantation. CONCLUSION: Clofarabine MTD was 32 mg/m(2) /d in this combination which appeared feasible and effective in this population. Pediatr Blood Cancer © 2015 Wiley Periodicals, Inc
Published: 2014
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16. Synovial sarcoma relapses in children and adolescents: prognostic factors, treatment, and outcome

Author: Frederick, Soole, Carole, Maupain, Anne-Sophie, Defachelles, Sophie, Taque, Veronique, Minard-Colin, Christophe, Bergeron, Yann, De Rycke, Daniel, Orbach, Département de Pédiatrie, Institut Curie [Paris], Service d'Hématologie et d'Oncologie pédiatrique, CHU Pontchaillou [Rennes], Département de cancérologie de l'enfant et de l'adolescent [Gustave Roussy], Institut Gustave Roussy (IGR), Hématologie et immunologie pédiatrique, Hospices Civils de Lyon (HCL)-CHU Lyon-Institut d'hématologie et d'oncologie pédiatrique [CHU - HCL] (IHOPe), Hospices Civils de Lyon (HCL)-Hôpital Femme-Mère-Enfant (HFME), and Department of Biostatistics
Subjects: Male, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, Neoplasm Recurrence Local/mortality/pathology/therapy, Child Preschool, [SDV]Life Sciences [q-bio], Age Factors, Sarcoma, [SDV.CAN]Life Sciences [q-bio]/Cancer, Disease-Free Survival, Synovial/mortality/pathology/therapy, Survival Rate, Sarcoma, Synovial, Child, Preschool, Humans, Female, Neoplasm Recurrence, Local, Child, Retrospective Studies
Abstract: International audience; Twenty-five to 32% of patients with synovial sarcoma (SS) relapse after appropriate treatment, and experience a poor outcome. Patients who can be salvaged by second-line therapy need to be more clearly identified. Data of patients treated in SFCE (Société Française des Cancers de l'Enfant) centers with an initial diagnosis of localized SS before the age of 18 years and treated from 1/1988 to 12/2008, and who experienced at least one relapse, were retrieved. After descriptive analysis, statistical analysis was performed to determine prognostic factors. Thirty-seven patients were identified. First relapse occurred after a median interval of 24 months and was localized in 73.0% of cases and metastatic in 24.3% of cases. Treatment of relapse consisted of new surgery in 75.7% of cases, second-line chemotherapy in 73.0% of cases and radiotherapy in 48.6% of cases. Response rate to ifosfamide-based regimens was 36.4%. Overall, 70.3% patients achieved a second complete remission. Median 5-year-event-free survival was 32.8% and 5-year overall survival was 42.1%. Factors significantly correlated with better survival were primary tumor involving the limbs, age less than 12 years at diagnosis, absence of chemotherapy or radiotherapy as initial treatment and local relapse. Despite its poor overall outcome, relapse of synovial sarcoma sometimes remains curable. Aggressive surgery, when possible, in combination with chemotherapy and radiotherapy is the recommended treatment. Ifosfamide-based regimens may remain effective in patients with relapsed SS. However, alternative therapies should be proposed in patients with poor prognostic factors.
Published: 2014
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17. Description and outcome of a cohort of 8 patients with WHIM syndrome from the French Severe Chronic Neutropenia Registry

Author: Philippe Bensaid, Gerard Daltroff, Gilles Devouassoux, Emmanuel Plouvier, Odile Fenneteau, Jean-François Nicolas, Yves Bertrand, Sarah Beaussant Cohen, Pierre Bordigoni, Fanny Fouyssac, Delphine Kerob, Jean Donadieu, Anne-Lise Delezoide, Françoise Bachelerie, Alain Dupuy, Blandine Beaupain, Pierre-Simon Rohrlich, Christine bellanne Chantelot, Karl Balabanian, Isabelle Plantier, CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service d'Hématologie et Oncologie pédiatrique [CHRU Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Service d'Hématologie Pédiatrique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Service de Pédiatrie, CH Belfort-Montbéliard, Service d'hématologie, Centre Hospitalier de Roubaix, Service de Dermatologie [Rennes] = Dermatology [Rennes], CHU Pontchaillou [Rennes], Service de Dermatologie [Saint-Louis], 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), Service de Médecine Infantile II [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service de Biologie du Développement, Service de Pneumologie, Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Service d'immunologie clinique et allergologie, Hématologie et immunologie pédiatrique, Hospices Civils de Lyon (HCL)-CHU Lyon-Institut d'hématologie et d'oncologie pédiatrique [CHU - HCL] (IHOPe), Hospices Civils de Lyon (HCL)-Hôpital Femme-Mère-Enfant (HFME), Cytokines, chimiokines et immunopathologie, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), The French registry is supported by grants from Amgen SAS, Chugai SA, GIS Maladies Rares, Institut de Veille Sanitaire and Inserm. This research is a study from the Centre de Référence des Déficits Immunitaires Héréditaires (CEREDIH: the French National Reference Center for Primary Immune Deficiencies, www.ceredih.fr) and has been supported by the Société Française d'Hématologie et d'Immunologie Pédiatrique. The K.B. laboratory is supported by the Agence Nationale de la Recherche, the Université Paris-Sud and Inserm, FB was supported by the ANR, AP-HP and E-rare (07 E-RARE 013-01), and K.B. and F.B. are members of the Laboratory of Excellence LERMIT supported by a grant from ANR (Investissements d'Avenir)., and BMC, Ed.
Subjects: Male, Pediatrics, WHIM, lcsh:Medicine, Monocytopenia, [SDV.GEN] Life Sciences [q-bio]/Genetics, Genital warts, Hypogammaglobulinemia, 0302 clinical medicine, Genetics(clinical), Pharmacology (medical), Registries, Child, Genetics (clinical), Medicine(all), 0303 health sciences, Bacterial Infections, General Medicine, Myelokathexis, Anti-Bacterial Agents, Pedigree, 3. Good health, Child, Preschool, Female, Warts, WHIM syndrome, Adult, Receptors, CXCR4, medicine.medical_specialty, Registry, Neutropenia, Adolescent, Primary Immunodeficiency Diseases, Infections, Young Adult, 03 medical and health sciences, medicine, Humans, Congenital Neutropenia, 030304 developmental biology, CXCR4, [SDV.GEN]Life Sciences [q-bio]/Genetics, business.industry, Research, lcsh:R, Immunologic Deficiency Syndromes, Infant, medicine.disease, Immunology, Skin cancer, business, 030215 immunology
Abstract: BackgroundWHIM syndrome (WS), a rare congenital neutropenia due to mutations of the CXCR4 chemokine receptor, is associated with Human Papillomavirus (HPV)-induced Warts, Hypogammaglobulinemia, bacterial Infections and Myelokathexis. The long term follow up of eight patients highlights the clinical heterogeneity of this disease as well as the main therapeutic approaches and remaining challenges in the light of the recent development of new CXCR4 inhibitors.ObjectiveThis study aims to describe the natural history of WS based on a French cohort of 8 patients.MethodsWe have reviewed the clinical, biological and immunological features of patients with WS enrolled into the French Severe Chronic Neutropenia Registry.ResultsWe identified four pedigrees with WS comprised of eight patients and one foetus. Estimated incidence for WS was of 0.23 per million births. Median age at the last visit was 29 years. Three pedigrees encompassing seven patients and the fetus displayed autosomal dominant heterozygous mutations of theCXCR4gene, while one patient presented a wild-typeCXCR4gene. Two subjects exhibited congenital conotruncal heart malformations. In addition to neutropenia and myelokathexis, all patients presented deep monocytopenia and lymphopenia. Seven patients presented repeated bacterial Ears Nose Throat as well as severe bacterial infections that were curable with antibiotics. Four patients with late onset prophylaxis developed chronic obstructive pulmonary disease (COPD). Two patients reported atypical mycobacteria infections which in one case may have been responsible for one patient’s death due to liver failure at the age of 40.6 years. HPV-related disease manifested in five subjects and progressed as invasive vulvar carcinoma with a fatal course in one patient at the age of 39.5 years. In addition, two patients developed T cell lymphoma skin cancer and basal cell carcinoma at the age of 38 and 65 years.ConclusionsContinuous prophylactic anti-infective measures, when started in early childhood, seem to effectively prevent further bacterial infections and the consequent development of COPD. Long-term follow up is needed to evaluate the effect of early anti-HPV targeted prophylaxis on the development of skin and genital warts.
Published: 2012
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18. A [c.566-2A>G] heterozygous mutation in the PAX6 gene causes aniridia with mild visual impairment

Author: F Beby, K Dieterich, P Calvas, Roux-Buisson, Nathalie, Service d'ophtalmologie pédiatrique, Hospices Civils de Lyon (HCL)-Hôpital Femme-Mère Enfant (HFME), Institut de Génomique Fonctionnelle de Lyon (IGFL), École normale supérieure - Lyon (ENS Lyon)-Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), INSERM U836, équipe 4, Muscles et pathologies, Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service Génétique Médicale [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA)-École normale supérieure - Lyon (ENS Lyon), Service de génétique médicale, CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF), and École normale supérieure de Lyon (ENS de Lyon)-Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL)
Subjects: congenital, hereditary, and neonatal diseases and abnormalities, medicine.medical_specialty, Visual acuity, MESH: Mutation, genetic structures, Eye disease, Visual impairment, [SDV.GEN] Life Sciences [q-bio]/Genetics, MESH: Visual Acuity, Neuro-ophthalmology, Vision disorder, 03 medical and health sciences, 0302 clinical medicine, MESH: Eye Proteins, MESH: Intraocular Pressure, Ophthalmology, Internal medicine, MESH: Homeodomain Proteins, Correspondence, medicine, MESH: Paired Box Transcription Factors, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, business.industry, MESH: Nystagmus, Congenital, medicine.disease, MESH: Infant, eye diseases, Endocrinology, Aniridia, MESH: Repressor Proteins, MESH: Vision Disorders, Mutation (genetic algorithm), MESH: Aniridia, 030221 ophthalmology & optometry, sense organs, PAX6, medicine.symptom, business, MESH: Female
Abstract: A [c.566-2A>G] heterozygous mutation in the PAX6 gene causes aniridia with mild visual impairment
Published: 2011
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19. A new GFP-tagged line reveals unexpected Otx2 protein localization in retinal photoreceptors

Author: Coralie Le Greneur, Francis Beby, Nicolas Fossat, Pierre Godement, Thomas Lamonerie, Gilles Chatelain, Stéphane D. Vincent, Institute of Developmental Biology and Cancer (IBDC), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Service d'ophtalmologie pédiatrique, Hospices Civils de Lyon (HCL)-Hôpital Femme-Mère Enfant (HFME), Laboratoire de biologie et modélisation de la cellule (LBMC UMR 5239), 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), Institut de Génomique Fonctionnelle de Lyon (IGFL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA)-École normale supérieure - Lyon (ENS Lyon), Laboratoire de Biologie Moléculaire de la Cellule (LBMC), 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, Université Nice Sophia Antipolis (1965 - 2019) (UNS), École normale supérieure de Lyon (ENS de 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 de Lyon (ENS de Lyon)-Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), LBMC - Laboratoire de Biologie Moléculaire de la Cellule, École normale supérieure - Lyon (ENS Lyon)-Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), and École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL)
Subjects: Genotype, Blotting, Western, Genetic Vectors, Green Fluorescent Proteins, Fluorescent Antibody Technique, In situ hybridization, Biology, Photoreceptor cell, Green fluorescent protein, Cell Line, 03 medical and health sciences, Mice, 0302 clinical medicine, Conditional gene knockout, medicine, Animals, Photoreceptor Cells, lcsh:QH301-705.5, Transcription factor, Embryonic Stem Cells, In Situ Hybridization, 030304 developmental biology, DNA Primers, Genetics, 0303 health sciences, Otx Transcription Factors, Methodology Article, Brain, Gene Expression Regulation, Developmental, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Embryo, Mammalian, Embryonic stem cell, Protein subcellular localization prediction, Cell biology, [SDV.GEN.GA]Life Sciences [q-bio]/Genetics/Animal genetics, medicine.anatomical_structure, [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, lcsh:Biology (General), Developmental biology, 030217 neurology & neurosurgery, Developmental Biology
Abstract: Background Dynamic monitoring of protein expression and localization is fundamental to the understanding of biological processes. The paired-class homeodomain-containing transcription factor Otx2 is essential for normal head and brain development in vertebrates. Recent conditional knockout studies have pointed to multiple roles of this protein during late development and post-natal life. Yet, later expression and functions remain poorly characterized as specific reagents to detect the protein at any stage of development are still missing. Results We generated a new mouse line harbouring an insertion of the GFP gene within the Otx2 coding sequence to monitor the gene activity while preserving most of its functions. Our results demonstrate that this line represents a convenient tool to capture the dynamics of Otx2 gene expression from early embryonic stages to adulthood. In addition, we could visualize the intracellular location of Otx2 protein. In the retina, we reinterpret the former view of protein distribution and show a further level of regulation of intranuclear protein localization, which depends on the cell type. Conclusion The GFP-tagged Otx2 mouse line fully recapitulates previously known expression patterns and brings additional accuracy and easiness of detection of Otx2 gene activity. This opens up the way to live imaging of a highly dynamic actor of brain development and can be adapted to any mutant background to probe for genetic interaction between Otx2 and the mutated gene.
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20. Clinical, radiological, and molecular diagnosis of congenital pituitary diseases causing short stature.

Author: Castets S, Villanueva C, Vergier J, Brue T, Saveanu A, and Reynaud R
Abstract: Short stature in children can be caused by congenital pituitary disorders involving at least one form of growth hormone deficiency. Clinical and radiological evaluations of the index case and family history assessments are essential to guide genetic diagnostic testing and interpret results. The first-line approach is panel testing of genes involved in pituitary development with variants known to be pathogenic in this context. It identifies a genetic cause in less than 10% of cases, however. Whole-exome and whole-genome sequencing techniques may provide original information but also raise new questions regarding the pathophysiological role of identified variants. These new tools can make genetic counselling more complex. The role of clinicians in these interpretations is therefore important. © 2022 French Society of Pediatrics. Published by Elsevier Masson SAS. All rights reserved., (Copyright © French Society of Pediatrics. Published by Elsevier Masson SAS. All rights reserved.)
Published: 2022
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20 results on '"Hospices Civils de Lyon (HCL)-Hôpital Femme-Mère-Enfant (HFME)"'

1. Langerhans cell histiocytosis: therapeutic strategy and outcome in a 30-year nationwide cohort of 1478 patients under 18 years of age

2. Indications and outcomes of antifungal therapy in French patients with haematological conditions or recipients of haematopoietic stem cell transplantation

3. Long-term event-free survival, chimerism and fertility outcomes in 234 patients with sickle-cell anemia younger than 30 years after myeloablative conditioning and matched-sibling transplantation in France

4. Lymphoid differentiation of hematopoietic stem cells requires efficient Cxcr4 desensitization

5. Employment in French young adult survivors of childhood leukemia: an LEA study (for Leucemies de l'Enfant et de l'Adolescent-childhood and adolescent leukemia)

6. Metabolic syndrome in long-term survivors of childhood acute leukemia ă treated without hematopoietic stem cell transplantation: an LEA study

7. The Impact of Donor Type on Long-Term Health Status and Quality of Life after Allogeneic Hematopoietic Stem Cell Transplantation for Childhood Acute Leukemia: A Leucemie de l'Enfant et de L'Adolescent Study

8. Late thyroid complications in survivors of childhood acute leukemia. An LEA study

9. Pharmacokinetic and Pharmacodynamic Characterization of Graspa Versus Native L-Asparaginase in Combination with Cooprall Chemotherapy in a Phase 3 Randomized Trial for the Treatment of Patients with Relapsed Acute Lymphoblastic Leukemia (NCT01 51851 7)

10. Updated Clinical Activity of Graspa Versus Native l-Asparaginase in Combination with Cooprall Regimen in Phase 3 Randomized Trial in Patients with Relapsed Acute Lymphoblastic Leukemia (NCT01518517)

11. Evaluation of the Impact of the Presence of Neutralizing L-Asparaginase Antibodies on the Efficacy and Safety of Graspa in Phase 3 Randomized Trial Versus Native L-Asparaginase in Patients with Relapsed Acute Lymphoblastic Leukemia (NCT01518517)

12. Different outcome of T cell acute lymphoblastic leukemia with translocation t(11;14) treated in two consecutive children leukemia group EORTC trials

13. Treatment of Childhood T-Cell Lymphoblastic Lymphoma-Long-Term Results of the SFOP LMT96 Trial

14. Abstract CT113: A phase III, multicenter, randomized study evaluating the efficacy and safety and efficacy of erythrocyte encapsulated l-asparaginase (Ery001) versus native l-asparaginase (L-asp) in combination with COOPRALL regimen in patients with first relapse of acut

15. A Phase I Study of Clofarabine With Multiagent Chemotherapy in Childhood High Risk Relapse of Acute Lymphoblastic Leukemia (VANDEVOL Study of the French SFCE Acute Leukemia Committee)

16. Synovial sarcoma relapses in children and adolescents: prognostic factors, treatment, and outcome

17. Description and outcome of a cohort of 8 patients with WHIM syndrome from the French Severe Chronic Neutropenia Registry

18. A [c.566-2A>G] heterozygous mutation in the PAX6 gene causes aniridia with mild visual impairment

19. A new GFP-tagged line reveals unexpected Otx2 protein localization in retinal photoreceptors

20. Clinical, radiological, and molecular diagnosis of congenital pituitary diseases causing short stature.

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