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1. The anti-HER3 (ErbB3) therapeutic antibody 9F7-F11 induces HER3 ubiquitination and degradation in tumors through JNK1/2- dependent ITCH/AIP4 activation

Author: Christel Larbouret, Marie Alix Poul, Thierry Chardès, André Pèlegrin, Gerry Melino, Philippe Mondon, Christophe Le Clorennec, Yassamine Lazrek, Olivier Dubreuil, Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Institut Pasteur de la Guyane, Réseau International des Instituts Pasteur (RIIP), Millegen SA, MILEGEN-Immeuble BIOSTEP, GamaMabs Pharma SA [Toulouse] ( Centre Pierre Potier), Oncopole de Toulouse-Centre Pierre Potier [Toulouse], LFB Biotechnologies [Lille, France], Università degli Studi di Roma Tor Vergata [Roma], University of Leicester, and Herrada, Anthony
Subjects: 0301 basic medicine, Cell cycle checkpoint, Receptor, ErbB-3, MESH: Down-Regulation, MESH: Antibodies, Monoclonal, Antibodies, Monoclonal, Murine-Derived, 0302 clinical medicine, Ubiquitin, antibody, Medicine, skin and connective tissue diseases, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, biology, treatment, Antibodies, Monoclonal, 3. Good health, Ubiquitin ligase, ITCH/AIP4, MESH: Receptor, ErbB-3, Oncology, MESH: Repressor Proteins, 030220 oncology & carcinogenesis, MESH: Mitogen-Activated Protein Kinase 9, Phosphorylation, MESH: Mitogen-Activated Protein Kinase 8, Research Paper, MESH: Cell Line, Tumor, MAP Kinase Signaling System, Ubiquitin-Protein Ligases, Down-Regulation, [SDV.CAN]Life Sciences [q-bio]/Cancer, Antineoplastic Agents, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, HER3, Cell Line, Tumor, cancer, Humans, Mitogen-Activated Protein Kinase 9, Mitogen-Activated Protein Kinase 8, Settore BIO/10, Protein kinase B, PI3K/AKT/mTOR pathway, MESH: Humans, business.industry, MESH: MAP Kinase Signaling System, Ubiquitination, MESH: Ubiquitin-Protein Ligases, body regions, Repressor Proteins, 030104 developmental biology, USP9X, MESH: Antibodies, Monoclonal, Murine-Derived, Cancer cell, Immunology, biology.protein, Cancer research, MESH: Ubiquitination, MESH: Antineoplastic Agents, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; We characterized the mechanism of action of the neuregulin-non-competitive anti-HER3 therapeutic antibody 9F7-F11 that blocks the PI3K/AKT pathway, leading to cell cycle arrest and apoptosis in vitro and regression of pancreatic and breast cancer in vivo. We found that 9F7-F11 induces rapid HER3 down-regulation. Specifically, 9F7-F11-induced HER3 ubiquitination and degradation in pancreatic, breast and prostate cancer cell lines was driven mainly by the itchy E3 ubiquitin ligase (ITCH/AIP4). Overexpression of the ITCH/AIP4 inhibitor N4BP1 or small-interfering RNA-mediated knockdown of ITCH/AIP4 inhibited HER3 ubiquitination/degradation and PI3K/AKT signaling blockade induced by 9F7-F11. Moreover, 9F7-F11-mediated JNK1/2 phosphorylation led to ITCH/AIP4 activation and recruitment to HER3 for receptor ubiquitination and degradation. ITCH/AIP4 activity was activated by the deubiquitinases USP8 and USP9X, as demonstrated by RNA interference. Taken together, our results suggest that 9F7-F11-induced HER3 ubiquitination and degradation in cancer cells mainly occurs through JNK1/2-dependent ITCH/AIP4 activation.
Published: 2016
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2. Neutrophils mediate antibody-induced antitumor effects in mice

Author: James P. Di Santo, Pierre Bruhns, Laurence Fiette, Friederike Jönsson, David A. Mancardi, Clifford A. Lowell, Bruno Iannascoli, Marcello Albanesi, Anticorps en Thérapie et Pathologie, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC), Histopathologie humaine et Modèles animaux, Institut Pasteur [Paris], Immunité Innée, University of California [San Francisco] (UCSF), University of California, This work was supported by the Institut Pasteur and the Institut National de la Santé et de la Recherche Médicale, by Agence Nationale de la Recherche (grant ANR-09-GENO-014-01), Fondation ARC pour la Recherche sur le Cancer and Ligue Nationale contre le Cancer (Comité de Paris) grants (P.B.), through an 'Equipe Labellisée Ligue Contre le Cancer' grant (J.P.D.S.), and by National Institutes of Health, National Institute of Allergy and Infectious Diseases grants AI065495 and AI068150 (C.A.L.)., The authors are thankful to our colleagues at Institut Pasteur (Paris, France): P. Bousso (Dynamics of Immune Responses Unit) for discussions and advice, M.-A. Nicola (Plate-Forme d'Imagerie Dynamique) for help with bioluminescence experiments, X. Montagutelli, Q. Mille, D. Montean, and G. Labas for help with mouse colony management (Central Animal Facility), C. Detchepare and C. Nizak for administrative help (Laboratoire Anticorps en Thérapie et Pathologie), and at University of California, San Francisco (San Francisco, CA): Y. Hu for animal husbandry. The authors are grateful to their colleagues for providing mice or reagents: R. Coffman (DNAX, Palo Alto, CA), B. Hann (University of California, San Francisco), J. J. Lee (Mayo Clinic, Scottsdale, AZ), H. Karasuyama (Tokyo Medical and Dental University Graduate School, Tokyo, Japan), M.P. Reilly (Jefferson Medical College, Philadelphia, PA), and M. Tarik (Montreal University, Montreal, QC, Canada)., ANR-09-GENO-0014,InflammAbs,Contrôle de l'inflammation par les RFc humains dans des modèles murins d'allergie et d'autoimmunité.(2009), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris] (IP), University of California [San Francisco] (UC San Francisco), University of California (UC), Martin, Marie, and Physiopathologie moléculaire: des maladies rares aux maladies communes - Contrôle de l'inflammation par les RFc humains dans des modèles murins d'allergie et d'autoimmunité. - - InflammAbs2009 - ANR-09-GENO-0014 - GENO - VALID
Subjects: MESH: Tumor Burden, Neutrophils, medicine.medical_treatment, Melanoma, Experimental, MESH: Neutrophils, MESH: Mice, Knockout, Biochemistry, Immunoglobulin G, MESH: Antibodies, Monoclonal, Antibodies, Monoclonal, Murine-Derived, Mice, 0302 clinical medicine, Conditional gene knockout, MESH: Animals, MESH: Trastuzumab, Mice, Knockout, 0303 health sciences, biology, Melanoma, Antibodies, Monoclonal, Hematology, Tumor Burden, 3. Good health, MESH: Melanoma, Experimental, 030220 oncology & carcinogenesis, [SDV.IMM]Life Sciences [q-bio]/Immunology, MESH: Rituximab, [SDV.IMM.IMM] Life Sciences [q-bio]/Immunology/Immunotherapy, Antibody, Rituximab, MESH: Xenograft Model Antitumor Assays, MESH: Cell Line, Tumor, [SDV.IMM] Life Sciences [q-bio]/Immunology, MESH: Mice, Transgenic, medicine.drug_class, Immunology, Mice, Nude, Breast Neoplasms, Mice, Transgenic, MESH: Receptors, IgG, Antibodies, Monoclonal, Humanized, Monoclonal antibody, 03 medical and health sciences, Antigen, MESH: Mice, Inbred C57BL, Cell Line, Tumor, MESH: Mice, Nude, MESH: Antibody-Dependent Cell Cytotoxicity, medicine, Animals, Humans, MESH: Mice, 030304 developmental biology, MESH: Humans, Receptors, IgG, Antibody-Dependent Cell Cytotoxicity, Cancer, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, Cell Biology, Immunotherapy, Trastuzumab, medicine.disease, Xenograft Model Antitumor Assays, Mice, Inbred C57BL, MESH: Antibodies, Monoclonal, Humanized, MESH: Antibodies, Monoclonal, Murine-Derived, biology.protein, MESH: Breast Neoplasms
Abstract: International audience; Tumor engraftment followed by monoclonal antibody (mAb) therapy targeting tumor antigens represents a gold standard for assessing the efficiency of mAbs to eliminate tumor cells. Mouse models have demonstrated that receptors for the Fc portion of immunoglobulin G (FcγRs) are critical determinants of mAb therapeutic efficacy, but the FcγR-expressing cell populations responsible remain elusive. We show that neutrophils are responsible for mAb-induced therapy of both subcutaneous syngeneic melanoma and human breast cancer xenografts. mAb-induced tumor reduction, abolished in neutropenic mice, could be restored in FcγR-deficient hosts upon transfer of FcγR+ neutrophils or upon human FcγRIIA/CD32A transgenic expression. Finally, conditional knockout mice unable to perform FcγR-mediated activation and phagocytosis specifically in neutrophils were resistant to mAb-induced therapy. Our work suggests that neutrophils are necessary and sufficient for mAb-induced therapy of subcutaneous tumors, and represent a new and critical focal point for optimizing mAb-induced immunotherapies that will impact on human cancer treatment.
Published: 2013
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3. Rituximab is an efficient and safe treatment in adults with steroid-dependent minimal change disease

Author: Rachid Mojaat, Emmanuelle Plaisier, Philippe Remy, Philippe Lang, Karine Dahan, Vincent Audard, Pierre Ronco, Helene Munyentwali, Georges Deschênes, Khedidja Bouachi, CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de néphrologie et transplantation, 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 référence du syndrome néphrotique idiopathique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor, 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), Unité de Néphrologie Pédiatrique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Remodelage et Reparation du Tissu Renal, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and RONCO, Pierre
Subjects: Male, medicine.medical_treatment, 030232 urology & nephrology, MESH: Antigens, CD20, law.invention, Antibodies, Monoclonal, Murine-Derived, 0302 clinical medicine, Randomized controlled trial, Recurrence, law, Minimal change disease, MESH: Aged, MESH: Middle Aged, MESH: Antigens, CD19, nephrotic syndrome, Middle Aged, 3. Good health, Immunosuppressive drug, Nephrology, MESH: Nephrosis, Lipoid, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Female, Rituximab, MESH: Immunosuppressive Agents, Immunosuppressive Agents, medicine.drug, Adult, medicine.medical_specialty, Adolescent, Nephrosis, Antigens, CD19, glomerulopathy, 03 medical and health sciences, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Internal medicine, medicine, Humans, Adverse effect, Aged, Retrospective Studies, MESH: Adolescent, 030203 arthritis & rheumatology, MESH: Humans, business.industry, Nephrosis, Lipoid, MESH: Adult, MESH: Retrospective Studies, Retrospective cohort study, Antigens, CD20, medicine.disease, clinical nephrology, MESH: Male, MESH: Recurrence, MESH: Antibodies, Monoclonal, Murine-Derived, Immunology, Prednisone, business, MESH: Prednisone, MESH: Female, Nephrotic syndrome
Abstract: International audience; Development of steroid dependency in patients with nephrotic syndrome may require a long-term multi-drug therapy at risk of drug toxicity and renal failure. Rituximab treatment reduces the steroid dosage and the need for immunosuppressive therapy in pediatric patients. Here we retrospectively analyze the efficacy and safety of rituximab in adult patients with steroid-dependent minimal change disease. To do this, we analyzed the outcome of all adult patients treated with rituximab for steroid-dependent minimal change nephrotic syndrome over a mean follow-up of 29.5 months (range 5.1-82 months). Seventeen patients with steroid-dependent or frequently relapsing minimal change nephrotic syndrome, unresponsive to several immunosuppressive medications, were treated with rituximab. Eleven patients had no relapses after rituximab infusion (mean follow-up 26.7 months, range 5.1-82 months) and nine of them were able to come off all other immunosuppressive drugs and steroids during follow-up. Six patients relapsed at least once after a mean time of 11.9 months (mean follow-up 34.5 months, range 16.9-50.1 months), but their immunosuppressive drug treatment could be stopped or markedly reduced during this time. No adverse events were recorded. Thus, rituximab is efficient and safe in adult patients suffering from severe steroid-dependent minimal change disease. Prospective randomized trials are needed to confirm this study.
Published: 2013
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4. Treatment of hepatitis C-associated mixed cryoglobulinemia vasculitis

Author: Patrice Cacoub, Aurélien Delluc, J.C. Piette, David Saadoun, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Groupe d'Etude de la Thrombose de Bretagne Occidentale (GETBO), 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)-Université de Brest (UBO), Département de Médecine Interne et Pneumologie [Brest] (DMIP - Brest), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Biologie et thérapeutique des pathologies immunitaires (BTPI), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Service de médecine interne [CHU Pitié-Salpétrière], 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), and Université de Brest (UBO)-Institut Brestois Santé Agro Matière (IBSAM)
Subjects: viruses, Fulminant, Gastroenterology, Polyethylene Glycols, MESH: Antibodies, Monoclonal, MESH: Recombinant Proteins, Antibodies, Monoclonal, Murine-Derived, 0302 clinical medicine, hemic and lymphatic diseases, B-Lymphocytes, MESH: Vasculitis, MESH: Immunologic Factors, Antibodies, Monoclonal, Glomerulonephritis, Hepatitis C, Cryoglobulinemia, Recombinant Proteins, MESH: Hepatitis C, Chronic, 3. Good health, Purpura, 030211 gastroenterology & hepatology, Rituximab, MESH: Interferon-alpha, medicine.symptom, Vasculitis, medicine.drug, MESH: Antiviral Agents, medicine.medical_specialty, MESH: Cryoglobulinemia, Alpha interferon, Interferon alpha-2, Antiviral Agents, 03 medical and health sciences, Rheumatology, MESH: Ribavirin, MESH: B-Lymphocytes, Internal medicine, Ribavirin, medicine, Humans, Immunologic Factors, 030203 arthritis & rheumatology, MESH: Humans, business.industry, Interferon-alpha, Hepatitis C, Chronic, medicine.disease, MESH: Polyethylene Glycols, MESH: Antibodies, Monoclonal, Murine-Derived, Immunology, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; PURPOSE OF REVIEW: Hepatitis C virus infection is the main cause of mixed cryoglobulinemia vasculitis. The disease expression of mixed cryoglobulinemia vasculitis is variable, ranging from mild clinical symptoms (purpura, arthralgia) to fulminant life-threatening complications (glomerulonephritis, widespread vasculitis). Treatment of hepatitis C virus-mixed cryoglobulinemia vasculitis may target either the viral trigger (hepatitis C virus) or the downstream B-cell arm of autoimmunity. This review focuses on recent advances in our understanding of the treatment of hepatitis C virus-mixed cryoglobulinemia vasculitis. RECENT FINDINGS: Aggressive antiviral therapy with Peg-IFNalpha and ribavirin should be considered as induction therapy for hepatitis C virus-mixed cryoglobulinemia vasculitis with mild to moderate disease severity and activity. In patients presenting with severe disease, an induction phase of immunosuppression is often necessary while awaiting the generally slow response to antiviral treatments. Combination therapy with rituximab and Peg-IFNalpha plus ribavirin appears logical as it may target both the viral trigger (hepatitis C virus) and cryoglobulin-producing B-cells. SUMMARY: Antiviral therapy and rituximab are the main therapeutic options in hepatitis C virus-mixed cryoglobulinemia vasculitis. Further studies are needed to better define the therapeutic strategy.
Published: 2008
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5. Data quality assessment of ungated flow cytometry data in high throughput experiments

Author: Maura Gasparetto, Robert Gentleman, Ryan R. Brinkman, Clay Smith, A. J. Rossini, Nolwenn Le Meur, Signalisation et Réponses aux Agents Infectieux et Chimiques (SeRAIC), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Fred Hutchinson Cancer Research Center [Seattle] (FHCRC), Terry Fox Laboratory, BC Cancer Agency (BCCRC)-British Columbia Cancer Agency Research Centre, and Université de Rennes (UR)
Subjects: Time Factors, Computer science, MESH: Quality Control, Graft vs Host Disease, MESH: Flow Cytometry, Cell Separation, computer.software_genre, Bioinformatics, MESH: Antibodies, Monoclonal, Antibodies, Monoclonal, Murine-Derived, 0302 clinical medicine, Data acquisition, Joint probability distribution, Cluster Analysis, MESH: Antigens, CD, 0303 health sciences, Antibodies, Monoclonal, exploratory data analysis, MESH: Reproducibility of Results, MESH: Artifacts, Data point, MESH: Cell Survival, Data Interpretation, Statistical, 030220 oncology & carcinogenesis, Data mining, MESH: Computer Graphics, Artifacts, Rituximab, Algorithms, Quality Control, Normalization (statistics), MESH: Cell Line, Tumor, Histology, quality assessment, Cell Survival, MESH: Graft vs Host Disease, Antineoplastic Agents, MESH: Algorithms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Sample (statistics), high throughput, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, MESH: Cell Separation, Article, Pathology and Forensic Medicine, MESH: Software, 03 medical and health sciences, Antigens, CD, Cell Line, Tumor, Histogram, Computer Graphics, Humans, visualization, 030304 developmental biology, Miniaturization, MESH: Humans, software, flow cytometry, MESH: Time Factors, MESH: Biological Markers, Reproducibility of Results, Cell Biology, MESH: Miniaturization, MESH: Cluster Analysis, Exploratory data analysis, MESH: Antibodies, Monoclonal, Murine-Derived, Data quality, MESH: Antineoplastic Agents, MESH: Data Interpretation, Statistical, computer, Biomarkers
Abstract: Traditionally, flow cytometry (FCM) has been a tube-based technique limited to small-scale laboratory and clinical studies. High throughput methods for FCM have recently been developed for drug discovery and advanced research methods (1-4). As an example, flow cytometry high content screening (FC-HCS) can process up to a thousand samples daily at a single workstation, and the results have been equivalent or superior to traditional manual multiparameter staining and analysis techniques. The amount of information generated by high throughput technologies, such as FC-HCS, need to be transformed into executive summaries, which are brief enough for creative studies by a human researcher (5). Quality control and quality assessment are crucial steps in the development, and use of new high throughput technologies and their associated information services (5-7). Quality control in clinical cell analysis by FCM has been considered (8,9). As an example, Edwards et al. (9) proposed some quality scores for monitoring the quality of immunophenotyping process (e.g., blood acquisition, cell preparation, lymphocyte staining). They showed that a low degree of temporal parameter variation exits within individual whereas significant variations can exist between donors with respect to the parameter monitored. However little has been done with high throughput FCM. For example, quality control of FCM experiments should include the assessment of instrument parameters that affect the accuracy and precision of data. In that respect, Gratama et al. (10) have proposed some guidelines such as monitoring the fluorescence measurements by computing calibration plots for each fluorescent parameter. However, such procedures are not yet systematically applied, and data quality assessment is often needed to overcome a lack of data quality control. The aim of data quality assessment is to detect whether any measurements of any samples are substantially different from the others, in ways that were not likely to be biologically motivated. The rationale is that such samples should be identified, investigated, and potentially removed from any downstream analyses. Quality control, on the other hand, measures such quantities during the assaying procedure and can alert the user to problems at a time where they can be corrected. Data quality assessment in high throughput FCM experiment is complicated by the volume of data involved and by the many processing steps required to produce those data. Each instrument manufacturer has created software to drive the data acquisition process of the cytometer (e.g., CellQuest Pro by BD Biosciences, San Jose, CA; Summit by DakoCytomation, Fort Collins, CO; or Expo32 by Beckman Coulter, Fullerton, CA). These tools are primarily designed for their proprietary instrument interface and offer few, or no, data quality assessment functions. Third party analysis and management tools, such as FlowJo (Tree Star, Ashland, OR), WinList (Verity Software House, Topsham, ME) or FCSExpress (Denovo Software, Thornhill, Canada) provide researchers with more capable “offline” analysis tools but remain limited in term of data quality assessment. We propose a number of one- and two-dimensional graphical methods for exploring the data in the hope that they would be of some use to the investigators. The basis of our approach is that, given a cell line, or a single sample, divided in several aliquots, the distribution of the same physical or chemical characteristics (e.g., side light scatter - SSC-or forward light scatter -FSC-) should be similar between aliquots. To test this hypothesis, we made use of graphical exploratory data analysis (EDA). Five distinct visualization methods were implemented to explore the distributions and densities of ungated FCM data: Empirical Cumulative Distribution Function (ECDF) plots, histograms, boxplots, and two types of bivariate plots. These different graphical methods should provide investigators with different views of the data. ECDF plots have been widely used in the analysis of microarray data where they help to detect defective print tips, or plates of reagents that have not been well handled (11). These plots can quickly reveal differences in the distributions, but are not particularly useful for understanding the shape of a distribution. Histograms help to visualize the shape of the distribution and can reveal structure, such as the mode. Boxplots summarize the location of the distribution and can reveal asymmetry but are mainly applicable to unimodal distributions. Boxplots are also commonly used in the processing of microarray data where they help to identify hybridization artifacts and assess the need for between-array normalization to deal with scale differences among different arrays (11). Finally, we use bivariate plots representation in two different ways. In fact in some cases, when comparing two samples, we found two-dimensional displays more informative, i.e., two-dimensional summaries can show differences in samples, while the one-dimensional summaries, mentioned earlier, are similar. One common use of bivariate plots in FCM experiments is to display the joint distribution of two continuous variables as dot plots (e.g., FSC versus SSC). However the analysis of such dot plots might be a challenge as the high density of plotted data points (an average of 10,000 data points per sample) might form a blot and the frequency of the observations might not be easily appreciated. To overcome this issue we propose to use contour plots where contour lines might be interpreted as the frequency of observations with respect to the x–y plane. The second use of bivariate plots, for high throughput FCM data, is to render per well summary statistics for a particular plate in the format of a scatterplot. In this view each point represents a single well and the x and y values are chosen to be various summary statistics. We illustrate the need and usefulness of those visualization tools to assess FCM data quality through examination of two FC-HCS datasets. Our results demonstrate that the application of these graphical analysis methods to ungated FCM data provides a systematic and efficient method of data quality assessment, preventing time-consuming gating and further analysis of unreliable samples. Although the methods we propose are primarily aimed at the discovery of data quality problems, they may detect differences that are biologically motivated. Hence, we discourage the automatic removal of aberrant samples and emphasize the need to check whether such underlying biological causes are present.
Published: 2007
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6. Sarcopenia is an independent prognostic factor in elderly patients with diffuse large B-cell lymphoma treated with immunochemotherapy

Author: Hervé Tilly, Hélène Lanic, Romain Modzelewski, Florian Clatot, Jean Michel Picquenot, Sylvain Mareschal, Jerôme Kraut-Tauzia, Fabrice Jardin, Aspasia Stamatoullas, Stéphane Leprêtre, Service d'Hématologie, Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), Equipe Quantification en Imagerie Fonctionnelle (QuantIF-LITIS), Laboratoire d'Informatique, de Traitement de l'Information et des Systèmes (LITIS), Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Université Le Havre Normandie (ULH), Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Normandie Université (NU), 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), Breton, Céline, Service d'Oncologie Médicale, CRLCC Haute Normandie-Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), service d'anatomo-pathologie, CRLCC Henri Becquerel, Equipe Quantification en Imagerie Fonctionnelle ( QuantIF-LITIS ), Laboratoire d'Informatique, de Traitement de l'Information et des Systèmes ( LITIS ), Université Le Havre Normandie ( ULH ), Normandie Université ( NU ) -Normandie Université ( NU ) -Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Institut national des sciences appliquées Rouen Normandie ( INSA Rouen Normandie ), Normandie Université ( NU ) -Université Le Havre Normandie ( ULH ), Normandie Université ( NU ), 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 ), and CRLCC Haute Normandie-CRLCC Henri Becquerel
Subjects: Male, Sarcopenia, MESH : Retrospective Studies, MESH : Antineoplastic Combined Chemotherapy Protocols, Body Surface Area, MESH : Aged, Gastroenterology, Body Mass Index, 0302 clinical medicine, Antineoplastic Combined Chemotherapy Protocols, MESH : Muscle, Skeletal, MESH: Sarcopenia, ComputingMilieux_MISCELLANEOUS, MESH: Treatment Outcome, Aged, 80 and over, 0303 health sciences, education.field_of_study, Prognosis, 3. Good health, [SDV] Life Sciences [q-bio], MESH: Antineoplastic Combined Chemotherapy Protocols, Oncology, Vincristine, 030220 oncology & carcinogenesis, Rituximab, MESH : Vincristine, medicine.medical_specialty, Tomography Scanners, X-Ray Computed, MESH : Tomography Scanners, X-Ray Computed, MESH: Prognosis, MESH: Body Mass Index, MESH: Doxorubicin, 03 medical and health sciences, Humans, MESH : Aged, 80 and over, education, Cyclophosphamide, Aged, Retrospective Studies, MESH: Age Factors, MESH: Humans, [ SDV ] Life Sciences [q-bio], MESH : Humans, MESH : Prednisone, MESH: Cyclophosphamide, MESH: Retrospective Studies, MESH : Organ Size, medicine.disease, MESH : Body Mass Index, MESH : Sarcopenia, MESH: Antibodies, Monoclonal, Murine-Derived, MESH: Prednisone, MESH: Female, Body mass index, Diffuse large B-cell lymphoma, Cancer Research, MESH: Organ Size, [SDV]Life Sciences [q-bio], MESH : Lymphoma, Large B-Cell, Diffuse, Antibodies, Monoclonal, Murine-Derived, MESH: Aged, 80 and over, MESH: Body Surface Area, International Prognostic Index, Prednisone, hemic and lymphatic diseases, MESH : Female, MESH : Cyclophosphamide, MESH: Aged, Body surface area, MESH: Muscle, Skeletal, MESH : Prognosis, Age Factors, Hematology, Organ Size, Treatment Outcome, Female, Lymphoma, Large B-Cell, Diffuse, medicine.drug, MESH : Body Surface Area, MESH : Male, Population, MESH: Vincristine, MESH : Treatment Outcome, Internal medicine, medicine, MESH : Doxorubicin, Muscle, Skeletal, 030304 developmental biology, MESH: Tomography Scanners, X-Ray Computed, business.industry, MESH: Male, MESH : Antibodies, Monoclonal, Murine-Derived, Surgery, Doxorubicin, MESH: Lymphoma, Large B-Cell, Diffuse, MESH : Age Factors, business
Abstract: International audience; Approximately 25-35% of patients with diffuse large B-cell lymphoma (DLBCL) are older than 70 years. The aim of this study was to investigate the prognostic impact of depletion of skeletal muscle (sarcopenia) in elderly patients with DLBCL. This retrospective analysis included 82 patients with DLBCL older than 70 years and treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, Oncovin, prednisone) or R-miniCHOP. Sarcopenia was measured by the analysis of stored computed tomography (CT) images at the L3 level at baseline. The surface of the muscular tissues was selected according to the CT Hounsfield unit. This value was normalized for stature in order to calculate the lumbar L3 skeletal muscle index (LSMI, in cm(2)/m(2)). The mean age of the population was 78 years. According to the defined cut-offs for LSMI, 45 patients with DLBCL were considered sarcopenic. Sarcopenic patients displayed a higher revised International Prognostic Index (R-IPI) compared with patients without sarcopenia, and were older, with a mean age of 80 years and 77 years, respectively (p = 0.006). With a median follow-up of 39 months, the 2-year overall survival in the sarcopenic population was 46% compared with 84% in the non-sarcopenic group (HR = 3.22; 95% CI = 1.73-5.98; p = 0.0002). In a multivariate analysis, sarcopenia remained predictive of outcome (p = 0.005). Sarcopenia is a relevant and predictive factor in elderly patients with DLBCL treated with rituximab plus chemotherapy.
Published: 2013

7. 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
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8. Management of noninfectious mixed cryoglobulinemia vasculitis: data from 242 cases included in the CryoVas survey

Author: Antoine Huart, Estibaliz Lazaro, P. Belenotti, Olivier Hermine, David Launay, Guillaume Le Guenno, Thierry Zenone, Adeline Lacraz, Patrice Cacoub, Evguenia Krastinova, Franck Bridoux, Patricia Senet, P. Rullier, Elisabeth Diot, Xavier Mariette, Luc de Saint-Martin, Thomas Quemeneur, Isabelle Marie, Emmanuelle Plaisier, Benjamin Terrier, Fabrice Carrat, Fabrice Bonnet, Olivier Hinschberger, Jean-Emmanuel Kahn, Jean-Marc Léger, Immunologie - Immunopathologie - Immunothérapeutique (I3), 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), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Médecine Interne [Rouen], Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, Normandie Université (NU), Physiopathologie et biothérapies des maladies inflammatoires et autoimmunes, Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Internal Medicine, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service de Néphrologie-Transplantation-Dialyse, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Service de Médecine Interne (MARSEILLE - Med Int), Assistance Publique - Hôpitaux de Marseille (APHM), Département de Médecine Interne et Pneumologie [Brest] (DMIP - Brest), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Groupe d'Etude de la Thrombose de Bretagne Occidentale (GETBO), Université de Brest (UBO)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Département de Médecine Interne (VALENCIENNES - Med Int), CH Valenciennes, Service de Néphrologie et Immunopathologie Clinique, Centre Hospitalier Universitaire de Toulouse, PRES Université de Toulouse, Foie, métabolismes et cancer, 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 Hospitalier Universitaire Estaing, CHU Estaing, Laboratoire d'Immunologie (EA 2686), Université de Lille, Droit et Santé, Service de Médecine Interne B, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service de Médecine Interne, Hôpital Bretonneau, Service de médecine interne et maladies tropicales, CHU Bordeaux [Bordeaux]-Groupe hospitalier Saint-André, Contrôle de la Réponse Immune B et des Lymphoproliférations (CRIBL), Centre National de la Recherche Scientifique (CNRS)-Université de Limoges (UNILIM)-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503), Service de néphrologie - hémodialyse et transplantation rénale, Centre hospitalier universitaire de Poitiers (CHU Poitiers), Médecine Interne (VALENCE - Med Int), Centre hospitalier de Valence, Epidémiologie des maladies infectieuses et modélisation (ESIM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Cytokines, hématopoïèse et réponse immune (CHRI), 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 neurologie 1 [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Régulation de la réponse immune, infection VIH-1 et autoimmunité, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Dermatologie [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Tenon [APHP], Remodelage et Reparation du Tissu Renal, Service de médecine interne [CHU Pitié-Salpétrière], Biologie et thérapeutique des pathologies immunitaires (BTPI), Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC), Immunologie - Immunopathologie - Immunothérapeutique ( I3 ), 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 ), Centre de recherche en épidémiologie et santé des populations ( CESP ), Université de Versailles Saint-Quentin-en-Yvelines ( UVSQ ) -Université Paris-Sud - Paris 11 ( UP11 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale ( INSERM ), CHU Rouen-Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ), Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Service de Médecine Interne ( MARSEILLE - Med Int ), Assistance Publique - Hôpitaux de Marseille ( APHM ), Département de Médecine Interne et Pneumologie [Brest] ( DMIP - Brest ), Centre Hospitalier Régional Universitaire de Brest ( CHRU Brest ), Groupe d'Etude de la Thrombose de Bretagne Occidentale ( GETBO ), Université de Brest ( UBO ), Département de Médecine Interne ( VALENCIENNES - Med Int ), 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 ), Laboratoire d'Immunologie ( EA 2686 ), Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ), Contrôle de la Réponse Immune B et des Lymphoproliférations ( CRIBL ), Centre National de la Recherche Scientifique ( CNRS ) -Université de Limoges ( UNILIM ) -Génomique, Environnement, Immunité, Santé, Thérapeutique ( GEIST FR CNRS 3503 ), Université de Poitiers-Centre hospitalier universitaire de Poitiers ( CHU Poitiers ), Médecine Interne ( VALENCE - Med Int ), Epidémiologie des maladies infectieuses et modélisation ( ESIM ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Cytokines, hématopoïèse et réponse immune ( CHRI ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Université Paris-Sud - Paris 11 ( UP11 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Tenon [APHP], Biologie et thérapeutique des pathologies immunitaires ( BTPI ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Centre National de la Recherche Scientifique ( CNRS ), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Service de Médecine Interne [CHU Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Université de Brest (UBO)-Université de Brest (UBO), CHU Clermont-Ferrand, Université de Limoges (UNILIM)-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-Centre National de la Recherche Scientifique (CNRS), Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de dermatologie et allergologie [CHU Tenon], CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service Médecine interne et immunopathologie clinique [CHU Toulouse], Pôle IUCT [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), 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 ), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut Brestois Santé Agro Matière (IBSAM), and Université de Brest (UBO)-Université de Brest (UBO)-Université de Brest (UBO)
Subjects: Male, MESH: Combined Modality Therapy, MESH : Retrospective Studies, [SDV]Life Sciences [q-bio], MESH : Aged, Arthritis, 030204 cardiovascular system & hematology, Biochemistry, Gastroenterology, MESH: Antibodies, Monoclonal, Cohort Studies, Antibodies, Monoclonal, Murine-Derived, 0302 clinical medicine, Prednisone, Adrenal Cortex Hormones, MESH : Female, MESH: Data Collection, MESH: Cohort Studies, MESH : Algorithms, MESH: Treatment Outcome, MESH: Aged, MESH: Middle Aged, Data Collection, MESH: Vasculitis, Antibodies, Monoclonal, Hematology, Middle Aged, Connective tissue disease, Combined Modality Therapy, 3. Good health, MESH : Vasculitis, MESH : Infection, Treatment Outcome, Cryoglobulinemia, MESH : Antibodies, Monoclonal, Rituximab, Female, medicine.symptom, MESH : Data Collection, Vasculitis, MESH: Infection, Algorithms, medicine.drug, medicine.medical_specialty, MESH: Cryoglobulinemia, MESH : Male, Immunology, MESH : Cohort Studies, MESH: Algorithms, MESH : Treatment Outcome, Infections, MESH : Adrenal Cortex Hormones, MESH: Adrenal Cortex Hormones, 03 medical and health sciences, Internal medicine, medicine, Humans, MESH : Middle Aged, Aged, Retrospective Studies, 030203 arthritis & rheumatology, MESH: Humans, [ SDV ] Life Sciences [q-bio], business.industry, MESH : Humans, MESH: Retrospective Studies, Cell Biology, Skin ulcer, medicine.disease, MESH : Cryoglobulinemia, MESH: Male, MESH : Antibodies, Monoclonal, Murine-Derived, Regimen, Peripheral neuropathy, MESH: Antibodies, Monoclonal, Murine-Derived, business, MESH : Combined Modality Therapy, MESH: Female
Abstract: Data on the clinical spectrum and therapeutic management of noninfectious mixed cryoglobulinemia vasculitis (CryoVas) in the era of hepatitis C virus screening are lacking. We analyzed data from 242 patients with noninfectious mixed CryoVas included in the French multicenter CryoVas survey. Baseline manifestations were purpura (75%), peripheral neuropathy (52%), arthralgia or arthritis (44%), glomerulonephritis (35%), cutaneous ulcers (16%), and cutaneous necrosis (14%). A connective tissue disease was diagnosed in 30% and B-cell non-Hodgkin lymphoma in 22%, whereas the CryoVas was considered to be essential in 48%. With the use of Cox-marginal structural models, rituximab plus corticosteroids showed the greater therapeutic efficacy compared with corticosteroids alone and alkylating agents plus corticosteroids to achieve complete clinical, renal, and immunologic responses and a prednisone dosage < 10 mg/d at 6 months. However, this regimen was also associated with severe infections, particularly when high doses of corticosteroids were used, whereas death rates did not differ between the therapeutic regimens. The role of each of these strategies remains to be defined in well-designed randomized controlled trials.
Published: 2012
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9. A novel antiangiogenic and vascular normalization therapy targeted against human CD160 receptor

Author: Stéphanie Brayer, Philippe Le Bouteiller, Nabila Jabrane-Ferrat, Fabienne Meggetto, Armand Bensussan, Salem Chouaib, Julie Tabiasco, Jean Kadouche, Olivier Chose, Maryse Aguerre-Girr, Muhammad Zaeem Noman, Sylvie Giuriato, Muriel Golzio, Sophie Chabot, Karine Bigot, Stéphane Galiacy, François Malecaze, Jérôme Giustiniani, Alexandra C. Provost, Jean-Philippe Jais, Elisabeth Bellard, Marc Abitbol, Justin Teissié, Centre de Physiopathologie Toulouse Purpan (CPTP), 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)-Centre National de la Recherche Scientifique (CNRS), Centre d'étude et de recherche thérapeutiques en ophtalmologie, Université Paris Descartes - Paris 5 (UPD5), Institut de pharmacologie et de biologie structurale (IPBS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Université Fédérale Toulouse Midi-Pyrénées, Cytokines et Immunologie des Tumeurs Humaines (U753), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Ophtalmologie [Hopital Purpan - Toulouse], CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Department of Cell Biology (DUMC), Duke University Medical Center, MAT Biopharma, MAT Ltd., Immunologie, dermatologie, oncologie, Oncodermatologie, immunologie et cellules souches cutanées (IDO (U976 / UMR_S 976)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Physiopathologie Toulouse Purpan ex IFR 30 et IFR 150 (CPTP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Institut de Sciences et Technologies du Medicament de Toulouse Toulouse, France. (UMR2587, CNRS-PIERRE FABRE), PIERRE FABRE-Centre National de la Recherche Scientifique (CNRS), Fonctions Cellulaires et Moleculaires de l'Appareil Respiratoire et des Vaisseaux, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service d'informatique médicale et biostatistiques [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Centre de biophysique moléculaire (CBM), Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Mondor de recherche biomédicale (IMRB), CHU Necker - Enfants Malades [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Physiopathologie de Toulouse Purpan ( CPTP ), Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Université Paris Descartes - Paris 5 ( UPD5 ), Institut de pharmacologie et de biologie structurale ( IPBS ), Centre National de la Recherche Scientifique ( CNRS ) -Université Toulouse III - Paul Sabatier ( UPS ), Cytokines et Immunologie des Tumeurs Humaines ( U753 ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Department of Cell Biology ( DUMC ), Oncodermatologie, immunologie et cellules souches cutanées ( DIO U976 ), and Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM )
Subjects: Male, Pathology, MESH : Retinal Diseases, MESH : Antineoplastic Combined Chemotherapy Protocols, Angiogenesis, MESH: Rabbits, Fibroblast growth factor, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Neovascularization, Antibodies, Monoclonal, Murine-Derived, Mice, MESH : Fibroblast Growth Factor 2, 0302 clinical medicine, Antineoplastic Combined Chemotherapy Protocols, MESH : Receptors, Immunologic, Immunology and Allergy, MESH : Female, MESH: Animals, Receptors, Immunologic, Melanoma, MESH: Antigens, CD, MESH : Cyclophosphamide, ComputingMilieux_MISCELLANEOUS, Mice, Inbred BALB C, 0303 health sciences, Neovascularization, Pathologic, MESH : Mice, Nude, 3. Good health, MESH: Antineoplastic Combined Chemotherapy Protocols, MESH : Colonic Neoplasms, MESH : Corneal Neovascularization, 030220 oncology & carcinogenesis, Colonic Neoplasms, Female, Fibroblast Growth Factor 2, Rabbits, MESH : GPI-Linked Proteins, medicine.symptom, Intravital microscopy, Retinopathy, medicine.medical_specialty, MESH: Melanoma, MESH : Male, Immunology, MESH : Melanoma, MESH: Mice, Inbred BALB C, Mice, Nude, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, GPI-Linked Proteins, Article, 03 medical and health sciences, Retinal Diseases, Antigens, CD, Cell surface receptor, MESH : Mice, MESH : Antigens, CD, medicine, MESH: Mice, Nude, Animals, Humans, Corneal Neovascularization, MESH : Rabbits, Cyclophosphamide, MESH: Mice, MESH: Receptors, Immunologic, MESH : Mice, Inbred BALB C, MESH: Retinal Diseases, 030304 developmental biology, MESH: Colonic Neoplasms, MESH: Humans, MESH: Corneal Neovascularization, MESH: Fibroblast Growth Factor 2, MESH : Humans, MESH : Neovascularization, Pathologic, MESH: Cyclophosphamide, medicine.disease, eye diseases, MESH: Male, MESH : Antibodies, Monoclonal, Murine-Derived, MESH: Antibodies, Monoclonal, Murine-Derived, Corneal neovascularization, MESH : Animals, MESH: GPI-Linked Proteins, MESH: Neovascularization, Pathologic, MESH: Female
Abstract: A monoclonal anti-CD160 antibody inhibits the growth of new vessels in pathological ocular and tumor neoangiogenesis but not in healthy tissues., Angiogenesis plays an essential role in several diseases of the eye and in the growth of solid tumors, but existing antiangiogenic therapies have limited benefits in several cases. We report the antiangiogenic effects of a monoclonal antibody, CL1-R2, in several animal models of neovascularization. CL1-R2 recognizes human CD160, a membrane receptor which is conserved in various mammal species. We show that CD160 is expressed on the endothelial cells of newly formed blood vessels in human colon carcinoma and mouse B16 melanoma but not in vessels of healthy tissues. CL1-R2 reduced fibroblast growth factor 2–induced neovascularization in the rabbit cornea, in a mouse model of oxygen-induced retinopathy, and in a mouse Matrigel plug assay. Treatment of B16 melanoma-bearing mice with CL1-R2 combined with cyclophosphamide chemotherapy caused regression of the tumor vasculature and normalization of the remaining vessels as shown by Doppler ultrasonography, intravital microscopy, and histology. These studies validate CD160 as a potential new target in cases of human pathological ocular and tumor neoangiogenesis that do not respond or become resistant to existing antiangiogenic drugs.
Published: 2011
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10. Preclinical studies on the mechanism of action and the anti-lymphoma activity of the novel anti-CD20 antibody GA101

Author: Stéphanie Herveau, Stéphane Dalle, Pablo Umana, Lina Reslan, Timothee Besseyre de Horts, Frank Herting, Thomas Friess, Charles Dumontet, Christian Klein, Adriana Plesa, Equipe 14, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Oncogénèse et progression tumorale, Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Hematology Laboratory, Hospices Civils de Lyon, Institut de Mathématiques de Bourgogne [Dijon] (IMB), Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université de Bourgogne (UB), Institut de Génomique Fonctionnelle ( IGF ), Centre National de la Recherche Scientifique ( CNRS ) -Université Montpellier 2 - Sciences et Techniques ( UM2 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Montpellier 1 ( UM1 ) -Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Montpellier 2 - Sciences et Techniques ( UM2 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Montpellier 1 ( UM1 ) -Université de Montpellier ( UM ) -Centre de Recherche en Cancérologie de Lyon ( CRCL ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université 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 ), 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 ), Institut de Mathématiques de Bourgogne [Dijon] ( IMB ), Université de Bourgogne ( UB ) -Centre National de la Recherche Scientifique ( CNRS ), and Centre de Recherche en Cancérologie de Lyon ( CRCL )
Subjects: Cancer Research, Follicular lymphoma, MESH: Antigens, CD20, Mice, SCID, Pharmacology, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, MESH: Antibodies, Monoclonal, Antibodies, Monoclonal, Murine-Derived, Mice, MESH: Lymphoma, Follicular, 0302 clinical medicine, immune system diseases, hemic and lymphatic diseases, MESH : Female, MESH: Animals, MESH: Mice, SCID, Cytotoxicity, Lymphoma, Follicular, MESH : Cyclophosphamide, CD20, 0303 health sciences, Antibodies, Monoclonal, 3. Good health, Oncology, 030220 oncology & carcinogenesis, MESH : Antibodies, Monoclonal, Monoclonal, Rituximab, Female, Antibody, MESH: Dose-Response Relationship, Immunologic, medicine.drug, MESH: Xenograft Model Antitumor Assays, MESH: Cell Line, Tumor, medicine.drug_class, Dose-Response Relationship, Immunologic, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, MESH : Xenograft Model Antitumor Assays, Monoclonal antibody, Antibodies, Monoclonal, Humanized, MESH : Antibodies, Monoclonal, Humanized, 03 medical and health sciences, MESH: Gene Expression Profiling, Antigen, MESH : Antigens, CD20, Cell Line, Tumor, MESH : Mice, medicine, Animals, Humans, Cyclophosphamide, MESH: Mice, 030304 developmental biology, MESH: Humans, MESH : Cell Line, Tumor, Gene Expression Profiling, MESH : Lymphoma, Follicular, MESH : Gene Expression Profiling, MESH : Humans, MESH: Cyclophosphamide, medicine.disease, Antigens, CD20, Xenograft Model Antitumor Assays, MESH : Mice, SCID, MESH : Antibodies, Monoclonal, Murine-Derived, MESH : Dose-Response Relationship, Immunologic, MESH: Antibodies, Monoclonal, Humanized, MESH: Antibodies, Monoclonal, Murine-Derived, biology.protein, MESH : Animals, MESH: Female
Abstract: GA101 is a novel glycoengineered Type II CD20 monoclonal antibody. When compared with rituximab, it mediates less complement-dependent cytotoxicity (CDC). As expected for a Type II antibody, GA101 appears not to act through CDC and is more potent than the Type I antibody rituximab in inducing cell death via nonclassical induction of apoptosis cytotoxicity, with more direct cytotoxicity and more antibody-dependent cell-mediated cytotoxicity. We evaluated the antitumor activity of GA101 against the human-transformed follicular lymphoma RL model in vivo in severe combined immunodeficient mice (SCID) mice. GA101 induced stronger inhibition of tumor growth than rituximab. Combination of GA101 with cyclophosphamide in vivo confirmed the superiority of GA101 over rituximab. Neutralizing the complement system with cobra venom factor partially impaired the antitumor activity of rituximab, but had no impact on the efficacy of GA101. In vitro GA101 more potently induced cell death of RL cells than rituximab. The expression of a limited number of genes was found to be induced by both antibodies after exposure in vitro. Among these, early growth response 1 and activation transcription factor 3 were confirmed to be increased at the protein level, suggesting a possible role of these proteins in the apoptotic signalling of anti-CD20 antibodies. These data imply that GA101 is superior to rituximab not only as a single agent, but also in combination with chemotherapy. These data suggest the presence of novel signalization pathways activated after exposure to anti-CD20 antibodies. Mol Cancer Ther; 10(1); 178–85. ©2011 AACR.
Published: 2011
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11. Effects of rituximab therapy on quality of life in patients with primary Sjögren's syndrome

Author: Devauchelle-Pensec V, Morvan J, Ac, Rat, Jousse-Joulin S, Pennec Y, Jo, Pers, Jamin C, Yves Renaudineau, Quintin-Roué I, Cochener B, Youinou P, Saraux A, CHRU Brest - Service de Rhumatologie (CHU - BREST - Rhumato), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Maladies chroniques, santé perçue, et processus d'adaptation (APEMAC), Université Paris Descartes - Paris 5 (UPD5)-Université de Lorraine (UL), Centre d'Investigation Clinique - Epidemiologie Clinique/essais Cliniques Nancy, Cancéropôle du Grand Est-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Epidémiologie et Evaluations Cliniques [CHRU Nancy] (Pôle S2R), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service de Rhumatologie [CHRU Nancy], Institut d’Électronique, de Microélectronique et de Nanotechnologie - UMR 8520 (IEMN), Centrale Lille-Institut supérieur de l'électronique et du numérique (ISEN)-Université de Valenciennes et du Hainaut-Cambrésis (UVHC)-Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Université Polytechnique Hauts-de-France (UPHF), Hôpital Morvan [Brest], CHRU Brest - Laboratoire d'Anatomo-Pathologie (CHU - AnaPath), Université de Brest (UBO), Service d'ophtalmologie [Brest], Université de Brest (UBO)-Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Immunologie et Pathologie (EA2216), Université de Brest (UBO)-IFR148, Centre d'Investigation Clinique (CIC - Brest), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Lorraine (UL), Lymphocyte B et Auto-immunité (LBAI), Université de Brest (UBO)-Institut Brestois Santé Agro Matière (IBSAM), Laboratoire de dynamique et structures des matériaux moléculaires (LDSMM), Université de Lille, Sciences et Technologies-Université du Littoral Côte d'Opale-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Immunologie et Immunothérapie, Laboratoire de Traitement de l'Information Medicale (LaTIM), Institut National de la Santé et de la Recherche Médicale (INSERM)-IMT Atlantique Bretagne-Pays de la Loire (IMT Atlantique), 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), Institut d’Électronique, de Microélectronique et de Nanotechnologie (IEMN) - UMR 8520 (IEMN), Centre National de la Recherche Scientifique (CNRS)-Université de Lille-Université Polytechnique Hauts-de-France (UPHF)-Ecole Centrale de Lille-Université Polytechnique Hauts-de-France (UPHF)-Institut supérieur de l'électronique et du numérique (ISEN), Unite mixte de recherche en droit comparé (UMRDC), Université Panthéon-Sorbonne (UP1)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire, CHRU Brest - Service de Rhumatologie ( CHU - BREST - Rhumato ), Centre Hospitalier Régional Universitaire de Brest ( CHRU Brest ), Maladies chroniques, santé perçue, et processus d'adaptation ( APEMAC ), Université Paris Descartes - Paris 5 ( UPD5 ) -Université de Lorraine ( UL ), Cancéropôle du Grand Est-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service d'Epidémiologie et Evaluations Cliniques [CHRU Nancy] ( Pôle S2R ), Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ), Institut d’Électronique, de Microélectronique et de Nanotechnologie (IEMN) - UMR 8520 ( IEMN ), Ecole Centrale de Lille-Institut supérieur de l'électronique et du nunérique (ISEN)-Université de Valenciennes et du Hainaut-Cambresis ( UVHC ) -Université de Lille-Centre National de la Recherche Scientifique ( CNRS ), Unite mixte de recherche en droit comparé ( UMRDC ), Université Panthéon-Sorbonne ( UP1 ) -Centre National de la Recherche Scientifique ( CNRS ), CHRU Brest - Laboratoire d'Anatomo-Pathologie ( CHU - AnaPath ), Université de Brest ( UBO ), Université de Brest ( UBO ) -Centre Hospitalier Régional Universitaire de Brest ( CHRU Brest ), Immunologie et Pathologie ( EA2216 ), Université de Brest ( UBO ) -IFR148, Centre d'Investigation Clinique ( CIC - Brest ), and Université de Brest ( UBO ) -Institut National de la Santé et de la Recherche Médicale ( INSERM )
Subjects: Male, MESH: Antirheumatic Agents, Health Status, Severity of Illness Index, Antibodies, Monoclonal, Murine-Derived, hemic and lymphatic diseases, Surveys and Questionnaires, MESH : Female, MESH: Health Status, MESH: Treatment Outcome, MESH: Middle Aged, MESH : Questionnaires, MESH : Adult, Middle Aged, MESH : Antirheumatic Agents, humanities, Sjogren's Syndrome, Treatment Outcome, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, MESH: Young Adult, Antirheumatic Agents, MESH : Severity of Illness Index, Female, MESH: Rituximab, MESH: Pain, Rituximab, MESH : Pain, Adult, Adolescent, MESH : Male, MESH : Young Adult, Pain, MESH : Treatment Outcome, Young Adult, MESH : Adolescent, [ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology, MESH: Severity of Illness Index, Humans, MESH : Middle Aged, MESH : Health Status, MESH: Surveys and Questionnaires, MESH: Adolescent, MESH: Humans, MESH: Questionnaires, MESH : Humans, MESH: Quality of Life, MESH: Adult, MESH : Quality of Life, MESH: Male, MESH : Antibodies, Monoclonal, Murine-Derived, stomatognathic diseases, MESH: Sjogren's Syndrome, MESH: Antibodies, Monoclonal, Murine-Derived, Quality of Life, MESH : Sjogren's Syndrome, MESH: Female, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; OBJECTIVES: To assess the efficacy of the anti-CD20 antibody rituximab in improving physical function and health-related quality of life (HRQoL) in patients with active primary Sjögren's syndrome (pSS), as well as the duration and sources of HRQoL improvements. METHODS: Sixteen patients with pSS received rituximab infusions (375 mg/m2) at weeks 0 and 1 and were followed up for 36 weeks. All patients fulfilled 2002 American-European Consensus Group criteria for pSS and had active disease defined as scores >50 mm on two of four 100-mm visual analogue scales (VAS) evaluating global disease activity, fatigue, pain, and dryness. Standardised evaluations including the Short Form 36 Health Survey (SF-36) were conducted. SF-36 score changes from baseline to weeks 12, 24, and 36 were assessed. RESULTS: Baseline mean SF-36 scores were considerably decreased, compared to the general same-age population. Role-physical (14.1 ± 27.4), role-emotional (12.5 ± 29.9), vitality (26.2 ± 14.3), and general health (32.6 ± 11.2) were the dimensions with the worst scores. Twelve weeks after rituximab, the mental component summary score was improved in 15 patients (mean improvement, 31.2 ± 36.4, p=0.001) and the physical component summary score in 14 patients (mean improvement, 16.9 ± 26.2, p=0.049). Further improvements occurred from week 12 to week 24, and most of the gains were sustained at week 36. Improvements in the physical and mental component summary scores failed to correlate with improvements in the VAS scores. CONCLUSIONS: Substantial alterations in HRQoL were noted in patients with pSS. Rituximab infusions without corticosteroid therapy produced meaningful improvements in HRQoL. Controlled studies of rituximab are needed.
Published: 2010

12. Immuno-fluorescence in situ hybridization index predicts survival in patients with diffuse large B-cell lymphoma treated with R-CHOP: a GELA study

Author: Copie-Bergman, Christiane, Gaulard, Philippe, Leroy, Karen, Briere, Josette, Baia, Maryse, Jais, Jean-Philippe, Salles, Gilles, Berger, Françoise, Haioun, Corinne, Tilly, Herve, Emile, Jean-François, Banham, Alison, Mounier, Nicolas, Gisselbrecht, Christian, Feugier, Pierre, Coiffier, Bertrand, Molina, Thierry, Groupe Henri Mondor-Albert Chenevier, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Henri Mondor-Hôpital Albert Chenevier, Institut Mondor de Recherche Biomédicale ( IMRB ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), Service d'anatomo-pathologie [Paris], Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Diderot - Paris 7 ( UPD7 ) -Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Service d'informatique médicale et biostatistiques [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Département de pathologie, Hospices Civils de Lyon ( HCL ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon, 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 ), Service d'Hématologie, CRLCC Henri Becquerel, Service d'anatomie pathologique, Université de Versailles Saint-Quentin-en-Yvelines ( UVSQ ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Ambroise Paré, Laboratoire épidémiologie et oncogénèse des tumeurs digestives, Université de Versailles Saint-Quentin-en-Yvelines ( UVSQ ), Nuffield Department of Clinical Laboratory Sciences, University of Oxford [Oxford], Service d'onco-hématologie, CHU Nice-Hôpital l'Archet, Service d'hématologie-oncologie adultes, Service d'Hématologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ), Département de Pathologie, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôtel-Dieu-Université Paris Descartes - Paris 5 ( UPD5 ), This study was supported by a grant from the Programme Hospitalier de Recherche Clinique AP-HP (AOM 03060), Dako A/S and ARTGIL (Association pour la Recherche Thérapeutique, Génétique et Immunologique dans les lymphomes). AHB was supported by Leukaemia Research, UK., Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Hôpital Albert Chenevier, 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), 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), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hospices Civils de Lyon (HCL), Université Claude Bernard Lyon 1 (UCBL), 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), Service d'anatomie pathologique [CHU Ambroise-Paré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Ambroise Paré [AP-HP], Biomarqueurs et essais cliniques en Cancérologie et Onco-Hématologie (BECCOH), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay, Centre Hospitalier Universitaire de Nice (CHU Nice)-Hôpital l'Archet, Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôtel-Dieu-Université Paris Descartes - Paris 5 (UPD5), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP]
Subjects: MESH : Antineoplastic Combined Chemotherapy Protocols, MESH : Aged, MESH : Dose-Response Relationship, Drug, MESH: Risk Assessment, MESH : Lymphoma, Large B-Cell, Diffuse, MESH: Antibodies, Monoclonal, MESH: Dose-Response Relationship, Drug, MESH : Proto-Oncogene Proteins c-bcl-2, MESH: Proportional Hazards Models, MESH: Aged, 80 and over, immune system diseases, hemic and lymphatic diseases, MESH : Female, MESH: In Situ Hybridization, Fluorescence, MESH : Risk Assessment, MESH : Cyclophosphamide, MESH: Treatment Outcome, MESH: Aged, MESH: Middle Aged, MESH : Prognosis, MESH: Enzyme-Linked Immunosorbent Assay, MESH : Enzyme-Linked Immunosorbent Assay, MESH: Predictive Value of Tests, MESH : In Situ Hybridization, Fluorescence, MESH: Antineoplastic Combined Chemotherapy Protocols, MESH : Genes, myc, MESH: Survival Analysis, MESH : Antibodies, Monoclonal, MESH : Severity of Illness Index, MESH : Vincristine, MESH: Probability, MESH : Probability, MESH : Male, MESH : Drug Administration Schedule, MESH: Vincristine, MESH : Treatment Outcome, MESH: Drug Administration Schedule, MESH: Multivariate Analysis, MESH: Prognosis, MESH: Doxorubicin, MESH: Severity of Illness Index, MESH : Doxorubicin, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH : Middle Aged, MESH : Predictive Value of Tests, MESH : Aged, 80 and over, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Genes, myc, MESH: Humans, MESH : Humans, MESH: Biological Markers, MESH: Cyclophosphamide, MESH : Multivariate Analysis, MESH : Prednisone, MESH : Proportional Hazards Models, MESH: Male, MESH : Antibodies, Monoclonal, Murine-Derived, MESH : Biological Markers, MESH: Proto-Oncogene Proteins c-bcl-2, MESH: Antibodies, Monoclonal, Murine-Derived, MESH: Lymphoma, Large B-Cell, Diffuse, MESH : Survival Analysis, MESH: Prednisone, MESH: Female
Abstract: International audience; PURPOSE: To evaluate the prognostic value of cell of origin immunohistochemical markers and BCL2, BCL6, and c-MYC translocations in a homogeneous cohort of patients with diffuse large B-cell lymphoma (DLBCL) treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). PATIENTS AND METHODS: Patients with CD20+ DLBCL were enrolled in the randomized LNH98-5 and 01-5B Groupe d'Etude des Lymphomes de l'Adulte trials. Paraffin-embedded tumor samples of 119 patients treated with R-CHOP were analyzed by immunohistochemistry for CD10, BCL6, MUM1/IRF4, LMO2, and forkhead box protein P1 (FOXP1) expression and for BCL2, BCL6, and c-MYC breakpoints by fluorescence in situ hybridization (FISH) on tissue microarray. RESULTS: LMO2 expression and BCL2 breakpoint were associated with the germinal center (GC) subtype defined by Hans' algorithm, respectively (P < .0001; P = .0002) whereas FOXP1 expression and BCL6 breakpoint were associated with the non-germinal center (non-GC) subtype (P = .008 and P = .0001, respectively). The immunohistochemical markers analyzed independently, GC/non-GC phenotype and BCL2 breakpoint did not predict overall survival (OS). BCL6 breakpoint was significantly associated with an unfavorable impact on OS (P = .04). Interestingly, an immunoFISH index, defined by positivity for at least two of three non-GC markers (FOXP1, MUM1/IRF4, BCL6 breakpoint) was significantly associated with a shorter 5-year OS rate (44%; 95% CI, 28 to 60 v 78%; 95% CI, 59 to 89; P = .01) which was independent (P = .04) of the age-adjusted International Prognostic Index (P = .04) in multivariate analysis. CONCLUSION: Our study demonstrates that combining immunohistochemistry with FISH allows construction of an immunoFISH index that significantly predicts survival in elderly DLBCL patients treated with R-CHOP.
Published: 2009
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13. Treatment of primary Sjögren syndrome with rituximab. In response

Author: Saraux, Alain, Nowak, Emmanuel, Devauchelle-Pensec, Valérie, Michel, Geneviève, CHRU Brest - Service de Rhumatologie (CHU - BREST - Rhumato), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Immunologie et Pathologie (EA2216), Université de Brest (UBO)-IFR148, Centre d'Investigation Clinique (CIC - Brest), and Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: MESH: Humans, MESH: Sjogren's Syndrome, [SDV.IMM] Life Sciences [q-bio]/Immunology, MESH: Antibodies, Monoclonal, Murine-Derived, MESH: Immunologic Factors, [SDV.IMM]Life Sciences [q-bio]/Immunology, MESH: Female, MESH: Male, ComputingMilieux_MISCELLANEOUS
Abstract: International audience
Published: 2014

14. Identification of a novel BET bromodomain inhibitor-sensitive, gene regulatory circuit that controls Rituximab response and tumour growth in aggressive lymphoid cancers

Author: Emadali, Anouk, Rousseaux, Sophie, Bruder-Costa, Juliana, Rome, Claire, Duley, Samuel, Hamaidia, Sieme, Betton, Patricia, Debernardi, Alexandra, Leroux, Dominique, Bernay, Benoit, Kieffer-Jaquinod, Sylvie, Combes, Florence, Ferri, Elena, Mckenna, Charles, Petosa, Carlo, Bruley, Christophe, Garin, Jérôme, Ferro, Myriam, Gressin, Rémy, Callanan, Mary, Khochbin, Saadi, Laboratoire de Biologie à Grande Échelle (BGE - UMR S1038), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), 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), Pôle recherche, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble, Service d'onco-hématologie et génétique, CHU Grenoble, Department of Chemistry, University of Southern California (USC), Institut de biologie structurale (IBS - UMR 5075 ), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Service d'hématologie clinique, INSERM U823, équipe 7 (Voies Oncogéniques Des Hémopathies Malignes), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), INCa-DHOS Translational Research program, 'ARC subvention libre' programs, Fondation de France and Ligue Contre le Cancer, Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)
Subjects: MESH: Cell Differentiation, MESH: Cell Nucleus, MESH: Cell Line, Tumor, cancer-testis factor, MESH: Antigens, CD20, MESH: Gene Expression Profiling, MESH: Protein Structure, Tertiary, immune system diseases, hemic and lymphatic diseases, MESH: Cell Proliferation, CD40, MESH: Animals, MESH: Gene Silencing, CCDC86, MESH: Epigenesis, Genetic, MESH: Mice, SCID, MESH: Mice, MESH: Gene Regulatory Networks, MESH: Lymphoma, B-Cell, Double hit B-cell non-Hodgkin's lymphoma, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, MESH: Proteomics, MESH: Gene Expression Regulation, Neoplastic, MESH: Triazoles, MESH: Antibodies, Monoclonal, Murine-Derived, MESH: Antineoplastic Agents, MESH: Lymphoma, MESH: Azepines, MESH: Neoplasm Transplantation, R- CHOP
Abstract: International audience; Immuno-chemotherapy elicit high response rates in B-cell non-Hodgkin lymphoma but heterogeneity in response duration is observed, with some patients achieving cure and others showing refractory disease or relapse. Using a transcriptome-powered targeted proteomics screen, we discovered a gene regulatory circuit involving the nuclear factor CYCLON which characterizes aggressive disease and resistance to the anti-CD20 monoclonal antibody, Rituximab, in high-risk B-cell lymphoma. CYCLON knockdown was found to inhibit the aggressivity of MYC-overexpressing tumours in mice and to modulate gene expression programs of biological relevance to lymphoma. Furthermore, CYCLON knockdown increased the sensitivity of human lymphoma B cells to Rituximab in vitro and in vivo. Strikingly, this effect could be mimicked by in vitro treatment of lymphoma B cells with a small molecule inhibitor for BET bromodomain proteins (JQ1). In summary, this work has identified CYCLON as a new MYC cooperating factor that autonomously drives aggressive tumour growth and Rituximab resistance in lymphoma. This resistance mechanism is amenable to next-generation epigenetic therapy by BET bromodomain inhibition, thereby providing a new combination therapy rationale for high-risk lymphoma.
Published: 2013
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15. The effect of B-cell depletion therapy on serological evidence of B-cell and plasmablast activation in patients with rheumatoid arthritis over multiple cycles of rituximab treatment

Author: Guy Serre, J. C. W. Edwards, H.C. Perry, I. de la Torre, Leonor Nogueira, M.C. Dickson, Maria J. Leandro, HM Parsons, Geraldine Cambridge, University College of London [London] (UCL), GlaxoSmithKline [Stevenage, UK] (GSK), GlaxoSmithKline [Headquarters, London, UK] (GSK), Unité différenciation épidermique et auto-immunité rhumatoïde (UDEAR), Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: MESH: B-Cell Activating Factor / genetics, Gene Expression, MESH: Lymphocyte Depletion, Lymphocyte Activation, Serology, Arthritis, Rheumatoid, Antibodies, Monoclonal, Murine-Derived, MESH: Aged, 80 and over, MESH: Arthritis, Rheumatoid / genetics, MESH: Arthritis, Rheumatoid / immunology, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Recurrence, MESH: Arthritis, Rheumatoid / pathology, B-Cell Activating Factor, Immunology and Allergy, Medicine, MESH: Aged, Aged, 80 and over, MESH: Middle Aged, biology, B-cell depletion, MESH: B-Lymphocyte Subsets / drug effects, Remission Induction, CD23, Cell Differentiation, Middle Aged, medicine.anatomical_structure, Rheumatoid arthritis, MESH: Receptors, IgE / genetics, Antirheumatic Agents, BAFF, Rituximab, MESH: Rituximab, Antibody, MESH: B-Lymphocyte Subsets / pathology, medicine.drug, MESH: Cell Differentiation, Adult, MESH: Gene Expression, MESH: Receptors, IgE / immunology, Immunology, Plasma Cells, MESH: Plasma Cells / drug effects, B-Lymphocyte Subsets, Lymphocyte Depletion, MESH: Immunoglobulin M / immunology, Humans, B-cell activating factor, MESH: Lymphocyte Activation, MESH: Plasma Cells / immunology, MESH: Autoantibodies / blood, B cell, MESH: B-Cell Activating Factor / immunology, Aged, Autoantibodies, MESH: Humans, MESH: Arthritis, Rheumatoid / therapy, business.industry, Receptors, IgE, MESH: Immunoglobulin M / genetics, Autoantibody, MESH: Adult, medicine.disease, MESH: Antibodies, Monoclonal, Murine-Derived / therapeutic use, MESH: Recurrence, Tumor Necrosis Factor Receptor Superfamily, Member 7, MESH: Plasma Cells / pathology, MESH: Tumor Necrosis Factor Receptor Superfamily, Member 7 / immunology, MESH: Biomarkers / metabolism, Immunoglobulin M, MESH: Tumor Necrosis Factor Receptor Superfamily, Member 7 / genetics, MESH: B-Lymphocyte Subsets / immunology, biology.protein, MESH: Antirheumatic Agents / therapeutic use, business, Biomarkers
Abstract: International audience; B-cell depletion therapy (BCDT) based on rituximab (RTX) induces clinical remission in a majority of seropositive patients with Rheumatoid arthritis (RA). However, all patients eventually relapse. The aim of this study was to determine whether dynamic changes in combinations of serological measures of B-cell activation were associated over up to three cycles of BCDT. We included only RA patients who gave an adequate clinical response, as measured by DAS28. Twenty three patients were studied over 1 cycle, 21 over 2, and 15 over 3 cycles of BCDT. Serum analytes including isotypes of Rheumatoid factors (RhF) and anti-citrullinated protein/peptide antibodies (ACPA), B-cell activating factor (BAFF), serum free light chains (SFLC), soluble CD23 (sCD23), antibodies to tetanus toxoid (TT) and to pneumococcal capsular polysaccharide (PCP) were measured by ELISA at 4 key points in each cycle, namely: Baseline (pre-RTX in each cycle); when B-cell depleted (CD19+B-cells < 5/μl); at B-cell return (CD19+B-cells ≥ 5/μl); and at clinical relapse (ΔDAS28 > 1.2). SFLC were used as a measure of plasmablast activity. As sCD23 is cleaved from naïve B-cells coincident with attaining CD27 expression, levels were used as a novel measure of maturation of B-cells to CD27+. The most consistent changes between baseline and B-cell depletion within all 3 cycles were in SFLC, sCD23 and IgM-RhF which fell and in BAFF levels which rose. After 3 complete cycles of BCDT, both IgM autoantibodies and IgG-CCP had decreased, BAFF levels were higher (all p < 0.05); other analytes remained unchanged compared with baseline. Dynamic changes in λSFLC, sCD23, IgM-RhF and BAFF were also consistently associated with relapse in patients with longer clinical responses after B-cell return. Incremental rises in sCD23 levels in cycles 2 and 3 were correlated with time to relapse. Repopulation of the periphery after BCDT is initiated by naïve B-cells and precedes relapse. Our study showed that differentiation into plasmablasts, attended by sCD23 and SFLC production and IgM-RhF specificity may be required to precipitate relapse in patients experiencing longer responses after RTX. These studies also provide novel information related to the resumption of autoimmune responses and their association with B-cell kinetics following BCDT.
Published: 2013
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16. The future of B cell-targeted therapies in Sjögren's syndrome

Author: Divi Cornec, Valérie Devauchelle-Pensec, Coralie Clodic, Alain Saraux, Jacques-Olivier Pers, LabEX IGO Immunothérapie Grand Ouest, CHRU Brest - Service de Rhumatologie (CHU - BREST - Rhumato), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Immunologie et Pathologie (EA2216), and Université de Brest (UBO)-IFR148
Subjects: MESH: Immunotherapy, Sialic Acid Binding Ig-like Lectin 2, MESH: Antigens, CD20, Disease, Antibodies, Monoclonal, Murine-Derived, 0302 clinical medicine, Immunology and Allergy, CD20, 0303 health sciences, B-Lymphocytes, Clinical Trials as Topic, biology, 3. Good health, Sjogren's Syndrome, Oncology, MESH: B-Cell Activation Factor Receptor, MESH: Sialic Acid Binding Ig-like Lectin 2, Monoclonal, [SDV.IMM]Life Sciences [q-bio]/Immunology, Rituximab, Immunotherapy, Antibody, medicine.drug, Lymphotoxin-beta, MESH: Clinical Trials as Topic, Immunology, Antibodies, Monoclonal, Humanized, 03 medical and health sciences, Antigen, MESH: Lymphotoxin-beta, MESH: B-Lymphocytes, medicine, Humans, B-cell activating factor, 030304 developmental biology, 030203 arthritis & rheumatology, MESH: Humans, business.industry, Interleukin-6, Antigens, CD20, MESH: Interleukin-6, MESH: Sjogren's Syndrome, MESH: Antibodies, Monoclonal, Humanized, MESH: Antibodies, Monoclonal, Murine-Derived, biology.protein, business, Epratuzumab, B-Cell Activation Factor Receptor
Abstract: International audience; Primary Sjögren's syndrome is a systemic autoimmune disease characterized by progressive exocrine gland destruction, resulting clinically in eyes and mouth dryness. To date, no treatment has been proven effective to modify the course of this slow-evolving disease. B cells are now considered to play a central role in the pathogenesis of primary Sjögren's syndrome because their functions are not restrained to antibody production. Thus, several B-cell targeting therapies are under clinical investigation. Rituximab, a monoclonal antibody directed to CD20 and leading to transient blood B-cell depletion, has shown partial improvements in subjective and objective sicca symptoms in small studies. However, the results of two large controlled trials are awaited before considering its use in large populations of patients. Several other therapeutic strategies are being studied, targeting other B-cell surface proteins (epratuzumab and anti-CD22) or major cytokines of B-cell homeostasis (e.g., BAFF, IL-6 and lymphotoxin-β). Although great hope is generated by the trials of these specific therapies, another challenge for clinical researchers is the development of reliable tools to assess the activity of Sjögren's syndrome and its response to treatment.
Published: 2013
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17. Identification of a novel BET bromodomain inhibitor-sensitive, gene regulatory circuit that controls Rituximab response and tumour growth in aggressive lymphoid cancers

Author: Emadali, Anouk, Rousseaux, Sophie, Bruder-Costa, Juliana, Rome, Claire, Duley, Samuel, Hamaidia, Sieme, Betton, Patricia, Debernardi, Alexandra, Leroux, Dominique, Bernay, Benoit, Kieffer-Jaquinod, Sylvie, Combes, Florence, Ferri, Elena, Mckenna, Charles, Petosa, Carlo, Bruley, Christophe, Garin, Jérôme, Ferro, Myriam, Gressin, Rémy, Callanan, Mary, Khochbin, Saadi, Duley, Samuel, Laboratoire de Biologie à Grande Échelle (BGE - UMR S1038), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), 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), Pôle recherche, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble, Service d'onco-hématologie et génétique, CHU Grenoble, Department of Chemistry, University of Southern California (USC), Institut de biologie structurale (IBS - UMR 5075 ), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Service d'hématologie clinique, INSERM U823, équipe 7 (Voies Oncogéniques Des Hémopathies Malignes), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), and INCa-DHOS Translational Research program, 'ARC subvention libre' programs, Fondation de France and Ligue Contre le Cancer
Subjects: MESH: Cell Differentiation, MESH: Cell Nucleus, MESH: Cell Line, Tumor, cancer-testis factor, MESH: Antigens, CD20, [SDV.GEN] Life Sciences [q-bio]/Genetics, MESH: Gene Expression Profiling, MESH: Protein Structure, Tertiary, immune system diseases, hemic and lymphatic diseases, MESH: Cell Proliferation, CD40, MESH: Animals, MESH: Gene Silencing, CCDC86, MESH: Epigenesis, Genetic, MESH: Mice, SCID, MESH: Mice, MESH: Gene Regulatory Networks, MESH: Lymphoma, B-Cell, Double hit B-cell non-Hodgkin's lymphoma, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, MESH: Proteomics, MESH: Gene Expression Regulation, Neoplastic, MESH: Triazoles, MESH: Antibodies, Monoclonal, Murine-Derived, MESH: Antineoplastic Agents, MESH: Lymphoma, MESH: Azepines, MESH: Neoplasm Transplantation, R- CHOP
Abstract: International audience; Immuno-chemotherapy elicit high response rates in B-cell non-Hodgkin lymphoma but heterogeneity in response duration is observed, with some patients achieving cure and others showing refractory disease or relapse. Using a transcriptome-powered targeted proteomics screen, we discovered a gene regulatory circuit involving the nuclear factor CYCLON which characterizes aggressive disease and resistance to the anti-CD20 monoclonal antibody, Rituximab, in high-risk B-cell lymphoma. CYCLON knockdown was found to inhibit the aggressivity of MYC-overexpressing tumours in mice and to modulate gene expression programs of biological relevance to lymphoma. Furthermore, CYCLON knockdown increased the sensitivity of human lymphoma B cells to Rituximab in vitro and in vivo. Strikingly, this effect could be mimicked by in vitro treatment of lymphoma B cells with a small molecule inhibitor for BET bromodomain proteins (JQ1). In summary, this work has identified CYCLON as a new MYC cooperating factor that autonomously drives aggressive tumour growth and Rituximab resistance in lymphoma. This resistance mechanism is amenable to next-generation epigenetic therapy by BET bromodomain inhibition, thereby providing a new combination therapy rationale for high-risk lymphoma.
Published: 2013
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18. Bordetella holmesii bacteremia in a renal transplant recipient: emergence of a new pathogen

Author: Frederique Bocquentin, Celine Lacour, Marie Essig, O. Barraud, T. Chambaraud, G. Ensergueix, J.P. Rerolle, Julien Allard, Zara Dickson, Jean-Claude Aldigier, Service de Néphrologie, Dialyse, Transplantations [CHU Limoges], CHU Limoges, Association Limousine pour l'Utlisation du Rein Artificiel à Domicile, ALURAD, Service de Bactériologie, Virologie, Hygiène [CHU Limoges], Pharmacologie des Immunosuppresseurs et de la Transplantation (PIST), Université de Limoges (UNILIM)-CHU Limoges-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Marquet, Pierre
Subjects: Adult, Male, Bordetella, MESH: Bordetella Infections, MESH: Kidney Transplantation, Antibodies, Monoclonal, Murine-Derived, Immunocompromised Host, 03 medical and health sciences, 0302 clinical medicine, MESH: Anti-Bacterial Agents, Membranoproliferative glomerulonephritis, medicine, MESH: Immunocompromised Host, Humans, Endocarditis, 030212 general & internal medicine, Kidney transplantation, Bordetella Infections, Bordetella holmesii, 0303 health sciences, Transplantation, MESH: Humans, biology, 030306 microbiology, business.industry, MESH: Adult, MESH: Bordetella, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, medicine.disease, biology.organism_classification, Kidney Transplantation, MESH: Male, Anti-Bacterial Agents, 3. Good health, [SDV.SP] Life Sciences [q-bio]/Pharmaceutical sciences, Pneumonia, Infectious Diseases, MESH: Antibodies, Monoclonal, Murine-Derived, Bacteremia, Immunology, MESH: Immunosuppressive Agents, Rituximab, business, Immunosuppressive Agents
Abstract: International audience; Bordetella holmesii is a gram-negative rod that was initially identified in 1995. It causes bacteremia, pneumonia, and endocarditis mostly in patients with anatomical or functional asplenia. We report here, to the best of our knowledge, the first case of B. holmesii bacteremia in a renal transplant recipient following rituximab therapy for recurrence of membranoproliferative glomerulonephritis.
Published: 2012
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19. A 4-weekly course of rituximab is safe and improves tumor control for patients with minimal residual disease persisting 3 months after autologous hematopoietic stem-cell transplantation: results of a prospective multicenter phase II study in patients with follicular lymphoma

Author: Corinne Haioun, Gilles Salles, Eric Deconinck, F. Lazreg, Loïc Bergougnoux, Pauline Brice, Christian Recher, Philippe Colombat, Norbert Vey, Michel Attal, Jean-François Rossi, Remy Gressin, Noel Milpied, Franck Morschhauser, Georges Delsol, Service d'hématologie, Hôpital Claude Huriez [Lille], CHU Lille-CHU Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], CHU Bordeaux [Bordeaux], CHU Grenoble-Hôpital Michallon, Service d'hématologie/oncologie, CHU Lyon-Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Service d'hématologie-oncologie adultes, 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), Service d'Hématologie, Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), 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), Service d'hématologie [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Service d'hématologie et oncologie médicale, Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Lapeyronie-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Roche, Laboratoire d'Hématologie [Purpan], Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], Saas, Philippe, 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), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris]
Subjects: autologous stem cell transplantation, Neoplasm, Residual, medicine.medical_treatment, Follicular lymphoma, Phases of clinical research, Hematopoietic stem cell transplantation, Gastroenterology, Polymerase Chain Reaction, MESH: Lymphoma, Follicular, Antibodies, Monoclonal, Murine-Derived, 0302 clinical medicine, Autologous stem-cell transplantation, Medicine, Prospective Studies, Lymphoma, Follicular, CD20, MESH: Aged, MESH: Middle Aged, biology, Hematopoietic Stem Cell Transplantation, Hematology, Middle Aged, 3. Good health, Oncology, MESH: Young Adult, 030220 oncology & carcinogenesis, [SDV.IMM]Life Sciences [q-bio]/Immunology, Rituximab, medicine.drug, Adult, medicine.medical_specialty, [SDV.IMM] Life Sciences [q-bio]/Immunology, Adolescent, Antineoplastic Agents, 03 medical and health sciences, Young Adult, follicular lymphoma, Internal medicine, Humans, MESH: Hematopoietic Stem Cell Transplantation, MESH: Neoplasm, Residual, Aged, MESH: Adolescent, MESH: Humans, business.industry, MESH: Adult, MESH: Polymerase Chain Reaction, medicine.disease, Minimal residual disease, MESH: Prospective Studies, Surgery, Transplantation, MESH: Antibodies, Monoclonal, Murine-Derived, biology.protein, minimal residual disease, MESH: Antineoplastic Agents, business, 030215 immunology
Abstract: International audience; BACKGROUND: This study explored the efficacy and safety of rituximab as treatment of clinical or molecular residual disease after autologous stem-cell transplantation (ASCT) in follicular lymphoma (FL). PATIENTS AND METHODS: Forty patients with CD20+ FL and clinically (group A, n = 14) or clono-specific PCR-detectable (group B, n = 25) residual disease persisting 3 months after ASCT received rituximab 375 mg/m² once weekly for 4 weeks. RESULTS: Response rate at day 50 was 36% [90% confidence interval (CI) 15-61] in group A (World Health Organization criteria) and 52% (90% CI 34-70) in group B (conversion PCR-undetectable status to undetectable status). The best response rate was 71% [nine complete responses (CRs) and one partial response] in group A and 76% in group B. At 36 months, all 10 responses persisted in group A, whereas 46% of patients in group B still had PCR-undetectable disease. Furthermore, 68% of patients in group B were still in clinical CR. Rituximab after ASCT was safe with few grade 3-4 toxic effects (15% patients), mainly acute reactions and infections. CONCLUSION: Rituximab induced a high rate of durable CRs in patients with clinically detectable disease, as well as durable eradication of PCR-detectable disease in patients with FL after ASCT. Continued molecular responses assessed with a highly sensitive and clono-specific PCR technique were correlated with an excellent disease control.
Published: 2012
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20. Combination of rituximab, bortezomib, doxorubicin, dexamethasone and chlorambucil (RiPAD+C) as first-line therapy for elderly mantle cell lymphoma patients: results of a phase II trial from the GOELAMS

Author: A. El Yamani, Roch Houot, J L Harousseau, Kamal Bouabdallah, Stéphane Courby, M. Ojeda Uribe, Nina Arakelyan, M. Alexis Vigier, Hervé Maisonneuve, Philippe Rodon, Caroline Dartigeas, S. Le Gouill, Remy Gressin, O. Tournilhac, Marie-Pierre Moles, Laurent Sutton, Luc Mathieu Fornecker, D. Assouline, Sylvie Caulet-Maugendre, Christiane Mounier, 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 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), Service d'hématologie clinique, Hôpital Hôtel-Dieu [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hematology, Centre Hospitalier Emile Muller [Mulhouse] (CH E.Muller Mulhouse), Groupe Hospitalier de Territoire Haute Alsace (GHTHA)-Groupe Hospitalier de Territoire Haute Alsace (GHTHA), Department of clinical hematology, CHU Grenoble, Nutrition, croissance et cancer (U 1069) (N2C), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), PRES Université Nantes Angers Le Mans (UNAM), Clinical Haematology, CHU Hôtel-Dieu, Service d'hématologie, 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 hospitalier du Mans, Centre Hospitalier Le Mans (CH Le Mans), Service greffe de moelle osseuse, 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 [Hôpital Edouard Herriot - HCL], Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Centre hospitalier La Roche-Sur-Yon, Université de Rennes (UR)-Hôpital Pontchaillou, Signalisation et Réponses aux Agents Infectieux et Chimiques (SeRAIC), Université de Rennes (UR), 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 Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), 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, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Tours, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), 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), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-IFR140
Subjects: Male, Oncology, medicine.medical_treatment, Kaplan-Meier Estimate, Lymphoma, Mantle-Cell, Dexamethasone, Antibodies, Monoclonal, Murine-Derived, 0302 clinical medicine, rituximab, MESH: Aged, 80 and over, immune system diseases, hemic and lymphatic diseases, Antineoplastic Combined Chemotherapy Protocols, MESH: Treatment Outcome, Aged, 80 and over, MESH: Aged, 0303 health sciences, Bortezomib, bortezomib, Hematology, MESH: Chlorambucil, Boronic Acids, Chemotherapy regimen, 3. Good health, MESH: Antineoplastic Combined Chemotherapy Protocols, Treatment Outcome, Pyrazines, 030220 oncology & carcinogenesis, MESH: Pyrazines, MESH: Dexamethasone, Female, Rituximab, MESH: Boronic Acids, medicine.drug, medicine.medical_specialty, Vincristine, lymphoma, [SDV.CAN]Life Sciences [q-bio]/Cancer, elderly, Disease-Free Survival, 03 medical and health sciences, MESH: Doxorubicin, Internal medicine, medicine, Humans, MESH: Kaplan-Meier Estimate, Aged, 030304 developmental biology, mantle cell, Chemotherapy, MESH: Humans, Chlorambucil, business.industry, medicine.disease, MESH: Male, Surgery, Regimen, Doxorubicin, MESH: Antibodies, Monoclonal, Murine-Derived, MESH: Disease-Free Survival, Mantle cell lymphoma, MESH: Lymphoma, Mantle-Cell, business, MESH: Female
Abstract: International audience; BACKGROUND: There is no consensual first-line chemotherapy for elderly patients with mantle cell lymphoma (MCL). The GOELAMS (Groupe Ouest-Est des Leucémies Aiguës et Maladies du Sang) group previously developed the (R)VAD+C regimen (rituximab, vincristine, doxorubicin, dexamethasone and chlorambucil), which appeared as efficient as R-CHOP (rituximab, cyclophosphamide, doxorubicine, vincristine, prednisone) while less toxic. Based on this protocol, we now added bortezomib (RiPAD+C: rituximab, bortezomib, doxorubicin, dexamethasone and chlorambucil) given its efficacy in relapsed/refractory MCL patients. The goal of the current phase II trial was to evaluate the feasibility and efficacy of the RiPAD+C regimen as frontline therapy for elderly patients with MCL. PATIENTS AND METHODS: Patients between 65 and 80 years of age with newly diagnosed MCL received up to six cycles of RiPAD+C. RESULTS: Thirty-nine patients were enrolled. Median age was 72 years (65-80). After four cycles of RiPAD+C, the overall response rate was 79%, including 51% complete responses (CRs). After six cycles, CR rate increased up to 59%. After a 27-month follow-up, median progression-free survival (PFS) is 26 months and median overall survival has not been reached. Four patients (10%) discontinued the treatment because of a severe toxicity and seven patients (18%) experienced grade 3 neurotoxicity. CONCLUSION: The bortezomib-containing RiPAD+C regimen results in high CR rates and prolonged PFS with predictable and manageable toxic effects in elderly patients with MCL.
Published: 2012
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21. Identification of patients with indolent B cell lymphoma sensitive to rituximab monotherapy

Author: Christophe Jamin, Pierre Youinou, Solène Querellou, Christian Berthou, Pascal Hutin, Yves Renaudineau, Boutahar Bendaoud, Jacques-Olivier Pers, Divi Cornec, Adrian Tempescul, Immunologie et Pathologie (EA2216), Université de Brest (UBO)-IFR148, CHRU Brest - Service de Rhumatologie (CHU - BREST - Rhumato), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), CHRU Brest - Service d'Hématologie (CHU-Brest-Hemato), Department of Nuclear Medicine, and Laboratoire d'Immunologie et Immunothérapie
Subjects: Oncology, Male, MESH: Tumor Burden, MESH: Complement C1q, MESH: Neoplasm Grading, Multimodal Imaging, Antibodies, Monoclonal, Murine-Derived, 0302 clinical medicine, hemic and lymphatic diseases, B-Cell Activating Factor, Norleucine, Medicine, B-cell lymphoma, MESH: Treatment Outcome, MESH: Aged, Hematology, MESH: Middle Aged, biology, General Medicine, Middle Aged, Prognosis, 3. Good health, Tumor Burden, Treatment Outcome, 030220 oncology & carcinogenesis, [SDV.IMM]Life Sciences [q-bio]/Immunology, Rituximab, Female, Antibody, medicine.drug, Adult, medicine.medical_specialty, Lymphoma, B-Cell, Antineoplastic Agents, MESH: Positron-Emission Tomography and Computed Tomography, MESH: Receptors, IgG, MESH: Prognosis, 03 medical and health sciences, Pharmacokinetics, Internal medicine, MESH: Polymorphism, Genetic, Humans, MESH: Norleucine, MESH: B-Cell Activating Factor, B-cell activating factor, Aged, MESH: Lymphoma, B-Cell, Polymorphism, Genetic, MESH: Humans, business.industry, Complement C1q, Receptors, IgG, MESH: Adult, medicine.disease, MESH: Male, Lymphoma, Non-Hodgkin's lymphoma, MESH: Antibodies, Monoclonal, Murine-Derived, Positron-Emission Tomography, Immunology, biology.protein, MESH: Antineoplastic Agents, Neoplasm Grading, business, Tomography, X-Ray Computed, MESH: Female, 030215 immunology
Abstract: International audience; The potential predictive value of tumor bulk, genetic, and immunological variants in patients with low-grade non-Hodgkin's lymphoma to respond to treatment with rituximab (RTX) monotherapy was evaluated. Thus, the value of assessing the effect of 18-fluoro-desoxy-D-glucose (FDG) uptake on PET scan, polymorphisms in Fc gamma receptor (FcγR) IIIa-158, FcγRIIa-131, and C1qA-276 genes in predicting the response to treatment were evaluated in 50 low-grade non-Hodgkin's lymphoma patients. The influence of RTX pharmacokinetics, plasma levels of the B cell-activating factor (BAFF), and human antichimeric antibodies was also investigated. The therapeutic response was evaluated 10 weeks after treatment using revised Cheson's criteria. Lower maximal standardized uptake values (SUV(max)) at baseline were predictive of complete response. FcγRIIIa-158 polymorphism was also associated with complete response to RTX confirming previous findings, whereas polymorphisms in the FcγRIIa-131 and C1qA-276 genes were not. Lower blood levels of RTX were observed in males, but the effectiveness of RTX in males and females was the same. BAFF was not detectable in plasma before or after treatment, and no patients developed human antichimeric antibodies. Low-grade non-Hodgkin's lymphoma patients with a low SUV(max) at baseline and an FcγRIIIa-158 V/V genotype generally had a complete response to RTX.
Published: 2012
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22. Sequential treatment with rituximab followed by CHOP chemotherapy in adult B-cell post-transplant lymphoproliferative disorder (PTLD): the prospective international multicentre phase 2 PTLD-1 trial

Author: Trappe, Ralf, Oertel, Stephan, Leblond, Veronique, Mollee, Peter, Sender, Monica, Reinke, Petra, Neuhaus, Ruth, Lehmkuhl, Hans, Horst, Heinz August, Salles, Gilles, Morschhauser, Franck, Jaccard, Arnaud, Lamy, Thierry, Leithäuser, Malte, Zimmermann, Heiner, Anagnostopoulos, Ioannis, Raphael, Martine, Riess, Hanno, Choquet, Sylvain, Renseigné, Non, Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Service d'hématologie, Hôpital Claude Huriez [Lille], CHU Lille-CHU Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Contrôle de la Réponse Immune B et des Lymphoproliférations (CRIBL), Université de Limoges (UNILIM)-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-Centre National de la Recherche Scientifique (CNRS), Service d'Hématologie clinique et thérapie cellulaire [CHU Limoges], and CHU Limoges
Subjects: Male, Epstein-Barr Virus Infections, Herpesvirus 4, Human, medicine.medical_treatment, MESH: Antigens, CD20, CHOP, Antibodies, Monoclonal, Murine-Derived, 0302 clinical medicine, MESH: Lymphoproliferative Disorders, hemic and lymphatic diseases, Germany, Antineoplastic Combined Chemotherapy Protocols, Clinical endpoint, Prospective Studies, MESH: Aged, MESH: Middle Aged, MESH: Epstein-Barr Virus Infections, Middle Aged, 3. Good health, MESH: Antineoplastic Combined Chemotherapy Protocols, Oncology, Vincristine, 030220 oncology & carcinogenesis, Prednisolone, [SDV.IMM]Life Sciences [q-bio]/Immunology, Rituximab, Female, France, medicine.drug, Adult, medicine.medical_specialty, Cyclophosphamide, Adolescent, MESH: Organ Transplantation, MESH: Vincristine, Post-transplant lymphoproliferative disorder, 03 medical and health sciences, MESH: Doxorubicin, Internal medicine, medicine, Humans, MESH: Germany, Aged, MESH: Adolescent, Chemotherapy, MESH: Humans, business.industry, MESH: Cyclophosphamide, MESH: Adult, MESH: Herpesvirus 4, Human, Organ Transplantation, medicine.disease, Antigens, CD20, MESH: Male, MESH: Prospective Studies, Lymphoproliferative Disorders, Surgery, MESH: France, MESH: Antibodies, Monoclonal, Murine-Derived, Doxorubicin, business, MESH: Prednisolone, MESH: Female, 030215 immunology
Abstract: International audience; BACKGROUND: Post-transplantation lymphoproliferative disorder (PTLD) develops in 1-10% of transplant recipients and can be Epstein-Barr virus (EBV) associated. To improve long-term efficacy after rituximab monotherapy and to avoid the toxic effects of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) chemotherapy seen in first-line treatment, we initiated a phase 2 trial to test whether the subsequent use of rituximab and CHOP would improve the outcome of patients with PTLD. METHODS: In this international multicentre open-label phase 2 trial, treatment-naive adult solid-organ transplant recipients diagnosed with CD20-positive PTLD who had failed to respond to upfront immunosuppression reduction received four courses of rituximab (375 mg/m(2) intravenously) once a week followed by 4 weeks without treatment and four cycles of CHOP every 3 weeks. In case of disease progression during rituximab monotherapy, CHOP was started immediately. Supportive therapy with granulocyte-colony stimulating factor after chemotherapy was mandatory and antibiotic prophylaxis was recommended. The primary endpoint was treatment efficacy measured as response rates in all patients who completed treatment with rituximab and CHOP, per protocol, and response duration, in all patients who completed all planned therapy and responded. Secondary endpoints were frequency of infections, treatment-related mortality, and overall survival. This study is registered at ClinicalTrials.gov, number NCT01458548. FINDINGS: 74 patients were enrolled between Dec 12, 2002 and May 5, 2008, of whom 70 patients were eligible to receive treatment. PTLD was of late type in 53 (76%) of 70 patients, monomorphic in 67 (96%) of 70, and histologically EBV associated in 29 (44%) of 66 cases. Four of 70 patients did not receive CHOP. 53 of 59 patients had a complete or partial response (90%, 95% CI 79-96), of which 40 (68%, 55-78) were complete responses. At data cutoff (June 1, 2011) median response duration in the 53 patients who had responded to treatment had not yet been reached (>79*1 months). The main adverse events were grade 3-4 leucopenia in 42 of 62 patients (68%, 55-78) and infections of grade 3-4 in 26 of 64 patients (41%, 29-53). Seven of 66 patients (11%, 5-21) had CHOP-associated treatment-related mortality. Median overall survival was 6*6 years (95% CI 2*8-10*4; n=70). INTERPRETATION: Our results support the use of sequential immunochemotherapy with rituximab and CHOP in PTLD. FUNDING: F Hoffmann-La Roche, Amgen Germany, Chugaï France.
Published: 2011
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23. Endogenous neurotrophins and Trk signaling in diffuse large B cell lymphoma cell lines are involved in sensitivity to rituximab-induced apoptosis

Author: Anne-Laure Fauchais, Dominique Bordessoule, Marie-Odile Jauberteau, Marie-Claude Lise, Cynthia Bellanger, Lydie Dubanet, D. Troutaud, Homéostasie Cellulaire et Pathologies (HCP), Université de Limoges (UNILIM)-CHU Limoges-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503), Service de Médecine interne A et polyclinique médicale [CHU Limoges], CHU Limoges, Contrôle de la Réponse Immune B et des Lymphoproliférations (CRIBL), Université de Limoges (UNILIM)-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-Centre National de la Recherche Scientifique (CNRS), Service d'Hématologie clinique et thérapie cellulaire [CHU Limoges], Service d'Immunologie et immunogénétique [CHU Limoges], and Université de Limoges (UNILIM)
Subjects: Cancer Treatment, lcsh:Medicine, Fluorescent Antibody Technique, MESH: Flow Cytometry, Tropomyosin receptor kinase A, MESH: Brain-Derived Neurotrophic Factor, Receptor, Nerve Growth Factor, Immunoenzyme Techniques, Antibodies, Monoclonal, Murine-Derived, 0302 clinical medicine, Neurotrophic factors, immune system diseases, hemic and lymphatic diseases, Nerve Growth Factor, Molecular Cell Biology, Tumor Cells, Cultured, lcsh:Science, MESH: Fluorescent Antibody Technique, MESH: Nerve Growth Factor, Apoptotic Signaling Cascade, Non-Hodgkin lymphoma, 0303 health sciences, Multidisciplinary, biology, Cell Death, MESH: Real-Time Polymerase Chain Reaction, MESH: Receptor, trkC, MESH: Receptor, trkB, MESH: Receptor, trkA, MESH: Enzyme-Linked Immunosorbent Assay, Hematology, Signaling in Selected Disciplines, Flow Cytometry, MESH: Drug Resistance, Neoplasm, Signaling Cascades, 3. Good health, Oncology, 030220 oncology & carcinogenesis, Medicine, Rituximab, Lymphomas, Lymphoma, Large B-Cell, Diffuse, Immunotherapy, Neurotrophin, medicine.drug, Research Article, Signal Transduction, Lymphoma, B-Cell, Blotting, Western, Immunology, Antineoplastic Agents, Enzyme-Linked Immunosorbent Assay, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Real-Time Polymerase Chain Reaction, 03 medical and health sciences, medicine, MESH: Blotting, Western, Humans, Receptor, trkB, Receptor, trkC, MESH: Tumor Cells, Cultured, Nerve Growth Factors, RNA, Messenger, Receptor, trkA, Autocrine signalling, MESH: Immunoenzyme Techniques, Biology, 030304 developmental biology, MESH: Lymphoma, B-Cell, MESH: RNA, Messenger, Brain-derived neurotrophic factor, Oncogenic Signaling, MESH: Humans, MESH: Nerve Growth Factors, Brain-Derived Neurotrophic Factor, lcsh:R, MESH: Receptor, Nerve Growth Factor, medicine.disease, nervous system, MESH: Antibodies, Monoclonal, Murine-Derived, Drug Resistance, Neoplasm, Trk receptor, Hematologic cancers and related disorders, Cancer research, biology.protein, MESH: Antineoplastic Agents, MESH: Lymphoma, Large B-Cell, Diffuse, lcsh:Q, Diffuse large B-cell lymphoma
Abstract: International audience; BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is a common and often fatal malignancy. Immunochemotherapy, a combination of rituximab to standard chemotherapy, has resulted in improved survival. However a substantial proportion of patients still fail to reach sustained remission. We have previously demonstrated that autocrine brain-derived neurotrophic factor (BDNF) production plays a function in human B cell survival, at least partly via sortilin expression. As neurotrophin receptor (Trks) signaling involved activation of survival pathways that are inhibited by rituximab, we speculated that neurotrophins may provide additional support for tumour cell survival and therapeutic resistance in DLBCL. METHODOLOGY/PRINCIPAL FINDINGS: In the present study, we used two DLBCL cell lines, SUDHL4 and SUDHL6, known to be respectively less and more sensitive to rituximab. We found by RT-PCR, western blotting, cytometry and confocal microscopy that both cell lines expressed, in normal culture conditions, BDNF and to a lesser extent NGF, as well as truncated TrkB and p75(NTR)/sortilin death neurotrophin receptors. Furthermore, BDNF secretion was detected in cell supernatants. NGF and BDNF production and Trk receptor expression, including TrkA, are regulated by apoptotic conditions (serum deprivation or rituximab exposure). Indeed, we show for the first time that rituximab exposure of DLBCL cell lines induces NGF secretion and that differences in rituximab sensitivity are associated with differential expression patterns of neurotrophins and their receptors (TrkA). Finally, these cells are sensitive to the Trk-inhibitor, K252a, as shown by the induction of apoptosis. Furthermore, K252a exhibits additive cytotoxic effects with rituximab. CONCLUSIONS/SIGNIFICANCE: Collectively, these data strongly suggest that a neurotrophin axis, such NGF/TrkA pathway, may contribute to malignant cell survival and rituximab resistance in DLBCL.
Published: 2011
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24. Positron emission tomography-computed tomography (PET-CT) after induction therapy is highly predictive of patient outcome in follicular lymphoma: analysis of PET-CT in a subset of PRIMA trial participants

Author: Didier Decaudin, Thierry Lamy, Thierry Vander Borght, Anne Sonet, Andrea Janíková, Judith Trotman, Hervé Tilly, Michael J. Fulham, Danielle Canioni, Gilles Salles, Jean Gabarre, Bruno Salles, Jane Estell, Marion Fournier, B. Fabiani, Ofer Shpilberg, Etienne Garin, Cecily Forsyth, John F. Seymour, Emmanuel Gyan, Eric Van Den Neste, 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 ), Etablissement Français du Sang Bretagne, EFS, Génétique, immunothérapie, chimie et cancer (GICC), UMR 6239 CNRS [2008-2011] (GICC UMR 6239 CNRS), Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS), Groupe d'étude des proliférations lymphoïdes (GPL), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Hématologie, Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), Département de Recherche Translationnelle, Institut Curie [Paris], Service d'Oncologie Médicale, CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Pitié-Salpêtrière [AP-HP], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Foie, métabolismes et cancer, Service de médecine nucléaire [Rennes], CRLCC Eugène Marquis (CRLCC), Service d'Hematologie, Hospices Civils de Lyon (HCL)-Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Groupe d'Etude des Lymphomes de l'Adulte, Paris, France, Grant No. 09/INS/2-03 from Cancer Institute, Sydney, New South Wales, Australia, 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 ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Département de recherche translationnelle, Service d'anatomie et cytologie pathologiques [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Saint-Antoine [AP-HP], Service d'Hématologie clinique [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université de Tours-Centre National de la Recherche Scientifique (CNRS), and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Subjects: Male, Cancer Research, Follicular lymphoma, Kaplan-Meier Estimate, MESH: Lymphoma, Follicular, Antibodies, Monoclonal, Murine-Derived, MESH: Aged, 80 and over, 0302 clinical medicine, International Prognostic Index, Antineoplastic Combined Chemotherapy Protocols, Positron emission, Lymphoma, Follicular, MESH: Treatment Outcome, Randomized Controlled Trials as Topic, MESH: Aged, Aged, 80 and over, MESH: Middle Aged, medicine.diagnostic_test, Middle Aged, MESH: Positron-Emission Tomography, 3. Good health, MESH: Antineoplastic Combined Chemotherapy Protocols, Treatment Outcome, Oncology, Positron emission tomography, Vincristine, 030220 oncology & carcinogenesis, Rituximab, Female, MESH: Tomography, X-Ray Computed, medicine.drug, Adult, MESH: Vincristine, [SDV.CAN]Life Sciences [q-bio]/Cancer, Disease-Free Survival, MESH: Doxorubicin, 03 medical and health sciences, medicine, Humans, Cyclophosphamide, MESH: Kaplan-Meier Estimate, Aged, Fluorodeoxyglucose, PET-CT, MESH: Humans, business.industry, MESH: Cyclophosphamide, MESH: Adult, medicine.disease, MESH: Male, Lymphoma, MESH: Randomized Controlled Trials as Topic, MESH: Antibodies, Monoclonal, Murine-Derived, Doxorubicin, Positron-Emission Tomography, MESH: Disease-Free Survival, Prednisone, business, Nuclear medicine, Tomography, X-Ray Computed, MESH: Female, MESH: Prednisone, 030215 immunology
Abstract: Purpose The utility of [18F]fluorodeoxyglucose (FDG) positron emission tomography–computed tomography (PET-CT) in assessing response at the end of induction therapy is well documented in Hodgkin's and diffuse large B-cell lymphomas, but its role in follicular lymphoma (FL) remains undetermined. We investigated the prognostic significance of PET-CT performed after first-line therapy in patients with FL treated in the prospective Primary Rituximab and Maintenance (PRIMA) study. Patients and Methods Results of PET-CT scans performed after induction immunochemotherapy were recorded retrospectively. Patients went on to either observation or rituximab maintenance per protocol independent of the PET-CT result. Patient characteristics and outcomes were then evaluated. Results Of 122 PET-CT scans performed at the end of the induction immunochemotherapy, 32 (26%) were reported as positive by the local investigator. Initial demographic or disease characteristics did not differ between PET-CT–positive (PET-positive) and PET-CT–negative (PET-negative) patients. PET status correlated with conventional response criteria (P < .001). Patients remaining PET positive had a significantly (P < .001) inferior progression-free survival at 42 months of 32.9% (95% CI, 17.2% to 49.5%) compared with 70.7% (95% CI, 59.3% to 79.4%) in those who became PET negative. PET status, but not conventional response (complete response or complete response unconfirmed v partial response) according to IWC 1999, was an independent predictive factor for lymphoma progression. The risk of death was also increased in PET-positive patients (hazard ratio 7.0; P = .0011). Conclusion [18F]FDG PET-CT status at the end of immunochemotherapy induction in patients with FL is strongly predictive of outcome and should be considered a meaningful clinical end point in future studies.
Published: 2011
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25. Time-resolved fluorescence resonance energy transfer (TR-FRET) to analyze the disruption of EGFR/HER2 dimers: a new method to evaluate the efficiency of targeted therapy using monoclonal antibodies

Author: Gaborit, Nadège, Larbouret, Christel, Vallaghe, Julie, Peyrusson, Frédéric, Bascoul-Mollevi, Caroline, Crapez, Evelyne, Azria, David, Chardes, Thierry, Poul, Marie-Alix, Mathis, Gérard, Bazin, Hervé, Pèlegrin, André, Institut de recherche en cancérologie de Montpellier (IRCM - U896 Inserm - UM1), CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1), CRLC Val d'Aurelle-Paul Lamarque, CRLCC Val d'Aurelle - Paul Lamarque, Cisbio, Research Department, and CIS BIOINTERNATIONAL
Subjects: MESH: Cell Line, Tumor, MESH: Humans, MESH: Phosphorylation, MESH: Fluorescence Resonance Energy Transfer, MESH: Protein Multimerization, MESH: Drug Screening Assays, Antitumor, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, MESH: Receptors, Fibroblast Growth Factor, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, MESH: Quinazolines, MESH: Antibodies, Neoplasm, MESH: Antibodies, Monoclonal, Murine-Derived, MESH: Receptor, erbB-2, MESH: Cell Proliferation, MESH: Protein Kinase Inhibitors, MESH: Antineoplastic Agents, [SDV.IMM]Life Sciences [q-bio]/Immunology, MESH: Animals, MESH: Neoplasms, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, skin and connective tissue diseases, neoplasms, MESH: Mice, MESH: NIH 3T3 Cells
Abstract: International audience; In oncology, simultaneous inhibition of epidermal growth factor receptor (EGFR) and HER2 by monoclonal antibodies (mAbs) is an efficient therapeutic strategy but the underlying mechanisms are not fully understood. Here, we describe a time-resolved fluorescence resonance energy transfer (TR-FRET) method to quantify EGFR/HER2 heterodimers on cell surface to shed some light on the mechanism of such therapies. First, we tested this antibody-based TR-FRET assay in NIH/3T3 cell lines that express EGFR and/or HER2 and in various tumor cell lines. Then, we used the antibody-based TR-FRET assay to evaluate in vitro the effect of different targeted therapies on EGFR/HER2 heterodimers in the ovarian carcinoma cell line SKOV-3. A simultaneous incubation with Cetuximab (anti-EGFR) and Trastuzumab (anti-HER2) disturbed EGFR/HER2 heterodimers resulting in a 72% reduction. Cetuximab, Trastuzumab or Pertuzumab (anti-HER2) alone induced a 48, 44, or 24% reduction, respectively. In contrast, the tyrosine kinase inhibitors Erlotinib and Lapatinib had very little effect on EGFR/HER2 dimers concentration. In vivo, the combination of Cetuximab and Trastuzumab showed a better therapeutic effect (median survival and percentage of tumor-free mice) than the single mAbs. These results suggest a correlation between the extent of the mAb-induced EGFR/HER2 heterodimer reduction and the efficacy of such mAbs in targeted therapies. In conclusion, quantifying EGFR/HER2 heterodimers using our antibody-based TR-FRET assay may represent a useful method to predict the efficacy and explain the mechanisms of action of therapeutic mAbs, in addition to other commonly used techniques that focus on antibody-dependent cellular cytotoxicity, phosphorylation, and cell proliferation.
Published: 2011
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26. CD137 stimulation enhances the antilymphoma activity of anti-CD20 antibodies

Author: Josh Brody, Antonia M.S. Müller, Mark P. Chao, Holbrook E Kohrt, Thomas F. Tedder, Ash A. Alizadeh, Matthew J. Goldstein, Ronald Levy, Lieping Chen, Roch Houot, Kipp Weiskopf, Steven Coutre, Debra K. Czerwinski, Russell K. Pachynski, 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 ), Department of Dermatology and Oncology, Johns Hopkins University School of Medicine, and 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 )
Subjects: MESH: Xenograft Model Antitumor Assays, medicine.drug_class, Immunology, MESH: Antigens, CD20, [SDV.CAN]Life Sciences [q-bio]/Cancer, Monoclonal antibody, Biochemistry, MESH: Drug Synergism, MESH: Antibodies, Monoclonal, 03 medical and health sciences, Interleukin 21, Antibodies, Monoclonal, Murine-Derived, Tumor Necrosis Factor Receptor Superfamily, Member 9, 0302 clinical medicine, Immune system, Antigen, immune system diseases, hemic and lymphatic diseases, medicine, Tumor Cells, Cultured, MESH: Antibody-Dependent Cell Cytotoxicity, Animals, Humans, MESH: Animals, MESH: Tumor Cells, Cultured, 030304 developmental biology, Antibody-dependent cell-mediated cytotoxicity, 0303 health sciences, MESH: Humans, biology, CD137, Antibody-Dependent Cell Cytotoxicity, Antibodies, Monoclonal, Drug Synergism, Cell Biology, Hematology, Antigens, CD20, Xenograft Model Antitumor Assays, 3. Good health, Retraction, MESH: Antibodies, Monoclonal, Murine-Derived, MESH: Antigens, CD137, 030220 oncology & carcinogenesis, biology.protein, Rituximab, Antibody, medicine.drug
Abstract: Antibody-dependent cell-mediated cytotoxicity (ADCC), which is largely mediated by natural killer (NK) cells, is thought to play an important role in the efficacy of rituximab, an anti-CD20 monoclonal antibody (mAb) used to treat patients with B-cell lymphomas. CD137 is a costimulatory molecule expressed on a variety of immune cells after activation, including NK cells. In the present study, we show that an anti-CD137 agonistic mAb enhances the antilymphoma activity of rituximab by enhancing ADCC. Human NK cells up-regulate CD137 after encountering rituximab-coated tumor B cells, and subsequent stimulation of these NK cells with anti-CD137 mAb enhances rituximab-dependent cytotoxicity against the lymphoma cells. In a syngeneic murine lymphoma model and in a xenotransplanted human lymphoma model, sequential administration of anti-CD20 mAb followed by anti-CD137 mAb had potent antilymphoma activity in vivo. These results support a novel, sequential antibody approach against B-cell malignancies by targeting first the tumor and then the host immune system.
Published: 2011
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27. Time-resolved fluorescence resonance energy transfer (TR-FRET) to analyze the disruption of EGFR/HER2 dimers: a new method to evaluate the efficiency of targeted therapy using monoclonal antibodies.: TR-FRET to quantify HER dimers and evaluate mAb efficiency

Author: Gaborit, Nadège, Larbouret, Christel, Vallaghe, Julie, Peyrusson, Frédéric, Bascoul-Mollevi, Caroline, Crapez, Evelyne, Azria, David, Chardes, Thierry, Poul, Marie-Alix, Mathis, Gérard, Bazin, Hervé, Pèlegrin, André, Le Ster, Yves, Institut de recherche en cancérologie de Montpellier (IRCM - U896 Inserm - UM1), Université Montpellier 1 (UM1)-CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), CRLC Val d'Aurelle-Paul Lamarque, CRLCC Val d'Aurelle - Paul Lamarque, Cisbio, Research Department, and CIS BIOINTERNATIONAL
Subjects: MESH: Cell Line, Tumor, [SDV.IMM] Life Sciences [q-bio]/Immunology, MESH: Fluorescence Resonance Energy Transfer, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, MESH: Receptors, Fibroblast Growth Factor, [SDV.CAN] Life Sciences [q-bio]/Cancer, MESH: Cell Proliferation, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Protein Kinase Inhibitors, MESH: Animals, MESH: Neoplasms, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, skin and connective tissue diseases, neoplasms, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, MESH: Mice, MESH: Humans, MESH: Phosphorylation, MESH: Protein Multimerization, MESH: Drug Screening Assays, Antitumor, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, [SDV.SP] Life Sciences [q-bio]/Pharmaceutical sciences, MESH: Quinazolines, MESH: Antibodies, Neoplasm, MESH: Antibodies, Monoclonal, Murine-Derived, MESH: Receptor, erbB-2, MESH: Antineoplastic Agents, [SDV.IMM]Life Sciences [q-bio]/Immunology, MESH: NIH 3T3 Cells
Abstract: International audience; In oncology, simultaneous inhibition of epidermal growth factor receptor (EGFR) and HER2 by monoclonal antibodies (mAbs) is an efficient therapeutic strategy but the underlying mechanisms are not fully understood. Here, we describe a time-resolved fluorescence resonance energy transfer (TR-FRET) method to quantify EGFR/HER2 heterodimers on cell surface to shed some light on the mechanism of such therapies. First, we tested this antibody-based TR-FRET assay in NIH/3T3 cell lines that express EGFR and/or HER2 and in various tumor cell lines. Then, we used the antibody-based TR-FRET assay to evaluate in vitro the effect of different targeted therapies on EGFR/HER2 heterodimers in the ovarian carcinoma cell line SKOV-3. A simultaneous incubation with Cetuximab (anti-EGFR) and Trastuzumab (anti-HER2) disturbed EGFR/HER2 heterodimers resulting in a 72% reduction. Cetuximab, Trastuzumab or Pertuzumab (anti-HER2) alone induced a 48, 44, or 24% reduction, respectively. In contrast, the tyrosine kinase inhibitors Erlotinib and Lapatinib had very little effect on EGFR/HER2 dimers concentration. In vivo, the combination of Cetuximab and Trastuzumab showed a better therapeutic effect (median survival and percentage of tumor-free mice) than the single mAbs. These results suggest a correlation between the extent of the mAb-induced EGFR/HER2 heterodimer reduction and the efficacy of such mAbs in targeted therapies. In conclusion, quantifying EGFR/HER2 heterodimers using our antibody-based TR-FRET assay may represent a useful method to predict the efficacy and explain the mechanisms of action of therapeutic mAbs, in addition to other commonly used techniques that focus on antibody-dependent cellular cytotoxicity, phosphorylation, and cell proliferation.
Published: 2011
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28. How pharmacogenomics of biological response modifiers will influence clinical response and toxicity in dermatology

Author: Dalle, Stéphane, Thomas, Luc, Shear, Neil H, Equipe 14, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Service de Dermatologie, Centre Hospitalier Sud, Hospices Civils, Lyon
Subjects: MESH: Pharmacogenetics, MESH: Piperazines, Drug Resistance, MESH: Skin Diseases, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH: Receptor, Epidermal Growth Factor, MESH: Receptors, IgG, Skin Diseases, Piperazines, Antibodies, Monoclonal, Murine-Derived, MESH: Polymorphism, Genetic, Humans, Immunologic Factors, Precision Medicine, MESH: Individualized Medicine, MESH: Humans, Polymorphism, Genetic, Tumor Necrosis Factor-alpha, MESH: Immunologic Factors, Receptors, IgG, ErbB Receptors, MESH: Dermatologic Agents, Pyrimidines, MESH: Antibodies, Monoclonal, Murine-Derived, Pharmacogenetics, MESH: Tumor Necrosis Factor-alpha, MESH: Pyrimidines, Benzamides, MESH: Drug Resistance, Imatinib Mesylate, Dermatologic Agents, Rituximab
Abstract: International audience; Biological response modifiers (BRMs) have dramatically changed therapeutic approaches in dermatology. Pharmacogenomic studies are increasingly integral to the early development phases of targeted therapies. The first evidence supporting the impact that genetic background has on responses to BRMs was from rituximab, where the clinical response was correlated with Fc-gamma receptor gene polymorphisms. Later, many studies were done to investigate the impact of gene polymorphism on the mechanism of action of BRMs. Growing evidence supports the view that both efficacy and toxicity of BRMs can be highly influenced by genetic background. The foreseeable objective is to select personalized therapeutics, based on genetics characteristics that will result in more efficient and less toxic treatment. We review the current data focusing on the BRMs widely used in the practice of dermatology.
Published: 2010
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29. Efficacy and safety of the combination of rituximab, fludarabine, and mitoxantrone for rituximab-naive, recurrent/refractory follicular non-Hodgkin lymphoma with high tumor burden: a multicenter phase 2 trial by the Groupe d'Etude des Lymphomes de l'Adulte (GELA) and Groupe Ouest Est des Leucémies et Autres Maladies du Sang (GOELAMS)

Author: Thierry Lamy, Christophe Fermé, Franck Morschhauser, Pierre Feugier, Hervé Tilly, Marie Christine Copin, Nicolas Mounier, Pauline Brice, Phillippe Solal-Celigny, Catherine Sebban, Service d'onco-hématologie, Centre Hospitalier Universitaire de Nice (CHU Nice)-Hôpital l'Archet, Service d'hématologie, Centre Léon Bérard [Lyon], 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 [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR), 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 ), 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), Université de Rennes 1 (UR1), and 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 )
Subjects: Male, Cancer Research, MESH: Tumor Burden, Follicular lymphoma, CHOP, fludarabine-based combination, Gastroenterology, MESH: Antibodies, Monoclonal, Antibodies, Monoclonal, Murine-Derived, MESH: Lymphoma, Follicular, 0302 clinical medicine, International Prognostic Index, Recurrence, Antineoplastic Combined Chemotherapy Protocols, Lymphoma, Follicular, MESH: Aged, MESH: Middle Aged, Antibodies, Monoclonal, Neoplasms, Second Primary, Middle Aged, MESH: Drug Resistance, Neoplasm, Tumor Burden, 3. Good health, Fludarabine, MESH: Antineoplastic Combined Chemotherapy Protocols, Oncology, 030220 oncology & carcinogenesis, MESH: Vidarabine, Female, Rituximab, MESH: Mitoxantrone, Refractory Follicular Lymphoma, Vidarabine, medicine.drug, Adult, medicine.medical_specialty, MESH: Neoplasms, Second Primary, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH: Drug Administration Schedule, Drug Administration Schedule, 03 medical and health sciences, follicular lymphoma, Internal medicine, medicine, Humans, Survival rate, Aged, Mitoxantrone, MESH: Humans, business.industry, MESH: Adult, medicine.disease, MESH: Male, Surgery, MESH: Recurrence, immunochemotherapy, Drug Resistance, Neoplasm, MESH: Antibodies, Monoclonal, Murine-Derived, high tumor burden, business, MESH: Female, 030215 immunology
Abstract: International audience; BACKGROUND: This phase 2 trial was undertaken to evaluate the efficacy and safety of rituximab combined with intravenous fludarabine and mitoxantrone (R-FM) for patients with recurrent/refractory follicular lymphoma who had high tumor burden according to Groupe d'Etude des Lymphomes Folliculaires (GELF) criteria. METHODS: Fifty patients were enrolled who had received a maximum of 2 previous regimens, including 1 cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)/CHOP-like regimen but no previous exposure to rituximab, fludarabine, or mitoxantrone. At baseline, 58% of patients had bulky disease (lesion > 7 cm), 56% had high-risk Follicular Lymphoma International Prognostic Index (FLIPI) scores (range, 3-5), and 22% were refractory. Treatment consisted of 4 courses of R-FM (rituximab 375 mg/m(2) intravenously on Day 1, fludarabine 25 mg/m(2) intravenously on Days 2 through 4, and mitoxantrone 10 mg/m(2) intravenously on Day 2, recycling at Day 28) and consolidation with 2 courses of fludarabine and mitoxantrone (the same regimen without rituximab). RESULTS: The best response (84% overall response rate including 68% complete response/complete response unconfirmed) was achieved after 4 courses of R-FM. Response rates were high regardless of age, refractoriness to last previous therapy, and FLIPI score. After a median follow-up of 4 years, the 3-year progression-free survival rate was 47%, the event-free survival rate was 41%, and the 3-year overall survival rate was 66%. Grade ≥ 3 neutropenia and infections were the most common toxicities and occurred in 72% and 14% of patients, respectively. CONCLUSIONS: Cytoreduction with 4 courses of R-FM was safe and highly efficient in patients with recurrent/refractory follicular lymphoma who had high tumor burden; however, better consolidation than FM is needed to further improve outcome.
Published: 2010
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30. Gene expression profile in the salivary glands of primary Sjögren's syndrome patients before and after treatment with rituximab

Author: Jacques-Olivier Pers, Gilles Chiocchia, Pierre Youinou, Alain Saraux, Nicolas Cagnard, Valérie Devauchelle-Pensec, Immunologie et Pathologie (EA2216), Université de Brest (UBO)-IFR148, plateforme de bioinformatique, Université Paris Descartes - Paris 5 (UPD5), Laboratoire d'Immunologie et Immunothérapie, Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Physiopathologie et Pharmacologie Clinique de la Douleur (LPPD), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'Immunothérapies et Pathologies lymphocytaires B (EA2216), Université de Bretagne Occidentale (UBO) - Institut National de la Santé et de la Recherche Médicale (INSERM), CHRU Brest, Physiopathologie et pharmacologie clinique de la douleur, Université de Versailles Saint-Quentin-en-Yvelines (UVSQ) - Institut National de la Santé et de la Recherche Médicale (INSERM), and Michel, Geneviève
Subjects: MESH: Signal Transduction, Male, MESH: Antirheumatic Agents, Salivary Glands, MESH: Antibodies, Monoclonal, Antibodies, Monoclonal, Murine-Derived, 0302 clinical medicine, Immunopathology, MESH: Reverse Transcriptase Polymerase Chain Reaction, Gene expression, Immunology and Allergy, Cluster Analysis, Pharmacology (medical), MESH: Treatment Outcome, Oligonucleotide Array Sequence Analysis, 0303 health sciences, B-Lymphocytes, Reverse Transcriptase Polymerase Chain Reaction, Antibodies, Monoclonal, 3. Good health, medicine.anatomical_structure, Sjogren's Syndrome, Treatment Outcome, Antirheumatic Agents, Monoclonal, [SDV.IMM]Life Sciences [q-bio]/Immunology, Rituximab, Female, medicine.drug, Signal Transduction, MESH: Salivary Glands, [SDV.IMM] Life Sciences [q-bio]/Immunology, Immunology, 03 medical and health sciences, MESH: Gene Expression Profiling, Rheumatology, MESH: B-Lymphocytes, medicine, Humans, RNA, Messenger, Gene, B cell, 030304 developmental biology, MESH: RNA, Messenger, 030203 arthritis & rheumatology, MESH: Humans, business.industry, Microarray analysis techniques, Gene Expression Profiling, MESH: Cluster Analysis, MESH: Male, Gene expression profiling, MESH: Sjogren's Syndrome, MESH: Antibodies, Monoclonal, Murine-Derived, MESH: Oligonucleotide Array Sequence Analysis, business, MESH: Female
Abstract: Objective Primary Sjogren's syndrome (SS) is a complex disorder, in part due to B cell abnormalities. Although anti–B cell therapy is promising in primary SS, no treatment has yet been demonstrated to modify the disease course. This open-label study was undertaken to evaluate the efficacy of rituximab in primary SS and to investigate whether expression of specific genes is associated with efficacy of this treatment. Methods Fifteen patients with primary SS were treated in an open-label trial. Salivary gland biopsy specimens were obtained, and total RNA was extracted and amplified. Microarray analysis with the Affymetrix Human Genome U133 Plus 2.0 Array was used to analyze >54,000 transcripts, and potential pathways were identified. Results With gene expression data obtained before treatment, patients could be correctly classified in terms of whether they would be responders or nonresponders to rituximab. Gene pathway analysis demonstrated that the B cell signaling pathway was the most profoundly differentially expressed before treatment in the responders compared with nonresponders. Subclassification of patients based on the level of infiltration also demonstrated differential expression of genes belonging to the interferon (IFN) pathway between responders and nonresponders. Furthermore, unsupervised analysis based on gene expression modification before and after treatment allowed identification of 8 genes that were differentially expressed between responders and nonresponders, with the difference remaining significant after Bonferroni correction. Conclusion Our results demonstrate the ability to elaborate a set of genes predictive of rituximab efficacy and highlight the importance of studying the differential expression of B cell and IFN pathway signaling molecules in relation to the response to anti-CD20 treatment. A randomized controlled study is currently ongoing to confirm these results.
Published: 2010

31. Prognostic significance of BAD and AIF apoptotic pathways in diffuse large B-cell lymphoma

Author: Daniel Petit, D. Troutaud, Agnès Olivrie, Barbara Petit, Marie-Odile Jauberteau, Marie-Pierre Gourin-Chaury, Benoît Marin, Cynthia Bellanger, Jean Feuillard, Dominique Bordessoule, Homéostasie Cellulaire et Pathologies (HCP), Université de Limoges (UNILIM)-CHU Limoges-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503), Université de Limoges (UNILIM), Physiologie Moléculaire de la Réponse Immune et des Lymphoproliférations (PMRIL), Université de Limoges (UNILIM)-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-Centre National de la Recherche Scientifique (CNRS), Service d'Anatomie Pathologique [CHU Limoges], CHU Limoges, Unité Fonctionnelle Registre Général des Cancers du Limousin (UFRGC), Service de l'Information Médicale et de l'Évaluation [CHU Limoges] (SIME), Neuroépidémiologie Tropicale et Comparée (NETEC), Université de Limoges (UNILIM)-Institut d'Epidémiologie Neurologique et de Neurologie Tropicale-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503), Service d'Hématologie clinique et thérapie cellulaire [CHU Limoges], Unité de Génétique Moléculaire Animale (UGMA), Université de Limoges (UNILIM)-Institut National de la Recherche Agronomique (INRA), Service de Médecine interne A et polyclinique médicale [CHU Limoges], Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-Institut d'Epidémiologie Neurologique et de Neurologie Tropicale-Université de Limoges (UNILIM), Unité de Génétique Moléculaire Animale (UMR GMA), Institut National de la Recherche Agronomique (INRA)-Université de Limoges (UNILIM), This work and C.B. were supported by Ligue Nationale Contre le Cancer (Comité Départemental de La Haute-Vienne) and CORC (Comité d'Orientation Recherche Cancer en Limousin)., and Université de Limoges (UNILIM)-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-CHU Limoges
Subjects: Male, Cancer Research, Pathology, bcl-2, Apoptosis, CHOP, MESH: Antibodies, Monoclonal, Antibodies, Monoclonal, Murine-Derived, 0302 clinical medicine, International Prognostic Index, clinical stage, MESH: Stilbenes, Antineoplastic Combined Chemotherapy Protocols, Stilbenes, Medicine, 0303 health sciences, B-Lymphocytes, MESH: Middle Aged, medicine.diagnostic_test, Antibodies, Monoclonal, Apoptosis Inducing Factor, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Hematology, Middle Aged, Prognosis, 3. Good health, pp1α, MESH: Antineoplastic Combined Chemotherapy Protocols, Oncology, Vincristine, 030220 oncology & carcinogenesis, Immunohistochemistry, Rituximab, Female, Lymphoma, Large B-Cell, Diffuse, medicine.drug, medicine.medical_specialty, Lymphoma, B-Cell, non-hodgkin lymphoma, MESH: Vincristine, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, MESH: Prognosis, chop, 03 medical and health sciences, MESH: Doxorubicin, MESH: B-Lymphocytes, Biopsy, Humans, Cyclophosphamide, 030304 developmental biology, MESH: Lymphoma, B-Cell, MESH: Humans, business.industry, MESH: Apoptosis, MESH: Cyclophosphamide, medicine.disease, MESH: Male, Lymphoma, MESH: Apoptosis Inducing Factor, Doxorubicin, MESH: Antibodies, Monoclonal, Murine-Derived, Cancer research, Prednisone, MESH: Lymphoma, Large B-Cell, Diffuse, business, Diffuse large B-cell lymphoma, MESH: Prednisone, MESH: Female
Abstract: Chantier qualité GA; International audience; BACKGROUND: To determine whether proapoptotic proteins were associated with clinicopathologic heterogeneity and influenced survival in patients with diffuse large B-cell lymphoma (DLBCL), we evaluated patterns of expression of the BCL-2 family member BAD, PP1alpha (the catalytic subunit of PP1 involved in activation of BAD), and apoptosis-inducing factor (AIF). PATIENTS AND METHODS: We retrospectively analyzed 46 patients all treated with standard chemotherapy ([CHOP] cyclophosphamide/doxorubicin/vincristine/prednisone-like); of these, 16 received rituximab. Immunohistochemical analyses were performed from biopsy samples of nodal DLBCL that were performed at initial diagnosis. Normal reactive lymph nodes were used as controls. RESULTS: BAD expression was found in 38 of 46 DLBCL cases and, though variable, was often strong. PP1alpha and AIF were detected in all tumors tested with a relative strong expression. Lower BAD expression was shown to be significantly associated with advanced clinical stages (Ann Arbor stage III + IV and International Prognostic Index intermediate-high to high; P = .006 and P = .0008, respectively). Moreover, BAD staining was positively correlated with BCL-2 (P = .022) and PP1alpha (P = .013) staining. Finally, high AIF expression proved to be predictive of a longer overall survival in non-rituximab-treated patients. CONCLUSION: Our study shows for the first time in DLBCL that differential BAD expression might play a role in the development of the disease, possibly reflecting its function as a tumor suppressor. Furthermore, our data highlight the interest in targeting BAD phosphatases and AIF-mediated mitochondrial apoptosis for new therapeutic strategies.
Published: 2010
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32. [Brucella bacteremia reactivation 70 years after the primary infection]

Author: A, Meneses, O, Epaulard, M, Maurin, R, Gressin, P, Pavese, J-P, Brion, B, Garin-Bastuji, J-P, Stahl, Service des Maladies Infectieuses, CHU Grenoble, Laboratoire Adaptation et pathogénie des micro-organismes [Grenoble] (LAPM), Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF), Department of Infectious Diseases, University Hospital, and Service de maladies infectieuses et médecine tropicale
Subjects: MESH: Combined Modality Therapy, Time Factors, Bacteremia, Brucellosis, MESH: Antibodies, Monoclonal, Antibodies, Monoclonal, Murine-Derived, Immunocompromised Host, MESH: Aged, 80 and over, MESH: Lymphoma, Non-Hodgkin, Recurrence, MESH: Brucellosis, Antineoplastic Combined Chemotherapy Protocols, Brucella melitensis, MESH: Immunocompromised Host, MESH: Spain, Humans, MESH: Doxycycline, MESH: Immunoglobulins, Intravenous, MESH: Bacteremia, Cyclophosphamide, Aged, 80 and over, MESH: Humans, Lymphoma, Non-Hodgkin, [SDV.BID.EVO]Life Sciences [q-bio]/Biodiversity/Populations and Evolution [q-bio.PE], MESH: Time Factors, Antibodies, Monoclonal, Immunoglobulins, Intravenous, MESH: Cyclophosphamide, Combined Modality Therapy, MESH: Rifampin, MESH: Recurrence, MESH: France, MESH: Drug Therapy, Combination, MESH: Antineoplastic Combined Chemotherapy Protocols, MESH: Brucella melitensis, Spain, MESH: Antibodies, Monoclonal, Murine-Derived, Doxycycline, MESH: Vidarabine, Drug Therapy, Combination, Female, France, Rifampin, Rituximab, MESH: Female, Vidarabine
Abstract: International audience; After primary infection, some bacteria can remain in a latent state for several years before a new bacteremia, often due to a weakened immune status. This is common for Mycobacterium tuberculosis, less for other pathogens more difficult to have in mind when facing patients with fever. We report the case of an 84-year-old female patient presenting with fever in the months following antilymphoma chemotherapy, due to bacteremic brucellosis (with a hemophagocytic syndrome) probably latent after primary infection as a child.
Published: 2010
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33. Development of a Murine model to dissect the CpG-oligonucleotide-enhancement of the killing of human B Cells by rituximab

Author: Jacques-Olivier Pers, Séverine Loisel, Christian Berthou, Virginie Buhé, Rémi Marianowski, Pierre Youinou, Immunologie et Pathologie (EA2216), Université de Brest (UBO)-IFR148, LabEX IGO Immunothérapie Grand Ouest, Department of ORL, Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Université européenne de Bretagne - European University of Brittany (UEB), Laboratoire de Sciences Actuarielle et Financière (SAF), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, and Michel, Geneviève
Subjects: Neutrophils, medicine.medical_treatment, Complement Pathway, Alternative, Cell, Mice, SCID, MESH: Neutrophils, MESH: Drug Synergism, MESH: Antibodies, Monoclonal, Antibodies, Monoclonal, Murine-Derived, Mice, 0302 clinical medicine, Immunology and Allergy, Macrophage, MESH: Animals, MESH: Mice, SCID, 0303 health sciences, Antibodies, Monoclonal, Drug Synergism, 3. Good health, medicine.anatomical_structure, Oligodeoxyribonucleotides, CpG site, MESH: Complement Factor H, Complement Factor H, [SDV.IMM]Life Sciences [q-bio]/Immunology, Rituximab, Lymphoma, B-Cell, MESH: Cell Line, Tumor, [SDV.IMM] Life Sciences [q-bio]/Immunology, medicine.drug_class, Immunology, Mice, Nude, Complement C5a, Mice, Inbred Strains, Granulocyte, Biology, Monoclonal antibody, MESH: Mice, Inbred Strains, Lymphocyte Depletion, 03 medical and health sciences, Cell Line, Tumor, MESH: Cell Proliferation, medicine, MESH: Mice, Nude, MESH: Antibody-Dependent Cell Cytotoxicity, Animals, Humans, MESH: Mice, Cell Proliferation, 030304 developmental biology, MESH: Lymphoma, B-Cell, MESH: Lymphocyte Depletion, MESH: Humans, Macrophages, Antibody-Dependent Cell Cytotoxicity, MESH: Macrophages, Immunotherapy, Molecular biology, Complement system, Disease Models, Animal, MESH: Antibodies, Monoclonal, Murine-Derived, MESH: Complement C5a, Alternative complement pathway, MESH: Oligodeoxyribonucleotides, MESH: Disease Models, Animal, MESH: Complement Pathway, Alternative, Neoplasm Transplantation, MESH: Neoplasm Transplantation, 030215 immunology
Abstract: International audience; As a model to dissect the effects of CpG-oligonucleotides (CpG) on rituximab (RTX)-mediated therapeutic killing of autoimmune or malignant B lymphocytes, nude mice were grafted with Daudi human B cells. These mice were then injected with RTX alone or together with CpG. The human B cell aggregate was measured, and the reactive infiltrate analyzed after selective depletion of murine circulating cells. Macrophages (MØ) were identified in infiltrates, but not polymorphonuclear neutrophils (PMN), as confirmed by the failure of quantitative polymerase chain reaction to detect transcripts for PMN-specific myeloperoxidase in graft extracts. Evidence that MØ predominate over PMN in the anti-B cell RTX-induced immune mechanisms, include the presence of MØ-derived cytokines, and the lack of consequences of depletion of NK cells or B lymphocytes on the CpG-mediated effects on RTX. Interestingly however, removal of circulating PMN reduced the number of MØ attracted by the Daudi B cells. Our interpretation that CpG-induced complement activation is required for PMN to influence MØ was first based on overproduction of C5a in treated mice. This excess was due to the binding of the inhibitor of the alternative pathway of complement to CpG, as demonstrated by the elution of factor H from CpG-affinity-chromatography columns. Thus MØ are recruited to the tissue in the presence of C5a, and exploited locally by RTX.
Published: 2010

34. The point on the ongoing B-cell depleting trials currently in progress over the world in primary Sjögren's syndrome

Author: Alain Saraux, Michel, Geneviève, Immunologie et Pathologie (EA2216), Université de Brest (UBO)-IFR148, CHRU Brest - Service de Rhumatologie (CHU - BREST - Rhumato), and Centre Hospitalier Régional Universitaire de Brest (CHRU Brest)
Subjects: medicine.medical_specialty, [SDV.IMM] Life Sciences [q-bio]/Immunology, Immunology, MESH: Drug Delivery Systems, Disease, Antibodies, Monoclonal, Humanized, MESH: Antibodies, Monoclonal, 03 medical and health sciences, Cevimeline, Antibodies, Monoclonal, Murine-Derived, 0302 clinical medicine, Drug Delivery Systems, Sicca syndrome, MESH: B-Lymphocytes, Immunology and Allergy, Medicine, Humans, 030304 developmental biology, Randomized Controlled Trials as Topic, 030203 arthritis & rheumatology, 0303 health sciences, B-Lymphocytes, MESH: Humans, business.industry, Antibodies, Monoclonal, Hydroxychloroquine, medicine.disease, Dermatology, eye diseases, 3. Good health, stomatognathic diseases, MESH: Randomized Controlled Trials as Topic, MESH: Sjogren's Syndrome, Sjogren's Syndrome, MESH: Antibodies, Monoclonal, Humanized, MESH: Antibodies, Monoclonal, Murine-Derived, Serum sickness, Tears, [SDV.IMM]Life Sciences [q-bio]/Immunology, Rituximab, business, Epratuzumab, medicine.drug
Abstract: International audience; Conventionnal therapy (moisturizers, pilocarpine, Cevimeline, local Cyclosporine, and hydroxychloroquine) remains the basis for the treatment of primary Sjögren's syndrome (pSS) but they do not modify the course of the disease. Rituximab is currently the most fully evaluated biologics in pSS. Open-label studies suggest that Rituximab is well tolerated (although infusion-related reactions and serum sickness remain possible), induces a rapid depletion of B cells in the blood and salivary glands, and could improve early active pSS or pSS with active extra glandular involvement. Two small double blind randomized studies have been conducted and now published, demonstrating its efficacy on fatigue and sicca syndrome in early disease. Two large double blind studies are currently ongoing or planned: The TEARS study (Tolerance and EfficAcy of Rituximab in primary Sjögren syndrome) in France, is currently including 120 patients having either a recent and active disease and/or at least one extraglandular severe signs. The 'TRACTISS' Study (Anti-B-Cell Therapy In Patients With Primary Sjögren's Syndrome), in UK, will include 100 patients having anti-Ro/La antibodies, reduced basal secretion but an increased salivary flow with stimulation, within 10years of diagnosis, symptomatic oral dryness, fatigue and at least one systemic feature.
Published: 2010

35. Immuno-fluorescence in situ hybridization index predicts survival in patients with diffuse large B-cell lymphoma treated with R-CHOP: a GELA study.: ImmunoFISH index in DLBCL patients treated with R-CHOP

Author: Copie-Bergman, Christiane, Gaulard, Philippe, Leroy, Karen, Briere, Josette, Baia, Maryse, Jais, Jean-Philippe, Salles, Gilles, Berger, Françoise, Haioun, Corinne, Tilly, Herve, Emile, Jean-François, Banham, Alison, Mounier, Nicolas, Gisselbrecht, Christian, Feugier, Pierre, Coiffier, Bertrand, Molina, Thierry, Guellaen, Georges, Groupe Henri Mondor-Albert Chenevier, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Hôpital Albert Chenevier, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service d'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), Service d'informatique médicale et biostatistiques [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Département de pathologie, Hospices Civils de Lyon (HCL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, 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), Service d'Hématologie, Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), Service d'anatomie pathologique [CHU Ambroise-Paré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Ambroise Paré [AP-HP], Biomarqueurs et essais cliniques en Cancérologie et Onco-Hématologie (BECCOH), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay, Nuffield Department of Clinical Laboratory Sciences, University of Oxford, Service d'onco-hématologie, Centre Hospitalier Universitaire de Nice (CHU Nice)-Hôpital l'Archet, Service d'hématologie-oncologie adultes, Service d'Hématologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Département de Pathologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôtel-Dieu-Université Paris Descartes - Paris 5 (UPD5), and This study was supported by a grant from the Programme Hospitalier de Recherche Clinique AP-HP (AOM 03060), Dako A/S and ARTGIL (Association pour la Recherche Thérapeutique, Génétique et Immunologique dans les lymphomes). AHB was supported by Leukaemia Research, UK.
Subjects: MESH: Probability, MESH: Vincristine, MESH: Drug Administration Schedule, MESH: Risk Assessment, MESH: Multivariate Analysis, MESH: Prognosis, MESH: Antibodies, Monoclonal, MESH: Dose-Response Relationship, Drug, MESH: Proportional Hazards Models, MESH: Doxorubicin, MESH: Aged, 80 and over, immune system diseases, hemic and lymphatic diseases, MESH: Severity of Illness Index, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: In Situ Hybridization, Fluorescence, MESH: Genes, myc, MESH: Treatment Outcome, MESH: Aged, MESH: Humans, MESH: Middle Aged, MESH: Biological Markers, MESH: Enzyme-Linked Immunosorbent Assay, MESH: Cyclophosphamide, MESH: Predictive Value of Tests, MESH: Male, MESH: Antineoplastic Combined Chemotherapy Protocols, MESH: Proto-Oncogene Proteins c-bcl-2, MESH: Antibodies, Monoclonal, Murine-Derived, MESH: Survival Analysis, MESH: Lymphoma, Large B-Cell, Diffuse, MESH: Prednisone, MESH: Female
Abstract: International audience; PURPOSE: To evaluate the prognostic value of cell of origin immunohistochemical markers and BCL2, BCL6, and c-MYC translocations in a homogeneous cohort of patients with diffuse large B-cell lymphoma (DLBCL) treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). PATIENTS AND METHODS: Patients with CD20+ DLBCL were enrolled in the randomized LNH98-5 and 01-5B Groupe d'Etude des Lymphomes de l'Adulte trials. Paraffin-embedded tumor samples of 119 patients treated with R-CHOP were analyzed by immunohistochemistry for CD10, BCL6, MUM1/IRF4, LMO2, and forkhead box protein P1 (FOXP1) expression and for BCL2, BCL6, and c-MYC breakpoints by fluorescence in situ hybridization (FISH) on tissue microarray. RESULTS: LMO2 expression and BCL2 breakpoint were associated with the germinal center (GC) subtype defined by Hans' algorithm, respectively (P < .0001; P = .0002) whereas FOXP1 expression and BCL6 breakpoint were associated with the non-germinal center (non-GC) subtype (P = .008 and P = .0001, respectively). The immunohistochemical markers analyzed independently, GC/non-GC phenotype and BCL2 breakpoint did not predict overall survival (OS). BCL6 breakpoint was significantly associated with an unfavorable impact on OS (P = .04). Interestingly, an immunoFISH index, defined by positivity for at least two of three non-GC markers (FOXP1, MUM1/IRF4, BCL6 breakpoint) was significantly associated with a shorter 5-year OS rate (44%; 95% CI, 28 to 60 v 78%; 95% CI, 59 to 89; P = .01) which was independent (P = .04) of the age-adjusted International Prognostic Index (P = .04) in multivariate analysis. CONCLUSION: Our study demonstrates that combining immunohistochemistry with FISH allows construction of an immunoFISH index that significantly predicts survival in elderly DLBCL patients treated with R-CHOP.
Published: 2009
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36. Anti-CD20 monoclonal antibody (rituximab) treatment for cryoglobulinemic vasculitis: where do we stand?

Author: Aurélien Delluc, Damien Sène, Dan A. Landau, Patrice Cacoub, David Saadoun, CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Groupe d'Etude de la Thrombose de Bretagne Occidentale (GETBO), Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-Université de Brest (UBO), Département de Médecine Interne et Pneumologie [Brest] (DMIP - Brest), and Centre Hospitalier Régional Universitaire de Brest (CHRU Brest)
Subjects: Male, MESH: Antigens, CD20, medicine.disease_cause, Gastroenterology, MESH: Antibodies, Monoclonal, Antibodies, Monoclonal, Murine-Derived, 0302 clinical medicine, hemic and lymphatic diseases, Immunology and Allergy, 030212 general & internal medicine, MESH: Treatment Outcome, CD20, MESH: Aged, MESH: Middle Aged, biology, MESH: Vasculitis, Antibodies, Monoclonal, Middle Aged, Cryoglobulinemia, 3. Good health, Treatment Outcome, Monoclonal, Rituximab, Female, Vasculitis, medicine.drug, Adult, medicine.medical_specialty, MESH: Cryoglobulinemia, Hepatitis C virus, Immunology, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Rheumatology, Internal medicine, medicine, Humans, Cryoglobulinemic vasculitis, Aged, 030203 arthritis & rheumatology, MESH: Humans, business.industry, MESH: Adult, medicine.disease, Antigens, CD20, MESH: Male, MESH: Antibodies, Monoclonal, Murine-Derived, biology.protein, business, Complication, MESH: Female, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; Mixed cryoglobulinemia (MC) vasculitis represents a complication of the B cell response to a variety of chronic inflammatory diseases. Recent reports describe the use of monoclonal antibodies directed to CD20 antigen (rituximab), a transmembrane protein expressed on pre-B lymphocytes and mature lymphocytes. The goal of this article is therefore to review published data in order to better analyse the efficacy and tolerance of rituximab treatment in patients with MC vasculitis. After systematic review of the literature and exclusion of review papers, 13 manuscripts were identified that reported on a total number of 57 cases of MC secondary to hepatitis C virus (HCV) infection (75.4%) or essential mixed cryoglobulinemia (24.6%). Previous treatments failed to control the main signs of vasculitis; these were either HCV (n = 37) or immunomodulating treatments. Most patients (48 out of 57) received four weekly consecutive intravenous infusions of 375 mg/m(2) of rituximab. The duration of follow-up after rituximab therapy was 9.7 months. Rituximab infusions had great efficacy on the main vasculitis signs, with a clinical response in 80-93% patients. A relapse of MC was noted in 14 out of 36 (39%) patients. A relatively small number of side effects were reported. We conclude that rituximab therapy for patients with mixed cryoglobulinemia vasculitis, HCV-induced or essential, shows great efficacy on the main vasculitis signs in the majority of reported patients. A relapse of cryoglobulinemia vasculitis was frequently noted. Randomised controlled trials with long-term study are needed to form definitive conclusions on the benefit/risk ratio of rituximab therapy in such patients.
Published: 2008
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37. T-cell lymphoid aggregates in bone marrow after rituximab therapy for B-cell follicular lymphoma: a marker of therapeutic efficacy?

Author: Diane Damotte, Anne Moreau, Sylvie Caulet-Maugendre, Marie C. Béné, Pascale Cornillet Lefebvre, Martine Patey, Gilles Salles, Marie Christine Rousselet, Jean François Rossi, Pierre Raynaud, Charles Foussard, Antoine Martin, Valérie Costes, Immunopathologie des maladies tumorales et autoimmunes, Université Montpellier 1 (UM1)-IFR76-Institut National de la Santé et de la Recherche Médicale (INSERM), Signalisation et Réponses aux Agents Infectieux et Chimiques (SeRAIC), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Service d'hématologie clinique, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou, 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, 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, Institut Jacques Monod (IJM (UMR_7592)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Haematology, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Hémodynamique, Interaction Fibrose et Invasivité tumorales Hépatiques (HIFIH), Université d'Angers (UA), Département de Pathologie Cellulaire et Tissulaire, PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Service d'Immunologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service de chirurgie thoracique et d'anatomopathologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Hôtel Dieu, Hôpital Robert Debré, Hôpital Robert Debré-Centre Hospitalier Universitaire de Reims (CHU Reims), Service de Rhumatologie, Hôpital de St Brieuc, university hospital, University Hospital, Université de Rennes (UR), Université de Rennes (UR)-Hôpital Pontchaillou, École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-IFR140, École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), and Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Hôtel Dieu
Subjects: Male, Pathology, T-Lymphocytes, T-cell infiltration, Follicular lymphoma, Translocation, Genetic, MESH: Antibodies, Monoclonal, Antibodies, Monoclonal, Murine-Derived, MESH: Lymphoma, Follicular, 0302 clinical medicine, hemic and lymphatic diseases, MESH: Reverse Transcriptase Polymerase Chain Reaction, Lymphoma, Follicular, MESH: Treatment Outcome, Gene Rearrangement, CD20, MESH: Aged, 0303 health sciences, MESH: Middle Aged, biology, medicine.diagnostic_test, Reverse Transcriptase Polymerase Chain Reaction, Anti-CD20 monoclonal antibodies, Antibodies, Monoclonal, DNA, Neoplasm, Middle Aged, MESH: Translocation, Genetic, 3. Good health, Survival Rate, Treatment Outcome, medicine.anatomical_structure, Proto-Oncogene Proteins c-bcl-2, 030220 oncology & carcinogenesis, Female, Rituximab, MESH: Bone Marrow, medicine.drug, Adult, medicine.medical_specialty, Bcl2, Lymphoma, B-Cell, MESH: Survival Rate, MESH: Gene Rearrangement, MESH: DNA, Neoplasm, Antineoplastic Agents, Pathology and Forensic Medicine, 03 medical and health sciences, Biopsy, medicine, Humans, Bone marrow, B cell, Aged, 030304 developmental biology, MESH: Lymphoma, B-Cell, Chromosomes, Human, Pair 14, MESH: Humans, business.industry, MESH: Adult, medicine.disease, MESH: Male, Lymphoma, MESH: T-Lymphocytes, MESH: Proto-Oncogene Proteins c-bcl-2, MESH: Antibodies, Monoclonal, Murine-Derived, biology.protein, MESH: Antineoplastic Agents, MESH: Chromosomes, Human, Pair 14, CD5, Chromosomes, Human, Pair 18, business, MESH: Chromosomes, Human, Pair 18, MESH: Female, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; Rituximab, an anti-CD20 monoclonal antibody, is widely used in the treatment of B-cell lymphoma. Some reports have outlined histologic modifications in bone marrow specimens from patients treated with this antibody, notably the presence of CD3(+) lymphoid aggregates morphologically mimicking residual lymphoma. To gain insight into the significance of such infiltrates, serial BM trephines obtained in 39 patients with B-cell follicular lymphoma treated by rituximab and enrolled in the GOELAMS-GELA intergroup FL2000 protocol were reexamined. The 39 patients were 22 women and 17 men with a median age of 50 years (range, 29-75 years). All pretreatment bone marrow biopsies showed CD20(+) lymphomatous cells. A second biopsy was obtained between 30 and 100 days after the last rituximab injection: 19 (48%) were morphologically diagnosed as negative (no lymphoid infiltrates or only minor lymphoid aggregates) and 20 (51%) as positive because of persistent lymphoid nodules. After immunohistochemical analysis, 13 (33%) cases were reinterpreted as false-positive because of the complete absence of CD20(+) cells, with the lymphoid nodules consisting of CD3(+) and CD5(+) T cells. Most of them also expressed CD4(+), whereas only a few CD8(+) cells were present. Among these 13 false-positive cases, 12 were BCL2-IGH polymerase chain reaction-negative in the bone marrow aspirate at the time of biopsy. The 13th case turned out to be negative in the 18th-month bone marrow aspirate. In all of these cases, lymphoid aggregates had disappeared on bone marrow biopsies performed 18 months after treatment. After a mean follow-up of 4.5 years, 9 of 13 patients were in remission as compared with only 2 among the 7 patients with postrituximab persistent CD20(+) lymphomatous cells. There was no statistically significant difference between this false-positive group of patients and that with negative postrituximab bone marrow regarding sex, age, medullar involvement pattern before treatment, delay between rituximab treatment, and molecular status. Interestingly, we noted a more favorable outcome (70% versus 52% remission) for the false-positive cases, suggesting that these T-cell reactions could be the hallmark of specific antitumoral immunity after rituximab treatment and should be properly investigated.
Published: 2008
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38. Rituximab's cost for the treatment of primary cold agglutinin disease should not limit its use

Author: Delluc, Aurelien, Pasquier, Elisabeth, De Saint Martin, Luc, Mottier, Dominique, Groupe d'Etude de la Thrombose de Bretagne Occidentale (GETBO), Université de Brest (UBO)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO), Département de Médecine Interne et Pneumologie [Brest] (DMIP - Brest), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), and Calvez, Ghislaine
Subjects: [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, MESH: Humans, Cost-Benefit Analysis, Antibodies, Monoclonal, MESH: Antibodies, Monoclonal, Antibodies, Monoclonal, Murine-Derived, MESH: Antibodies, Monoclonal, Murine-Derived, Humans, Anemia, Hemolytic, Autoimmune, MESH: Anemia, Hemolytic, Autoimmune, Rituximab, ComputingMilieux_MISCELLANEOUS, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, MESH: Cost-Benefit Analysis
Abstract: International audience
Published: 2006

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