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1. Radiotherapy or Autologous Stem-Cell Transplantation for Primary CNS Lymphoma in Patients Age 60 Years and Younger: Long-Term Results of the Randomized Phase II PRECIS Study

Author: Houillier, Caroline, Dureau, S, Taillandier, Luc, Houot, Roch, Chinot, O., Molucon-Chabrot, Cécile, Schmitt, Anna, Gressin, Rémy, Choquet, Sylvain, Damaj, Gandhi, Peyrade, Frédéric, Abraham, Julie, Delwail, V, Gyan, Emmanuel, Sanhes, Laurence, Cornillon, Jerome, Garidi, Reda, Delmer, Alain, Al Jijakli, Ahmad, Morel, Pierre, Waultier, Agathe, Paillassa, Jérôme, Chauchet, A, Gastinne, Thomas, Laadhari, Mouna, Plissonnier, Anne-Sophie, Feuvret, Loïc, Cassoux, Nathalie, Touitou, Valerie, Ricard, Jean-Damien, Hoang-Xuan, Khe, Soussain, Carole, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut Curie [Paris], Centre Hospitalier Universitaire de Nancy (CHU Nancy), Microenvironment and B-cells: Immunopathology,Cell Differentiation, and Cancer (MOBIDIC), Université de Rennes (UR)-Etablissement français du sang [Rennes] (EFS Bretagne)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pontchaillou [Rennes], Hôpital de la Timone [CHU - APHM] (TIMONE), CHU Louise Michel [Clermont-Ferrand], CHU Clermont-Ferrand, Institut Bergonié [Bordeaux], UNICANCER, Centre Hospitalier Universitaire [Grenoble] (CHU), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), CHU Amiens-Picardie, Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), CHU Limoges, CIC - Poitiers, Université de Poitiers-Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Direction Générale de l'Organisation des Soins (DGOS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d’Investigation Clinique [Tours] CIC 1415 (CIC ), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau-Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Saint Jean de Perpignan, Institut de Cancérologie Lucien Neuwirth, Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Centre Hospitalier Universitaire de Reims (CHU Reims), Centre Hospitalier de Lens, Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Centre hospitalier universitaire de Nantes (CHU Nantes), Hôpital d'instruction des Armées Percy, Service de Santé des Armées, Immunité et cancer (U932), and Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Adult, Cancer Research, Adolescent, Lymphoma, [SDV]Life Sciences [q-bio], Hematopoietic Stem Cell Transplantation, Middle Aged, Transplantation, Autologous, Combined Modality Therapy, Central Nervous System Neoplasms, Young Adult, Oncology, Antineoplastic Combined Chemotherapy Protocols, Humans, Neoplasm Recurrence, Local
Abstract: Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. We previously reported the results of a randomized phase II study in patients with newly diagnosed primary CNS lymphoma (age 18-60 years). Patients were treated with high-dose methotrexate-based induction chemotherapy followed by whole-brain radiotherapy (WBRT) or high-dose chemotherapy (thiotepa-busulfan-cyclophosphamide) with autologous stem-cell transplantation (ASCT). The median follow-up was 33 months. In this report, we provide long-term data (median follow-up, 8 years) regarding the outcomes and toxicities. Fifty-three and 44 patients received induction chemotherapy followed by WBRT or ASCT, respectively. Their 8-year event-free survival from random assignment was 67% and 39% in the ASCT and WBRT arms, respectively ( P = .03), with a significantly lower risk of relapse after ASCT (hazard ratio, 0.13; P < .001). One third of patients who relapsed after WBRT were alive after salvage treatment. Five and four patients died of ASCT and WBRT-related toxicities, respectively. The 8-year overall survival was 69% and 65% in the ASCT and WBRT arms, respectively (not significant). Balance (52% v 10%, P ≤ 0.001) and neurocognition (64% v 13%, P < .001) significantly deteriorated after WBRT compared with ASCT during the follow-up. This study shows that 40 Gy WBRT should be avoided in first-line treatment because of its neurotoxicity and suboptimal efficacy in reducing relapses while ASCT appears to be highly efficient in preventing relapses.
Published: 2022

2. Efficacy and Safety of ABP 798: Results from the JASMINE Trial in Patients with Follicular Lymphoma in Comparison with Rituximab Reference Product

Author: Vladimir Hanes, Caroline Hamm, Alessandra Tucci, Mindy Mo, Cecily Forsyth, Dietger Niederwieser, David Chien, Patrick Cobb, Vincent Delwail, and Roman Hájek
Subjects: Male, 0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, Follicular lymphoma, 03 medical and health sciences, Antineoplastic Agents, Immunological, 0302 clinical medicine, Double-Blind Method, immune system diseases, Internal medicine, hemic and lymphatic diseases, Follicular phase, medicine, Clinical endpoint, Humans, Pharmacology (medical), Original Research Article, Lymphoma, Follicular, CD20, Hematology, biology, business.industry, Correction, Middle Aged, medicine.disease, Confidence interval, Lymphoma, Treatment Outcome, 030104 developmental biology, 030220 oncology & carcinogenesis, biology.protein, Female, Rituximab, business, medicine.drug
Abstract: Introduction ABP 798 is being developed as a biosimilar to rituximab reference product (RP), a CD20-directed cytolytic antibody that is approved in the US and EU for the treatment of non-Hodgkin lymphoma (NHL). Methods This randomized, double-blind, comparative clinical study (JASMINE) evaluated the efficacy and safety of ABP 798 compared with rituximab RP. Adult, anti-CD20 treatment naïve patients diagnosed with grade 1, 2, or 3a follicular B-cell NHL expressing CD20 were randomized 1:1 to receive a 375 mg/m2 infusion of either ABP 798 or rituximab RP once weekly for 4 weeks and at weeks 12 and 20. Tumor assessments were performed at baseline and weeks 12 and 28. Primary endpoint was the risk difference (RD) of overall response rate (ORR) of complete response, unconfirmed complete response, or partial response by week 28 based on data from central, independent, and blinded assessments of disease. Results Of the 256 randomized patients, 254 were treated with ABP 798 (n = 128; 100%) or rituximab RP (n = 126; 98.4%); 96 (78.0%) patients in the ABP 798 group and 87 (70.2%) in the rituximab RP group had a best ORR by week 28. The point estimate of RD in ORR between ABP 798 and rituximab RP from the adjusted generalized linear model for stratification factors was 7.7%. Clinical equivalence was based on sequential testing of the one-sided 95% lower confidence limits and one-sided 95% upper confidence limits of RD in ORR (− 1.4% and 16.8%, respectively) which was within the prespecified non-inferiority margin (− 15%) and non-superiority margin (35.5%), respectively. Results of sensitivity analyses were consistent with the primary efficacy analysis. ABP 798 was also comparable to rituximab RP across additional secondary endpoints, further supporting the conclusion of similarity, and including: RD of ORR at week 12; trough serum concentrations; percent of patients with complete depletion of CD19+ cell count at day 8; safety; and immunogenicity. Conclusions These results support a conclusion of similar clinical efficacy between ABP 798 and rituximab RP in patients with follicular lymphoma. NCT Number NCT02747043; first posted April 21, 2016. EudraCT Number 2013-005,542-11; submitted 14 October, 2014.
Published: 2020

3. Study of the Role of the Tyrosine Kinase Receptor MerTK in the Development of Kidney Ischemia-Reperfusion Injury in RCS Rats

Author: Omar Benzakour, Adriana Delwail, Sébastien Giraud, Sandrine Joffrion, Thierry Hauet, Thomas Pelé, Jean-Michel Goujon, Laurent Macchi, Virginie Ameteau, Fatima Dkhissi, Ischémie Reperfusion en Transplantation d’Organes Mécanismes et Innovations Thérapeutiques ( IRTOMIT), Université de Poitiers-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre hospitalier universitaire de Poitiers (CHU Poitiers), Université de Poitiers - Faculté de Médecine et de Pharmacie, Université de Poitiers, Signalisation et Transports Ioniques Membranaires (STIM), Université de Poitiers-Université de Tours-Centre National de la Recherche Scientifique (CNRS), Université de Poitiers-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS), and Pinet, Nicolas
Subjects: Nitric Oxide Synthase Type II, 030204 cardiovascular system & hematology, Kidney, Receptor tyrosine kinase, ischemia-reperfusion, chemistry.chemical_compound, 0302 clinical medicine, Biology (General), Spectroscopy, Chemokine CCL2, microparticles, 0303 health sciences, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, biology, phagocytosis, General Medicine, Acute Kidney Injury, Apoptotic body, Computer Science Applications, Chemistry, medicine.anatomical_structure, Myeloperoxidase, Creatinine, Reperfusion Injury, RCS rats, medicine.medical_specialty, QH301-705.5, Nitric Oxide, Catalysis, Article, Inorganic Chemistry, 03 medical and health sciences, MerTK, Lipocalin-2, Internal medicine, medicine, Animals, Humans, Aspartate Aminotransferases, Physical and Theoretical Chemistry, QD1-999, Molecular Biology, 030304 developmental biology, Peroxidase, Renal ischemia, L-Lactate Dehydrogenase, c-Mer Tyrosine Kinase, business.industry, Macrophages, Organic Chemistry, MERTK, medicine.disease, Rats, Endocrinology, chemistry, inflammation, biology.protein, business, Reperfusion injury, Cell Adhesion Molecules, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; Renal ischaemia reperfusion (I/R) triggers a cascade of events including oxidative stress, apoptotic body and microparticle (MP) formation as well as an acute inflammatory process that may contribute to organ failure. Macrophages are recruited to phagocytose cell debris and MPs. The tyrosine kinase receptor MerTK is a major player in the phagocytosis process. Experimental models of renal I/R events are of major importance for identifying I/R key players and for elaborating novel therapeutical approaches. A major aim of our study was to investigate possible involvement of MerTK in renal I/R. We performed our study on both natural mutant rats for MerTK (referred to as RCS) and on wild type rats referred to as WT. I/R was established by of bilateral clamping of the renal pedicles for 30′ followed by three days of reperfusion. Plasma samples were analysed for creatinine, aspartate aminotransferase (ASAT), lactate dehydrogenase (LDH), kidney injury molecule -1 (KIM-1), and neutrophil gelatinase-associated lipocalin (NGAL) levels and for MPs. Kidney tissue damage and CD68-positive cell requirement were analysed by histochemistry. monocyte chemoattractant protein-1 (MCP-1), myeloperoxidase (MPO), inducible nitric oxide synthase (iNOS), and histone 3A (H3A) levels in kidney tissue lysates were analysed by western blotting. The phagocytic activity of blood-isolated monocytes collected from RCS or WT towards annexin-V positive bodies derived from cultured renal cell was assessed by fluorescence-activated single cell sorting (FACS) and confocal microscopy analyses. The renal I/R model for RCS rat described for the first time here paves the way for further investigations of MerTK-dependent events in renal tissue injury and repair mechanisms.
Published: 2021

4. Intensive chemotherapy followed by autologous stem cell transplantation in primary central nervous system lymphomas (PCNSLs). Therapeutic outcomes in real life-experience of the French Network

Author: Laurence, Schenone, Caroline, Houillier, Marie Laure, Tanguy, Sylvain, Choquet, Kossi, Agbetiafa, Hervé, Ghesquières, Gandhi, Damaj, Anna, Schmitt, Krimo, Bouabdallah, Guido, Ahle, Remy, Gressin, Jérôme, Cornillon, Roch, Houot, Jean-Pierre, Marolleau, Luc-Matthieu, Fornecker, Olivier, Chinot, Frédéric, Peyrade, Reda, Bouabdallah, Cécile, Moluçon-Chabrot, Emmanuel, Gyan, Adrien, Chauchet, Olivier, Casasnovas, Lucie, Oberic, Vincent, Delwail, Julie, Abraham, Virginie, Roland, Agathe, Waultier-Rascalou, Lise, Willems, Franck, Morschhauser, Michel, Fabbro, Renata, Ursu, Catherine, Thieblemont, Fabrice, Jardin, Adrian, Tempescul, Denis, Malaise, Valérie, Touitou, Lucia, Nichelli, Magali, Le Garff-Tavernier, Aurélie, Plessier, Philippe, Bourget, Caroline, Bonmati, Sophie, Wantz-Mézières, Quentin, Giordan, Véronique, Dorvaux, Cyril, Charron, Waliyde, Jabeur, Khê, Hoang-Xuan, Luc, Taillandier, Carole, Soussain, and Thomas, Gastinne
Subjects: Central Nervous System, Lymphoma, Hematopoietic Stem Cell Transplantation, Carmustine, Transplantation, Autologous, Central Nervous System Neoplasms, Treatment Outcome, Antineoplastic Combined Chemotherapy Protocols, Humans, Prospective Studies, Neoplasm Recurrence, Local, Busulfan, Cyclophosphamide, Thiotepa, Etoposide
Abstract: We analysed the therapeutic outcomes of all consecutive patients with primary central nervous system lymphoma (PCNSL) registered in the prospective French database for PCNSL and treated with intensive chemotherapy (IC) followed by autologous stem cell transplantation (IC-ASCT) between 2011 and November 2019 (271 patients recruited, 266 analysed). In addition, treatment-related complications of thiotepa-based IC-ASCT were analysed from the source files of 85 patients from 3 centers. Patients had received IC-ASCT either in first-line treatment (n = 147) or at relapse (n = 119). The median age at IC-ASCT was 57 years (range: 22-74). IC consisted of thiotepa-BCNU (n = 64), thiotepa-busulfan (n = 24), BCNU-etoposide-cytarabine-melphalan (BEAM, n = 36) and thiotepa-busulfan-cyclophosphamide (n = 142). In multivariate analysis, BEAM and ASCT beyond the first relapse were adverse prognostic factors for relapse risk. The risk of treatment-related mortality was higher for ASCT performed beyond the first relapse and seemed higher for thiotepa-busulfan-cyclophosphamide. Thiotepa-BCNU tends to result in a higher relapse rate than thiotepa-busulfan-cyclophosphamide and thiotepa-busulfan. This study confirms the role of IC-ASCT in first-line treatment and at first-relapse PCNSL (5-year overall survival rates of 80 and 50%, respectively). The benefit/risk ratio of thiotepa-busulfan/thiotepa-busulfan-cyclophosphamide-ASCT could be improved by considering ASCT earlier in the course of the disease and dose adjustment of the IC.
Published: 2021

5. Cytokine Signature in Schnitzler Syndrome: Proinflammatory Cytokine Production Associated to Th Suppression

Author: Marie Masson Regnault, Eric Frouin, Isabelle Jéru, Adriana Delwail, Sandrine Charreau, Sébastien Barbarot, Antoine Néel, Agathe Masseau, Xavier Puéchal, Xavier Kyndt, Stephane Gayet, François Lifermann, Bouchra Asli, Xavier Balguerie, Claire Blanchard-Delaunay, François Aubin, Rita Rizzi, Franco Rongioletti, Thierry Boyé, Laurence Gusdorf, Didier Bessis, Franck Morel, Ewa Hainaut, Dan Lipsker, Jean-Claude Lecron, Masson Regnault, M., Frouin, E., Jeru, I., Delwail, A., Charreau, S., Barbarot, S., Neel, A., Masseau, A., Puechal, X., Kyndt, X., Gayet, S., Lifermann, F., Asli, B., Balguerie, X., Blanchard-Delaunay, C., Aubin, F., Rizzi, R., Rongioletti, F., Boye, T., Gusdorf, L., Bessis, D., Morel, F., Hainaut, E., Lipsker, D., and Lecron, J. -C.
Subjects: lcsh:Immunologic diseases. Allergy, 0301 basic medicine, Adult, Lipopolysaccharides, Male, PBMC (peripheral blood mononuclear cells), medicine.medical_treatment, Immunology, Inflammation, Peripheral blood mononuclear cell, Proinflammatory cytokine, 03 medical and health sciences, 0302 clinical medicine, Schnitzler syndrome, inflammasome, Gammopathy, medicine, Immunology and Allergy, Humans, Cells, Cultured, Original Research, Aged, Aged, 80 and over, business.industry, IL-1, IL-1 antagonist, Interleukin, T-Lymphocytes, Helper-Inducer, Middle Aged, medicine.disease, cytokines, Interleukin 1 Receptor Antagonist Protein, 030104 developmental biology, Cytokine, 030228 respiratory system, Antirheumatic Agents, ex vivo, Tumor necrosis factor alpha, Female, medicine.symptom, lcsh:RC581-607, business
Abstract: BackgroundSchnitzler syndrome (SchS) is a rare autoinflammatory disease characterized by urticarial exanthema, bone and joint alterations, fever and monoclonal IgM gammopathy. Overactivation of the interleukin(IL)-1 system is reported, even though the exact pathophysiological pathways remain unknown.ObjectiveTo determine ex vivo cytokine profiles of Peripheral Blood Mononuclear Cells (PBMCs) from SchS patients prior to treatment and after initiation of anti-IL-1 therapy (anakinra). The sera cytokine profile was studied in parallel.MethodsWe collected blood samples from thirty-six untreated or treated SchS. PBMCs were cultured with and without LPS or anti-CD3/CD28. Cytokine levels were evaluated in serum and cell culture supernatants using Luminex technology.ResultsSpontaneous TNFα, IL-6, IL-1β, IL-1α, and IL-1RA release by PBMCs of SchS patients were higher than in controls. LPS-stimulation further induced the secretion of these cytokines. In contrast, after T-cell stimulation, TNFα, IL-10, IFNγ, IL-17A, and IL-4 production decreased in SchS patients compared to healthy controls, but less in treated patients. Whereas IL-1β serum level was not detected in most sera, IL-6, IL-10, and TNFα serum levels were higher in patients with SchS and IFNγ and IL-4 levels were lower. Of note, IL-6 decreased after treatment in SchS (p = 0.04).ConclusionOur data strengthen the hypothesis of myeloid inflammation in SchS, mediated in particular by IL-1β, TNFα, and IL-6, associated with overproduction of the inhibitors IL-1RA and IL-10. In contrast, we observed a loss of Th1, Th2, and Th17 cell functionalities that tends to be reversed by anakinra.
Published: 2020

6. Waldenström macroglobulinemia and relationship to immune deficiency

Author: Emmanuel Fleck, Vincent Delwail, Isabelle Princet, Arthur Bobin, Xavier Leleu, Thomas Systchenko, Elodie Dindinaud, Anthony Levy, Niels Moya, Laly Nsiala, Stéphanie Guidez, Anne Corby, Celine Dieval, Gaelle Olivier, Florence Sabirou, Laura Cailly, Carine Motard, Sabrina Bouyer, Christophe Roul, Guillaume Denis, Cécile Tomowiak, Cécile Gruchet, Céline Debiais, and Helene Gardeney
Subjects: Cancer Research, Lymphoma, B-Cell, business.industry, medicine.medical_treatment, Incidence (epidemiology), Incidence, Immunologic Deficiency Syndromes, Waldenstrom macroglobulinemia, Immunosuppression, Hematology, medicine.disease, 03 medical and health sciences, 0302 clinical medicine, Immune system, Oncology, 030220 oncology & carcinogenesis, Secondary immune deficiency, Immunology, medicine, Humans, Risk factor, Waldenstrom Macroglobulinemia, business, 030215 immunology
Abstract: Primary or secondary immune deficiency (ID) is a risk factor, although rare, to develop Waldenström macroglobulinemia (WM). We aimed to better understand the incidence of this occurrence in the real-life and the outcome of either entity. We conducted a review of 194 WM in the Poitou-Charentes registry and identified 7 (3.6%) with a prior history of ID. Across the 7 WM with ID, 4 progressed to active WM disease and required treatment for WM with a median time between WM diagnosis and the first treatment of 1.5 years (range 0-3). The median time from ID to WM occurrence was 8 years (1-18). WM could develop from ID, although a rare event. Our first action was to systematically decrease immunosuppression with long-term control of ID. Half of indolent WM remained indolent despite ID and for remaining WM none appeared of poor risk WM.
Published: 2021

7. Radiotherapy or Autologous Stem-Cell Transplantation for Primary CNS Lymphoma in Patients 60 Years of Age and Younger: Results of the Intergroup ANOCEF-GOELAMS Randomized Phase II PRECIS Study

Author: Olivier Chinot, Khê Hoang-Xuan, Emmanuel Gyan, Luc Taillandier, Vincent Delwail, Thomas Gastinne, Thierry Lamy, Pierre Soubeyran, Jean-Marc Constans, Adrien Chauchet, Caroline Houillier, Nadine Martin-Duverneuil, Marie-Laure Tanguy, Mouna Laadhari, Reda Garidi, Damien Ricard, Antoine Martin, Alain Delmer, Isabelle Turbiez, Loïc Feuvret, P. Moisson, Intergroupe Goelams–Anocef, Antoine Thyss, Jérôme Cornillon, Marie-Pierre Moles, Nathalie Cassoux, Carole Soussain, A. Langer, Cécile Moluçon-Chabrot, Sylvain Choquet, Ahmad Al Jijakli, Remy Gressin, Julie Abraham, Lucette Lacomblez, Pierre Morel, Gandhi Damaj, Daniel Delgadillo, Valérie Touitou, Sylvain Dureau, Laurence Sanhes, and Pascal Bourquard
Subjects: Adult, Male, Oncology, Cancer Research, medicine.medical_specialty, Adolescent, Lymphoma, medicine.medical_treatment, Disease-Free Survival, law.invention, Central Nervous System Neoplasms, Young Adult, Autologous stem-cell transplantation, Randomized controlled trial, Chemoimmunotherapy, law, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, Humans, Medicine, Combined Modality Therapy, Young adult, Autografts, Febrile Neutropenia, business.industry, Alopecia, Induction Chemotherapy, Middle Aged, Clinical trial, Transplantation, Radiation therapy, Treatment Outcome, Female, business, Stem Cell Transplantation
Abstract: PURPOSE To determine the efficacy and toxicity of chemoimmunotherapy followed by either whole-brain radiotherapy (WBRT) or intensive chemotherapy and autologous stem-cell transplantation (ASCT) as a first-line treatment of primary CNS lymphoma (PCNSL). PATIENTS AND METHODS Immunocompetent patients (18 to 60 years of age) with untreated PCNSL were randomly assigned to receive WBRT or ASCT as consolidation treatment after induction chemotherapy consisting of two cycles of R-MBVP (rituximab 375 mg/m2 day (D) 1, methotrexate 3 g/m2 D1; D15, VP16 100 mg/m2 D2, BCNU 100 mg/m2 D3, prednisone 60 mg/m2/d D1-D5) followed by two cycles of R-AraC (rituximab 375 mg/m2 D1, cytarabine 3 g/m2/D, D1, and D2). Intensive chemotherapy consisted of thiotepa (250 mg/m2/d D9; D8; D7), busulfan (8 mg/kg D6 through D4), and cyclophosphamide (60 mg/kg/d D3; D2). WBRT delivered 40 Gy (2 Gy/fraction). The primary end point was 2-year progression-free survival. Cognitive outcome was the main secondary end point. Analysis was intention to treat in a noncomparative phase II trial. RESULTS Between October 2008 and February 2014, 140 patients were recruited from 23 French centers. Both WBRT and ASCT met the predetermined threshold (among the first 38 patients in each group, at least 24 patients were alive and disease free at 2 years). The 2-year progression-free survival rates were 63% (95% CI, 49% to 81%) and 87% (95% CI, 77% to 98%) in the WBRT and ASCT arms, respectively. Toxicity deaths were recorded in one and five patients after WBRT and ASCT, respectively. Cognitive impairment was observed after WBRT, whereas cognitive functions were preserved or improved after ASCT. CONCLUSION WBRT and ASCT are effective consolidation treatments for patients with PCNSL who are 60 years of age and younger. The efficacy end points tended to favor the ASCT arm. The specific risk of each procedure should be considered.
Published: 2019

8. Rituximab plus Lenalidomide in Advanced Untreated Follicular Lymphoma

Author: Morschhauser, Franck, Fowler, Nathan H, Feugier, Pierre, Bouabdallah, Reda, Tilly, Hervé, Palomba, M Lia, Fruchart, Christophe, Libby, Edward N, Casasnovas, Rene-Olivier, Flinn, Ian W, Haioun, Corinne, Maisonneuve, Hervé, Ysebaert, Loic, Bartlett, Nancy L, Bouabdallah, Kamal, Brice, Pauline, Ribrag, Vincent, Daguindau, Nicolas, Le Gouill, Steven, Pica, Gian M, Martin Garcia-Sancho, Alejandro, López-Guillermo, Armando, Larouche, Jean-François, Ando, Kiyoshi, Gomes da Silva, Maria, André, Marc, Zachée, Pierre, Sehn, Laurie H, Tobinai, Kensei, Cartron, Guillaume, Liu, David, Wang, Jianming, Xerri, Luc, Salles, Gilles A, Abdel-Samad N, Abdo-Matkiwsky M, Abraham J, Abrisqueta P, Anglaret B, Barnes JA, Benbrahim O, Bierman PJ, Bonnet C, Brault P, Bron D, Brooks BJ Jr, Byeff P, Casanova M, Cheung M, Choudhary Y, Comeau T, Cooper B, Couban S, Cox MC, Crump M, Deau Fischer B, Deconinck E, Deeren D, de la Cruz Vicente F, Delarue R, Del Campo R, Delmer A, Delwail V, Duggan PR, Eisenmann DJRM, El Yamani A, Eradat HA, Fabbro M, Farber C, Fisher DC, Fleischman RA, Fleck E, Fornecker LM, Foussard C, Gabarre J, Gaffar YA, Gallardo D, Ghazal H, Giagounidis A, Gill K, Glaisner S, Gonzalez H, Greenberg RH, Goubran Messiha H, Goy A, Gressin R, Gyan E, Hart LL, Hatake K, Hiddemann W, Hodossy B, Horkheimer I, Hoyer RJ, Huebel K, Ishikawa T, Izutsu K, Jardel H, Jhangiani HS, Johnson N, Joly B, Jourdan E, Kargar Samani K, Kato K, Kiguchi T, Kobayashi T, Kohser F, Koike M, Kouroukis C T, Laferriere N, Lamy de la Chapelle T, Landau DA, Lawler WE, Lemieux B, Levitan DA, Longree L, Lopez J, Mace J, Maerevoet M, Maigre M, Marjanovic Z, Michel J, Mounier C, Muntanola A, Ngirabacu MC, Nicolas-Virelizier E, Novelli S, Offner F, Palomera L, Pandit LH, Panwalkar A, Pierre P, Pignon JM, Pinto A, Plöger C, Pranger D, Quick DP, Reyes EA, Robin V, Robu D, Rodriguez Salazar MJ, Rosen PJ, Rosenbluth J, Sadot-Lebouvier S, Sangha R, Segota Z, Shapira I, Shtivelband M, Simon M, Soekler M, Soubeyran P, Taper J, Tereblo HR, Terol MJ, The AS, Ueda Y, van den Neste E, van Eygen K, van Hoof A, Vanstraelen G, Verner E, Warburton P, Yamamoto G, Yokoyama H, Zerazhi H, Zinzani PL., Morschhauser, Franck, Fowler, Nathan H, Feugier, Pierre, Bouabdallah, Reda, Tilly, Hervé, Palomba, M Lia, Fruchart, Christophe, Libby, Edward N, Casasnovas, Rene-Olivier, Flinn, Ian W, Haioun, Corinne, Maisonneuve, Hervé, Ysebaert, Loic, Bartlett, Nancy L, Bouabdallah, Kamal, Brice, Pauline, Ribrag, Vincent, Daguindau, Nicola, Le Gouill, Steven, Pica, Gian M, Martin Garcia-Sancho, Alejandro, López-Guillermo, Armando, Larouche, Jean-Françoi, Ando, Kiyoshi, Gomes da Silva, Maria, André, Marc, Zachée, Pierre, Sehn, Laurie H, Tobinai, Kensei, Cartron, Guillaume, Liu, David, Wang, Jianming, Xerri, Luc, Salles, Gilles A, Abdel-Samad N, Abdo-Matkiwsky M, Abraham J, Abrisqueta P, Anglaret B, Barnes JA, Benbrahim O, Bierman PJ, Bonnet C, Brault P, Bron D, Brooks BJ Jr, Byeff P, Casanova M, Cheung M, Choudhary Y, Comeau T, Cooper B, Couban S, Cox MC, Crump M, Deau Fischer B, Deconinck E, Deeren D, de la Cruz Vicente F, Delarue R, Del Campo R, Delmer A, Delwail V, Duggan PR, Eisenmann DJRM, El Yamani A, Eradat HA, Fabbro M, Farber C, Fisher DC, Fleischman RA, Fleck E, Fornecker LM, Foussard C, Gabarre J, Gaffar YA, Gallardo D, Ghazal H, Giagounidis A, Gill K, Glaisner S, Gonzalez H, Greenberg RH, Goubran Messiha H, Goy A, Gressin R, Gyan E, Hart LL, Hatake K, Hiddemann W, Hodossy B, Horkheimer I, Hoyer RJ, Huebel K, Ishikawa T, Izutsu K, Jardel H, Jhangiani HS, Johnson N, Joly B, Jourdan E, Kargar Samani K, Kato K, Kiguchi T, Kobayashi T, Kohser F, Koike M, Kouroukis C T, Laferriere N, Lamy de la Chapelle T, Landau DA, Lawler WE, Lemieux B, Levitan DA, Longree L, Lopez J, Mace J, Maerevoet M, Maigre M, Marjanovic Z, Michel J, Mounier C, Muntanola A, Ngirabacu MC, Nicolas-Virelizier E, Novelli S, Offner F, Palomera L, Pandit LH, Panwalkar A, Pierre P, Pignon JM, Pinto A, Plöger C, Pranger D, Quick DP, Reyes EA, Robin V, Robu D, Rodriguez Salazar MJ, Rosen PJ, Rosenbluth J, Sadot-Lebouvier S, Sangha R, Segota Z, Shapira I, Shtivelband M, Simon M, Soekler M, Soubeyran P, Taper J, Tereblo HR, Terol MJ, The AS, Ueda Y, van den Neste E, van Eygen K, van Hoof A, Vanstraelen G, Verner E, Warburton P, Yamamoto G, Yokoyama H, Zerazhi H, Zinzani PL., Groupe de Recherche sur les formes Injectables et les Technologies Associées - ULR 7365 (GRITA), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Department of Lymphoma and Myeloma [Houston, TX, USA], The University of Texas M.D. Anderson Cancer Center [Houston], Service d'Hématologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département d’Hématologie [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU), Institut d'Hématologie de Basse-Normandie (IHBN), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN)-Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-UNICANCER, Service d'Hématologie Clinique (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Unité des hémopathies lymphoïdes [CHU Henri Mondor], CHU Henri Mondor, Service d’Onco-Hématologie [La Roche sur Yon], Centre Hospitalier Départemental - Hôpital de La Roche-sur-Yon (CHD Vendée), Service Hématologie - IUCT-Oncopole [CHU Toulouse], Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle IUCT [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Service d'hématologie [CHU Bordeaux], CHU Bordeaux [Bordeaux]-Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], Service d'onco-hématologie [AP-HP Hôpital 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), Département d'hématologie [Gustave Roussy], Institut Gustave Roussy (IGR), Centre Hospitalier Annecy-Genevois [Saint-Julien-en-Genevois], Regulation of Bcl2 and p53 Networks in Multiple Myeloma and Mantle Cell Lymphoma (CRCINA-ÉQUIPE 10), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Service d'Hématologie Clinique [Hôpital Hôtel Dieu, Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes)-Hôpital Hôtel Dieu, Service Hématologie [CH Métropole Savoie, Chambery], Centre Hospitalier Métropole Savoie [Chambéry], Département d'Hématologie [CHU de Montpellier], Centre Hospitalier Universitaire de Montpellier (CHU Montpellier ), Département d'Hématologie [CH Lyon-Sud], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), RELEVANCE Trial Investigators : Abdel-Samad N, Abdo-Matkiwsky M, Abraham J, Abrisqueta P, Anglaret B, Barnes JA, Benbrahim O, Bierman PJ, Bonnet C, Brault P, Bron D, Brooks BJ Jr, Byeff P, Casanova M, Cheung M, Choudhary Y, Comeau T, Cooper B, Couban S, Cox MC, Crump M, Deau Fischer B, Deconinck E, Deeren D, de la Cruz Vicente F, Delarue R, Del Campo R, Delmer A, Delwail V, Duggan PR, Eisenmann DJRM, El Yamani A, Eradat HA, Fabbro M, Farber C, Fisher DC, Fleischman RA, Fleck E, Fornecker LM, Foussard C, Gabarre J, Gaffar YA, Gallardo D, Ghazal H, Giagounidis A, Gill K, Glaisner S, Gonzalez H, Greenberg RH, Goubran Messiha H, Goy A, Gressin R, Gyan E, Hart LL, Hatake K, Hiddemann W, Hodossy B, Horkheimer I, Hoyer RJ, Huebel K, Ishikawa T, Izutsu K, Jardel H, Jhangiani HS, Johnson N, Joly B, Jourdan E, Kargar Samani K, Kato K, Kiguchi T, Kobayashi T, Kohser F, Koike M, Kouroukis C T, Laferriere N, Lamy de la Chapelle T, Landau DA, Lawler WE, Lemieux B, Levitan DA, Longree L, Lopez J, Mace J, Maerevoet M, Maigre M, Marjanovic Z, Michel J, Mounier C, Muntanola A, Ngirabacu MC, Nicolas-Virelizier E, Novelli S, Offner F, Palomera L, Pandit LH, Panwalkar A, Pierre P, Pignon JM, Pinto A, Plöger C, Pranger D, Quick DP, Reyes EA, Robin V, Robu D, Rodriguez Salazar MJ, Rosen PJ, Rosenbluth J, Sadot-Lebouvier S, Sangha R, Segota Z, Shapira I, Shtivelband M, Simon M, Soekler M, Soubeyran P, Taper J, Tereblo HR, Terol MJ, The AS, Ueda Y, van den Neste E, van Eygen K, van Hoof A, Vanstraelen G, Verner E, Warburton P, Yamamoto G, Yokoyama H, Zerazhi H, Zinzani PL., Bernardo, Elizabeth, CHU Henri Mondor [Créteil], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille, Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Université de Caen Normandie (UNICAEN), Normandie Université (NU), Centre Hospitalier Départemental Vendée, Service d'Hématologie [IUCT Toulouse], Université Fédérale Toulouse Midi-Pyrénées-Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), and Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)
Subjects: Adult, Male, medicine.medical_specialty, Neutropenia, Intention to Treat Analysi, Follicular lymphoma, [SDV.CAN]Life Sciences [q-bio]/Cancer, Gastroenterology, Skin Diseases, Disease-Free Survival, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Maintenance therapy, immune system diseases, Internal medicine, hemic and lymphatic diseases, Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, Survival rate, Lenalidomide, Lymphoma, Follicular, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocol, business.industry, Skin Disease, General Medicine, Middle Aged, medicine.disease, 3. Good health, Intention to Treat Analysis, Thalidomide, Survival Rate, Regimen, 030220 oncology & carcinogenesis, Rituximab, Female, business, Febrile neutropenia, 030215 immunology, medicine.drug, Human
Abstract: International audience; BACKGROUND:Rituximab plus chemotherapy has been shown to be effective in patients with advanced-stage, previously untreated follicular lymphoma; nevertheless, most patients will have a relapse. Combination immunotherapy with lenalidomide and rituximab is an immunomodulatory regimen that has shown promising activity in patients with indolent B-cell non-Hodgkin's lymphoma.METHODS:We conducted this multicenter, international, phase 3 superiority trial to evaluate rituximab plus lenalidomide, as compared with rituximab plus chemotherapy, in patients with previously untreated follicular lymphoma. Patients were randomly assigned to receive one of the two regimens, followed by maintenance monotherapy with rituximab. Treatment with rituximab plus lenalidomide consisted of 18 cycles of the two drugs, followed by rituximab maintenance therapy every 8 weeks for 12 cycles (six additional doses). Treatment with rituximab plus chemotherapy consisted of the investigator's choice of one of three rituximab-based regimens, followed by maintenance monotherapy with rituximab every 8 weeks for 12 cycles. The primary end points were complete response (confirmed or unconfirmed) at 120 weeks and progression-free survival.RESULTS:A total of 1030 patients were randomly assigned to receive rituximab plus lenalidomide (513 patients) or rituximab plus chemotherapy (517 patients). The rate of confirmed or unconfirmed complete response at 120 weeks was similar in the two groups: 48% (95% confidence interval [CI], 44 to 53) in the rituximab-lenalidomide group and 53% (95% CI, 49 to 57) in the rituximab-chemotherapy group (P=0.13). The interim 3-year rate of progression-free survival was 77% (95% CI, 72 to 80) and 78% (95% CI, 74 to 82), respectively. A higher percentage of patients in the rituximab-chemotherapy group had grade 3 or 4 neutropenia (32% vs. 50%) and febrile neutropenia of any grade (2% vs. 7%), and a higher percentage of patients in the rituximab-lenalidomide group had grade 3 or 4 cutaneous reactions (7% vs. 1%).CONCLUSIONS:Among patients with previously untreated follicular lymphoma, efficacy results were similar with rituximab plus lenalidomide and rituximab plus chemotherapy (with both regimens followed by rituximab maintenance therapy). The safety profile differed in the two groups. (Funded by Celgene; RELEVANCE ClinicalTrials.gov numbers, NCT01476787 and NCT01650701 , and EudraCT number, 2011-002792-42 .).
Published: 2018

9. Patterns of use and safety of ibrutinib in real-life practice

Author: Claire Lafay-Chebassier, Cécile Tomowiak, Marion Allouchery, Vincent Delwail, Paul Delaunay, Francesco Salvo, Marie-Christine Perault-Pochat, and Stéphanie Guidez
Subjects: Male, medicine.medical_specialty, 030226 pharmacology & pharmacy, Cohort Studies, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Piperidines, Interquartile range, Internal medicine, medicine, Humans, Pharmacology (medical), Cumulative incidence, 030212 general & internal medicine, Aged, Pharmacology, Aged, 80 and over, Proportional hazards model, business.industry, Adenine, Hazard ratio, Pharmacoepidemiology, Leukemia, Lymphocytic, Chronic, B-Cell, Confidence interval, Pyrimidines, chemistry, Ibrutinib, Pyrazoles, Female, business, Cohort study
Abstract: Aims To provide real-life data on patterns of use and safety of ibrutinib. Methods A cohort study including all patients initiating ibrutinib between 21 November 2014 and 21 November 2018, and followed for 1 year was conducted. Patient characteristics, ibrutinib use and adverse drug reactions (ADRs) were collected from medical records. Kaplan-Meier analysis estimated the probability of developing ibrutinib-associated serious ADRs (SADRs) with a 95% confidence interval (CI). A Cox proportional hazards model was used to investigate factors associated with SADR occurrence. Results In total, 102 patients were included in the study. The median age was 70.3 years (interquartile range 64.7-75.6), the male/female gender ratio was 2.9. Almost half the patients (47.1%) were prescribed ibrutinib for chronic lymphocytic leukaemia (CLL). Forty-three patients (42.1%) permanently discontinued ibrutinib in the first year, mostly for progression (51.2%) or ADRs (32.6%). Forty-eight patients (47.1%) experienced at least one ibrutinib-associated SADR. Haematological, infectious and vascular disorders were the most frequent SADRs. The probability of developing ibrutinib-associated SADR was 35.1% (95% CI 26.3-45.7%) at 3 months, 44.8% (35.2%; 55.8%) at 6 months and 54.3% (44.0%; 65.2%) at 12 months. Age ≥80 years (hazard ratio [HR] 2.03; 95% CI 1.02-4.05) and CLL (HR 1.81; 95% CI 1.01-3.25) were significantly associated with a higher risk of SADR occurrence. Conclusion This study found a high cumulative incidence of ibrutinib-associated SADRs within the first year of treatment. In view of the risk of SADR, patients aged ≥80 years or treated for CLL deserve special attention.
Published: 2020

10. Skin inflammatory response and efficacy of anti-epidermal growth factor receptor therapy in metastatic colorectal cancer (CUTACETUX)

Author: David Tougeron, Sheik Emambux, Laure Favot, Thierry Lecomte, Ewa Wierzbicka-Hainaut, Mahtab Samimi, Eric Frouin, Nicolas Azzopardi, Jocelyn Chevrier, Laura Serres, Julie Godet, Pierre Levillain, Gilles Paintaud, Aurélie Ferru, Laetitia Rouleau, Adriana Delwail, Christine Silvain, Jean-Pierre Tasu, Franck Morel, Stéphanie Ragot, Jean-Claude Lecron, Service de Gastroentérologie, Centre hospitalier universitaire de Poitiers (CHU Poitiers), Laboratoire Inflammation, Tissus épithéliaux et Cytokines (LITEC), Université de Poitiers, Service d'Oncologie Médicale, Service de Gastroentérologie [CHRU Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), GICC EA 7501, PATCH (Pharmacologie des anticorps thérapeutiques chez l'Homme) (PATCH), Groupe innovation et ciblage cellulaire (GICC), EA 7501 [2018-...] (GICC EA 7501), Université de Tours (UT)-Université de Tours (UT), Département de Dermatologie [CHU Poitiers], Service de dermatologie (CHRU de Tours), Infectiologie et Santé Publique (UMR ISP), Université de Tours (UT)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Service de Pathologie [CHU Poitiers], Service de pharmacologie, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, ImageUP (Plateforme d'Imagerie de l'Université de Poitiers), Signalisation et Transports Ioniques Membranaires (STIM), Université de Poitiers-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS), Service de Radiologie (POITIERS - Radio), Laboratoire de Traitement de l'Information Medicale (LaTIM), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire de Brest (CHRU Brest)-IMT Atlantique Bretagne-Pays de la Loire (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), CIC - Poitiers, Université de Poitiers-Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Direction Générale de l'Organisation des Soins (DGOS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service Immunologie/Inflammation [CHU Poitiers], Ligue contre le Cancer (départements de la Vienne, des Deux-Sèvres, de la Charente et de la Charente-Maritime), fondation 'Sport et Collection', Institut de Recherche des Maladies de l'Appareil Digestif (IRMAD) grant from Societe Nationale Francaise de Gastro-Enterologie (SNFGE) and Merck Sante SAS (Lyon, France)., Chanteloup, Nathalie Katy, Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire de Brest (CHRU Brest)-IMT Atlantique (IMT Atlantique), Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Université de Tours-Université de Tours, Université de Tours-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Université de Poitiers-Université de Tours-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-IMT Atlantique Bretagne-Pays de la Loire (IMT Atlantique), and Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Centre Hospitalier Régional Universitaire de Brest (CHRU Brest)-Université de Brest (UBO)-Institut Brestois Santé Agro Matière (IBSAM)
Subjects: [SDV]Life Sciences [q-bio], Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Antibodies, Monoclonal, Antineoplastic Agents, [SDV.CAN]Life Sciences [q-bio]/Cancer, Skin toxicity, RC581-607, cytokines, [SDV] Life Sciences [q-bio], ErbB Receptors, inflammatory factors, [SDV.CAN] Life Sciences [q-bio]/Cancer, cetuximab, Humans, Prospective Studies, monoclonal antibodies, Immunologic diseases. Allergy, Colorectal Neoplasms, RC254-282, Research Article, Original Research
Abstract: International audience; Anti-epidermal growth factor receptor (EGFR) monoclonal antibody is a standard treatment of metastatic colorectal cancer (mCRC) and its most common adverse effect is a papulopustular acneiform rash. The aim of the CUTACETUX study was to characterize the skin inflammatory response associated with this rash and its relation to treatment efficacy.This prospective study included patients with mCRC treated with first-line chemotherapy plus cetuximab. Patients underwent skin biopsies before the initiation of cetuximab (D0) and before the third infusion (D28), one in a rash zone and one in an unaffected zone. Expression of Th17-related cytokines (IL-17A, IL-21, IL-22), antimicrobial peptides (S100A7 and BD-2), innate response-related cytokines (IL-1 beta, IL-6, TNF-alpha and OSM), T-reg-related cytokines (IL-10 and TGF-beta), Th1-related cytokine (IFN-gamma), Th2-related cytokine (IL-4), Thymic stromal lymphopoietin and keratinocyte-derived cytokines (IL-8, IL-23 and CCL20) were determined by RT-PCR.Twenty-seven patients were included. Levels of most of the cytokines increased at D28 in the rash zone compared to D0. No significant association was observed between variations of cytokines levels and treatment response in the rash zone and only the increase of IL-4 (p = .04) and IL-23 (p = .02) levels between D0 and D28 in the unaffected zone was significantly associated with treatment response. Increased levels of IL-8 (p = .02), BD-2 (p = .02), IL-1 beta (p = .004) and OSM (p = .02) in the rash zone were associated with longer progression-free survival.Expression of Th2-related and keratinocyte-derived cytokines in the skin was associated with anti-EGFR efficacy. If this inflammatory signature can explain the rash, the exact mechanism by which these cytokines are involved in anti-EGFR tumor response remains to be studied.
Published: 2020

11. R-CHOP appears to be the best first-line treatment for second primary diffuse large B cell lymphoma: a cancer registry study

Author: T, Systchenko, G, Defossez, S, Guidez, C, Laurent, M, Puyade, C, Debiais-Delpech, B, Dreyfus, A, Machet, X, Leleu, V, Delwail, and P, Ingrand
Subjects: Adult, Aged, 80 and over, Male, Neoplasms, Second Primary, Middle Aged, Prognosis, Neoadjuvant Therapy, Young Adult, Treatment Outcome, Doxorubicin, Vincristine, Antineoplastic Combined Chemotherapy Protocols, Humans, Prednisone, Female, France, Lymphoma, Large B-Cell, Diffuse, Registries, Rituximab, Cyclophosphamide, Aged
Abstract: Second primary diffuse large B cell lymphoma (spDLBCL) is defined as a metachronous tumor occurring after a first primary cancer. To date, while R-CHOP is the standard first-line treatment for de novo DLBCL, no available data show that R-CHOP is the optimal treatment for spDLBCL. This exploratory study aimed to investigate treatment of spDLBCL. From 2008 to 2015, the Poitou-Charentes general cancer registry recorded 68 cases of spDLBCL ≤ 80 years old, having received a first-line treatment with either R-CHOP (78%) or other regimens (22%). Patients without R-CHOP have worse overall survival in univariate (HR 2.89 [1.33-6.24], P = 0.007) and multivariate (HR 2.98 [1.34-6.67], P = 0.008) analyses. Patients without R-CHOP more frequently had PS 1 (67% vs. 28%, P = 0.007) and prior chemotherapy (60% vs. 26%, P = 0.02), which suggests that both of these factors influence a clinician's decision to not use R-CHOP. Prior chemotherapy had no prognostic impact in univariate and multivariate analyses; this result could call into question the risk-benefit balance of not using R-CHOP to prevent toxicity. In our study, one DLBCL out of ten occurred after a first primary cancer, and as regards de novo DLBCL, R-CHOP appeared to be the best first-line treatment. Larger series are needed to confirm these results.
Published: 2019

12. High-dose thiotepa-based chemotherapy with autologous stem cell support in elderly patients with primary central nervous system lymphoma: a European retrospective study

Author: Caroline Houillier, Vincent Delwail, Kate Cwynarski, Asterios Tzalavras, Lisa K. Isbell, D De-Silva, Valérie Touitou, J. P. Marolleau, Ruth Witherall, Jerome Tamburini, Christopher P. Fox, Nathalie Cassoux, Kristina Fritsch, Andreas Neubauer, Benjamin Kasenda, Carole Soussain, Sylvain Choquet, Elisabeth Schorb, Outi Kuittinen, Gerald Illerhaus, Khê Hoang-Xuan, Roch Houot, Hämatologie, Onkologie und Stammzelltransplantation, Universitäts Klinikum Freiburg, Service de neurologie 2 [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service d'Ophtalmologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Pierre et Marie Curie - Paris 6 (UPMC), Institut Curie [Paris], CRLCC René Huguenin, CHU Amiens-Picardie, Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Pontchaillou [Rennes], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Universitäts Klinikum Freiburg = University Medical Center Freiburg (Uniklinik), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), 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: medicine.medical_specialty, Transplantation Conditioning, medicine.medical_treatment, [SDV.CAN]Life Sciences [q-bio]/Cancer, ThioTEPA, Transplantation, Autologous, Disease-Free Survival, Central Nervous System Neoplasms, 03 medical and health sciences, 0302 clinical medicine, Autologous stem-cell transplantation, medicine, Humans, Antineoplastic Agents, Alkylating, Survival analysis, Aged, Retrospective Studies, Aged, 80 and over, Transplantation, Chemotherapy, business.industry, Remission Induction, Hematopoietic Stem Cell Transplantation, Primary central nervous system lymphoma, Retrospective cohort study, Hematology, medicine.disease, Combined Modality Therapy, Survival Analysis, 3. Good health, Surgery, Europe, 030220 oncology & carcinogenesis, business, Thiotepa, Progressive disease, 030215 immunology, medicine.drug
Abstract: International audience; In this retrospective multicentre study, we investigated the outcomes of elderly primary central nervous system lymphoma (PCNSL) patients (greater than or equal to65 years) who underwent high-dose chemotherapy followed by autologous stem cell transplantation (HDT-ASCT) at 11 centres between 2003 and 2016. End points included remission, progression-free survival (PFS), overall survival (OS) and treatment-related mortality. We identified 52 patients (median age 68.5 years, median Karnofsky Performance Status before HDT-ASCT 80%) who all underwent thiotepa-based HDT-ASCT. Fifteen patients (28.8%) received HDT-ASCT as first-line treatment and 37 (71.2%) received it as second or subsequent line. Remission status before HDT-ASCT was: CR 34.6%, PR 51.9%, stable disease 3.8% and progressive disease 9.6%. Following completion of HDT-ASCT, 36 patients (69.2%) achieved CR (21.2% first-line setting and 48.1% second or subsequent line setting) and 9 (17.3%) PR (5.8% first-line setting and 11.5% second or subsequent line setting). With a median follow-up of 22 months after HDT-ASCT, median PFS and OS were reached after 51.1 and 122.3 months, respectively. The 2-year PFS and OS rates were 62.0% and 70.8%, respectively. We observed two HDT-ASCT-associated deaths (3.8%). In selected elderly PCNSL patients, HDT-ASCT, using thiotepa-based conditioning regimes, is feasible and effective. Further prospective and comparative studies are warranted to further evaluate the role of HDT-ASCT in elderly PCNSL patients.
Published: 2017

13. Management and outcome of primary CNS lymphoma in the modern era: An LOC network study

Author: Daniel Delgadillo, Carole Soussain, Bachir Aidaoui, Eileen M Boyle, Philippe Agapé, Vincent Delwail, Agusti Alentorn, Adrien Chauchet, Olivier Casasnovas, Hassen Douzane, Franck Morschhauser, Magali Le Garff-Tavernier, Marie Blonski, Olivier Chinot, Luc Taillandier, Matthieu Peyre, Myrto Costopoulos, Chantal Campello, Fabrice Jardin, Jerome Tamburini, Aurélie Kas, Alexandra Amiel, Frédéric Charlotte, Michel Fabbro, Karima Mokhtari, Emeline Tabouret, Caroline Houillier, Valérie Touitou, Agathe Waultier, Jacques-Olivier Bay, Gandhi Damaj, Nadine Martin-Duverneuil, Lucie Oberic, Julie Abraham, Roch Houot, Hervé Ghesquières, Marie-Pierre Moles-Moreau, Remy Gressin, Corinne Haioun, Adrian Tempescul, Diane Genet, Thierry Lamy, Safia Chebrek, Philippe Colin, Anna Schmitt, Sylvain Choquet, Cécile Moluçon-Chabrot, Jean-Pierre Marolleau, Guido Ahle, Loïc Feuvret, Luc-Matthieu Fornecker, Khê Hoang-Xuan, Emmanuel Gyan, Kamel Laribi, Bertrand Mathon, Caroline Serrier, Pierre Soubeyran, Nathalie Cassoux, Centre d’Investigation Clinique [Tours] CIC 1415 (CIC ), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau-Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de neurophysiopathologie (INP), Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Microenvironment, Cell Differentiation, Immunology and Cancer (MICMAC), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Pontchaillou [Rennes], CIC - Poitiers, Université de Poitiers-Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Direction Générale de l'Organisation des Soins (DGOS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Curie [Paris], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau-Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)
Subjects: Adult, medicine.medical_specialty, Antimetabolites, Antineoplastic, Palliative care, Adolescent, Databases, Factual, Lymphoma, Population, [SDV.CAN]Life Sciences [q-bio]/Cancer, Transplantation, Autologous, Article, Central Nervous System Neoplasms, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Antineoplastic Agents, Immunological, Internal medicine, hemic and lymphatic diseases, Outcome Assessment, Health Care, medicine, Humans, Progression-free survival, Young adult, education, Aged, Retrospective Studies, education.field_of_study, business.industry, Age Factors, Retrospective cohort study, Middle Aged, Combined Modality Therapy, Progression-Free Survival, 3. Good health, Transplantation, Clinical trial, Methotrexate, 030220 oncology & carcinogenesis, Rituximab, Neurology (clinical), France, Cranial Irradiation, business, 030217 neurology & neurosurgery, medicine.drug, Stem Cell Transplantation
Abstract: ObjectiveReal-life studies on patients with primary CNS lymphoma (PCNSL) are scarce. Our objective was to analyze, in a nationwide population-based study, the current medical practice in the management of PCNSL.MethodsThe French oculo-cerebral lymphoma network (LOC) database prospectively records all newly diagnosed PCNSL cases from 32 French centers. Data of patients diagnosed between 2011 and 2016 were retrospectively analyzed.ResultsWe identified 1,002 immunocompetent patients (43% aged >70 years, median Karnofsky Performance Status [KPS] 60). First-line treatment was high-dose methotrexate-based chemotherapy in 92% of cases, with an increasing use of rituximab over time (66%). Patients 60 years of age, WBRT and HCT-ASCT consolidation were administered in only 9% and 2%, respectively. The complete response rate to initial chemotherapy was 50%. Median progression-free survival was 10.5 months. For relapse, second-line chemotherapy, HCT-ASCT, WBRT, and palliative care were offered to 55%, 17%, 10%, and 18% of patients, respectively. The median, 2-year, and 5-year overall survival was 25.3 months, 51%, and 38%, respectively (60 years: 15.4 months, 44%, and 28%). Age, KPS, sex, and response to induction CT were independent prognostic factors in multivariate analysis.ConclusionsOur study confirms the increasing proportion of elderly within the PCNSL population and shows comparable outcome in this population-based study with those reported by clinical trials, reflecting a notable application of recent PCNSL advances in treatment.
Published: 2019

14. Clinicopathological spectrum of renal parenchymal involvement in B-cell lymphoproliferative disorders

Author: Laure Ecotiere, Jean-Michel Goujon, Sophie Chauvet, Vincent Delwail, Cécile Vigneau, Nathalie Rioux-Leclerc, Arnaud Jaccard, Elise Gand, Antoine Thierry, Cécile Tomowiak, Vincent Javaugue, Xavier Leleu, Céline Debiais-Delpech, Frank Bridoux, Jean-Paul Fermand, Estelle Desport, Stéphanie Guidez, Mathilde Nouvier, Guy Touchard, Contrôle de la Réponse Immune B et des Lymphoproliférations (CRIBL), Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), CIC - Poitiers, Université de Poitiers-Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Direction Générale de l'Organisation des Soins (DGOS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre hospitalier universitaire de Poitiers (CHU Poitiers), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Service d'Hématologie clinique et thérapie cellulaire [CHU Limoges], CHU Limoges, Service d'anatomie et cytologie pathologiques [Rennes] = Anatomy and Cytopathology [Rennes], CHU Pontchaillou [Rennes], 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 ), 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), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Ischémie Reperfusion en Transplantation d’Organes Mécanismes et Innovations Thérapeutiques ( IRTOMIT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Poitiers, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM), École pratique des hautes études (EPHE)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (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 ), Hopital Saint-Louis, Assistance Publique – Hôpitaux de Paris (AP-HP), Université de Poitiers-Institut National de la Santé et de la Recherche Médicale (INSERM), École Pratique des Hautes Études (EPHE), 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 ), 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: Adult, Male, 0301 basic medicine, medicine.medical_specialty, Kidney Cortex, Adolescent, Biopsy, [SDV]Life Sciences [q-bio], kidney biopsy, 030232 urology & nephrology, Lymphoproliferative disorders, Gastroenterology, Nephropathy, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Renal Dialysis, Internal medicine, medicine, Humans, Renal Insufficiency, Chronic, Multiple myeloma, Aged, Retrospective Studies, Aged, 80 and over, Kidney, business.industry, urogenital system, B-cell lymphoma, Incidence, monoclonal gammopathy, Acute kidney injury, Macroglobulinemia, Middle Aged, medicine.disease, Lymphoproliferative Disorders, 3. Good health, Proteinuria, 030104 developmental biology, medicine.anatomical_structure, acute kidney injury, Nephrology, Female, business, Enlarged kidney, Kidney disease
Abstract: International audience; The clinicopathological characteristics of kidney infiltration in B-cell lymphoproliferative disorders remain poorly described. We retrospectively studied 52 adults with biopsy-proven malignant B-cell kidney infiltration, including Waldenström's macroglobulinemia (n=21), chronic lymphocytic leukemia (n=11), diffuse large B-cell lymphoma (DLBCL) (n=8), other lymphoma (n=11), and multiple myeloma (n=1). Kidney disease varied according to the underlying lymphoproliferative disorder. In DLBCL, malignant kidney infiltration was prominent, resulting in acute kidney injury (AKI, 75%) and kidney enlargement (88%). In the other types, associated immunoglobulin-related nephropathy (most commonly AL amyloidosis) was more common (45%), and chronic kidney disease with proteinuria was the primary presentation. All patients received chemotherapy. Over a median follow-up of 31 months, 20 patients died and 21 reached end-stage kidney disease. Renal response, achieved in 25 patients (48%), was associated with higher overall survival (97 vs. 37 months in non-renal responders). In univariate analysis, percentage of sclerotic glomeruli, kidney enlargement, and complete hematological response at 6 months were predictive of renal response. In multivariate analysis, concomitant immunoglobulin-related nephropathy was the sole independent predictor of poor renal outcome. In conclusion, clinical presentation of renal lymphomatous infiltration depends on the nature of the underlying lymphoproliferative disorder. In DLBCL, massive renal infiltration manifests with enlarged kidneys and AKI, and the diagnosis primarily relies on lymph node biopsy. In other B-cell lymphoproliferative disorders, the clinicopathological spectrum is more heterogeneous, with a high frequency of immunoglobulin-related nephropathy that may affect renal outcome; thus kidney biopsy is required for early diagnosis and prognostic assessment. © 2019 International Society of Nephrology
Published: 2019

15. GAPDH Expression Predicts the Response to R-CHOP, the Tumor Metabolic Status, and the Response of DLBCL Patients to Metabolic Inhibitors

Author: Vincent Delwail, Jean-Ehrland Ricci, Isabelle Peyrottes, Celine Delpech-Debiais, Sandrine Marchetti, Julie Reverso-Meinietti, Jacqueline Lehmann-Che, Gabriel Brisou, Jozef P. Bossowski, Manuel Grima-Reyes, Christiane Copie-Bergman, Camila Rubio-Patiño, Konstantina Fragaki, Eric de Kerviler, Véronique Paquis-Flucklinger, Thierry Jo Molina, Frederic Peyrade, Annabelle Mouchotte, Tony Petrella, Emma Proïcs, Bertrand Nadel, Els Verhoeyen, Bruno Taillan, Richard Delarue, Catherine Thieblemont, Laetitia Shintu, Agnès Paquet, Rana Mhaidly, Johanna Chiche, Elodie Villa, Georges Garnier, Pascal Barbry, Josette Brière, Damien Ambrosetti, Nicolas Mounier, André Bosly, Jean-François Michiels, COMUE Université Côte d'Azur (2015-2019) (COMUE UCA), Université Nice Sophia Antipolis - Faculté de Médecine (UNS UFR Médecine), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA), Centre méditerranéen de médecine moléculaire (C3M), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), Institut de pharmacologie moléculaire et cellulaire (IPMC), 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), Institut de Recherche sur le Cancer et le Vieillissement (IRCAN), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Service d'anatomo-pathologie [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Pasteur [Nice] (CHU), Hôpital Hôtel Dieu, INSERM U955, équipe 9, Département de pathologie [Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-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 National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Pathologie cellulaire : aspects moléculaires et viraux / Pathologie et Virologie Moléculaire, Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), Department of Pathology, Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA)-UNICANCER-Université Côte d'Azur (UCA), UNICANCER-Université Côte d'Azur (UCA), Hôpital Princesse Grace [Monaco], Institut National de la Santé et de la Recherche Médicale (INSERM), Institut des Sciences Moléculaires de Marseille (ISM2), Aix Marseille Université (AMU)-École Centrale de Marseille (ECM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), CIC - Poitiers, Université de Poitiers-Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Direction Générale de l'Organisation des Soins (DGOS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre hospitalier universitaire de Poitiers (CHU Poitiers), Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Cliniques universitaires UCL de Mont-Godinne 5530 Yvoir, Centre de pathologie [Dijon], Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), 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), Service hématologie Nice, Centre Hospitalier Universitaire de Nice (CHU Nice), Service d'onco-hématologie [AP-HP Hôpital Saint-Louis], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Physiopathologie de la survie et de la mort cellulaire et infection virale, COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-IFR50-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), Université Nice Sophia Antipolis (... - 2019) (UNS), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de pathologie, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Université Côte d'Azur (UCA), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Nice Sophia Antipolis (... - 2019) (UNS), 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)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut Mondor de Recherche Biomédicale (IMRB), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), CRLCC Antoine Lacassagne, Centre Antoine Lacassagne, Aix Marseille Université (AMU)-École Centrale de Marseille (ECM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR50-Université Nice Sophia Antipolis (... - 2019) (UNS), UCL - (MGD) Service d'hématologie, UCL - SSS/IREC/MIRO - Pôle d'imagerie moléculaire, radiothérapie et oncologie, and UCL - SSS/IREC/MONT - Pôle Mont Godinne
Subjects: 0301 basic medicine, Male, Physiology, Phenformin, Cohort Studies, chemistry.chemical_compound, Mice, 0302 clinical medicine, immune system diseases, hemic and lymphatic diseases, Antineoplastic Combined Chemotherapy Protocols, Glyceraldehyde 3-phosphate dehydrogenase, Cells, Cultured, Aged, 80 and over, Predictive marker, biology, GAPDH, Glyceraldehyde-3-Phosphate Dehydrogenases, OxPhos, Middle Aged, glycolysis, Prognosis, 3. Good health, Metformin, Gene Expression Regulation, Neoplastic, medicine.anatomical_structure, Treatment Outcome, Vincristine, R-CHOP, mTOR, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Lymphoma, Large B-Cell, Diffuse, Rituximab, predictive marker, medicine.drug, Adult, Antimetabolites, Antineoplastic, Mice, Transgenic, Gene Expression Regulation, Enzymologic, 03 medical and health sciences, Young Adult, stomatognathic system, medicine, Animals, Humans, Molecular Biology, Cyclophosphamide, PI3K/AKT/mTOR pathway, B cell, Aged, Retrospective Studies, Glutaminolysis, business.industry, Cell Biology, medicine.disease, L-asparaginase, Mice, Inbred C57BL, 030104 developmental biology, HEK293 Cells, chemistry, Doxorubicin, DLBCL, biology.protein, Cancer research, Prednisone, business, Diffuse large B-cell lymphoma, 030217 neurology & neurosurgery
Abstract: International audience; Diffuse large B cell lymphoma (DLBCL) is a heterogeneous disease treated with anti-CD20-based immuno-chemotherapy (R-CHOP). We identified that low levels of GAPDH predict a poor response to R-CHOP treatment. Importantly, we demonstrated that GAPDH(low) lymphomas use OxPhos metabolism and rely on mTORC1 signaling and glutaminolysis. Consistently, disruptors of OxPhos metabolism(phenformin) or glutaminolysis (L-asparaginase) induce cytotoxic responses in GAPDH(low) B cells and improve GAPDH(low) B cell-lymphoma-bearing mice survival, while they are low or not efficient on GAPDH(high) B cell lymphomas. Ultimately, we selected four GAPDH(low) DLBCL patients, who were refractory to all anti-CD20-based therapies, and targeted DLBCL metabolism-using L-asparaginase (K), mTOR inhibitor (T), and metformin (M) (called KTM therapy). Three out of the four patients presented a complete response upon one cycle of KTM. These findings establish that the GAPDH expression level predicts DLBCL patients' response to R-CHOP treatment and their sensitivity to specific metabolic inhibitors.
Published: 2019

16. Brentuximab vedotin with chemotherapy for CD30-positive peripheral T-cell lymphoma (ECHELON-2): a global, double-blind, randomised, phase 3 trial

Author: Steven Horwitz, Owen A O'Connor, Barbara Pro, Tim Illidge, Michelle Fanale, Ranjana Advani, Nancy L Bartlett, Jacob Haaber Christensen, Franck Morschhauser, Eva Domingo-Domenech, Giuseppe Rossi, Won Seog Kim, Tatyana Feldman, Anne Lennard, David Belada, Árpád Illés, Kensei Tobinai, Kunihiro Tsukasaki, Su-Peng Yeh, Andrei Shustov, Andreas Hüttmann, Kerry J Savage, Sam Yuen, Swaminathan Iyer, Pier Luigi Zinzani, Zhaowei Hua, Meredith Little, Shangbang Rao, Joseph Woolery, Thomas Manley, Lorenz Trümper, David Aboulafia, Onder Alpdogan, Kiyoshi Ando, Luca Arcaini, Luca Baldini, Naresh Bellam, Nancy Bartlett, Dina Ben Yehuda, Fabio Benedetti, Peter Borchman, Dominique Bordessoule, Pauline Brice, Javier Briones, Dolores Caballero, Angelo Michele Carella, Hung Chang, June Weon Cheong, Seok-Goo Cho, Ilseung Choi, Sylvain Choquet, Andrei Colita, Angela Giovanna Congui, Francesco D'amore, Nam Dang, Kelly Davison, Sophie de Guibert, Peter de Nully Brown, Vincent Delwail, Judit Demeter, Francesco di Raimondo, Young Rok Do, Eva Domingo, Michael Douvas, Martin Dreyling, Thomas Ernst, Keith Fay, Silvia Fernandez Ferrero, Ian Winchester Flinn, Andres Forero-Torres, Christopher Fox, Jonathan Friedberg, Noriko Fukuhara, Jose Garcia-Marco, Jorge Gayoso Cruz, Jose Gomez Codina, Remy Gressin, Andrew Grigg, Ronit Gurion, Corinne Haioun, Roman Hajek, Mathias Hanel, Kiyohiko Hatake, Robert Hensen, Netanel Horowitz, Andreas Huttmann, Arpad Illes, Kenichi Ishizawa, Miguel Islas-Ohlmayer, Eric Jacobsen, Murali Janakiram, Wojciech Jurczak, Mark Kaminski, Koji Kato, Ilya Kirgner, Ching-Yuan Kuo, Mihaela Cornelia Lazaroiu, Katell Le Du, Jong-Seok Lee, Steven LeGouill, Paul LaRosee, Itai Levi, Brian Link, Herve Maisonneuve, Dai Maruyama, Jiri Mayer, John McCarty, Pam McKay, Yosuke Minami, Heidi Mocikova, Enrica Morra, Javier Munoz, Hirokazu Nagai, Owen O'Connor, Stephen Opat, Ruth Pettengell, Antonio Pezzutto, Michael Pfreundschuh, Andrzej Pluta, PierLuigi Porcu, Hang Quach, Alessandro Rambaldi, William Renwick, Ruben Reyes, Antonia Rodriguez Izquierdo, Jia Ruan, Chiara Rusconi, Gilles Salles, Armando Santoro, Jose Sarriera, Kerry Savage, Hirohiko Shibayama, Cheolwon Suh, Anna Sureda, Mitsune Tanimoto, Masafumi Taniwaki, Herve Tilly, Marek Trneny, Lorenz Trumper, Norifumi Tsukamoto, Umberto Vitolo, Jan Walewski, Eckhart Weidmann, Martin Wilhelm, Mathias Witzens-Harig, Abdulraheem Yacoub, Kazuhito Yamamoto, Sung-Soo Yoon, Hwan Jung Yun, Jasmine Zain, Horwitz, Steven, O'Connor, Owen A, Pro, Barbara, Illidge, Tim, Fanale, Michelle, Advani, Ranjana, Bartlett, Nancy L, Christensen, Jacob Haaber, Morschhauser, Franck, Domingo-Domenech, Eva, Rossi, Giuseppe, Kim, Won Seog, Feldman, Tatyana, Lennard, Anne, Belada, David, Illés, Árpád, Tobinai, Kensei, Tsukasaki, Kunihiro, Yeh, Su-Peng, Shustov, Andrei, Hüttmann, Andrea, Savage, Kerry J, Yuen, Sam, Iyer, Swaminathan, Zinzani, Pier Luigi, Hua, Zhaowei, Little, Meredith, Rao, Shangbang, Woolery, Joseph, Manley, Thoma, Trümper, Lorenz, and ECHELON-2 Study Group
Subjects: Male, Immunoconjugates, Lydia Becker Institute, medicine.medical_treatment, Medizin, 030204 cardiovascular system & hematology, CHOP, Gastroenterology, Cyclophosphamide/administration & dosage, 0302 clinical medicine, International Prognostic Index, Prednisone/administration & dosage, Prednisone, Antineoplastic Combined Chemotherapy Protocols, Vincristine/administration & dosage, 030212 general & internal medicine, Brentuximab vedotin, Brentuximab Vedotin, Manchester Cancer Research Centre, General Medicine, Orvostudományok, Middle Aged, 3. Good health, Antineoplastic Agents/administration & dosage, Intention to Treat Analysis, Immunoconjugates/administration & dosage, Vincristine, Lymphoma, Large-Cell, Anaplastic, Female, Immunologic Factors/administration & dosage, medicine.drug, Adult, medicine.medical_specialty, Antineoplastic Agents, Lymphoma, T-Cell, Klinikai orvostudományok, Lymphoma, Large-Cell, Anaplastic/drug therapy, Article, Disease-Free Survival, 03 medical and health sciences, Double-Blind Method, Internal medicine, ResearchInstitutes_Networks_Beacons/lydia_becker_institute_of_immunology_and_inflammation, medicine, Humans, Immunologic Factors, Cyclophosphamide, Aged, Chemotherapy, business.industry, ResearchInstitutes_Networks_Beacons/mcrc, Doxorubicin/administration & dosage, medicine.disease, Peripheral T-cell lymphoma, Brentuximab vedotin , CD30-positive peripheral T-cell lymphoma, ECHELON-2, Doxorubicin, Antineoplastic Combined Chemotherapy Protocols/therapeutic use, business, Febrile neutropenia
Abstract: BACKGROUND: Based on the encouraging activity and manageable safety profile observed in a phase 1 study, the ECHELON-2 trial was initiated to compare the efficacy and safety of brentuximab vedotin, cyclophosphamide, doxorubicin, and prednisone (A+CHP) versus cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) for the treatment of CD30-positive peripheral T-cell lymphomas.METHODS: ECHELON-2 is a double-blind, double-dummy, randomised, placebo-controlled, active-comparator phase 3 study. Eligible adults from 132 sites in 17 countries with previously untreated CD30-positive peripheral T-cell lymphomas (targeting 75% with systemic anaplastic large cell lymphoma) were randomly assigned 1:1 to receive either A+CHP or CHOP for six or eight 21-day cycles. Randomisation was stratified by histological subtype according to local pathology assessment and by international prognostic index score. All patients received cyclophosphamide 750 mg/m2 and doxorubicin 50 mg/m2 on day 1 of each cycle intravenously and prednisone 100 mg once daily on days 1 to 5 of each cycle orally, followed by either brentuximab vedotin 1·8 mg/kg and a placebo form of vincristine intravenously (A+CHP group) or vincristine 1·4 mg/m2 and a placebo form of brentuximab vedotin intravenously (CHOP group) on day 1 of each cycle. The primary endpoint, progression-free survival according to blinded independent central review, was analysed by intent-to-treat. This trial is registered with ClinicalTrials.gov, number NCT01777152.FINDINGS: Between Jan 24, 2013, and Nov 7, 2016, 601 patients assessed for eligibility, of whom 452 patients were enrolled and 226 were randomly assigned to both the A+CHP group and the CHOP group. Median progression-free survival was 48·2 months (95% CI 35·2-not evaluable) in the A+CHP group and 20·8 months (12·7-47·6) in the CHOP group (hazard ratio 0·71 [95% CI 0·54-0·93], p=0·0110). Adverse events, including incidence and severity of febrile neutropenia (41 [18%] patients in the A+CHP group and 33 [15%] in the CHOP group) and peripheral neuropathy (117 [52%] in the A+CHP group and 124 [55%] in the CHOP group), were similar between groups. Fatal adverse events occurred in seven (3%) patients in the A+CHP group and nine (4%) in the CHOP group.INTERPRETATION: Front-line treatment with A+CHP is superior to CHOP for patients with CD30-positive peripheral T-cell lymphomas as shown by a significant improvement in progression-free survival and overall survival with a manageable safety profile.FUNDING: Seattle Genetics Inc, Millennium Pharmaceuticals Inc, a wholly owned subsidiary of Takeda Pharmacuetical Company Limited, and National Institutes of Health National Cancer Institute Cancer Center.
Published: 2019

17. A phase 2 study of rituximab, bendamustine, bortezomib and dexamethasone for first-line treatment of older patients with mantle cell lymphoma

Author: Loic Ysebaert, Anne Banos, Vincent Delwail, Roch Houot, Nicolas Daguindau, Reda Garidi, Margaret Macro, Ghandi Damaj, Bertrand Joly, Jean Pierre Vilque, Sylvain Carras, Mary Callanan, Fabrice Jardin, Marie Pierre Moles, Magda Alexis, Steven Le Gouill, Emmanuelle Tchernonog, Laurent Voillat, Hacene Zerazhi, Christiane Mounier, J. Fleury, Sandy Amorin, Anne Moreau, Jean Michel Pignon, Adrian Tempescul, Véronique Dorvaux, Yazid Arkam, Luc Fornecker, Caroline Dartigeas, Cecile Chabrot, Philippe Solal Celigny, Pierre Feugier, Remy Gressin, Anna Schmitt, Jean Fontan, Clémentine Sarkozy, Nadine Morineau, Jehan Dupuis, Selim Corm, Krimo Bouadallah, Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Service d'Hématologie [CH Annecy], CH Annecy, CHRU Brest - Service d'Hématologie (CHU-Brest-Hemato), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Lymphocyte B et Auto-immunité (LBAI), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Département de Pathologie [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Département d'hématologie biologique[Montpellier], Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-CHU Saint-Eloi, Dpt hématologie [CHU Bordeaux], CHU Bordeaux [Bordeaux], Département d'Hématologie Clinique [CHU Rennes], CHU Pontchaillou [Rennes], Département d’Hématologie Clinique [CHU Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Service d'hématologie (CH de Dunkerque), Centre Hospitalier Dunkerque, Service Hématologie [CH Métropole Savoie, Chambery], Centre Hospitalier Métropole Savoie [Chambéry], Hôpital de Bayonne, CH de la Côte Basque, Hématologie de liaison avec Institut de Cancérologie de la Loire [CHU de Saint-Etienne], CHU Saint-Etienne, Centre hospitalier universitaire Henri-Mondor [Créteil], Hôpital Universitaire de Caen, Laboratoire d'Hématologie Biologique [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Service d’Hématologie [CHU de Clermont Ferrand], Centre Hospitalier Universitaire de Clermont-Ferrand, Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), Département d’Hématologie [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU), Service d’Hématologie [Centre Hospitalier Lyon Sud - HCL], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Service hématologie Amiens, CHU Amiens-Picardie, Service d'Hématologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Département d'Oncologie et Hématologie [Strasbourg], Les Hôpitaux Universitaires de Strasbourg (HUS), Service d'hématologie [CHR Metz-Thionville], Centre hospitalier régional Metz-Thionville (CHR Metz-Thionville), Service d'Hématologie [Bordeaux], Institut de Recherche Saint-Louis - Hématologie Immunologie Oncologie (Département de recherche de l’UFR de médecine, ex-Institut Universitaire Hématologie-IUH) (IRSL), Université Paris Diderot - Paris 7 (UPD7), Hôpital Saint-Quentin, Service d'hématologie et oncologie [Centre Hospitalier de Chalon-sur-Saône William Morey], Centre Hospitalier Chalon-sur-Saône William Morey, Hôpital de Corbeil, Service d'Oncologie médicale [Clinique Victor Hugo], Clinique Victor Hugo, Centre Catherine-de-Sienne [Nantes] (CCS), Département d'Hématologie Clinique [CHU d'Angers], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Médecine Interne Onco-hématologie, Centre Hospitalier Général, Hopital d'Avignon, Service d'hématologie, Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Hôpital Jean Minjoz, Service Hématologie, Mulhouse, Centre Hospitalier Emile Muller [Mulhouse] (CH E.Muller Mulhouse), Groupe Hospitalier de Territoire Haute Alsace (GHTHA)-Groupe Hospitalier de Territoire Haute Alsace (GHTHA), Hématologie Biologique [CHR d'Orléans], Centre Hospitalier Régional d'Orléans (CHR), Service d’Oncologie Hématologique et Thérapie Cellulaire [CHU Poitiers], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Centre Régional de Lutte contre le Cancer François Baclesse (CRLC François Baclesse ), Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Hématologie [Nantes], Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Université de Brest (UBO)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d’Hématologie Clinique [Rennes], Service d’Hématologie Biologique [CHU Clermont-Ferrand], CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand-CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand, Laboratoire d'Hématologie [CHU Amiens], Centre Hospitalier Henri Duffaut (Avignon), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Centre Hospitalier Régional d'Orléans (CHRO), Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), and Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)
Subjects: Bendamustine, Male, medicine.medical_specialty, Time Factors, Non-Hodgkin Lymphoma, Lymphoma, Mantle-Cell, Neutropenia, Gastroenterology, Dexamethasone, Disease-Free Survival, Article, Bortezomib, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, medicine, Bendamustine Hydrochloride, Humans, Survival rate, Aged, Aged, 80 and over, business.industry, Hematology, Middle Aged, medicine.disease, Minimal residual disease, 3. Good health, Lymphoma, Survival Rate, 030220 oncology & carcinogenesis, [SDV.IMM]Life Sciences [q-bio]/Immunology, Rituximab, Mantle cell lymphoma, Female, business, 030215 immunology, medicine.drug
Abstract: International audience; We present results of a prospective, multicenter, phase II study evaluating rituximab, bendamustine, bortezomib and dexamethasone as first-line treatment for patients with mantle cell lymphoma aged 65 years or older. A total of 74 patients were enrolled (median age, 73 years). Patients received a maximum of six cycles of treatment at 28-day intervals. The primary objective was to achieve an 18-month progression-free survival rate of 65% or higher. Secondary objectives were to evaluate toxicity and the prognostic impact of mantle cell lymphoma prognostic index, Ki67 expression, [18F]fluorodeoxyglucose-positron emission tomography and molecular minimal residual disease, in peripheral blood or bone marrow. With a median follow-up of 52 months, the 24-month progression-free survival rate was 70%, hence the primary objective was reached. After six cycles of treatment, 91% (54/59) of responding patients were analyzed for peripheral blood residual disease and 87% of these (47/54) were negative. Four-year overall survival rates of the patients who did not have or had detectable molecular residual disease in the blood at completion of treatment were 86.6% and 28.6%, respectively (P
Published: 2018

18. Added Value of Spectroscopy to Perfusion MRI in the Differential Diagnostic Performance of Common Malignant Brain Tumors

Author: Jean-Noël Vallée, M. Wager, Rémy Guillevin, Alexandre Vallée, Carole Guillevin, and V. Delwail
Subjects: Adult, Male, Magnetic Resonance Spectroscopy, Neuroimaging, Multimodal Imaging, Sensitivity and Specificity, 030218 nuclear medicine & medical imaging, Diagnosis, Differential, 03 medical and health sciences, 0302 clinical medicine, Text mining, Medicine, Humans, Radiology, Nuclear Medicine and imaging, Spectroscopy, Aged, Receiver operating characteristic analysis, business.industry, Brain Neoplasms, Adult Brain, Middle Aged, Mr imaging, Magnetic Resonance Imaging, Female, Neurology (clinical), Signal intensity, business, Nuclear medicine, Perfusion, 030217 neurology & neurosurgery
Abstract: BACKGROUND AND PURPOSE: Perfusion and spectroscopic MR imaging provide noninvasive physiologic and metabolic characterization of tissues, which can help in differentiating brain tumors. We investigated the diagnostic role of perfusion and spectroscopic MR imaging using individual and combined classifiers of these modalities and assessed the added performance value that spectroscopy can provide to perfusion using optimal combined classifiers that have the highest differential diagnostic performance to discriminate lymphomas, glioblastomas, and metastases. MATERIALS AND METHODS: From January 2013 to January 2016, fifty-five consecutive patients with histopathologically proved lymphomas, glioblastomas, and metastases were included after undergoing MR imaging. The perfusion parameters (maximum relative CBV, maximum percentage of signal intensity recovery) and spectroscopic concentration ratios (lactate/Cr, Cho/NAA, Cho/Cr, and lipids/Cr) were analyzed individually and in optimal combinations. Differences among tumor groups, differential diagnostic performance, and differences in discriminatory performance of models with quantification of the added performance value of spectroscopy to perfusion were tested using 1-way ANOVA models, receiver operating characteristic analysis, and comparisons between receiver operating characteristic analysis curves using a bivariate χ2, respectively. RESULTS: The highest differential diagnostic performance was obtained with the following combined classifiers: maximum percentage of signal intensity recovery–Cho/NAA to discriminate lymphomas from glioblastomas and metastases, significantly increasing the sensitivity from 82.1% to 95.7%; relative CBV–Cho/NAA to discriminate glioblastomas from lymphomas and metastases, significantly increasing the specificity from 92.7% to 100%; and maximum percentage of signal intensity recovery–lactate/Cr and maximum percentage of signal intensity recovery–Cho/Cr to discriminate metastases from lymphomas and glioblastomas, significantly increasing the specificity from 83.3% to 97.0% and 100%, respectively. CONCLUSIONS: Spectroscopy yielded an added performance value to perfusion using optimal combined classifiers of these modalities, significantly increasing the differential diagnostic performances for these common brain tumors.
Published: 2018

19. Central nervous system relapse in patients over 80 years with diffuse large B-cell lymphoma: an analysis of two LYSA studies

Author: Cabannes‐Hamy, Aurélie, Peyrade, Frederic, Jardin, Fabrice, Emile, Jean‐François, Delwail, Vincent, Mounier, Nicolas, Haioun, Corinne, Perrot, Aurore, Fitoussi, Olivier, Lara, Diane, Delarue, Richard, André, Marc, Offner, Fritz, Ghesquières, Hervé, Pascal, Laurent, Soussain, Carole, Lazarovici, Julien, Schiano, Jean-Marc, Gaulard, Philippe, Tilly, Hervé, Thieblemont, Catherine, LYSA (LYmphoma Study Association), Bosly, André, Van Den Neste, Eric, Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Biomarqueurs et essais cliniques en Cancérologie et Onco-Hématologie (BECCOH), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay, CIC - Poitiers, Université de Poitiers-Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Direction Générale de l'Organisation des Soins (DGOS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d’Oncologie Hématologique et Thérapie Cellulaire [CHU Poitiers], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Gvh et Gvl : Physiopathologie Chez l'Homme et Chez l'Animal, Incidence et Role Therapeutique, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'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), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Polyclinique Bordeaux Nord Aquitaine, Université Paris Descartes - Faculté de Médecine (UPD5 Médecine), Université Paris Descartes - Paris 5 (UPD5), Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Groupe de Recherche d'Histoire (GRHis), Normandie Université (NU)-Normandie Université (NU)-Institut de Recherche Interdisciplinaire Homme et Société (IRIHS), Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Universiteit Gent = Ghent University [Belgium] (UGENT), Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL), CRLCC René Huguenin, Département d'hématologie [Gustave Roussy], Institut Gustave Roussy (IGR), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), 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), 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, École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Polyclinique Bordeaux Nord Aquitaine (PBNA), Universiteit Gent = Ghent University (UGENT), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Centre Antoine Lacassagne, CRLCC Antoine Lacassagne, Laboratoire épidémiologie et oncogénèse des tumeurs digestives, Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), 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)-CHU Necker - Enfants Malades [AP-HP], Ghent University [Belgium] (UGENT), Université de Lille, CHU Lille, UCL - (MGD) Service d'hématologie, UCL - SSS/IREC/MIRO - Pôle d'imagerie moléculaire, radiothérapie et oncologie, UCL - SSS/DDUV - Institut de Duve, UCL - SSS/DDUV/BCHM - Biochimie-Recherche métabolique, and UCL - (SLuc) Service d'hématologie
Subjects: Male, Cancer Research, CHOP CHEMOTHERAPY, [SDV]Life Sciences [q-bio], Aggressive lymphoma, Central Nervous System Neoplasms, chemistry.chemical_compound, 0302 clinical medicine, Recurrence, Medicine and Health Sciences, SINGLE-ARM, Medicine, Cumulative incidence, ELDERLY-PATIENTS, ComputingMilieux_MISCELLANEOUS, Original Research, CNS relapse, Aged, 80 and over, education.field_of_study, Incidence (epidemiology), 3. Good health, CNS PROPHYLAXIS, Oncology, 030220 oncology & carcinogenesis, Female, Rituximab, Lymphoma, Large B-Cell, Diffuse, medicine.drug, medicine.medical_specialty, Population, PHASE-2 TRIAL, Ofatumumab, elderly, STUDY-GROUP DSHNHL, 03 medical and health sciences, Internal medicine, Humans, Radiology, Nuclear Medicine and imaging, NON-HODGKINS-LYMPHOMA, education, Aged, Retrospective Studies, AGGRESSIVE LYMPHOMA, business.industry, Clinical Cancer Research, Retrospective cohort study, medicine.disease, chemistry, Aged 80 and over, RITUXIMAB ERA, DLBCL, RISK-FACTORS, business, Diffuse large B-cell lymphoma, 030215 immunology
Abstract: CNS relapse is reported in 2–5% of diffuse large B‐cell lymphoma (DLBCL) patients, dramatically decreasing overall survival (OS). Very few studies address incidence and risk factors of CNS relapse in very elderly patients, a challenging population to treat given their commonly associated comorbidities. A retrospective analysis was performed of 270 DLBCL patients >80 years treated between 2004 and 2013 in two multicentre phase II LYSA trials (LNH03‐7B, LNH09‐7B) evaluating the addition of rituximab or ofatumumab to mini‐CHOP as front‐line therapy. No patients received CNS prophylaxis. CNS relapse was evaluated according to cumulative incidence, patient characteristics, risk factors, and survival. Median age was 83 years (range: 79–95). After a median follow‐up of 28.7 months, eight patients had CNS relapse (3.0%). Median time between inclusion and CNS relapse was 19.2 months (range: 3.2–32.6). Patients survived a median of 1.5 months after CNS relapse (range: 0.4–4.1). Median OS from relapse was significantly lower in CNS relapse patients (1.5 months, 95% CI: 0.4–3.5) compared to patients with non‐CNS relapse (6.6 months; 95% CI: 4.6–11.9). No baseline characteristics were associated with CNS relapse. The proportion of patients with CNS disease did not differ significantly between patients with low‐intermediate risk according to CNS‐IPI and patients with high risk (3% vs. 2.8%, P = 1.00). CNS relapse cumulative incidence in very elderly treatment‐naive patients is 1.8% at 2 years and is associated with poor survival. This population had a long median time to CNS relapse. Absence of prophylaxis did not strongly impact CNS relapse incidence.
Published: 2018

20. R-CHOP 14 with or without radiotherapy in non-bulky limited-stage diffuse large B-cell lymphoma (DLBCL)

Author: Gandhi Damaj, Katell Le Du, J. Fleury, Jean Pierre Marolleau, Vincent Delwail, Krimo Bouabdallah, Anne Devillers, Guillaume Cartron, Pierre Soubeyran, Valérie Costes, Olivier Tournilhac, Pascal Godmer, Emmanuel Gyan, Marie C. Béné, Steven Le Gouill, Marie-Pierre Moles, Jean Philippe Vuillez, Mohamed Benchalal, Philippe Colombat, Jérôme Cornillon, Thierry Fest, Hervé Maisonneuve, Eric Deconinck, Kamel Laribi, Vanessa Szablewski, Roch Houot, Bernard Branger, Thierry Lamy, Remy Gressin, Anne Banos, CHU Pontchaillou [Rennes], Microenvironment, Cell Differentiation, Immunology and Cancer (MICMAC), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre de référence des mastocytoses (CEREMAST), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Plateforme de génétique moléculaire des cancers d'Aquitaine, Institut Bergonié [Bordeaux], UNICANCER-UNICANCER, Service d'hématologie, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Service d'hématologie et oncologie médicale, Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Lapeyronie-Université de Montpellier (UM), Dynamique des interactions membranaires normales et pathologiques (DIMNP), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), CHU Bordeaux [Bordeaux], CHU Grenoble-Hôpital Michallon, Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Hôpital de Bayonne, Centre Hospitalier de la Côte Basque (CHCB), Centre Eugène Marquis (CRLCC), Regulation of Bcl2 and p53 Networks in Multiple Myeloma and Mantle Cell Lymphoma (CRCINA-ÉQUIPE 10), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Service de médecine interne [CHU Bretagnes Atlantique], CHU Bretagnes Atlantique, Centre hospitalier La Roche-Sur-Yon, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Service d'hématologie clinique, Université de Rennes (UR)-Hôpital Pontchaillou, Role of intra-Clonal Heterogeneity and Leukemic environment in ThErapy Resistance of chronic leukemias (CHELTER), Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Réseau Sécurité Naissance - Naître Ensemble, Nantes, Département de médecine nucléaire [Rennes], CRLCC Eugène Marquis (CRLCC), Service d'hématologie [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Pathogénèse et contrôle des infections chroniques (PCCI), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre hospitalier universitaire de Nantes (CHU Nantes), Service d'Anatomie et de Cytologie Pathologiques [Poitiers], Centre hospitalier universitaire de Poitiers (CHU Poitiers), CIC - Poitiers, Université de Poitiers-Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Direction Générale de l'Organisation des Soins (DGOS)-Institut National de la Santé et de la Recherche Médicale (INSERM), This work was supported by Roche., Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Montpellier 1 (UM1), CHU Saint-Etienne, CH de la Côte Basque, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre Hospitalier Universitaire de Montpellier (CHU Montpellier ), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Hôpital Lapeyronie-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), BOUAKAZ, Amel, Centre de référence des mastocytoses, Institut Bergonié - CRLCC Bordeaux, Regulation of Bcl2 and p53 networks in Multiple Myeloma and Mantle Cell Lymphoma (CRCINA - Département NOHMAD - Equipe 10), Centre de recherche de Cancérologie et d'Immunologie / Nantes - Angers (CRCINA), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Hôpital Jean Minjoz, Role of intra-Clonal Heterogeneity and Leukemic environment in ThErapy Resistance of chronic leukemias - Clermont Auvergne (CHELTER), Université Clermont Auvergne (UCA), and Centre Hospitalier Universitaire de Montpellier (CHU Montpellier )-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)
Subjects: Male, [SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, genetic structures, Clinical Trials and Observations, [SDV]Life Sciences [q-bio], Kaplan-Meier Estimate, Biochemistry, Gastroenterology, law.invention, Antibodies, Monoclonal, Murine-Derived, 0302 clinical medicine, International Prognostic Index, Randomized controlled trial, law, immune system diseases, hemic and lymphatic diseases, Antineoplastic Combined Chemotherapy Protocols, Prospective Studies, Child, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Hazard ratio, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Hematology, Middle Aged, Chemotherapy regimen, Progression-Free Survival, 3. Good health, [SDV] Life Sciences [q-bio], Treatment Outcome, Vincristine, 030220 oncology & carcinogenesis, Female, Lymphoma, Large B-Cell, Diffuse, Rituximab, medicine.drug, Adult, medicine.medical_specialty, Randomization, Immunology, 03 medical and health sciences, Internal medicine, medicine, Humans, Progression-free survival, Cyclophosphamide, business.industry, Patient Selection, Cell Biology, medicine.disease, Surgery, Doxorubicin, Prednisone, business, Diffuse large B-cell lymphoma, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030215 immunology
Abstract: International audience; The benefit of radiotherapy (RT) after chemotherapy in limited-stage diffuse large B-cell lymphoma (DLBCL) remains controversial. We conducted a randomized trial in patients with nonbulky limited-stage DLBCL to evaluate the benefit of RT after rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Patients were stratified according to the modified International Prognostic Index, including lactate dehydrogenase, Eastern Cooperative Oncology Group performance status, age, and disease stage. The patients received 4 or 6 consecutive cycles of R-CHOP delivered once every 2 weeks, followed or not by RT at 40 Gy delivered 4 weeks after the last R-CHOP cycle. All patients were evaluated by fluorodeoxyglucose-positron emission tomography scans performed at baseline, after 4 cycles of R-CHOP, and at the end of treatment. The primary objective of the trial was event-free survival (EFS) from randomization. The trial randomly assigned 165 patients in the R-CHOP arm and 169 in the R-CHOP plus RT arm. In an intent-to-treat analysis with a median follow-up of 64 months, 5-year EFS was not statistically significantly different between the 2 arms, with 89% ± 2.9% in the R-CHOP arm vs 92% ± 2.4% in the R-CHOP plus RT arm (hazard ratio, 0.61; 95% confidence interval [CI], 0.3-1.2; = .18). Overall survival was also not different at 92% (95% CI, 89.5%-94.5%) for patients assigned to R-CHOP alone and 96% (95% CI, 94.3%-97.7%) for those assigned to R-CHOP plus RT ( = not significant). R-CHOP alone is not inferior to R-CHOP followed by RT in patients with nonbulky limited-stage DLBCL. This trial was registered at www.clinicaltrials.gov as #NCT00841945.
Published: 2018

21. Characterization of skin Th17 transcriptional profiles in psoriatic patients under adalimumab biotherapy

Author: E. Couderc, Adriana Delwail, Laure Favot, Elisabeth Solau, Jean-François Jégou, F. Morel, Gérard Guillet, Jean-Claude Lecron, Amandine Buffiere-Morgado, Laboratoire Inflammation, Tissus épithéliaux et Cytokines (LITEC), Université de Poitiers, Centre hospitalier universitaire de Poitiers (CHU Poitiers), Signalisation et Transports Ioniques Membranaires (STIM), Université de Tours-Université de Poitiers-Centre National de la Recherche Scientifique (CNRS), and Université de Poitiers-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS)
Subjects: medicine.drug_class, medicine.medical_treatment, Anti-Inflammatory Agents, Inflammation, Dermatology, Monoclonal antibody, Systemic inflammation, Severity of Illness Index, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, Statistics, Nonparametric, 030207 dermatology & venereal diseases, 03 medical and health sciences, 0302 clinical medicine, Psoriasis, Adalimumab, Humans, Medicine, RNA, Messenger, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], ComputingMilieux_MISCELLANEOUS, Skin, Membrane Glycoproteins, business.industry, Gene Expression Profiling, Antibodies, Monoclonal, medicine.disease, 3. Good health, Biological Therapy, Treatment Outcome, Cytokine, medicine.anatomical_structure, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, Immunology, Cytokines, Th17 Cells, RNA, Long Noncoding, Tumor necrosis factor alpha, medicine.symptom, business, Keratinocyte, [SDV.MHEP.DERM]Life Sciences [q-bio]/Human health and pathology/Dermatology, 030215 immunology, medicine.drug
Abstract: In psoriasis, a specific cytokine network has been described to play a central role in the pathophysiology of the disease. Anti-cytokine therapeutic approaches have been largely developed and TNFα constitutes the main target. Adalimumab is a human anti-TNFα monoclonal antibody that has been reported to demonstrate clinical efficacy and safety, resulting in reversal of epidermal hyperplasia and cutaneous inflammation. We aimed to analyse changes in the skin inflammatory transcriptomic profile in psoriatic patients during adalimumab therapy. In addition, the circulating cytokine profile was analysed to define systemic inflammation. Eighteen patients with chronic plaque psoriasis were treated with adalimumab. After four and 16 weeks, clinical efficacy was assessed using PASI and DLQI, and skin mRNA profiles were determined and circulating cytokines quantified. We identified a rapid effect of adalimumab therapy on a large array of Th17 cytokines of the skin, which may account for the modification of keratinocyte expression profile and clinical response. In contrast, analysis of serum cytokine concentrations was uninformative, confirming the need for characterization of local cytokines in skin lesions. Finally, in non-responders, local cytokine expression was shown to be unchanged. We show that TNFα inhibition in psoriasis patients treated with adalimumab has a broad effect on the expression profile of cytokines and keratinocyte markers of skin inflammation, which may account for its clinical efficacy.
Published: 2017

22. High plasma levels of the pro-inflammatory cytokine IL-22 and the anti-inflammatory cytokines IL-10 and IL-1ra in acute pancreatitis

Author: Iris Devaure, Philippe Vasseur, Christine Silvain, Jean-Pierre Tasu, Hanitriniaina Rabeony, Carine Chagneau-Derrode, David Tougeron, Florian Charier, Jean-Claude Lecron, Adriana Delwail, and Jacques Sellier
Subjects: Adult, Male, Necrosis, medicine.drug_class, Pleural effusion, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Infections, Anti-inflammatory, Interleukin 22, Young Adult, medicine, Humans, Prospective Studies, Aged, Aged, 80 and over, Hepatology, Pancreatitis, Acute Necrotizing, business.industry, Interleukins, Gastroenterology, Middle Aged, Prognosis, medicine.disease, Interleukin-10, Pleural Effusion, Malignant, Interleukin 1 Receptor Antagonist Protein, Interleukin 10, Cytokine, Acute Disease, Immunology, Acute pancreatitis, Female, Tumor necrosis factor alpha, medicine.symptom, Tomography, X-Ray Computed, business
Abstract: Pancreatic acinar cells are major targets of IL-22. Our aim is to study early plasma levels of IL-22, of pro- and anti-inflammatory cytokines in acute pancreatitis, and their association with severity or necrosis infection.Consecutive patients admitted to the Department of Hepato-Gastroenterology at Poitiers University of Medicine Hospital (France) with a diagnosis of AP were prospectively enrolled. Plasma concentrations of IL-22, IL-6, IL-8, IL-1 α, IL-1β, TNF- α, IFN-γ, IL-17A, IL-10, IL-1ra and IL-4 were assessed by multiple immunoassay at the admission time. A thoracoabdominal contrast-enhanced CT scan was performed at day 2.Sixty-two patients were included; 13 patients (21%) had a severe acute pancreatitis, 5 patients (8%) developed necrosis infection and 29 patients (47%) had pleural effusion. Plasma levels of IL-22 were high in AP (135 ± 31 vs 4.2 ± 1.8 pg/ml for controls, p0.05), but did not correlate with the severity of the disease, whereas IL-6, IL-10 and IL-1ra where enhanced in patients with severe acute pancreatitis and with pleural effusion. Patients who further developed necrosis infection had higher levels of IL-1ra at admission (p = 0.0004).In acute pancreatitis, high plasma levels of IL-22 are observed, regardless the severity of the disease. In contrast, severe forms were associated with increased levels of IL-6, IL-10 and IL-1ra. The beneficial or deleterious role of IL-22 in AP remains to be further studied.
Published: 2014

23. Combination of ofatumumab and reduced-dose CHOP for diffuse large B-cell lymphomas in patients aged 80 years or older: an open-label, multicentre, single-arm, phase 2 trial from the LYSA group

Author: Hervé Tilly, Bertrand Coiffier, Vincent Delwail, Olivier Fitoussi, Christophe Fermé, Bernadette Corront, Corinne Haioun, Jean-Marc Schiano, Hassan Farhat, Christophe Fruchart, Hervé Ghesquières, Serge Bologna, Frederic Peyrade, Richard Delarue, Jean-François Emile, Jean Gabarre, Bachra Choufi, Margaret Macro, Laurent Pascal, Fabrice Jardin, Centre Antoine Lacassagne, CRLCC Antoine Lacassagne, Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ), Service d'Anatomie et de Cytologie Pathologiques [Poitiers], Université de Poitiers-CHU de Poitiers, Service de pathologie [CHU Ambroise Paré], Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Ambroise Paré, Unité Mixte de Recherche Epidémiologique et de Surveillance Transport Travail Environnement ( UMRESTTE UMR T9405 ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut Français des Sciences et Technologies des Transports, de l'Aménagement et des Réseaux ( IFSTTAR ), Institut Gustave Roussy ( IGR ), Centre de Recherche en Cancérologie de Lyon ( CRCL ), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Service d’Hématologie [Centre Hospitalier Lyon Sud - HCL], Centre Hospitalier Lyon Sud [CHU - HCL] ( CHLS ), Hospices Civils de Lyon ( HCL ) -Hospices Civils de Lyon ( HCL ), Centre hospitalier d'Annecy, CH Annecy, Institut d'Electronique et de Télécommunications de Rennes ( IETR ), Université de Nantes ( UN ) -Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Institut National des Sciences Appliquées - Rennes ( INSA Rennes ) -CentraleSupélec-Centre National de la Recherche Scientifique ( CNRS ), Maison des Sciences de l'Homme et de l'Environnement Claude Nicolas Ledoux ( MSHE ), Centre National de la Recherche Scientifique ( CNRS ) -Université de Franche-Comté ( UFC ), Laboratoire Chrono-environnement ( LCE ), Université Bourgogne Franche-Comté ( UBFC ) -Centre National de la Recherche Scientifique ( CNRS ) -Université de Franche-Comté ( UFC ), Hôpital Universitaire de Caen, 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 ), Laboratoire d'Immunologie ( EA 2686 ), Université de Lille, Droit et Santé, Service d'hématologie biologique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Polyclinique Bordeaux Nord Aquitaine, Service d'hématologie clinique, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), Université de Poitiers-Centre hospitalier universitaire de Poitiers ( CHU Poitiers ), Laboratoire Chrono-environnement - UFC (UMR 6249) ( LCE ), Université Bourgogne Franche-Comté [COMUE] ( UBFC ) -Centre National de la Recherche Scientifique ( CNRS ) -Université de Franche-Comté ( UFC ), Service d'immuno-hématologie pédiatrique [CHU Necker], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Université de Poitiers - CHU de Poitiers, Institut de Physique de Rennes (IPR), Université de Rennes 1 (UR1) - Centre National de la Recherche Scientifique (CNRS), Hôpital Saint-Vincent de Paul, Département de médecine oncologique, Institut Gustave Roussy (IGR), Service de Radio-Oncologie [Lyon], Hospices Civils de Lyon - Centre Hospitalier Lyon Sud [Pierre Bénite], Institut d'Electronique et de Télécommunications de Rennes (IETR), Université de Rennes 1 (UR1) - Institut National des Sciences Appliquées - Rennes (INSA Rennes) - SUPELEC - Centre National de la Recherche Scientifique (CNRS), Maison des Sciences de l'Homme et de l'Environnement Claude Nicolas Ledoux (MSHE), Centre National de la Recherche Scientifique (CNRS) - Université de Franche-Comté (UFC), Centre Léon Bérard [Lyon], Laboratoire d'Immunologie (EA 2686), Service d'hématologie biologique, Assistance publique - Hôpitaux de Paris (AP-HP) - Université Paris Descartes - Paris 5 (UPD5) - AP-HP Hôpital Necker - Enfants Malades [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) - Hôpital Henri Mondor - Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Groupe d'étude des proliférations lymphoïdes, and Université de Rouen - Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Male, medicine.medical_specialty, Vincristine, Sialic Acid Binding Ig-like Lectin 2, Population, CHOP, Neutropenia, Ofatumumab, Antibodies, Monoclonal, Humanized, Gastroenterology, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, International Prognostic Index, Antineoplastic Agents, Immunological, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, Medicine, Humans, education, Cyclophosphamide, ComputingMilieux_MISCELLANEOUS, Aged, 80 and over, education.field_of_study, business.industry, Antibodies, Monoclonal, Hematology, medicine.disease, Surgery, Regimen, Treatment Outcome, chemistry, Doxorubicin, 030220 oncology & carcinogenesis, Prednisone, Female, Lymphoma, Large B-Cell, Diffuse, business, Febrile neutropenia, 030215 immunology, medicine.drug
Abstract: Summary Background In 2011 we reported a rituximab plus miniCHOP (reduced-dose cyclophosphamide, doxorubicin, vincristine, and prednisone) combination for patients older than 80 years with diffuse large B-cell lymphoma (DLBCL). The 2-year overall survival was 59% (95% CI 49–67) with an excess of early toxicity. To improve those results we tested the same chemotherapy protocol in combination with ofatumumab and a pre-phase treatment. Methods For this open-label, multicentre, single-group, phase 2 trial, we recruited patients older than 80 years with untreated histologically-proven CD20-positive DLBCL, Ann Arbor stage I to IV, from 41 academic and hospital centres in France and Belgium. Patients received a pre-phase with oral vincristine (1 mg total dose 1 week before cycle 1 [day −7]) and oral prednisone (60 mg total dose starting 1 week before cycle 1, for 4 days [day −7 to day −4]) before the first cycle of the ofatumumab plus miniCHOP regimen. The regimen consisted of 1000 mg total dose of intravenous ofatumumab, 25 mg/m 2 of intravenous doxorubicin, 400 mg/m 2 of intravenous cyclophosphamide, and 1 mg of intravenous vincristine, on day 1 of each cycle; and 40 mg/m 2 of oral prednisone on days 1–5. Ofatumumab was administered with 1000 mg of paracetamol and 50 mg of diphenhydramine. The primary endpoint was overall survival in the intention-to-treat population. The statistical analysis has been done on an intention-to-treat principle. This study was registered with ClinicalTrials.gov, number NCT01195714. Findings Between June 2, 2010, and Nov 4, 2011, we enrolled 120 patients. Age-adjusted International Prognostic Index was 2–3 in 68 (57%) of them. The median follow-up time was 26·8 months (IQR 24·5–30·1). The 2-year overall survival was 64·7% (95% CI 55·3–72·7) and median overall survival was not reached (95% CI 30·2–not reached). 45 patients died during the treatment, of whom 28 (62%) died due to lymphoma. The most common side-effect was haematological toxicity. Among the 120 patients, grade 3–4 neutropenia was reported in 24 (21%) patients and thrombocytopenia in two (2%), during the treatment period. Grade 3–4 anaemia was reported in six (5%) patients; seven (6%) patients had one episode of febrile neutropenia. 17 (15%) of 115 patients in the modified intention-to-treat population had red blood cell transfusions and three (3%) had platelet transfusions. Interpretation Our result suggest that, in patients older than 80 years with DLBCL, ofatumumab and pre-phase treatment seem to improve overall survival compared with the previously reported data. The combination of pre-phase treatment, a monoclonal antibody against CD20, and miniCHOP can be considered a new treatment platform for use in randomised clinical trial design for DLBCL treatment in patients older than 80 years. Funding The Lymphoma Study Association, GlaxoSmithKline.
Published: 2017

24. Ibrutinib monotherapy in relapsed/refractory CNS lymphoma: A retrospective case series

Author: Khê Hoang-Xuan, Caroline Houillier, Ahmad Al Jijakli, Vincent Delwail, Delphine Larrieu-Ciron, Vanessa Delrieu, Franck Morschhauser, Carole Soussain, Sylvain Choquet, Eileen M Boyle, Kamal Chamoun, Hôpital René HUGUENIN (Saint-Cloud), CIC CHU ( Lille)/inserm, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre hospitalier universitaire de Poitiers (CHU Poitiers), Groupe de Recherche sur les formes Injectables et les Technologies Associées - ULR 7365 (GRITA), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: Male, Lymphoma, [SDV]Life Sciences [q-bio], International Cooperation, Antineoplastic Agents, Central Nervous System Neoplasms, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Refractory, Piperidines, immune system diseases, hemic and lymphatic diseases, medicine, Humans, Objective response, ComputingMilieux_MISCELLANEOUS, Aged, Retrospective Studies, business.industry, Adenine, breakpoint cluster region, Retrospective cohort study, CD79B, Middle Aged, medicine.disease, Magnetic Resonance Imaging, Pyrimidines, chemistry, 030220 oncology & carcinogenesis, Ibrutinib, Relapsed refractory, Cancer research, Pyrazoles, Female, Neurology (clinical), Neoplasm Recurrence, Local, business, 030217 neurology & neurosurgery, Follow-Up Studies
Abstract: Therapeutic improvements are required for primary CNS lymphoma (PCNSL) and secondary CNS lymphoma. PCNSLs are predominantly diffuse large B-cell lymphoma (DLBCL) classified in the non-germinal center (non-GC) subgroup.1 The role of B-cell receptor (BCR) signaling to continuously activate the NF-κB pathway is well-established in non-GC DLBCL.2 Mutations of MYD88 , CD79B , and TBL1XR1 , genes involved in the NF-κB pathway, are frequently encountered in PCNSL.3 Ibrutinib, an inhibitor of BCR signaling, led to an objective response rate of 50% in patients with relapsed or refractory systemic non-GC DLBCL.4 As a small molecule (MW = 440), with promising CNS distribution,5 ibrutinib represents a potential treatment for PCNSL. We report a retrospective case series of patients with relapsed and refractory CNS lymphoma treated with ibrutinib.
Published: 2016

25. Obinutuzumab plus bendamustine versus bendamustine monotherapy in patients with rituximab-refractory indolent non-Hodgkin lymphoma (GADOLIN): a randomised, controlled, open-label, multicentre, phase 3 trial

Author: Marek Trněný, Gregg Dueck, Pieternella J. Lugtenburg, Gilles Salles, John G. Gribben, Anne Lennard, Vincent Delwail, Bruce D. Cheson, Natalie Dimier, Elisabeth Wassner-Fritsch, Laurie H. Sehn, Jiri Mayer, Nathan Fowler, Oliver W. Press, Neil Chua, Günter Fingerle-Rowson, Kamal Bouabdallah, Hematology, BC Cancer Agency, Vancouver, Department of Internal Medicine, Hemato-Oncology, Medical Faculty of Masaryk University Brno, Charles University and General University Hospital, Université Mohamed Boudiaf de M'sila, Service d'Anatomie et de Cytologie Pathologiques [Poitiers], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Service d’Hématologie [Centre Hospitalier Lyon Sud - HCL], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Centre de Recherche en Cancérologie de Lyon (CRCL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Barts and the London Medical School, F. Hoffmann-La Roche [Basel], Faculty of Medicine [Brno] (MED / MUNI), Masaryk University [Brno] (MUNI)-Masaryk University [Brno] (MUNI), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Male, Survival, Lymphoma, analysis, Follicular lymphoma, Phases of clinical research, chemistry.chemical_compound, 0302 clinical medicine, Obinutuzumab, London, Antineoplastic Combined Chemotherapy Protocols, Indolent Non-Hodgkin Lymphoma, Bendamustine Hydrochloride, Lymphoma, Non-Hodgkin, Middle Aged, Prognosis, 3. Good health, Europe, Survival Rate, Oncology, 030220 oncology & carcinogenesis, Rituximab, Female, France, Switzerland, medicine.drug, Bendamustine, medicine.medical_specialty, Canada, Asia, Neutropenia, Patients, Population, [SDV.CAN]Life Sciences [q-bio]/Cancer, Antibodies, Monoclonal, Humanized, Antibodies, methods, Time, 03 medical and health sciences, Internal medicine, medicine, Humans, Survival rate, Aged, Neoplasm Staging, therapy, business.industry, toxicity, Interim analysis, medicine.disease, Thrombocytopenia, Surgery, chemistry, Drug Resistance, Neoplasm, Neoplasm Recurrence, Local, business, 030215 immunology, Follow-Up Studies
Abstract: International audience; BACKGROUND: Patients with indolent non-Hodgkin lymphoma who fail to achieve adequate disease control with rituximab-based treatment have few treatment options and a poor prognosis. We aimed to assess a combination of obinutuzumab (GA101), a novel glyco-engineered type II anti-CD20 monoclonal antibody, and bendamustine in this patient population. METHODS: In this open-label, randomised, phase 3 study (GADOLIN), patients aged 18 years or older with histologically documented, CD20-positive indolent non-Hodgkin lymphoma refractory to rituximab were enrolled at 83 hospital and community sites in 14 countries in Europe, Asia, and North and Central America. Patients were randomly assigned (1:1) using a hierarchical dynamic randomisation scheme stratified by indolent non-Hodgkin lymphoma subtype, rituximab-refractory type, number of previous therapies, and geographical region, to receive induction treatment (six 28-day cycles) with obinutuzumab plus bendamustine or bendamustine monotherapy, both given intravenously. Obinutuzumab plus bendamustine dosing was obinutuzumab 1000 mg (days 1, 8, and 15, cycle 1; day 1, cycles 2-6) plus bendamustine 90 mg/m(2) per day (days 1 and 2, cycles 1-6), and bendamustine monotherapy dosing was 120 mg/m(2) per day (days 1 and 2, all cycles). Non-progressing patients in the obinutuzumab plus bendamustine group received obinutuzumab maintenance (1000 mg every 2 months) for up to 2 years. The primary endpoint was progression-free survival in all randomised patients, as assessed by an independent review committee. Safety was assessed in all patients who received any amount of obinutuzumab or bendamustine. This study is registered with ClinicalTrials.gov, number NCT01059630, and has stopped recruiting patients. FINDINGS: Between April 15, 2010, and Sept 1, 2014, when the study was stopped after a pre-planned interim analysis, 396 patients were randomly assigned (194 to obinutuzumab plus bendamustine and 202 to bendamustine monotherapy). After a median follow-up time of 21.9 months (IQR 12.1-31.0) in the obinutuzumab plus bendamustine group and 20.3 months (9.5-29.7) in the bendamustine monotherapy group, progression-free survival was significantly longer with obinutuzumab plus bendamustine (median not reached [95% CI 22.5 months-not estimable]) than with bendamustine monotherapy (14.9 months [12.8-16.6]; hazard ratio 0.55 [95% CI 0.40-0.74]; p=0.0001). Grade 3-5 adverse events occurred in 132 (68%) of 194 patients in the obinutuzumab plus bendamustine group and in 123 (62%) of 198 patients in the bendamustine monotherapy group. The most frequent grade 3 or worse adverse events were neutropenia (64 [33%] in the obinutuzumab plus bendamustine group vs 52 [26%] in the bendamustine monotherapy group), thrombocytopenia (21 [11%] vs 32 [16%]), anaemia (15 [8%] vs 20 [10%]) and infusion-related reactions (21 [11%] vs 11 [6%]). Serious adverse events occurred in 74 patients (38%) in the obinutuzumab plus bendamustine group and in 65 patients (33%) in the bendamustine monotherapy group, and deaths due to adverse events occurred in 12 patients (6%) and 12 patients (6%), respectively. Three (25%) of 12 adverse event-related deaths in the obinutuzumab plus bendamustine group and five (42%) of 12 in the bendamustine monotherapy group were treatment related. INTERPRETATION: Obinutuzumab plus bendamustine followed by obinutuzumab maintenance has improved efficacy over bendamustine monotherapy in rituximab-refractory patients with indolent non-Hodgkin lymphoma, with manageable toxicity, and is a new treatment option for patients who have relapsed after or are no longer responding to rituximab-based therapy. FUNDING: F Hoffmann-La Roche Ltd
Published: 2016

26. Recurrent Mutations of MYD88 and TBL1XR1 in Primary Central Nervous System Lymphomas

Author: Catherine Miquel, Khê Hoang-Xuan, Emmanuel Gyan, Marta Rossetto, Carole Soussain, Dominique Figarella-Branger, Karima Mokhtari, Pierre Soubeyran, Olivier Chinot, Marc Polivka, Vincent Delwail, Anne Vital, Remy Gressin, Luc Taillandier, Alice Laurenge, Blandine Boisselier, Clovis Adam, Anne Jouvet, Marie Laure Tanguy, Naima Habbita, Ahmed Idbaih, Hervé Ghesquières, Aurelie Bruno, Caroline Houillier, Alberto González-Aguilar, Yannick Marie, and Sylvain Choquet
Subjects: Adult, Male, Cancer Research, Candidate gene, Pathology, medicine.medical_specialty, Receptors, Cytoplasmic and Nuclear, Single-nucleotide polymorphism, Biology, Gene mutation, medicine.disease_cause, Polymorphism, Single Nucleotide, Disease-Free Survival, Central Nervous System Neoplasms, symbols.namesake, CDKN2A, Chromosomal Instability, medicine, Humans, Aged, Aged, 80 and over, Sanger sequencing, Primary central nervous system lymphoma, Nuclear Proteins, Middle Aged, medicine.disease, Repressor Proteins, Cell Transformation, Neoplastic, Treatment Outcome, Oncology, Mutation, Myeloid Differentiation Factor 88, symbols, Cancer research, Female, Lymphoma, Large B-Cell, Diffuse, Carcinogenesis, Diffuse large B-cell lymphoma
Abstract: Purpose: Our objective was to identify the genetic changes involved in primary central nervous system lymphoma (PCNSL) oncogenesis and evaluate their clinical relevance. Experimental Design: We investigated a series of 29 newly diagnosed, HIV-negative, PCNSL patients using high-resolution single-nucleotide polymorphism (SNP) arrays (n = 29) and whole-exome sequencing (n = 4) approaches. Recurrent homozygous deletions and somatic gene mutations found were validated by quantitative real-time PCR and Sanger sequencing, respectively. Molecular results were correlated with prognosis. Results: All PCNSLs were diffuse large B-cell lymphomas, and the patients received chemotherapy without radiotherapy as initial treatment. The SNP analysis revealed recurrent large and focal chromosome imbalances that target candidate genes in PCNSL oncogenesis. The most frequent genomic abnormalities were (i) 6p21.32 loss (HLA locus), (ii) 6q loss, (iii) CDKN2A homozygous deletions, (iv) 12q12-q22, and (v) chromosome 7q21 and 7q31 gains. Homozygous deletions of PRMD1, TOX, and DOCK5 and the amplification of HDAC9 were also detected. Sequencing of matched tumor and blood DNA samples identified novel somatic mutations in MYD88 and TBL1XR1 in 38% and 14% of the cases, respectively. The correlation of genetic abnormalities with clinical outcomes using multivariate analysis showed that 6q22 loss (P = 0.006 and P = 0.01) and CDKN2A homozygous deletion (P = 0.02 and P = 0.01) were significantly associated with shorter progression-free survival and overall survival. Conclusions: Our study provides new insights into the molecular tumorigenesis of PCNSL and identifies novel genetic alterations in this disease, especially MYD88 and TBL1XR1 mutations activating the NF-κB signaling pathway, which may be promising targets for future therapeutic strategies. Clin Cancer Res; 18(19); 5203–11. ©2012 AACR.
Published: 2012

27. Ofatumumab monotherapy in rituximab-refractory follicular lymphoma: results from a multicenter study

Author: Charlotte A. Russell, Andrzej Hellmann, Steen Lisby, John Radford, Martin Schultz, Luis Fayad, Myron S. Czuczman, Eric D. Jacobsen, Ira Gupta, Kazimierz Kuliczkowski, Christine G. DiRienzo, Eve Gallop-Evans, Vincent Delwail, Lauren Pinter-Brown, Thomas S. Lin, Anton Hagenbeek, Nancy Goldstein, Guillaume Cartron, Roxanne C. Jewell, Brian K. Link, CCA -Cancer Center Amsterdam, and Clinical Haematology
Subjects: Adult, medicine.medical_specialty, Immunology, Population, Follicular lymphoma, Antineoplastic Agents, Neutropenia, Ofatumumab, Antibodies, Monoclonal, Humanized, Biochemistry, Gastroenterology, Disease-Free Survival, chemistry.chemical_compound, Antibodies, Monoclonal, Murine-Derived, International Prognostic Index, Internal medicine, hemic and lymphatic diseases, medicine, Humans, Prospective Studies, education, Lymphoma, Follicular, Aged, Aged, 80 and over, education.field_of_study, B-Lymphocytes, Leukopenia, business.industry, Antibodies, Monoclonal, Cell Biology, Hematology, Middle Aged, medicine.disease, Prognosis, Surgery, chemistry, Drug Resistance, Neoplasm, Rituximab, medicine.symptom, Refractory Follicular Lymphoma, business, medicine.drug
Abstract: New treatments are required for rituximab-refractory follicular lymphoma (FL). In the present study, patients with rituximab-refractory FL received 8 weekly infusions of ofatumumab (CD20 mAb; dose 1, 300 mg and doses 2-8, 500 or 1000 mg; N = 116). The median age of these patients was 61 years, 47% had high-risk Follicular Lymphoma International Prognostic Index scores, 65% were chemotherapy-refractory, and the median number of prior therapies was 4. The overall response rate was 13% and 10% for the 500-mg and 1000-mg arms, respectively. Among 27 patients refractory to rituximab monotherapy, the overall response rate was 22%. The median progression-free survival was 5.8 months. Forty-six percent of patients demonstrated tumor reduction 3 months after therapy initiation, and the median progression-free survival for these patients was 9.1 months. The most common adverse events included infections, rash, urticaria, fatigue, and pruritus. Three patients experienced grade 3 infusion-related reactions, none of which were considered serious events. Grade 3-4 neutropenia, leukopenia, anemia, and thrombocytopenia occurred in a subset of patients. Ofatumumab was well tolerated and modestly active in this heavily pretreated, rituximab-refractory population and is therefore now being studied in less refractory FL and in combination with other agents in various B-cell neoplasms. The present study was registered at www.clinicaltrials.gov as NCT00394836.
Published: 2012

28. Reduced versus full doses of irradiation after 3 cycles of combined doxorubicin, bleomycin, vinblastine, and dacarbazine in early stage Hodgkin lymphomas

Author: Nina, Arakelyan, Jean-Philippe, Jais, Vincent, Delwail, Josette, Brière, Marie-Pierre, Moles-Moreau, Delphine, Sénécal, Christian, Berthou, Bernard, Desablens, Pierre, Colonna, Jean-Marie, Andrieu, and Christiane, Ghando
Subjects: Adult, Male, Cancer Research, medicine.medical_specialty, Adolescent, Dacarbazine, Urology, Vinblastine, Bleomycin, chemistry.chemical_compound, Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, Doxorubicin, Aged, business.industry, Cancer, Radiotherapy Dosage, Middle Aged, medicine.disease, Combined Modality Therapy, Hodgkin Disease, Chemotherapy regimen, Lymphoma, Surgery, Oncology, ABVD, chemistry, Female, business, Follow-Up Studies, medicine.drug
Abstract: BACKGROUND: The combination of 3 cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) and a tailored, extended irradiation schedule has been used to treat patients with early Hodgkin lymphoma (HL) in the authors’ group since 1981. The randomized H97-E trial (1997-2004) was designed to assess the impact of a slightly reduced irradiation dose on the freedom from treatment failure (FFTF) rate. METHODS: Patients with supradiaphragmatic HL at clinical stages I and II who had � 2 affected lymph node areas and a mediastinal mass ratio
Published: 2010

29. Overall Survival Benefit in Patients With Rituximab-Refractory Indolent Non-Hodgkin Lymphoma Who Received Obinutuzumab Plus Bendamustine Induction and Obinutuzumab Maintenance in the GADOLIN Study

Author: Oliver W. Press, Nathan Fowler, Neil Chua, Vincent Delwail, Jiri Mayer, Anne Lennard, John G. Gribben, Andrea Knapp, Pieternella J. Lugtenburg, Federico Mattiello, Greg Dueck, Kamal Bouabdallah, Günter Fingerle-Rowson, Bruce D. Cheson, Marek Trněný, Gilles Salles, Laurie H. Sehn, and Hematology
Subjects: Adult, Male, Bendamustine, Cancer Research, medicine.medical_specialty, Follicular lymphoma, Kaplan-Meier Estimate, Antibodies, Monoclonal, Humanized, Gastroenterology, Maintenance Chemotherapy, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Obinutuzumab, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, medicine, Indolent Non-Hodgkin Lymphoma, Bendamustine Hydrochloride, Humans, Progression-free survival, Lymphoma, Follicular, Survival rate, Aged, Aged, 80 and over, CD20, biology, business.industry, Lymphoma, Non-Hodgkin, Induction Chemotherapy, Middle Aged, medicine.disease, Progression-Free Survival, 3. Good health, Survival Rate, Oncology, chemistry, Drug Resistance, Neoplasm, 030220 oncology & carcinogenesis, biology.protein, Female, Rituximab, business, 030215 immunology, medicine.drug
Abstract: Purpose To perform an updated analysis of the randomized phase III GADOLIN trial in patients with rituximab-refractory indolent non-Hodgkin lymphoma treated with obinutuzumab (GA101; G) and bendamustine (B). Patients and Methods Patients with histologically documented, rituximab-refractory CD20+ indolent non-Hodgkin lymphoma received G 1,000 mg (days 1, 8, and 15, cycle 1; day 1, cycles 2 to 6) plus B 90 mg/m2/d (days 1 and 2, all cycles) or B 120 mg/m2/d monotherapy. Patients who did not experience disease progression with G-B received G maintenance (1,000 mg every 2 months) for up to 2 years. The primary end point was progression-free survival (PFS). Results Of 413 randomly assigned patients (intention-to-treat [ITT]: G-B, n = 204; B monotherapy, n = 209), 335 had follicular lymphoma (FL; G-B, n = 164; B monotherapy, n = 171). After a median follow-up of 31.8 months, median PFS in ITT patients was 25.8 months (G-B) and 14.1 months (B monotherapy; hazard ratio [HR], 0.57; 95% CI, 0.44 to 0.73; P < .001). Overall survival (OS) also was prolonged (HR, 0.67; 95% CI, 0.47 to 0.96; P = .027). PFS and OS benefits were similar in patients with FL. Grade 3 to 5 adverse events (AEs) were reported by 148 (72.5%) and 133 (65.5%) patients in the G-B and B monotherapy arms, respectively, most commonly neutropenia (G-B, 34.8%; B monotherapy, 27.1%), thrombocytopenia (10.8% and 15.8%), anemia (7.4% and 10.8%), and infusion-related reactions (9.3% and 3.4%). Serious AEs occurred in 89 G-B patients (43.6%) and 75 B monotherapy patients (36.9%); fatal AEs occurred in 16 (7.8%) and 13 (6.4%), respectively. Conclusion This updated analysis confirms the PFS benefit for G-B shown in the primary analysis. A substantial OS benefit also was demonstrated in the ITT population and in patients with FL. Toxicity was similar for both treatments.
Published: 2018

30. Specific increase in caspase-1 activity and secretion of IL-1 family cytokines: a putative link between mevalonate kinase deficiency and inflammation

Author: Christine Silvain, Adriana Delwail, Gilles Grateau, Jean-Claude Lecron, Sylvain Normand, B. Massonnet, Laure Favot, Franck Morel, and Laurence Cuisset
Subjects: Inflammation, Mevalonate kinase deficiency, biology, medicine.medical_treatment, Caspase 1, Clinical Biochemistry, Immunology, Mevalonate kinase, Familial Mediterranean fever, medicine.disease, Disease Models, Animal, Cytokine, Mevalonic aciduria, medicine, biology.protein, Animals, Humans, Immunology and Allergy, Mevalonate pathway, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Mevalonate Kinase Deficiency, Periodic fever syndrome, Interleukin-1
Abstract: The mevalonate kinase deficiency (MKD), including hyperimmunoglobulinemia D periodic fever syndrome (HIDS) and the more severe mevalonic aciduria are rare, autosomal recessive, autoinflammatory diseases belonging to the hereditary periodic fever (HPF) family. Other members include: familial mediterranean fever (FMF), the cryopyrin-associated periodic syndromes (CAPS) and TNFR-associated periodic syndromes (TRAPS). MKD is caused by mutations in the gene encoding mevalonate kinase (MK), an enzyme of the cholesterol pathway, leading to its inactivation. The molecular mechanisms linking MKD and abnormalities of isoprenoid biosynthesis to cytokine production and inflammation have yet to be fully elucidated. Statins, which are extensively prescribed for lowering cholesterol, are potent inhibitors of 3-hydroxy-3-methylglutaryl-CoA reductase, the enzyme directly upstream of MK. In this review, we discuss recent reports demonstrating that in vitro inhibition of the mevalonate pathway by statins specifically increases the production, by activated monocytes, of cytokines of the IL-1 family, by enhancing caspase-1 activity, the enzyme responsible for IL-1beta and IL-18 maturation. The molecular mechanisms involve geranylgeranylation and the enhancement of the activity of G proteins such as Rac-1. Interestingly, activated fibroblasts from MKD patients secrete more IL-1beta than fibroblasts from healthy donors. Taken together, these data highlight the specific enhancement of the IL-1 family of cytokines, the maturation of which is caspase-1-dependent in MKD. Finally, the spectacular decrease in febrile attacks in patients with severe HIDS under IL-1 receptor antagonist (anakinra) treatment, reinforces this hypothesis. Deregulated caspase-1 activation could be responsible for the inflammatory component of MKD, thereby mechanistically linking MKD to FMF and CAPS through cytokines of the IL-1 family.
Published: 2009

31. High-dose therapy followed by autologous purged stem cell transplantation and doxorubicin-based chemotherapy in patients with advanced follicular lymphoma: a randomized multicenter study by the GOELAMS with final results after a median follow-up of 9 years

Author: Emmanuel Gyan, Christian Berthou, Steven Le Gouill, Philippe Colombat, Roselyne Delepine, Jean-Pierre Vilque, Philippe Quittet, Bernard Desablens, Antoine Thyss, Philippe Bertrand, Eric Deconinck, Jean-François Ramée, Vincent Delwail, Patrick Michenet, Nina Arakelyan, Remi Gressin, Noel Milpied, Jérôme Jaubert, Hervé Maisonneuve, Cécile Moluçon-Chabrot, Charles Foussard, Service d'hématologie [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Service d'hématologie, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel Dieu, Département de biostatistiques, Faculté de Médecine de Tours, Service de pathologie, CHU Orléans, Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Centre hospitalier La Roche-Sur-Yon, Service Hématologie, Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Hôpital Jean Bernard, CHU Grenoble, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), Laboratoire d'Hématologie [CHU Amiens], CHU Amiens-Picardie, CHU Saint-Etienne, Clinique Catherine de Sienne, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), CHU Clermont-Ferrand, CHU Bordeaux [Bordeaux], Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (RIGHT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté]), Groupe Ouest-Est des Leucémies et des Autres Maladies du Sang (GOELAMS), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), and Saas, Philippe
Subjects: Male, Oncology, Transplantation Conditioning, MESH: Immunotherapy, medicine.medical_treatment, Follicular lymphoma, Hematopoietic stem cell transplantation, Biochemistry, MESH: Lymphoma, Follicular, 0302 clinical medicine, Autologous stem-cell transplantation, Lymphoma, Follicular, MESH: Transplantation Conditioning, MESH: Middle Aged, Bone Marrow Purging, Neoplasms, Second Primary, MESH: Follow-Up Studies, Hematology, Middle Aged, Total body irradiation, MESH: Transplantation, Autologous, 3. Good health, Survival Rate, 030220 oncology & carcinogenesis, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Immunotherapy, MESH: Stem Cell Transplantation, MESH: Whole-Body Irradiation, MESH: Bone Marrow Purging, Whole-Body Irradiation, medicine.drug, Adult, MESH: Myeloablative Agonists, MESH: Neoplasms, Second Primary, medicine.medical_specialty, [SDV.IMM] Life Sciences [q-bio]/Immunology, Adolescent, MESH: Survival Rate, Cyclophosphamide, Immunology, Transplantation, Autologous, Disease-Free Survival, 03 medical and health sciences, Internal medicine, medicine, Humans, Survival rate, MESH: Adolescent, Chemotherapy, MESH: Humans, business.industry, MESH: Cyclophosphamide, MESH: Adult, Cell Biology, Myeloablative Agonists, medicine.disease, MESH: Male, Surgery, Transplantation, MESH: Disease-Free Survival, business, MESH: Female, Follow-Up Studies, Stem Cell Transplantation, 030215 immunology
Abstract: Autologous stem cell transplantation (ASCT) as first-line therapy for follicular lymphoma (FL) remains controversial. The multicenter study randomized 172 patients with untreated FL for either immunochemotherapy or high-dose therapy (HDT) followed by purged ASCT. Conditioning was performed with total body irradiation (TBI) and cyclophosphamide. The 9-year overall survival (OS) was similar in the HDT and conventional chemotherapy groups (76% and 80%, respectively). The 9-year progression-free survival (PFS) was higher in the ASCT than the chemotherapy group (64% vs 39%; P = .004). A PFS plateau was observed in the HDT group after 7 years. On multivariate analysis, OS and PFS were independently affected by the per-formance status score, the number of nodal areas involved, and the treatment group. Secondary malignancies were more frequent in the HDT than in the chemotherapy group (6 secondary myelodysplastic syndrome/acute myeloid leukemia and 6 second solid tumor cancers vs 1 acute myeloid leukemia, P = .01). The occurrence of a PFS plateau suggests that a subgroup of patients might have their FL cured by ASCT. However, the increased rate of secondary malignancies may discourage the use of purged ASCT in combination with TBI as first-line treatment for FL. This trial has been registered with ClinicalTrials.gov under identifier NCT00696735.
Published: 2009

32. Methotrexate and temozolomide versus methotrexate, procarbazine, vincristine, and cytarabine for primary CNS lymphoma in an elderly population: an intergroup ANOCEF-GOELAMS randomised phase 2 trial

Author: Daniel Delgadillo, Caroline Houillier, Pierre Soubeyran, Vincent Delwail, Antonio Omuro, Lucette Lacomblez, Khê Hoang-Xuan, Emmanuel Gyan, Marie Laure Tanguy, Thierry Lamy, Olivier Chinot, Monica Sierra del Rio, Valérie Touitou, Carole Soussain, Hervé Ghesquières, Aymeri Huchet, Sophie Lebouvier-Sadot, Alberto González-Aguilar, Alexandra Benouaich-Amiel, Maryline Barrie, Sylvain Choquet, Luc Taillandier, and Remy Gressin
Subjects: Male, medicine.medical_specialty, Vincristine, Antimetabolites, Antineoplastic, Lymphoma, Population, Antineoplastic Agents, Procarbazine, Gastroenterology, Disease-Free Survival, Central Nervous System Neoplasms, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, medicine, Temozolomide, Humans, Prospective Studies, education, Aged, Aged, 80 and over, education.field_of_study, business.industry, Cytarabine, Hematology, Middle Aged, Chemotherapy regimen, Surgery, Dacarbazine, Regimen, Methotrexate, Treatment Outcome, Quality of Life, Female, business, medicine.drug
Abstract: Summary Background No standard chemotherapy regimen exists for primary CNS lymphoma, reflecting an absence of randomised studies. We prospectively tested two promising methotrexate-based regimens, one more intensive and a milder regimen, for primary CNS lymphoma in the elderly population, who account for most patients. Methods In this open-label, randomised phase 2 trial, done in 13 French institutions, we enrolled immunocompetent patients who had neuroimaging and histologically confirmed newly diagnosed primary CNS lymphoma, were aged 60 years and older, and had a Karnofsky performance scale score of 40 or more. Participants were stratified by Karnofsky performance scale score ( vs ≥60) and treating institution and randomly assigned (1:1) to receive methotrexate (3·5 g/m 2 ) with temozolomide (150 mg/m 2 ) or methotrexate (3·5 g/m 2 ), procarbazine (100 mg/m 2 ), vincristine (1·4 mg/m 2 ), and cytarabine (3 mg/m 2 ). Neither regimen included radiotherapy; both included prophylactic G-CSF and corticosteroids. The primary endpoint was 1-year progression-free survival. Analysis was intent to treat, in a non-comparative phase 2 trial design. This study is registered with ClinicalTrials.gov, number NCT00503594. Findings Between July 16, 2007, and March 25, 2010, 98 patients were enrolled, of whom 95 were randomly assigned and analysed; 48 to methotrexate with temozolomide and 47 to methotrexate, procarbazine, vincristine, and cytarabine. 1-year progression-free survival was 36% (95% CI 22–50) in the methotrexate, procarbazine, vincristine, and cytarabine group and 36% (22–50) in the methotrexate with temozolomide group; median progression-free survival was 9·5 months (95% CI 5·3–13·8) versus 6·1 months (3·8–11·9), respectively. Objective responses were noted in 82% (95% CI 68–92) of patients in the methotrexate, procarbazine, vincristine, and cytarabine group versus 71% (55–84) of patients in the methotrexate with temozolomide group. Median overall survival was 31 months (95% CI 12·2–35·8) in the methotrexate, procarbazine, vincristine, and cytarabine group and 14 months (8·1–28·4) in the methotrexate with temozolomide group. No differences were noted in toxic effects between the two groups. The most common grades 3 and 4 toxicities in both groups were liver dysfunction (21 [4%] in the the methotrexate and temozolomide group and 18 [38%] in the methotrexate, procarbazine, vincristine, and cytarabine group), lymphopenia (14 [29%] and 14 [30%]), and infection (six [13%] and seven [15%]). To date, 33 (69%) patients in the methotrexate and temozolomide group have died, versus 31 (55%) in the methotrexate, procarbazine, vincristine and cytarabine group. Quality-of-life evaluation (QLQ-C30 and BN20) showed improvements in most domains (p=0·01–0·0001) compared with baseline in both groups. Prospective neuropsychological testing showed no evidence of late neurotoxicity. Interpretation In this study of two different methotrexate-based combination regimens in elderly patients, the efficacy endpoints tended to favour the methotrexate, procarbazine, vincristine, and cytarabine group. Both regimens were associated with similar, moderate toxicity, but quality of life improved with time, suggesting pursuing treatment in these poor prognosis patients is worthwhile. New alternatives are needed to improve response duration in this population. Funding Schering-Plough/Merck and French Government.
Published: 2015

33. A uniform activated B-cell–like immunophenotype might explain the poor prognosis of primary central nervous system lymphomas: analysis of 83 cases

Author: Philippe Broët, Martine Raphael, Vincent Delwail, Michèle Kujas, Philippe Colombat, Khê Hoang-Xuan, Catherine Sautès-Fridman, Karima Mokhtari, Antoine Martin, Emmanuelle Crinière, Anne Moreau, Wafae Iraqi, and Sophie Camilleri-Broët
Subjects: Adult, Male, Pathology, medicine.medical_specialty, Lymphoma, B-Cell, Immunology, Lymphocyte Activation, Biochemistry, Central Nervous System Neoplasms, Central nervous system disease, Immunophenotyping, Antigen, Antigens, Neoplasm, hemic and lymphatic diseases, medicine, Humans, B cell, Aged, Aged, 80 and over, B-Lymphocytes, business.industry, Primary central nervous system lymphoma, Germinal center, Cell Biology, Hematology, Middle Aged, Germinal Center, Prognosis, medicine.disease, Immunohistochemistry, Survival Analysis, Phenotype, medicine.anatomical_structure, Female, business, Diffuse large B-cell lymphoma
Abstract: Most primary central nervous system lymphomas (PCNSLs) in immunocompetent patients are diffuse large B-cell lymphomas (DLBCLs), characterized by poor prognosis, compared with systemic forms. A germinal center B-cell-like (GCB) origin of PCNSL was hypothesized on the basis of BCL-6 expression and ongoing mutational activity. Our goal herein was to determine, for 83 PCNSLs, the percentages of GCB and activated B-cell-like (ABC) phenotypes and their prognostic significance. CD10, BCL-6, MUM1, BCL-2, and CD138 antigens were immunohistochemically labeled on paraffin-embedded sections; the first 4 were positive in 2.4%, 55.5%, 92.6%, and 55.5% of the tumors, respectively. None of the 56 tested samples expressed CD138. Among the 82 patients with complete information, 79 (96.3%) were classified as ABC; 42 (51.2%) expressed BCL-6+ MUM1+, suggesting an "activated GCB" origin; 33 (40.2%) were exclusively MUM1+, and the remaining 4 (4.9%) were negative for all markers tested. These findings provide new insights into interpreting the poor PCNSL prognostic, which may, in part, be due to biologic aggressiveness associated with its activated B-cell-like pattern. We postulate assigning PCNSL a histogenetic "time-slot," overlapping late GC and early post-GC, that could explain the predominant ABC phenotype observed.
Published: 2005

34. High-dose therapy followed by autologous purged stem-cell transplantation and doxorubicin-based chemotherapy in patients with advanced follicular lymphoma: a randomized multicenter study by GOELAMS

Author: Philippe Bertrand, Vincent Delwail, Patrick Michenet, Annick Le Pourhiet-Le Mevel, Martine Escoffre-Barbe, Noel Milpied, Antoine Thyss, Remy Gressin, Jean-Pierre Vilque, Eric Legouffe, Bernard Desablens, Roselyne Delepine, Eric Deconinck, Philippe Colombat, Pascale Cornillet-Lefebvre, Jean-François Ramée, Arash Jenabian, Philippe Travade, Charles Foussard, Jérôme Jaubert, and Hervé Maisonneuve
Subjects: Adult, Male, Oncology, medicine.medical_specialty, Cyclophosphamide, medicine.medical_treatment, Immunology, Follicular lymphoma, Transplantation, Autologous, Biochemistry, Recurrence, Internal medicine, Humans, Medicine, Lymphoma, Follicular, Survival rate, Neoplasm Staging, Chemotherapy, business.industry, Cell Biology, Hematology, Middle Aged, medicine.disease, Chemotherapy regimen, Surgery, Survival Rate, Transplantation, Regimen, Doxorubicin, Disease Progression, Feasibility Studies, Female, France, business, Follow-Up Studies, Stem Cell Transplantation, Teniposide, medicine.drug
Abstract: Doxorubicin-based immunochemotherapy, with interferon, has been shown to improve survival in patients with advanced follicular lymphoma. High-dose chemotherapy with stem-cell support is effective in follicular lymphoma in relapse but remains controversial as a first-line therapy. In a randomized study using a purged autologous stem-cell support, we compared these 2 approaches in patients with advanced follicular lymphoma. Newly diagnosed advanced follicular lymphoma patients (172 patients) were randomly assigned either to an immunochemotherapy regimen (cyclophosphamide, doxorubicin, teniposide, prednisone, and interferon) or to a high-dose therapy followed by purged autologous stem-cell transplantation. Compared with the patients who received chemotherapy and interferon, patients treated with high-dose therapy had a higher response rate (69% vs 81%, P = .045) and a longer median event-free survival (not reached vs 45 months). This did not translate into a better survival rate due to an excess of secondary malignancies after transplantation. The Follicular Lymphoma Prognostic Index identified a subgroup of patients with a significantly higher event-free survival rate after high-dose therapy. Autologous stem-cell transplantation cannot be considered as the standard first-line treatment of follicular lymphoma for patients younger than 60 years old with a high tumor burden.
Published: 2005

35. Cutting Edge: IL-21 Is a Switch Factor for the Production of IgG1 and IgG3 by Human B Cells

Author: Jérôme Pène, Sandrine Lécart, Jean-Claude Lecron, Don Foster, Vera Boulay, Paul Guglielmi, Jean-François Gauchat, Elodie Drouet, Adriana Delwail, and Hans Yssel
Subjects: Immunoglobulin gamma-Chains, medicine.medical_treatment, Antigens, CD19, Immunology, B-Lymphocyte Subsets, Spleen, Lymphocyte Activation, Immunoglobulin E, Immunoglobulin G, CD19, Cytosine Deaminase, Antigen, Cytidine Deaminase, medicine, Humans, Immunology and Allergy, CD40 Antigens, Cells, Cultured, CD40, biology, Immunoglobulin mu-Chains, Interleukins, hemic and immune systems, Cytidine deaminase, Molecular biology, Immunoglobulin A, Immunoglobulin Switch Region, Immunoglobulin Isotypes, medicine.anatomical_structure, Cytokine, biology.protein, Cell Division
Abstract: IL-21 is a cytokine that regulates the activation of T and NK cells and promotes the proliferation of B cells activated via CD40. In this study, we show that rIL-21 strongly induces the production of all IgG isotypes by purified CD19+ human spleen or peripheral blood B cells stimulated with anti-CD40 mAb. Moreover, it was found to specifically induce the production of IgG1 and IgG3 by CD40-activated CD19+CD27− naive human B cells. Although stimulation of CD19+ B cells via CD40 alone induced γ1 and γ3 germline transcripts, as well as the expression of activation-induced cytidine deaminase, only stimulation with both anti-CD40 mAb and rIL-21 resulted in the production of Sγ/Sμ switch circular DNA. These results show that IL-21, in addition to promoting growth and differentiation of committed B cells, is a specific switch factor for the production of IgG1 and IgG3.
Published: 2004

36. SECRETION OF IL-6, IL-11 AND LIF BY HUMAN CARDIOMYOCYTES IN PRIMARY CULTURE

Author: Hugues Gascan, Jean-Claude Lecron, Daniel Potreau, John Wijdenes, Pierre Corbi, Cecile Ancey, Adriana Delwail, and Josy Froger
Subjects: medicine.medical_specialty, Time Factors, Immunology, Oncostatin M, Ciliary neurotrophic factor, Leukemia Inhibitory Factor, Biochemistry, Paracrine signalling, Antigens, CD, Internal medicine, Cytokine Receptor gp130, medicine, Humans, Immunology and Allergy, Ciliary Neurotrophic Factor, Autocrine signalling, Interleukin 6, Molecular Biology, Cells, Cultured, Aged, Membrane Glycoproteins, biology, Interleukin-6, Myocardium, Proteins, Interleukin, Hematology, Fibroblasts, Middle Aged, Interleukin-11, Glycoprotein 130, Receptors, Interleukin-6, Cell biology, Kinetics, Endocrinology, Microscopy, Fluorescence, biology.protein, Cytokines, Peptides, Leukemia inhibitory factor, Molecular Chaperones
Abstract: Interleukin (IL)-6-type cytokines are multifunctional proteins involved in cardiac hypertrophy and myocardial protection. Recent studies, performed on animal models, report the production of these cytokines by heart. The aim of this study was to analyse the capacity of myocytes and fibroblasts isolated from human atrium to secrete IL-6, leukaemia inhibitory factor (LIF), cardiotrophin-1 (CT-1), IL-11, oncostatin M (OSM), ciliary neurotrophic factor (CNTF) and the soluble receptor subunits sIL-6R and sgp130 during primary culture. We detected LIF, IL-11, sgp130 and a large amount of IL-6, but not OSM, CT-1, CNTF nor IL-6R in these culture supernatants. Both cardiomyocytes and fibroblasts are able to spontaneously produce IL-6. The increase of IL-6 production all along the culture period appears to be the consequence of fibroblast proliferation and gp130 stimulation. This is the first demonstration that human cardiac cells are able to secrete IL-6, but also LIF and IL-11 in vitro. These cytokines could be involved in an autocrine and/or a paracrine networks regulating myocardial cyto-protection, hypertrophy and fibrosis.
Published: 2002

37. Cyclosporin A inhibition of macrophage colony-stimulating factor (M-CSF) production by activated human T lymphocytes

Author: Valérie Leprivey-Lorgeot, Jean-Claude Lecron, Stéphanie Frétier, Martine Garcia, John Wijdenes, Vincent Praloran, Arnaud Besse, Adriana Delwail, and Franck Morel
Subjects: CD4-Positive T-Lymphocytes, Macrophage colony-stimulating factor, CD3 Complex, medicine.medical_treatment, CD3, Immunology, Anti-Inflammatory Agents, Biology, Lymphocyte Activation, Methylprednisolone, Cyclosporin a, medicine, Humans, Immunology and Allergy, Macrophage, IL-2 receptor, Macrophage Colony-Stimulating Factor, Monocyte, Granulocyte-Macrophage Colony-Stimulating Factor, CD28, Cell Biology, Molecular biology, Clone Cells, medicine.anatomical_structure, Cytokine, Depression, Chemical, Cyclosporine, biology.protein, Interleukin-2, Interleukin-4, Immunosuppressive Agents
Abstract: M-CSF is a pleiotropic cytokine involved in the survival, proliferation, and differentiation of cells of the monocyte/macrophagelineage. M-CSF is produced by numerous cells including CD3-activated Tcells. M-CSF serum levels are increased during acute graft rejection. We tested the in vitro production of M-CSF, GM-CSF, IL-2, and IL-4 byT-cell clones costimulated by CD3 and accessory activation pathways and the effects of cyclosporin A and methylprednisolone. The nine clonesstudied and CD4+ cells purified from peripheral bloodmononuclear cells (PBMC) spontaneously produced low levels of M-CSF, which PMA and CD3 mAb strongly enhanced. In contrast to IL-2, CD28 mAbdid not further enhance this production. CsA inhibited M-CSF productionby clones and purified CD4 T cells. Addition of IL-2, anti IL-2, oranti CD25 mAb to the cultures demonstrated that CsA down-regulatedM-CSF synthesis by activated T cells through its inhibition of IL-2synthesis. These results could help to better understand the complexmechanisms of acute graft rejection and immunosuppression.
Published: 2002

38. High level of soluble programmed cell death ligand 1 in blood impacts overall survival in aggressive diffuse large B-Cell lymphoma: results from a french multicenter clinical trial

Author: Emmanuel GYAN, Delphine Rossille, Vincent Delwail, Corinne Haioun, Thierry Fest, Remy GRESSIN, Karin Tarte, Philippe Moreau, Eric DECONINCK, Delphine Maucort-Boulch, Celine PANGAULT, Noel Milpied, Guillaume Cartron, Steven Le gouill, Diane Damotte, Pierre-Louis Soubeyran, Microenvironnement et cancer (MiCa), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Biostatistiques [Lyon], Hospices Civils de Lyon (HCL), Biostatistiques santé, Département biostatistiques et modélisation pour la santé et l'environnement [LBBE], Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Centre hospitalier universitaire de Nantes (CHU Nantes), 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), Université Bordeaux Segalen - Bordeaux 2, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université Paris Descartes - Paris 5 (UPD5)-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), Microenvironnement et cancer ( MiCa ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre de Recherche des Cordeliers ( CRC (UMR_S 872) ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -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 ), Laboratoire Biostatistique-Santé ( LBS ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Hospices Civils de Lyon ( HCL ) -Centre National de la Recherche Scientifique ( CNRS ), Université de Lyon, Centre hospitalier universitaire de Nantes ( CHU Nantes ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), Laboratoire Biostatistique-Santé (LBS), Université de Lyon-Université de Lyon-Hospices Civils de Lyon (HCL)-Centre National de la Recherche Scientifique (CNRS), and Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)
Subjects: Adult, Male, Cancer Research, medicine.medical_specialty, Pathology, Adolescent, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Gastroenterology, B7-H1 Antigen, Young Adult, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, CD274, Neoplasm Staging, Chemotherapy, Intention-to-treat analysis, [ SDV ] Life Sciences [q-bio], business.industry, immune escape, Cancer, Hematology, Middle Aged, Prognosis, medicine.disease, Intention to Treat Analysis, 3. Good health, Lymphoma, Clinical trial, B7-H1, Treatment Outcome, medicine.anatomical_structure, Clinical Trials, Phase III as Topic, Oncology, DLBCL, Disease Progression, Biomarker (medicine), biomarker, Female, France, Lymphoma, Large B-Cell, Diffuse, Bone marrow, business, Diffuse large B-cell lymphoma, soluble PD-L1, Follow-Up Studies
Abstract: The dosage of soluble programmed cell death ligand 1 (sPD-L1) protein in the blood of adults with cancer has never been performed in a prospective patient cohort. We evaluated the clinical impact of sPD-L1 level measured at the time of diagnosis for newly diagnosed diffuse large B-cell lymphoma (DLBCL). Soluble PD-L1 was measured in the plasma of 288 patients enrolled in a multicenter, randomized phase III trial that compared R-high-dose chemotherapy with R-CHOP. The median follow-up was 41.4 months. A cutoff of 1.52 ng/ml of PD-L1 level was determined and related to overall survival (OS). Patients with elevated sPD-L1 experienced a poorer prognosis with a 3-year OS of 76% versus 89% (P0.001). Considering clinical characteristics, the multivariate analysis retained this biomarker besides bone marrow involvement and abnormal lymphocyte-monocyte score as independently related to poor outcome. sPD-L1 was detectable in the plasma and not in the serum, found elevated in patients at diagnosis compared with healthy subjects and its level dropped back to normal value after CR. The intention-to-treat analysis showed that elevated sPD-L1 was associated with a poorer prognosis for patients randomized within the R-CHOP arm (P0.001). Plasma PD-L1 protein is a potent predicting biomarker in DLBCL and may indicate usefulness of alternative therapeutic strategies using PD-1 axis inhibitors.
Published: 2014

39. Ex vivo PBMC cytokine profile in familial Mediterranean fever patients: Involvement of IL-1β, IL-1α and Th17-associated cytokines and decrease of Th1 and Th2 cytokines

Author: Adriana Delwail, Joelle Abou-Ghoch, Myrna Medlej-Hashim, Nabiha Salem, André Mégarbané, José-Noel Ibrahim, Jean-Claude Lecron, Eliane Chouery, and Rania Jounblat
Subjects: Adult, Lipopolysaccharides, Male, medicine.medical_treatment, Immunology, Interleukin-1beta, Familial Mediterranean fever, Biochemistry, Peripheral blood mononuclear cell, Monocytes, Th2 Cells, Interleukin-1alpha, medicine, Immunology and Allergy, Humans, Molecular Biology, business.industry, CD28, Inflammasome, Hematology, Pyrin, Th1 Cells, medicine.disease, Pathophysiology, Familial Mediterranean Fever, Cytoskeletal Proteins, Cytokine, Case-Control Studies, Leukocytes, Mononuclear, Th17 Cells, Tumor necrosis factor alpha, Female, business, Ex vivo, medicine.drug, Acute-Phase Proteins
Abstract: In order to clarify the inflammatory mechanism underlying familial Mediterranean fever (FMF), we aimed to evaluate the ex vivo cytokine profile of FMF patients during acute attacks and attack-free periods, and compare it with that of healthy controls. The study included 34 FMF patients, of whom 9 were studied during attack and remission and 24 healthy controls. Cytokine levels were evaluated by Luminex technology in serum and supernatants of PBMC (Peripheral Blood Mononuclear Cells) cultures with and without 24h stimulation of monocytes by LPS and T lymphocytes by anti-CD3/CD28 beads. Levels of IL-6 and TNF-α were higher in unstimulated and LPS-stimulated PBMC supernatants of FMF patients in crises compared to controls. In response to LPS stimulation, higher levels of IL-1β and IL-1α were found in PBMC supernatants of patients during crises compared to those in remission and to controls. IFN-γ and IL-4 levels were the lowest in unstimulated and anti-CD3/CD28 stimulated PBMCs supernatants of patients during crises compared to remission and controls. The Th17 cytokines IL-17 and IL-22 were respectively higher in anti-CD3/CD28 stimulated PBMC supernatants of FMF patients during and between crises compared to controls. Amongst cytokines tested in serum, only IL-6 and TNFα were enhanced in FMF patients. The ex vivo study represents an interesting approach to evaluate cytokines' involvement in FMF. Our results suggest an ongoing subclinical inflammation and define an elevated inflammatory cytokine signature, distinctly for M694V homozygous patients. The absence of spontaneous IL-1β release by PBMCs reflects no constitutive activation of the inflammasome in FMF physiopathology.
Published: 2014

40. A phase 1 dose escalation study of idarubicin combined with methotrexate, vindesine, and prednisolone for untreated elderly patients with primary central nervous system lymphoma. The GOELAMS LCP 99 trial

Author: Gaelle, Olivier, Aline, Clavert, Laurence, Lacotte-Thierry, Martine, Gardembas, Martine, Escoffre-Barbe, Annie, Brion, Isabelle, Cumin, Eric, Legouffe, Philippe, Solal-Celigny, Michèle, Chabin, Pierre, Ingrand, Philippe, Colombat, and Vincent, Delwail
Subjects: Male, Neutropenia, Vindesine, Prednisolone, Kaplan-Meier Estimate, Infections, Disease-Free Survival, Central Nervous System Neoplasms, Recurrence, Antineoplastic Combined Chemotherapy Protocols, Humans, Renal Insufficiency, Aged, Dose-Response Relationship, Drug, Lymphoma, Non-Hodgkin, Palliative Care, Remission Induction, Chemoradiotherapy, Middle Aged, Thrombocytopenia, Methotrexate, Treatment Outcome, Female, Lymphoma, Large B-Cell, Diffuse, Idarubicin, Immunocompetence
Abstract: Treatment of primary central nervous system lymphoma (PCNSL) in elderly patients remains unsatisfactory. To develop a new high-dose methotrexate (HD-MTX)-based regimen including idarubicin, a phase 1 multicenter dose escalation study was conducted to determine the maximum-tolerated dose (MTD) of idarubicin. Thirty-five immunocompetent patients with PCNSL were enrolled. The median age was 65 years (range, 60-70 years). MTX and vindesine (VDS) were given at the fixed dose of 3 g/m(2) (6-hr intravenous [IV]) and 3 mg/m(2) IV on day 1, respectively. Prednisolone (PRED) was given at the fixed dose of 60 mg/m(2) (IV or orally) on days 1-5. Idarubicin was escalated in increments of 2 mg/m(2) with doses ranging from 12-18 mg/m(2) IV on day 1. Treatment was repeated three times every 3 weeks. Dose-limiting toxicity (DLT) was defined as grade 4 neutropenia for more than 7 days, thrombocytopenia grade 4 or nonhaematological toxicity more than grade 2. The MTD of idarubicin was reached at 16 mg/m(2) . At this level, the main haematological toxicities were thrombocytopenia grade 4: 5% and neutropenia grade 3 or 4 (52%); the main nonhaematological toxicities were grade 3 or 4 infectious disease (5%) and grade 2 renal failure (9%). For the study population, median overall and progression-free survival were 19 and 13 months, respectively. Our study suggests that the MTD of idarubicin in combination with HD-MTX, VDS, and PRED, should be 16 mg/m(2) . Further studies will be necessary to challenge a standard treatment in elderly patients with PCNSL.
Published: 2014

41. Treatment of B-lymphoproliferative disorder with a monoclonal anti-interleukin-6 antibody in 12 patients: a multicenter phase 1-2 clinical trial

Author: Vincent Delwail, John Wijdenes, Dominique Debray, Marc Stern, Jean Marie Seigneurin, Anne Durandy, Christophe Duvoux, Véronique Leblond, Bruno Hurault De Ligny, Alain Fischer, Philippe Hubert, Sophie Paczesny, Antoine Achkar, Marc Bauwens, and Elie Haddad
Subjects: Adult, Male, Herpesvirus 4, Human, medicine.medical_specialty, Adolescent, medicine.medical_treatment, Immunology, Antibodies, Viral, Biochemistry, Gastroenterology, Refractory, Internal medicine, medicine, Humans, Child, Immunodeficiency, B-Lymphocytes, Interleukin-6, business.industry, Antibodies, Monoclonal, Infant, Immunosuppression, Cell Biology, Hematology, Immunotherapy, Middle Aged, medicine.disease, Lymphoproliferative Disorders, Surgery, Clinical trial, C-Reactive Protein, Treatment Outcome, medicine.anatomical_structure, Therapeutic Equivalency, Child, Preschool, Tissue Transplantation, Monoclonal, Female, Bone marrow, Complication, business
Abstract: Severe T-cell immunodeficiency after solid organ or bone marrow transplantation may result in the uncontrolled outgrowth of latently Epstein-Barr virus-infected B cells, leading to B-lymphoproliferative disorder (BLPD). Given the potentially important pathogenic role of IL-6 in BLPD, it was tested whether the in vivo neutralization of IL-6 by a monoclonal anti-IL-6 antibody could contribute to the control of BLPD. Safety and efficacy were assessed in 12 recipients of transplanted organs who had BLPD refractory to the reduction of immunosuppression over 8 days. Five patients received 0.4 mg/kg per day. The next 7 patients received 0.8 mg/kg per day. Treatment was scheduled to last 15 days. It was completed in 10 patients, and in the other 2 patients was discontinued early (days 10 and 13, respectively) because of disease progression. Treatment tolerance was good, and no major side effects were observed. High C-reactive protein levels were found in 9 patients before treatment but were normalized under treatment in all patients, demonstrating efficient IL-6 neutralization. Complete remission (CR) was observed in 5 patients and partial remission (PR) in 3 patients. Relapse was observed in 1 of these 8 patients in whom remission was observed. This relapse was unresponsive to treatment. Disease was stable in 1 patient, but it progressed in 3 patients. Seven patients are alive and well. Two patients died because of disease progression, and 3 patients died while in CR (chronic rejection in 2 patients and BLPD sequelae in 1 patient). These data suggest that the anti-IL-6 antibody is safe and should be further explored in the treatment of BLPD.
Published: 2001

42. Circulating soluble gp130, soluble IL-6R, and IL-6 in patients undergoing cardiac surgery, with or without extracorporeal circulation

Author: Daniel Potreau, John Wijdenes, Pierre Corbi, Mohammad Rahmati, Jean-Claude Lecron, Paul Menu, and Adriana Delwail
Subjects: Male, Pulmonary and Respiratory Medicine, Extracorporeal Circulation, medicine.medical_specialty, Morpholines, Gastroenterology, law.invention, Coronary artery bypass surgery, law, Internal medicine, Cardiopulmonary bypass, Humans, Medicine, Coronary Artery Bypass, Receptor, Interleukin 6, Aged, biology, Interleukin-6, business.industry, Extracorporeal circulation, General Medicine, Middle Aged, Receptors, Interleukin-6, Cardiac surgery, surgical procedures, operative, medicine.anatomical_structure, Anesthesia, biology.protein, Female, Surgery, Cardiology and Cardiovascular Medicine, business, Complication, circulatory and respiratory physiology, Artery
Abstract: Objective: Soluble forms of interleukin-6 (IL-6) receptors are known to modulate biological activities of IL-6. The purpose of the study was to measure circulating levels of IL-6, sIL-6R and sgp130 in patients undergoing coronary artery bypass grafting with cardiopulmonary bypass (CPB group) or without CPB (non-CPB group). Methods: The CPB group included 19 patients and the non-CPB group 12 patients. Sera levels of IL-6, sIL-6R and sgp130 were measured by specific ELISA at the beginning of the operation (T0, 15 min before skin incision) and 6 h later (T1). Results: IL-6 sera levels were respectively 9 ^ 20 pg/ml (mean ^ SD) and 13 ^ 19 pg/ml at T0 and reached 340 ^ 250 pg/ml and 965 ^ 1060 pg/ml at T1 in CPB and non-CPB groups, indicating a significant increase from T0 to T1, but no differences between the two groups. When compared to T0 values, sgp130 levels decreased in both groups (respectively 105 ^ 37 and 115 ^ 35 ng/ml at T0 for CPB and non-CPB groups, and 72 ^ 25 and 84 ^ 29 ng/ml at T1) while we are not able to detect differences between the groups. Whatever the group or the time, sIL-6R concentrations remained unchanged. Conclusions: We showed that the increase of IL-6 after artery bypass grafting was similar between patients operated with CPB or without CPB. We conclude that the main inductor of IL-6 release is linked to surgical trauma rather than a reaction to CPB. Since it is known that gp130 inhibits IL-6-biological activities, we suggest that the decrease of sgp130 sera levels could further enhance the inflammatory effects of IL-6 in cardiac surgery. q 2000 Elsevier Science B.V. All rights reserved.
Published: 2000

43. Primary intracerebral malignant lymphoma: report of 248 cases

Author: Vincent Delwail, Guy G, Benoit Bataille, Emmanuelle Menet, Michel Wager, Pierre Vandermarcq, Francoise Lapierre, and Pierre Ingrand
Subjects: Adult, Male, Pathology, medicine.medical_specialty, Adolescent, Corpus callosum, medicine, Humans, Child, Survival rate, Aged, Retrospective Studies, Aged, 80 and over, medicine.diagnostic_test, Brain Neoplasms, business.industry, Lymphoma, Non-Hodgkin, Large cell, Primary central nervous system lymphoma, Brain, Magnetic resonance imaging, Retrospective cohort study, Middle Aged, medicine.disease, Combined Modality Therapy, Lymphoma, Non-Hodgkin's lymphoma, Survival Rate, Treatment Outcome, Child, Preschool, Female, business
Abstract: Object. The authors present a retrospective analysis of 248 immunocompetent patients with primary intracerebral lymphoma treated at 19 French and Belgian medical centers between January 1980 and December 1995.Methods. This study involved 127 female and 121 male patients with a median age of 61 years (range 2–88 years). All tumors available for review were classic diffuse non-Hodgkin's lymphoma, for which the phenotype was determined in 220 patients: 212 (96.4%) were B-cell and eight (3.6%) were T-cell type tumors. According to the Revised European—American classification of lymphoid neoplasms, most lesions were diffuse large cell tumors (62%). A total of 196 tumors were reviewed in 127 patients for whom preoperative computerized tomography and magnetic resonance studies were available. There was a single lesion in 66% of the cases, with a supratentorial location in 87%. Tumor location in the basal ganglia, corpus callosum, or fornix, infiltration of the periventricular ependyma, or a mirror pattern, were strongly suggestive of a lesion of lymphomatous origin. The histological diagnosis was obtained after surgical resection in 116 patients, with the remainder undergoing biopsy sampling only. Of the 248 patients studied, 129 (52%) received chemotherapy plus radiation therapy, 60 (24%) received radiation therapy alone, 35 (14%) received chemotherapy alone, and 24 (10%) received no postsurgical treatment.Conclusions. Using univariate analysis, the authors determined prognostic factors that were significantly associated with a favorable impact on survival including age younger than 60 years, radiation therapy (without evidence of a dose—response relationship), radiation therapy combined with chemotherapy, and chemotherapy consisting of anthracycline. Partial surgical resection was an unfavorable prognostic factor. Multivariate analysis was used to confirm the independent prognostic value of radiation therapy, age, chemotherapy consisting of anthracyclines or methotrexate, and partial surgical resection. This European survey provides a reasonable basis for the treatment of primary intracerebral lymphoma with the following sequence: stereotactic biopsy sampling, chemotherapy with a methotrexate- and anthracycline-based regimen, followed by cranial irradiation.
Published: 2000

44. [KHSV/EBV associated germinotropic lymphoproliferative disorder: a rare entity, case report and review of the literature]

Author: Michaël, Taris, Antoine, de Mascarel, Mercédès, Riols, Vincent, Delwail, Noël, Milpied, Pierre, Dubus, and Marie, Parrens
Subjects: B-Lymphocytes, Epstein-Barr Virus Infections, Herpesvirus 4, Human, Plasma Cells, Remission Induction, Middle Aged, Germinal Center, Hodgkin Disease, Immunohistochemistry, Lymphoproliferative Disorders, Diagnosis, Differential, Herpesvirus 8, Human, Humans, Female, Lymph Nodes, Sarcoma, Kaposi, In Situ Hybridization
Abstract: We report a case of KSHV/EBV associated germinotropic lymphoproliferative disorder (LPG) in a 49-year-old African patient, without immunosuppression. LPG is a rare entity arising in immunocompetent patients in opposition to other lymphoproliferative disorders associated to Kaposi sarcoma-associated herpes virus (KSHV). The disease presents itself as localized lymphadenopathy with an infiltration of germinal centers by plasmablastic cells coinfected by KSHV and EBV (Epstein-Barr Virus). After treatment, the outcome is favorable. Differential diagnosis in our case, due to the presence of clusters of Hodgkin-like cells in the mantle zone, included lymphocyte rich classic Hodgkin lymphoma (LHCRL) and nodular lymphocyte predominant Hodgkin lymphoma (LHNPL). Finally, we highlight the differential diagnostic criteria of KSHV lymphoproliferative diseases.
Published: 2013

45. Long-term follow up of the FL2000 study comparing CHVP-interferon to CHVP-interferon plus rituximab in follicular lymphoma

Author: Karim Belhadj, Gilles Salles, Steven Le Gouill, Sophie Lefort, Pauline Brice, Anne Sonet, Catherine Sebban, Bruno Audhuy, Emmanuel Bachy, Roch Houot, Guillaume Cartron, Pierre Feugier, F. Morschhauser, Nicole Brousse, Hervé Maisonneuve, Christophe Fermé, Charles Foussard, Vincent Delwail, Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Microenvironnement et cancer (MiCa), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service d'hématologie, Hôpital Claude Huriez [Lille], CHU Lille-CHU Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Université Catholique de Louvain = Catholic University of Louvain (UCL), Service d'hématologie-oncologie adultes, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'Hématologie Biologique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Dynamique des interactions membranaires normales et pathologiques (DIMNP), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Service d'Hématologie, Hospices civils Colmar, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR), Service d'Hématologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Relations Hôte-Environnement (RHEM), Université Henri Poincaré - Nancy 1 (UHP), Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Centre Léon Bérard [Lyon], Service d'Anatomie et de Cytologie Pathologiques [Poitiers], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Centre hospitalier La Roche-Sur-Yon, Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Hospitalier de Brive-la-Gaillarde (CH Brive), Department of Pathology, Université Paris Descartes - Paris 5 (UPD5)-PRES Sorbonne Paris Cité-Assistance Publique-Hopitaux de Paris-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel Dieu, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Montpellier 1 (UM1), Centre Hospitalier Brive-la-Gaillarde, Université Paris Descartes - Paris 5 (UPD5)-PRES Sorbonne Paris Cité-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance Publique-Hopitaux de Paris, Centre Hospitalier Lyon Sud [CHU - HCL] ( CHLS ), Hospices Civils de Lyon ( HCL ), Microenvironnement et cancer ( MiCa ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Hôpital Claude Huriez-Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Université Catholique de Louvain ( UCL ), Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Diderot - Paris 7 ( UPD7 ) -Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ), Dynamique des interactions membranaires normales et pathologiques ( DIMNP ), Université Montpellier 1 ( UM1 ) -Université Montpellier 2 - Sciences et Techniques ( UM2 ) -Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut Gustave Roussy ( IGR ), Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ), Relations Hôte-Environnement ( RHEM ), Université Henri Poincaré - Nancy 1 ( UHP ), Nutrition-Génétique et Exposition aux Risques Environnementaux ( NGERE ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Lorraine ( UL ), Université de Poitiers-Centre hospitalier universitaire de Poitiers ( CHU Poitiers ), Centre de Recherche en Cancérologie / Nantes - Angers ( CRCNA ), CHU Angers-Centre hospitalier universitaire de Nantes ( CHU Nantes ) -Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Hôpital Laennec-Centre National de la Recherche Scientifique ( CNRS ) -Faculté de Médecine d'Angers, Université Paris Descartes - Paris 5 ( UPD5 ) -PRES Sorbonne Paris Cité-CHU Necker - Enfants Malades [AP-HP]-Assistance Publique-Hopitaux de Paris, CHU Angers-Hôtel Dieu, Le Corre, Morgane, Hôpital Claude Huriez-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Université Catholique de Louvain (UCL), 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)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Centre de Recherche en Cancérologie / Nantes - Angers (CRCNA), Centre hospitalier universitaire de Nantes (CHU Nantes)-Faculté de Médecine d'Angers-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Centre National de la Recherche Scientifique (CNRS)-Hôpital Laennec-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôtel-Dieu de Nantes, and Université Paris Descartes - Paris 5 (UPD5)-PRES Sorbonne Paris Cité-CHU Necker - Enfants Malades [AP-HP]-Assistance Publique-Hopitaux de Paris
Subjects: Oncology, [SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, Male, Time Factors, medicine.medical_treatment, Follicular lymphoma, THERAPY, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Cohort Studies, Antibodies, Monoclonal, Murine-Derived, 0302 clinical medicine, International Prognostic Index, hemic and lymphatic diseases, Antineoplastic Combined Chemotherapy Protocols, [ SDV.MHEP.HEM ] Life Sciences [q-bio]/Human health and pathology/Hematology, Prospective Studies, Lymphoma, Follicular, Etoposide, 0303 health sciences, IMPROVED SURVIVAL, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Hematology, CHEMOTHERAPY, Middle Aged, 3. Good health, Survival Rate, 030220 oncology & carcinogenesis, Rituximab, Drug Therapy, Combination, Female, [SDV.IMM.IMM] Life Sciences [q-bio]/Immunology/Immunotherapy, medicine.drug, Adult, medicine.medical_specialty, Cyclophosphamide, Adolescent, UNITED-STATES, [ SDV.IMM.IMM ] Life Sciences [q-bio]/Immunology/Immunotherapy, [SDV.CAN]Life Sciences [q-bio]/Cancer, 03 medical and health sciences, Young Adult, [SDV.CAN] Life Sciences [q-bio]/Cancer, Median follow-up, Internal medicine, medicine, Humans, VINCRISTINE, 030304 developmental biology, Aged, Teniposide, Chemotherapy, business.industry, Interferon-alpha, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, medicine.disease, PHASE-III, Surgery, Regimen, Doxorubicin, Prednisone, Original Articles and Brief Reports, business, Follow-Up Studies
Abstract: Anti-CD20-containing chemotherapy regimens have become the standard of care for patients with follicular lymphoma needing cytotoxic therapy. Four randomized trials demonstrated a clinical benefit for patients treated with rituximab. However, no long-term follow up (i.e. > 5 years) of these trials is yet available. Between May 2000 and May 2002, 358 newly diagnosed patients with high tumor burden follicular lymphoma were randomized to receive cyclophosphamide, adriamycin, etoposide and prednisolone plus interferon-α2a or a similar chemotherapy-based regimen plus rituximab, and outcome was up-dated. With a median follow up of 8.3 years, addition of rituximab remained significantly associated with prolonged event-free survival (primary end point) (P=0.0004) with a trend towards a benefit for overall survival (P=0.076). The Follicular Lymphoma International Prognostic Index score was strongly associated with outcome for both event-free and overall survival in univariate analysis and its prognostic value remained highly significant after adjusting for other significant covariates in multivariate models (P
Published: 2013

46. Comparison of PET-CT and magnetic resonance diffusion weighted imaging with body suppression (DWIBS) for initial staging of malignant lymphomas

Author: Guilhot Joelle, Velasco Stéphane, Perdrisot Remy, Guilhot Gaudeffroy Francois, Tasu Jean-Pierre, Burg Samuel, and Delwail Vincent
Subjects: Adult, Male, medicine.medical_specialty, Ann Arbor staging, Adolescent, Lymphoma, Whole body imaging, Context (language use), Multimodal Imaging, Sensitivity and Specificity, Young Adult, medicine, Effective diffusion coefficient, Humans, Radiology, Nuclear Medicine and imaging, Whole Body Imaging, Aged, Neoplasm Staging, Aged, 80 and over, PET-CT, medicine.diagnostic_test, business.industry, Reproducibility of Results, Magnetic resonance imaging, General Medicine, Middle Aged, medicine.disease, Diffusion Magnetic Resonance Imaging, Positron emission tomography, Positron-Emission Tomography, Subtraction Technique, Female, Radiology, business, Nuclear medicine, Tomography, X-Ray Computed
Abstract: To evaluate the clinical impact of diffusion-weighted whole-body imaging with background body signal suppression (DWIBS) in staging of malignant lymphoma.Twenty-three patients with proven malignant lymphomas were prospectively enrolled. DWIBS (b=0, 1000 s/mm(2)) examinations and PET-CT were performed respectively on an Intera 1.5 T unit and a Gyroscan PET-CT scan (Philips Medical system, Best, the Netherland). The criteria for positive node involvement were a size over 10 mm or an apparent diffusion coefficient (ADC) value under 0.7510(-3) mm(2)/s for nodes under 10mm. For extranodal analysis, a high or heterogeneous signal on DWIBS was considered as positive. In cases of discordance, the reference standard for each region or organ was established at 6 months after the diagnosis according to all available clinical, biological information, as well as histological evidence or follow-up to prove or disprove the presence of disease.DWIBS and PET-CT results were congruent in 333 node regions on the 345 areas analyzed, with excellent agreement (κ=0.97, P0.0001). From 433 organs analyzed (one patient had splenectomy) extranodal disease was detected in 22 organs on DWIBS. The two imaging techniques agreed on 430 organs (κ=0.99, P0.0001). Finally, Ann Arbor stages based on DWIBS and those of PET/CT were in agreement for 23 patients.For malignant lymphoma in a pre-therapeutic context, agreement between diffusion-weighted whole-body imaging and PET/CT is high for Ann Arbor staging.
Published: 2013

47. Involvement of IL-1 and Oncostatin M in Acanthosis Associated With Hypertensive Leg Ulcer

Author: V. Huguier, Gérard Guillet, Martine Garcia, Julien Garnier, Jean-Philippe Giot, Franck Morel, François-Xavier Bernard, Jean-Claude Lecron, G. Dagregorio, Isabelle Paris, Sandrine Charreau, Adrianna Delwail, Laure Favot, Pierre Levillain, Laboratoire Inflammation, Tissus épithéliaux et Cytokines (LITEC), Université de Poitiers, Centre hospitalier universitaire de Poitiers (CHU Poitiers), BIOalternatives (BIOalternatives SAS), and entreprise privé
Subjects: Keratinocytes, Male, Pathology, Necrosis, Interleukin-1beta, Acanthosis, Constriction, Pathologic, 030204 cardiovascular system & hematology, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, Melanosis, Muscle, Smooth, Vascular, Pathogenesis, Mice, 0302 clinical medicine, Leukocytes, ComputingMilieux_MISCELLANEOUS, 0303 health sciences, biology, Leg Ulcer, Oncostatin M, Cell Differentiation, Pathophysiology, 3. Good health, medicine.anatomical_structure, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, Hypertension, Female, medicine.symptom, Infiltration (medical), Adult, medicine.medical_specialty, Myocytes, Smooth Muscle, Models, Biological, Pathology and Forensic Medicine, Hypertensive leg ulcer, 03 medical and health sciences, Dermis, medicine, Animals, Humans, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Aged, Cell Proliferation, 030304 developmental biology, Interleukin-6, business.industry, Keratin-10, medicine.disease, Mice, Inbred C57BL, Ki-67 Antigen, Microvessels, biology.protein, Epidermis, business, [SDV.MHEP.DERM]Life Sciences [q-bio]/Human health and pathology/Dermatology
Abstract: Hypertensive leg ulcer (HLU) is an inflammatory disease characterized by intense pain, alteration of vascularization, and skin necrosis. The optimal treatment relies on surgical removal of necrotic tissues covered by a split-skin graft. We studied the histomorphology of the lesions and investigated the involvement of inflammatory cells and cytokines to further define the physiopathology of HLU. We report epidermis acanthosis and a preferential occlusion of the precapillary arterioles with infiltration of neutrophils, macrophages, and T lymphocytes in the dermis. OSM, IL-1β, and IL-6 were overexpressed in the ulcer, whereas the Th17-derived cytokines were not. In vitro , the addition of IL-1β and OSM promoted acanthosis and destructuring of reconstructed epidermis. Exogenous IL-1β and OSM synergistically induced epidermal acanthosis in mice. These data show that OSM and IL-1β are not only a biological characteristic signature of HLU, but these cytokines reflect a specific inflammatory state, directly involved in the pathogenesis. We suggest that anti-cytokine biotherapies could be an alternative strategy to surgery to treat HLU.
Published: 2013

48. Rituximab induction immunotherapy for first-line low-tumor-burden follicular lymphoma: survival analyses with 7-year follow-up

Author: Gilles Salles, Philippe Colombat, Charles Foussard, Franck Morschhauser, F. Lazreg, Pierre Soubeyran, Corinne Haioun, Vincent Delwail, Nicole Brousse, Catherine Sebban, Pauline Brice, Philippe Solal-Celigny, Hervé Tilly, Catherine Thieblemont, Loïc Bergougnoux, Eric Deconinck, Service d'hématologie [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Service d'anatomie pathologique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Service d'Hematologie, Hospices Civils de Lyon (HCL)-Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Service d'hématologie, Hôpital Claude Huriez-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service d'hématologie-oncologie adultes, 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), Plateforme de génétique moléculaire des cancers d'Aquitaine, Institut Bergonié - CRLCC Bordeaux, Service d'Anatomie et de Cytologie Pathologiques [Poitiers], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Hôpital Jean Minjoz, Service d'hématologie clinique, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel Dieu, Service d'Oncologie Médicale, Centre Léon Bérard [Lyon], Service d'oncologie, CRLCC Henri Becquerel, Service d'Hématologie, Roche, Onco-radiothérapie, hématologie, Centre Jean Bernard, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Claude Huriez [Lille], CHU Lille-CHU Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Université Paris Diderot - Paris 7 (UPD7)-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), Institut Bergonié [Bordeaux], UNICANCER-UNICANCER, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), Centre Jean Bernard [Institut Inter-régional de Cancérologie - Le Mans], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Hôpital Bretonneau-CHRU Tours, Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Hospices Civils de Lyon ( HCL ) -Centre Hospitalier Lyon Sud [CHU - HCL] ( CHLS ), Hospices Civils de Lyon ( HCL ), Hôpital Claude Huriez-Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Diderot - Paris 7 ( UPD7 ) -Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Université de Poitiers-Centre hospitalier universitaire de Poitiers ( CHU Poitiers ), Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -hopital Jean Minjoz, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), CHU Angers-Hôtel Dieu, and Saas, Philippe
Subjects: Male, MESH : Immunization, Passive, MESH : Induction Chemotherapy, Follicular lymphoma, Kaplan-Meier Estimate, Gastroenterology, Antibodies, Monoclonal, Murine-Derived, MESH: Lymphoma, Follicular, 0302 clinical medicine, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, MESH : Female, Lymphoma, Follicular, MESH: Treatment Outcome, education.field_of_study, MESH: Middle Aged, MESH : Neoplasm Recurrence, Local, Induction Chemotherapy, Hematology, MESH: Follow-Up Studies, MESH : Adult, Middle Aged, MESH: Induction Chemotherapy, 3. Good health, MESH : Antineoplastic Agents, Treatment Outcome, Oncology, 030220 oncology & carcinogenesis, MESH : Disease-Free Survival, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Rituximab, MESH: Immunization, Passive, MESH: Neoplasm Recurrence, Local, medicine.drug, Adult, medicine.medical_specialty, [SDV.IMM] Life Sciences [q-bio]/Immunology, MESH : Male, Population, Antineoplastic Agents, MESH : Treatment Outcome, Disease-Free Survival, MESH : Kaplan-Meier Estimate, 03 medical and health sciences, Internal medicine, medicine, Humans, MESH : Middle Aged, Progression-free survival, education, MESH: Kaplan-Meier Estimate, MESH: Humans, business.industry, MESH : Lymphoma, Follicular, MESH : Humans, Immunization, Passive, Induction chemotherapy, MESH : Follow-Up Studies, MESH: Adult, medicine.disease, MESH: Male, MESH : Antibodies, Monoclonal, Murine-Derived, Lymphoma, Surgery, MESH: Antibodies, Monoclonal, Murine-Derived, MESH: Disease-Free Survival, MESH: Antineoplastic Agents, Neoplasm Recurrence, Local, business, Diffuse large B-cell lymphoma, MESH: Female, Progressive disease, Follow-Up Studies, 030215 immunology
Abstract: International audience; BACKGROUND: The purpose of this study was to report long-term results of rituximab induction monotherapy in patients with low-tumor-burden follicular lymphoma (LTBFL). PATIENTS AND METHODS: Of 49 first-line LTBFL patients who received weekly doses of rituximab (375 mg/m(2)), 46 have been followed with a long-term analysis of clinical and molecular responses. RESULTS: Best clinical response (at any staging within a year following treatment) was 80%, 24 (52%) patients had complete or unconfirmed complete response, 13 (28%) had partial response and 9 (20%) had stable or progressive disease. Of 31 patients having a positive bcl2-JH rearrangement, 15 (48%) became negative following treatment. After 83.9 months of follow-up (95% confidence interval 6.4-92.8 months), the median progression-free survival is 23.5 months and overall survival (OS) is 91.7%. Five patients died (one progression, one myelodysplasia, one diffuse large B-cell lymphoma and two solid tumors). Seven patients (15%) are progression-free including five who are bcl2 informative. No unexpected long-term adverse event has been observed. CONCLUSION: A significant proportion of patients remain progression-free 7 years after a single 4-dose rituximab treatment in first-line LTBFL. The 7-year overall survivalOS is very high in this selected population of patients.
Published: 2012

49. Failure of fluorodeoxyglucose positron emission tomography to detect the high-grade transformation of nodular lymphocyte predominant Hodgkin's lymphoma

Author: Mathieu, Puyade, Mokrane, Yacoub, Cécile, Tomowiak, Marine, Diviné, Rémy, Perdrisot, François, Guilhot, and Vincent, Delwail
Subjects: Adult, Male, Middle Aged, Hodgkin Disease, ROC Curve, Doxorubicin, Fluorodeoxyglucose F18, Vincristine, Positron-Emission Tomography, Antineoplastic Combined Chemotherapy Protocols, Humans, Prednisone, Female, Diagnostic Errors, Tomography, X-Ray Computed, Cyclophosphamide
Published: 2012

50. Role of interleukin-1β in NLRP12-associated autoinflammatory disorders and resistance to anti-interleukin-1 therapy

Author: Jean-Claude Lecron, Véronique Hentgen, Philippe Duquesnoy, Serge Amselem, Adriana Delwail, Sylvain Normand, Emmanuelle Cochet, Gilles Grateau, Sandrine Marlin, Isabelle Jéru, Physiopathologie des maladies génétiques d'expression pédiatrique, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier de Versailles André Mignot (CHV), Laboratoire Inflammation, Tissus épithéliaux et Cytokines (LITEC), Université de Poitiers, CHU Tenon [AP-HP], Centre hospitalier universitaire de Poitiers (CHU Poitiers), the European Union Sixth Framework Programme (EURAMY project grant LSHM-CT-2006-037525), and Couvet, Sandrine
Subjects: Male, [SDV.IMM] Life Sciences [q-bio]/Immunology, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Immunology, Interleukin-1beta, Enzyme-Linked Immunosorbent Assay, [SDV.GEN] Life Sciences [q-bio]/Genetics, Peripheral blood mononuclear cell, Rheumatology, In vivo, medicine, Immunology and Allergy, Humans, Pharmacology (medical), Prospective Studies, Anakinra, [SDV.GEN]Life Sciences [q-bio]/Genetics, business.industry, Hereditary Autoinflammatory Diseases, Intracellular Signaling Peptides and Proteins, Interleukin, Pathophysiology, [SDV] Life Sciences [q-bio], Interleukin 1 Receptor Antagonist Protein, Cytokine, [SDV.IMM]Life Sciences [q-bio]/Immunology, Tumor necrosis factor alpha, business, Ex vivo, medicine.drug, Signal Transduction
Abstract: Objective A new class of autoinflammatory syndromes called NLRP12-associated disorders (NLRP12AD) has been associated with mutations in NLRP12. Conflicting data on the putative role of NLRP12 in interleukin-1β (IL-1β) signaling have been found in in vitro analyses. This prospective study was undertaken to assess the secretion of IL-1β and 3 IL-1β–induced cytokines (IL-1 receptor antagonist [IL-1Ra], IL-6, and tumor necrosis factor α [TNFα]) in patients' peripheral blood mononuclear cells (PBMCs) cultured ex vivo and to evaluate the patients' response to IL-1Ra (anakinra), a major drug used in the treatment of autoinflammatory disorders. Methods Patients' disease manifestations and cytokine measurements were recorded before anakinra treatment was started, during 14 months of therapy, and after discontinuation of anakinra treatment. Results Spontaneous secretion of IL-1β by patients' PBMCs was found to be dramatically increased (80–175 fold) compared to healthy controls. Consistent with these findings, anakinra initially led to a marked clinical improvement and to a rapid near-normalization of IL-1β secretion. However, a progressive clinical relapse occurred secondarily, associated with an increase in TNFα secretion, persistent elevated levels of IL-1Ra and IL-6, and a reactivation of IL-1β secretion. Anakinra was discontinued after 14 months of therapy. Conclusion Our findings provide in vivo evidence of the crucial role of IL-1β in the pathophysiology of NLRP12AD. This is the first time anakinra has been used to treat this disorder. This study provides new insights into the mechanisms underlying resistance to anti–IL-1 therapy observed in a few patients with autoinflammatory syndromes. Our data also point to the potential of ex vivo cytokine measurements as predictors of response to treatment.
Published: 2011

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