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1. Evaluation of a new ELISA assay for monoclonal free‐light chain detection in patients with cardiac amyloidosis

Author

Hajer Abroud, Asma Beldi‐Ferchiou, Vincent Audard, François Lemonnier, Fabien Le Bras, Karim Belhadj, Anissa Moktefi, Elsa Poullot, Khalil El Karoui, Jehan Dupuis, Alizée Maarek, Louise Roulin, Marie‐Hélène Delfau‐Larue, Silvia Oghina, Mounira Kharoubi, Mélanie Bézard, Amira Zaroui, Thibaud Damy, and Valérie Molinier‐Frenkel

Subjects
AL amyloidosis, cardiac amyloidosis, ELISA, free‐light chain, monoclonal gammopathy, Diseases of the blood and blood-forming organs, RC633-647.5
Abstract

Abstract The causal protein of amyloid light‐chain (AL) amyloidosis is a monoclonal immunoglobulin free light chain (mFLC), which must be quantified in the serum for patient diagnosis and monitoring. Several manufacturers commercialize immunoassays that quantify total kappa (κ) and lambda (λ) FLC, but results can differ greatly between these tests. Here, we compared a recently developed enzyme‐linked immunosorbent assay (ELISA) (Sebia) with N‐Latex immunonephelometry (Siemens) in 96 patients diagnosed with AL amyloidosis (histologically confirmed) and 48 non‐AL patients sent to our referral center for suspicion of cardiac amyloidosis. ELISA free‐light chain difference (dFLC) were lower than N‐Latex values, and agreement between methods was reduced in the case of involved λ FLC. Diagnosis sensitivity and specificity were >85% with both assays. A receiver operating characteristic analysis indicated that ELISA performances could be improved by using a higher value for the lower limit of the κ/λ ratio. We also assessed Freelite (The Binding Site) in a subgroup of these same AL patients, including 18 cases with normal κ/λ ratio by at least one assay. Only two patients had normal κ/λ ratio with all three assays. Overall, ELISA demonstrated slightly lower sensitivity than N‐Latex but may be an alternative to nephelometry/turbidimetry in certain difficult cases.

Published
2022
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2. Alveolar compartmentalization of inflammatory and immune cell biomarkers in pneumonia-related ARDS

Author

Inès Bendib, Asma Beldi-Ferchiou, Frédéric Schlemmer, Mathieu Surenaud, Bernard Maitre, Anne Plonquet, Guillaume Carteaux, Keyvan Razazi, Veronique Godot, Sophie Hüe, Armand Mekontso Dessap, and Nicolas de Prost

Subjects
Respiratory distress syndrome, Adult, Pneumonia, Cytokines, HLA-DR antigens, PD-1, Medical emergencies. Critical care. Intensive care. First aid, RC86-88.9
Abstract

Abstract Background Biomarkers of disease severity might help individualizing the management of patients with the acute respiratory distress syndrome (ARDS). Whether the alveolar compartmentalization of biomarkers has a clinical significance in patients with pneumonia-related ARDS is unknown. This study aimed at assessing the interrelation of ARDS/sepsis biomarkers in the alveolar and blood compartments and explored their association with clinical outcomes. Methods Immunocompetent patients with pneumonia-related ARDS admitted between 2014 and 2018 were included in a prospective monocentric study. Bronchoalveolar lavage (BAL) fluid and blood samples were obtained within 48 h of admission. Twenty-two biomarkers were quantified in BAL fluid and serum. HLA-DR+ monocytes and CD8+ PD-1+ lymphocytes were quantified using flow cytometry. The primary clinical endpoint of the study was hospital mortality. Patients undergoing a bronchoscopy as part of routine care were included as controls. Results Seventy ARDS patients were included. Hospital mortality was 21.4%. The BAL fluid-to-serum ratio of IL-8 was 20 times higher in ARDS patients than in controls (p

Published
2021
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3. TNFR2 blockade of regulatory T cells unleashes an antitumor immune response after hematopoietic stem-cell transplantation

Author

Frédéric Charlotte, Allan Thiolat, Audrey Moatti, Anais Debesset, Caroline Pilon, Asma Beldi-Ferchiou, Mathieu Leclerc, Rabah Redjoul, Nhu Hanh To, Adeline Bak, Yazid Belkacemi, Benoît Laurent Salomon, Fadi Issa, David Michonneau, Sebastien Maury, and José Laurent Cohen

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Published
2022
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4. Human Apoptotic Cells, Generated by Extracorporeal Photopheresis, Modulate Allogeneic Immune Response

Author

Caroline Pilon, Thomas Stehlé, Asma Beldi-Ferchiou, Marie Matignon, Allan Thiolat, Aude Burlion, Cynthia Grondin, Brigitte Birebent, France Pirenne, Hélène Rouard, Philippe Lang, Gilles Marodon, Philippe Grimbert, and José L. Cohen

Subjects
tolerance, NSG mice, immunomodulation, transplantation, apoptotic cell, Immunologic diseases. Allergy, RC581-607
Abstract

The induction of specific and sustainable tolerance is a challenging issue in organ transplantation. The discovery of the immunosuppressive properties of apoptotic cells in animal models has paved the way for their use in human transplantation. In this work, we aimed to define a stable, reproducible, and clinically compatible production procedure of human apoptotic cells (Apo-cells). Using a clinically approved extracorporeal photopheresis technique, we have produced and characterized phenotypically and functionally human apoptotic cells. These Apo-cells have immunosuppressive properties proved in vitro and in vivo in NOD/SCID/γC mice by their capacity to modulate an allogeneic response following both a direct and an indirect antigen presentation. These results brought the rationale for the use of Apo-cells in tolerance induction protocol for organ transplantation.

Published
2019
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5. Total metabolic tumor volume, circulating tumor cells, cell-free DNA: distinct prognostic value in follicular lymphoma

Author

Marie-Hélène Delfau-Larue, Axel van der Gucht, Jehan Dupuis, Jean-Philippe Jais, Isabelle Nel, Asma Beldi-Ferchiou, Salma Hamdane, Ichrafe Benmaad, Gaelle Laboure, Benjamin Verret, Corinne Haioun, Christiane Copie-Bergman, Alina Berriolo-Riedinger, Philippine Robert, René-Olivier Casasnovas, and Emmanuel Itti

Subjects
Specialties of internal medicine, RC581-951
Abstract

Abstract: Outcomes for follicular lymphoma (FL) have greatly improved, but most patients will ultimately relapse. High total metabolic tumor volume (TMTV), computed from baseline 18F-fluorodeoxyglucose–positron emission tomography (PET), is associated with shorter progression-free survival (PFS), but circulating tumor cells (CTCs) and cell-free DNA (cfDNA) may also reflect tumor burden and be of prognostic value. The aim of our study was to correlate CTCs and cfDNA with TMTV in FL at diagnosis and to determine their prognostic values. We retrospectively analyzed 133 patients (with previously untreated FL and a baseline PET) from 2 cohorts with either a baseline plasma sample (n = 61) or a bcl2-JH-informative peripheral blood (PB) sample (n = 68). Quantification of circulating bcl2-JH+ cells and cfDNA was performed by droplet digital polymerase chain reaction. A significant correlation was found between TMTV and both CTCs (P < .0001) and cfDNA (P < .0001). With a median 48-month follow-up, 4-year PFS was lower in patients with TMTV > 510 cm3 (P = .0004), CTCs >0.0018 PB cells (P = .03), or cfDNA >2550 equivalent-genome/mL (P = .04). In comparison with TMTV alone, no additional prognostic information was obtained by measuring CTCs. In contrast, Cox multivariate analysis, including cfDNA and TMTV, showed that both cfDNA and TMTV remained predictive of outcome. In conclusion, CTCs and cfDNA correlate with TMTV in FL, and all 3 influence patient outcome. PFS was shorter for patients with high cfDNA and TMTV, suggesting that these parameters provide relevant information for tumor-tailored therapy.

Published
2018
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6. Functional Ex Vivo Testing of Alveolar Monocytes in Patients with Pneumonia-Related ARDS

Author

Inès Bendib, Asma Beldi-Ferchiou, Frédéric Schlemmer, Bernard Maitre, Mathieu Surenaud, Sophie Hüe, Guillaume Carteaux, Keyvan Razazi, Jean-Daniel Lelièvre, Yves Lévy, Armand Mekontso Dessap, Véronique Godot, and Nicolas de Prost

Subjects
acute respiratory distress syndrome, pneumonia, HLA-DR, TNF, phagocytosis, Cytology, QH573-671
Abstract

Biomarkers of disease severity might help with individualizing the management of patients with acute respiratory distress syndrome (ARDS). During sepsis, a sustained decreased expression of the antigen-presenting molecule human leucocyte antigen-DR (HLA-DR) on circulating monocytes is used as a surrogate marker of immune failure. This study aimed at assessing whether HLA-DR expression on alveolar monocytes in the setting of a severe lung infection is associated with their functional alterations. BAL fluid and blood from immunocompetent patients with pneumonia-related ARDS admitted between 2016 and 2018 were isolated in a prospective monocentric study. Alveolar and blood monocytes were immunophenotyped using flow cytometry. Functional tests were performed on alveolar and blood monocytes after in vitro lipopolysaccharide (LPS) stimulation. Phagocytosis activity and intracellular tumor necrosis factor (TNF) production were quantified using fluorochrome-conjugated-specific antibodies. Ten ARDS and seven non-ARDS control patients were included. Patients with pneumonia-related ARDS exhibited significantly lower HLA-DR expression both on circulating (p < 0.0001) and alveolar (p = 0.0002) monocytes. There was no statistically significant difference observed between patient groups (ARDS vs. non-ARDS) regarding both alveolar and blood monocytes phagocytosis activity. After LPS stimulation, alveolar (p = 0.027) and blood (p = 0.005) monocytes from pneumonia-related ARDS patients had a significantly lower intracellular TNF expression than non-ARDS patients. Monocytes from pneumonia-related ARDS patients have a deactivated status and an impaired TNF production capacity but display potent phagocytic activity. HLA-DR level expression should not be used as a surrogate marker of the phagocytic activity or the TNF production capacity of alveolar monocytes.

Published
2021
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7. Abnormal repression of SHP-1, SHP-2 and SOCS-1 transcription sustains the activation of the JAK/STAT3 pathway and the progression of the disease in multiple myeloma.

Author

Asma Beldi-Ferchiou, Nour Skouri, Cyrine Ben Ali, Ines Safra, Abderrahman Abdelkefi, Saloua Ladeb, Karima Mrad, Tarek Ben Othman, and Mélika Ben Ahmed

Subjects
Medicine, Science
Abstract

Sustained activation of JAK/STAT3 signaling pathway is classically described in Multiple Myeloma (MM). One explanation could be the silencing of the JAK/STAT suppressor genes, through the hypermethylation of SHP-1 and SOCS-1, previously demonstrated in MM cell lines or in whole bone marrow aspirates. The link between such suppressor gene silencing and the degree of bone marrow invasion or the treatment response has not been evaluated in depth. Using real-time RT-PCR, we studied the expression profile of three JAK/STAT suppressor genes: SHP-1, SHP-2 and SOCS-1 in plasma cells freshly isolated from the bone marrows of MM patients and healthy controls. Our data demonstrated an abnormal repression of such genes in malignant plasma cells and revealed a significant correlation between such defects and the sustained activation of the JAK/STAT3 pathway during MM. The repressed expression of SHP-1 and SHP-2 correlated significantly with a high initial degree of bone marrow infiltration but was, unexpectedly, associated with a better response to the induction therapy. Collectively, our data provide new evidences that substantiate the contribution of JAK/STAT suppressor genes in the pathogenesis of MM. They also highlight the possibility that the decreased gene expression of SHP-1 and SHP-2 could be of interest as a new predictive factor of a favorable treatment response, and suggest new potential mechanisms of action of the therapeutic molecules. Whether such defect helps the progression of the disease from monoclonal gammopathy of unknown significance to MM remains, however, to be determined.

Published
2017
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8. Control of NK Cell Activation by Immune Checkpoint Molecules

Author

Asma Beldi-Ferchiou and Sophie Caillat-Zucman

Subjects
NK cells, immune checkpoint molecules, cancer immunotherapy, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract

The development of cancer and chronic infections is facilitated by many subversion mechanisms, among which enhanced expression of immune checkpoints molecules, such as programmed death-1 (PD-1) and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), on exhausted T cells. Recently, immune checkpoint inhibitors have shown remarkable efficiency in the treatment of a number of cancers. However, expression of immune checkpoints on natural killer (NK) cells and its functional consequences on NK cell effector functions are much less explored. In this review, we focus on the current knowledge on expression of various immune checkpoints in NK cells, how it can alter NK cell-mediated cytotoxicity and cytokine production. Dissecting the role of these inhibitory mechanisms in NK cells is critical for the full understanding of the mode of action of immunotherapies using checkpoint inhibitors in the treatment of cancers and chronic infections.

Published
2017
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9. Lenalidomide maintenance fails to overcome the unfavourable prognosis of low NK‐cell counts in rituximab–chemotherapy responsive elderly DLBCL patients: A LYSA group study

Author

Asma Beldi‐Ferchiou, Jean‐Philippe Jais, Hervé Ghesquieres, Rene Olivier Casasnovas, Hervé Tilly, Christophe Fruchart, Franck Morschhauser, Corinne Haioun, Julien Lazarovici, Aurore Perrot, Emmanuelle Nicolas‐Virelizier, Gilles Salles, Nathalie Godard, Imen Zamali, Jean‐Marc Schiano De Colella, Alexis Claudel, Bernadette Corront, Lucie Oberic, Josette Briere, Philippe Gaulard, Catherine Thieblemont, and Marie‐Hélène Delfau‐Larue

Subjects
Hematology
Published
2023

10. TNFR2 blockade of regulatory T cells unleashes an antitumor immune response after hematopoietic stem-cell transplantation

Author

Audrey Moatti, Anais Debesset, Caroline Pilon, Asma Beldi-Ferchiou, Mathieu Leclerc, Rabah Redjoul, Frederic Charlotte, Nhu Hanh To, Adeline Bak, Yazid Belkacemi, Benoît Laurent Salomon, Fadi Issa, David Michonneau, Sebastien Maury, José Laurent Cohen, and Allan Thiolat

Subjects
Pharmacology, Cancer Research, Leukemia, Immunology, Hematopoietic Stem Cell Transplantation, Immunity, Graft vs Host Disease, T-Lymphocytes, Regulatory, Mice, Oncology, Recurrence, Hematologic Neoplasms, Molecular Medicine, Immunology and Allergy, Animals, Humans, Receptors, Tumor Necrosis Factor, Type II, Transplantation, Homologous
Abstract

BackgroundTargeting immune checkpoints that inhibit antitumor immune responses has emerged as a powerful new approach to treat cancer. We recently showed that blocking the tumor necrosis factor receptor-type 2 (TNFR2) pathway induces the complete loss of the protective function of regulatory T cells (Tregs) in a model of graft-versus-host disease (GVHD) prevention that relies on Treg-based cell therapy. Here, we tested the possibility of amplifying the antitumor response by targeting TNFR2 in a model of tumor relapse following hematopoietic stem-cell transplantation, a clinical situation for which the need for efficient therapeutic options is still unmet.MethodWe developed appropriate experimental conditions that mimic patients that relapsed from their initial hematological malignancy after hematopoietic stem-cell transplantation. This consisted of defining in allogeneic bone marrow transplantation models developed in mice, the maximum number of required tumor cells and T cells to infuse into recipient mice to develop a model of tumor relapse without inducing GVHD. We next evaluated whether anti-TNFR2 treatment could trigger alloreactivity and consequently antitumor immune response. In parallel, we also studied the differential expression of TNFR2 on T cells including Treg from patients in post-transplant leukemia relapse and in patients developing GVHD.ResultsUsing experimental conditions in which neither donor T cells nor TNFR2-blocking antibody per se have any effect on tumor relapse, we observed that the coadministration of a suboptimal number of T cells and an anti-TNFR2 treatment can trigger alloreactivity and subsequently induce a significant antitumor effect. This was associated with a reduced percentage of activated CD4+ and CD8+ Tregs. Importantly, human Tregs over-expressed TNFR2 relative to conventional T cells in healthy donors and in patients experiencing leukemia relapse or cortico-resistant GVHD after hematopoietic stem cell transplantation.ConclusionsThese results highlight TNFR2 as a new target molecule for the development of immunotherapies to treat blood malignancy relapse, used either directly in grafted patients or to enhance donor lymphocyte infusion strategies. More widely, they open the door for new perspectives to amplify antitumor responses against solid cancers by directly targeting Tregs through their TNFR2 expression.

Published
2022

11. Uncontrolled Innate and Impaired Adaptive Immune Responses in Patients with COVID-19 Acute Respiratory Distress Syndrome

Author

Sophie Hue, Mathieu Surenaud, Marie Héléne Delfau-Larue, Keyvan Razazi, Etienne Audureau, Guillaume Carteaux, Asma Beldi-Ferchiou, Thomas Frapard, Inès Bendib, Armand Mekontso-Dessap, Slim Fourati, Simon Rivoal, and Nicolas de Prost

Subjects
Adult, Male, Pulmonary and Respiratory Medicine, Patients, Coronavirus disease 2019 (COVID-19), Disease, Acute respiratory distress, Antibodies, Viral, Critical Care and Intensive Care Medicine, medicine.disease_cause, Immune system, Humans, Medicine, Clinical severity, In patient, Prospective Studies, Pandemics, Aged, Coronavirus, Biological Products, Respiratory Distress Syndrome, SARS-CoV-2, business.industry, Immunity, Editorials, COVID-19, Original Articles, Middle Aged, Viral Load, Acquired immune system, cytokines, Immunity, Innate, Immunology, ARDS, Female, France, Chemokines, business, COVID-19/Critical Care
Abstract

Rationale: Uncontrolled inflammatory innate response and impaired adaptive immune response are associated with clinical severity in patients with coronavirus disease (COVID-19). Objectives: To compare the immunopathology of COVID-19 acute respiratory distress syndrome (ARDS) with that of non–COVID-19 ARDS, and to identify biomarkers associated with mortality in patients with COVID-19 ARDS. Methods: Prospective observational monocenter study. Immunocompetent patients diagnosed with RT-PCR–confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and ARDS admitted between March 8 and March 30, 2020, were included and compared with patients with non–COVID-19 ARDS. The primary clinical endpoint of the study was mortality at Day 28. Flow cytometry analyses and serum cytokine measurements were performed at Days 1–2 and 4–6 of ICU admission. Measurements and Main Results: As compared with patients with non–COVID-19 ARDS (n = 36), those with COVID-19 (n = 38) were not significantly different regarding age, sex, and Sequential Organ Failure Assessment and Simplified Acute Physiology Score II scores but exhibited a higher Day-28 mortality (34% vs. 11%, P = 0.030). Patients with COVID-19 showed profound and sustained T CD4+ (P = 0.002), CD8+ (P

Published
2020

12. Daratumumab is safe and induces a rapid hematological response in light-chain amyloidosis with severe cardiac impairment

Author

Corinne Haioun, Asma Beldi-Ferchiou, Amandine Ladaique, Jehan Dupuis, Louise Roulin, S. Oghina, Thibaud Damy, Diane Bodez, François Lemonnier, Alizee Maarek, Karim Belhadj, Fabien Le Bras, Romain Gounot, Elsa Poullot, and Valérie Molinier-Frenkel

Subjects
Cancer Research, Pathology, medicine.medical_specialty, Chemistry, Amyloidosis, Organ dysfunction, Antibodies, Monoclonal, Daratumumab, Hematological response, Hematology, Immunoglobulin light chain, medicine.disease, 03 medical and health sciences, 0302 clinical medicine, Oncology, 030220 oncology & carcinogenesis, Plasma cell disorder, medicine, Extracellular, Humans, medicine.symptom, Deposition (chemistry), 030215 immunology
Abstract

Systemic light-chain (AL) amyloidosis is a plasma cell disorder characterized by extracellular deposition of monoclonal immunoglobulin light chains leading to organ dysfunction. Cardiac involvement...

Published
2020

13. Optimized Flow Cytometry Strategy for Phenotyping Intramuscular Leukocytes: Application to the Evaluation of Myopathological Processes

Author

Tassadit Saidj, Yasmine Baba Amer, Anne Plonquet, Adeline Henry, Sarah Souvannanorath, Frederic Relaix, Asma Beldi-Ferchiou, and François Jérôme Authier

Subjects
Cellular and Molecular Neuroscience, Mice, Neurology, Animals, Neurology (clinical), General Medicine, HLA-DR Antigens, CD8-Positive T-Lymphocytes, Flow Cytometry, Biomarkers, Pathology and Forensic Medicine
Abstract

Phenotyping intramuscular immune cells is essential for the characterization of dysimmune/inflammatory myopathies (DIM). Flow cytometry (FC) is the most reliable technique for analyzing leukocyte subpopulations and evaluating their activation levels. We developed a purely mechanical protocol for extracting cells from muscle tissue allowing us to preserve cell surface epitopes and determined its applicability to experimental pathology in mice and myopathological diagnosis in human. Skeletal muscle regeneration in mice was associated with a transient enrichment of macrophages (CD11bhighGr-1+), myeloid dendritic cells (CD3−C8+CD11bhigh), CD8+ T cells (CD3+C8+), and NK cells (CD3− CD11bhighNKp46+). In murine models of inherited muscle dystrophies, leukocytes represented 23%–84% of intramuscular mononuclear cells, with a percentage of CD8+ T cells (4%–17%) mirroring that of all CD45+ cells, while MDCs remained a minority. In human 16 samples (DIM: n = 9; nonimmune conditions: n = 7), DIM was associated with intramuscular recruitment of CD8+ T cells, but not CD4+ T cells and NK cells. FC allowed concomitant quantification of HLA-DR, CD25, CD38, and CD57 activation/differentiation biomarkers and showed increased activation levels of CD4+ and CD8+ T cells in DIM. In conclusion, FC is an appropriate method for quantifying intramuscular leukocyte subpopulations and analyzing their activation states.

Published
2022

14. Neutrophil Extracellular Traps Are Elevated in Patients with Pneumonia-related Acute Respiratory Distress Syndrome

Author

Mathieu Surenaud, Vanessa Granger, Sophie Hue, Inès Bendib, Armand Mekontso Dessap, Keyvan Razazi, Frédéric Schlemmer, Guillaume Carteaux, Nicolas de Prost, Asma Beldi-Ferchiou, Bernard Maitre, Sylvie Chollet-Martin, and Luc de Chaisemartin

Subjects
Adult, Male, 0301 basic medicine, medicine.medical_specialty, Extracellular Traps, ARDS, Neutrophils, Arbitrary unit, medicine.medical_treatment, Gastroenterology, Cohort Studies, Pathogenesis, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Humans, Prospective Studies, Aged, Mechanical ventilation, Respiratory Distress Syndrome, medicine.diagnostic_test, business.industry, Pneumonia, Neutrophil extracellular traps, Middle Aged, medicine.disease, Respiration, Artificial, 030104 developmental biology, Anesthesiology and Pain Medicine, Bronchoalveolar lavage, 030220 oncology & carcinogenesis, Female, business, Bronchoalveolar Lavage Fluid
Abstract

Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New Background Neutrophil extracellular traps have been associated with tissue damage. Whether these are involved in the pathogenesis of human acute respiratory distress syndrome (ARDS) and could be a potential therapeutic target is unknown. The authors quantified bronchoalveolar and blood neutrophil extracellular traps in patients with pneumonia-related ARDS and assessed their relationship with ventilator-free days. Methods Immunocompetent patients with pneumonia and moderate or severe ARDS (n = 35) and controls (n = 4) were included in a prospective monocentric study. Neutrophil extracellular trap concentrations were quantified (as DNA–myeloperoxidase complexes) in bronchoalveolar lavage fluid and serum by enzyme-linked immunosorbent assay. The relationship between bronchoalveolar lavage neutrophil extracellular trap concentrations and the primary clinical endpoint (i.e., the number of live ventilator-free days at day 28) was assessed using linear regression analyses. Results There was no significant relationship between bronchoalveolar lavage neutrophil extracellular trap concentrations and ventilator-free days by multiple regression analysis (β coefficient = 2.40; 95% CI, −2.13 to 6.92; P = 0.288). Neutrophil extracellular trap concentrations were significantly higher in bronchoalveolar lavage than in blood of ARDS patients (median [first to third quartiles]:154 [74 to 1,000] vs. 26 [4 to 68] arbitrary units, difference: −94; 95% CI, −341 to −57; P < 0.0001). Bronchoalveolar concentrations of patients were higher than those of controls (154 [74 to 1,000] vs. 4 [4 to 4] arbitrary units, difference: −150; 95% CI, −996 to −64; P < 0.001) and associated with bronchoalveolar interleukin-8 (Spearman’s ρ = 0.42; P = 0.012) and neutrophil concentrations (ρ = 0.57; P < 0.0001). Intensive care unit mortality (12%, n = 2 of 17 vs. 17%, n = 3 of 18; P > 0.99) and the number of ventilator-free days at day 28 (22 [14 to 25] vs. 14 [0 to 21] days; difference: −5; 95% CI, −15 to 0; P = 0.066) did not significantly differ between patients with higher (n = 17) versus lower (n = 18) bronchoalveolar neutrophil extracellular trap concentrations. Conclusions Bronchoalveolar neutrophil extracellular trap concentration was not significantly associated with mechanical ventilation duration in pneumonia-related ARDS.

Published
2019

15. Maturation and persistence of the anti-SARS-CoV-2 memory B cell response

Author

Mickaël M. Ménager, Marine Luka, Marc Michel, Sophie Hue, Slim Fourati, Aurélien Sokal, Simon Fillatreau, Claude-Agnès Reynaud, Giovanna Barba-Spaeth, Annalisa Meola, Laetitia Languille, Jean-Michel Pawlotsky, Matthieu Mahévas, Jérôme Mégret, Félix A. Rey, Etienne Crickx, Asma Beldi-Ferchiou, Magali Bouvier-Alias, Jean-Claude Weill, Imane Azzaoui, Alexis Vandenberghe, Pascal Chappert, Samia Baloul, Anaïs Roeser, Ignacio Fernandez, Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Service de médecine interne [Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Inovarion, Virologie Structurale - Structural Virology, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Service de bactériologie, virologie, hygiène [Mondor], Molecular virology and immunology – Physiopathology and therapeutic of chronic viral hepatitis (Team 18) (Inserm U955), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, IMRB - 'Transfusion et Maladies du Globule Rouge' [Créteil] (U955 Inserm - UPEC), Hôpital Henri Mondor, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, Vaccine Research Institute (VRI), Physiopathologie et immunothérapies dans l’infection VIH [Créteil] (Inserm U955 Équipe 16), Clinical Epidemiology and Ageing : Geriatrie Soins Primaires et Santé Publique (CEpiA), Inflammatory Responses and Transcriptomic Networks in diseases (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Structure Fédérative de Recherche Necker (SFR Necker - UMS 3633 / US24), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), This work was supported by a grant from the Agence Nationale de la Recherche and the Fondation pour la Recherche Médicale (ANR, MEMO-COV-2), by the Fondation Princesse Grace, and, in part by an ERC Advanced Investigator Grant (B-response). Assistance Publique – Hôpitaux de Paris (AP-HP, Département de la Recherche Clinique et du Développement) was the promotor and the sponsor of MEMO-COV-2. A.S. was supported by a Poste d’Accueil from Inserm, A.R. by an Année Recherche from AP-HP and by a SNFMI fellowship., ANR-20-COVI-0072,MEMO-COV-2,Lymphocytes B et T CD4 mémoires spécifiques du virus chez les patients guéris du Covid-19(2020), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Vaccine Research Institute [Créteil, France] (VRI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)

Subjects
Adult, Somatic cell, Cell, Somatic hypermutation, Context (language use), Biology, Lymphocyte Activation, spike protein, Severity of Illness Index, Article, General Biochemistry, Genetics and Molecular Biology, plasma cells, RBD, 03 medical and health sciences, 0302 clinical medicine, Single-cell analysis, medicine, Humans, neutralizing antibodies, Memory B cell, B cell, 030304 developmental biology, B-Lymphocytes, 0303 health sciences, Germinal center, COVID-19, OC43, Middle Aged, Flow Cytometry, 3. Good health, somatic hypermutation, medicine.anatomical_structure, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, germinal center, Spike Glycoprotein, Coronavirus, Immunology, extrafollicular response, Single-Cell Analysis, HKU1, Immunologic Memory, 030217 neurology & neurosurgery
Abstract

Memory B cells play a fundamental role in host defenses against viruses, but to date, their role has been relatively unsettled in the context of SARS-CoV-2. We report here a longitudinal single-cell and repertoire profiling of the B cell response up to 6 months in mild and severe COVID-19 patients. Distinct SARS-CoV-2 spike-specific activated B cell clones fueled an early antibody-secreting cell burst as well as a durable synchronous germinal center response. While highly mutated memory B cells, including pre-existing cross-reactive seasonal Betacoronavirus-specific clones, were recruited early in the response, neutralizing SARS-CoV-2 RBD-specific clones accumulated with time and largely contributed to the late, remarkably stable, memory B cell pool. Highlighting germinal center maturation, these cells displayed clear accumulation of somatic mutations in their variable region genes over time. Overall, these findings demonstrate that an antigen-driven activation persisted and matured up to 6 months after SARS-CoV-2 infection and may provide long-term protection., Graphical abstract, The B cell response against SARS-CoV-2 shows a temporal shift from an extrafollicular reaction that includes memory B cells against seasonal coronaviruses toward a germinal center-dependent memory response encoding (spike-specific) neutralizing antibodies.

Published
2021

16. Integrative analysis of a phase 2 trial combining lenalidomide with CHOP in angioimmunoblastic T-cell lymphoma

Author

Audrey Letourneau, Philippe Gaulard, Vincent Camus, Olivier Casasnovas, Edoardo Missiaglia, Corinne Haioun, François Lemonnier, Laurent Voillat, Cyrielle Robe, Caroline Régny, Virginie Fataccioli, Violaine Safar, Céline Bossard, Guillaume Cartron, Emmanuel Bachy, Slim Fourati, Michel Meignan, Marie-Pierre Moles-Moreau, Laura Pelletier, Alain Delmer, Asma Beldi-Ferchiou, Victoria Cacheux, Marie Parrens, Stéphanie Becker, Marie-Hélène Delfau-Larue, Anne-Ségolène Cottereau, Reda Bouabdallah, Laurence de Leval, 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), Anti-Tumor Immunosurveillance and Immunotherapy (CRCINA-ÉQUIPE 3), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), and Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Oncology, Vincristine, medicine.medical_specialty, Angioimmunoblastic T-cell lymphoma, Cyclophosphamide, [SDV]Life Sciences [q-bio], CHOP, Lymphoma, T-Cell, 03 medical and health sciences, 0302 clinical medicine, Prednisone, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, Prospective Studies, Lenalidomide, 030304 developmental biology, Aged, Aged, 80 and over, 0303 health sciences, Lymphoid Neoplasia, business.industry, Hematology, Middle Aged, medicine.disease, 3. Good health, Discontinuation, Lymphoma, Antineoplastic Combined Chemotherapy Protocols/adverse effects, Rituximab, 030220 oncology & carcinogenesis, business, medicine.drug
Abstract

Angioimmunoblastic T-cell lymphoma (AITL) is a frequent T-cell lymphoma in the elderly population that has a poor prognosis when treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) therapy. Lenalidomide, which has been safely combined with CHOP to treat B-cell lymphoma, has shown efficacy as a single agent in AITL treatment. We performed a multicentric phase 2 trial combining 25 mg lenalidomide daily for 14 days per cycle with 8 cycles of CHOP21 in previously untreated AITL patients aged 60 to 80 years. The primary objective was the complete metabolic response (CMR) rate at the end of treatment. Seventy-eight of the 80 patients enrolled were included in the efficacy and safety analysis. CMR was achieved in 32 (41%; 95% confidence interval [CI], 30%-52.7%) patients, which was below the prespecified CMR rate of 55% defined as success in the study. The 2-year progression-free survival (PFS) was 42.1% (95% CI, 30.9%-52.8%), and the 2-year overall survival was 59.2% (95% CI, 47.3%-69.3%). The most common toxicities were hematologic and led to treatment discontinuation in 15% of patients. This large prospective and uniform series of AITL treatment data was used to perform an integrative analysis of clinical, pathologic, biologic, and molecular data. TET2, RHOA, DNMT3A, and IDH2 mutations were present in 78%, 54%, 32%, and 22% of patients, respectively. IDH2 mutations were associated with distinct pathologic and clinical features and DNMT3A was associated with shorter PFS. In conclusion, the combination of lenalidomide and CHOP did not improve the CMR in AITL patients. This trial clarified the clinical impact of recurrent mutations in AITL. This trial was registered at www.clincialtrials.gov as #NCT01553786.

Published
2021

17. Alveolar compartmentalization of inflammatory and immune cell biomarkers in pneumonia-related ARDS

Author

Keyvan Razazi, Véronique Godot, Frédéric Schlemmer, Guillaume Carteaux, Bernard Maitre, Armand Mekontso Dessap, Sophie Hue, Mathieu Surenaud, Inès Bendib, A. Plonquet, Nicolas de Prost, and Asma Beldi-Ferchiou

Subjects
Adult, medicine.medical_specialty, ARDS, Respiratory distress syndrome, medicine.medical_treatment, Critical Care and Intensive Care Medicine, Gastroenterology, Sepsis, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, PD-1, Clinical endpoint, Medicine, Clinical significance, 030212 general & internal medicine, medicine.diagnostic_test, business.industry, HLA-DR antigens, lcsh:Medical emergencies. Critical care. Intensive care. First aid, 030208 emergency & critical care medicine, Pneumonia, lcsh:RC86-88.9, medicine.disease, Bronchoalveolar lavage, Cytokine, Shock (circulatory), Cytokines, medicine.symptom, business
Abstract

Background Biomarkers of disease severity might help individualizing the management of patients with the acute respiratory distress syndrome (ARDS). Whether the alveolar compartmentalization of biomarkers has a clinical significance in patients with pneumonia-related ARDS is unknown. This study aimed at assessing the interrelation of ARDS/sepsis biomarkers in the alveolar and blood compartments and explored their association with clinical outcomes. Methods Immunocompetent patients with pneumonia-related ARDS admitted between 2014 and 2018 were included in a prospective monocentric study. Bronchoalveolar lavage (BAL) fluid and blood samples were obtained within 48 h of admission. Twenty-two biomarkers were quantified in BAL fluid and serum. HLA-DR+ monocytes and CD8+ PD-1+ lymphocytes were quantified using flow cytometry. The primary clinical endpoint of the study was hospital mortality. Patients undergoing a bronchoscopy as part of routine care were included as controls. Results Seventy ARDS patients were included. Hospital mortality was 21.4%. The BAL fluid-to-serum ratio of IL-8 was 20 times higher in ARDS patients than in controls (p p = 0.026), IL-6 (p = 0.002), IP-10/CXCL10 (p = 0.024) and IL-10 (p = 0.023) than others. The BAL fluid-to-serum ratio of IL-1Ra was more elevated in hospital survivors than decedents (p = 0.006), even after adjusting for SOFA and driving pressure (p = 0.036). There was no significant association between alveolar or alveolar/blood monocytic HLA-DR or CD8+ lymphocytes PD-1 expression and hospital mortality. Conclusions IL-8 was the most compartmentalized cytokine and lower BAL fluid-to-serum concentration ratios of IL-1Ra were associated with hospital mortality in patients with pneumonia-associated ARDS.

Published
2021

18. Venetoclax induces profound and sustained responses in patients with relapsed/refractory light-chain amyloidosis

Author

Corinne Haioun, Fabien Le Bras, Romain Gounot, Antoine Galat, Hélène Pasquer, Alizée Maarek, Valérie Molinier-Frenkel, Karim Belhadj, Sylvia Oghina, Amandine Ladaique, Elsa Poulot, Jehan Dupuis, Thibaud Damy, Asma Beldi-Ferchiou, François Lemonnier, and Louise Roulin

Subjects
Adult, Male, Immunoglobulin light chain, chemistry.chemical_compound, AL amyloidosis, Medicine, Humans, In patient, Immunoglobulin Light-chain Amyloidosis, Aged, Retrospective Studies, Aged, 80 and over, Bh3 mimetics, Sulfonamides, business.industry, Venetoclax, Amyloidosis, Hematology, Middle Aged, medicine.disease, Bridged Bicyclo Compounds, Heterocyclic, Cardiac amyloidosis, chemistry, Relapsed refractory, Cancer research, Female, business
Published
2020

19. High effector-memory CD8+ T-cell levels correlate with high PML risk in natalizumab-treated patients

Author

Marie-Hélène Delfau-Larue, Jérôme Hodel, Valérie Molinier-Frenkel, Asma Beldi-Ferchiou, Abir Wahab, Alain Créange, Ivania Patry, Matthieu Duchmann, IMRB - I-BIOT/'Immunorégulation et Biothérapie' [Créteil] (U955 Inserm - UPEC), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Hôpital Henri Mondor, Excitabilité nerveuse et thérapeutique (ENT), Hôpital Henri Mondor-EA 4391, Service de Physiologie Explorations Fonctionnelles-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Centre Hospitalier Sud Francilien, Université Paris-Est (UPE), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), and CCSD, Accord Elsevier

Subjects
medicine.medical_specialty, CD3, [SDV]Life Sciences [q-bio], Lower risk, Gastroenterology, Flow cytometry, Multiple sclerosis, 03 medical and health sciences, 0302 clinical medicine, Natalizumab, Progressive multifocal leukoencephalopathy, Internal medicine, Medicine, Cytotoxic T cell, 030212 general & internal medicine, Lymphocytes, medicine.diagnostic_test, biology, business.industry, virus diseases, General Medicine, Biomarker, medicine.disease, [SDV] Life Sciences [q-bio], Neurology, biology.protein, Neurology (clinical), business, 030217 neurology & neurosurgery, CD8, medicine.drug
Abstract

Background Progressive multifocal leukoencephalopathy (PML) is a severe complication of natalizumab (NTZ) treatment in multiple sclerosis (MS) patients. Based on the analysis of cryopreserved cells, several reports have showed that CD62L+ CD4+ T-cells percentage drops before PML onset. Objective To analyze CD62L and CD45RA expression on fresh-blood CD4+ and CD8+ T-cells from NTZ-treated patients, according to their estimated PML risk. Methods We prospectively enrolled 74 MS patients, including 62 NTZ-treated, and stratified them into low, intermediate and high PML risk groups. Circulating naive and memory T-cell subsets were analyzed by flow cytometry. Results We found no correlation between the percentage of CD62L+ CD4+ T-cells and PML risk. In contrast, the repartition of CD8+ T-cells subpopulations was altered in the high risk group: both the percentage and absolute count of CD8+ CD62L- CD45RA- effector memory T- cells (TEM) was significantly higher compared to patients at lower risk despite similar CD3+ and CD8+ T-cell counts. One high-risk patient with elevated CD8+ TEM and CD62L+ CD4+ T-cell levels developed PML six months after sampling. Conclusion Our results suggest that CD8+ TEM cells should be evaluated in larger studies as a potential surrogate marker of PML risk in NTZ-treated patients.

Published
2020

20. Maturation and persistence of the anti-SARS-CoV-2 memory B cell response

Author

Aurélien Sokal, Pascal Chappert, Anais Roeser, Giovanna Barba-Spaeth, Slim Fourati, Imane Azzaoui, Alexis Vandenberghe, Ignacio Fernandez, Magali Bouvier-Alias, Etienne Crickx, Asma Beldi Ferchiou, Sophie Hue, Laetitia Languille, Samia Baloul, France Noizat-Pirenne, Marine Luka, Jérôme Megret, Mickaël Ménager, Jean-Michel Pawlotsky, Simon Fillatreau, Felix A Rey, Jean-Claude Weill, Claude-Agnès Reynaud, and Matthieu Mahévas

Subjects
medicine.anatomical_structure, Somatic cell, Repertoire, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Cell, Immunology, medicine, Germinal center, Biology, Memory B cell, Gene, B cell
Abstract

Memory B cells play a fundamental role in host defenses against viruses, but to date, their role have been relatively unsettled in the context of SARS-CoV-2. We report here a longitudinal single-cell and repertoire profiling of the B cell response up to 6 months in mild and severe COVID-19 patients. Distinct SARS-CoV-2 Spike-specific activated B cell clones fueled an early antibody-secreting cell burst as well as a durable synchronous germinal center response. While highly mutated memory B cells, including preexisting cross-reactive seasonal Betacoronavirus-specific clones, were recruited early in the response, neutralizing SARS-CoV-2 RBD-specific clones accumulated with time and largely contributed to the late remarkably stable memory B-cell pool. Highlighting germinal center maturation, these cells displayed clear accumulation of somatic mutations in their variable region genes over time. Overall, these findings demonstrate that an antigen-driven activation persisted and matured up to 6 months after SARS-CoV-2 infection and may provide long-term protection.

Published
2020

21. Molecular response after obinutuzumab plus high-dose cytarabine induction for transplant-eligible patients with untreated mantle cell lymphoma (LyMa-101): a phase 2 trial of the LYSA group

Author

Hervé Maisonneuve, Lucie Oberic, Barbara Burroni, Krimo Bouabdallah, Elizabeth Macintyre, Catherine Thieblemont, Caroline Bodet-Milin, Marie-Hélène Delfau-Larue, Olivier Hermine, Hervé Tilly, Steven Le Gouill, Vincent Ribrag, Marion Alcantara, Thomas Gastinne, Arnaud Jaccard, Danielle Canioni, Roch Houot, Anne Moreau, Asma Beldi-Ferchiou, Nicolas Daguindau, Ghandi Damaj, Charles Bescond, Victoria Cacheux, Violaine Safar, Stéphanie Guidez, Centre hospitalier universitaire de Nantes (CHU Nantes), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), 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), CHU Henri Mondor, Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Clermont-Ferrand, Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Hôpital Cochin [AP-HP], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Hopital Saint-Louis [AP-HP] (AP-HP), Centre Hospitalier Départemental - Hôpital de La Roche-sur-Yon (CHD Vendée), CHU Pontchaillou [Rennes], Microenvironment and B-cells: Immunopathology,Cell Differentiation, and Cancer (MOBIDIC), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Etablissement français du sang [Rennes] (EFS Bretagne)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Bordeaux [Bordeaux], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Institut d'Hématologie de Basse-Normandie (IHBN), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN)-Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-UNICANCER, CHU Limoges, Centre Hospitalier Annecy-Genevois [Saint-Julien-en-Genevois], Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris-Saclay, Département d'hématologie [Gustave Roussy], Institut Gustave Roussy (IGR), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), CHU Henri Mondor [Créteil], Université de Rennes (UR)-Etablissement français du sang [Rennes] (EFS Bretagne)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), CCSD, Accord Elsevier, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Centre Hospitalier Départemental - Hôpital de La Roche-sur-Yon, Microenvironment, Cell Differentiation, Immunology and Cancer (MICMAC), 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 référent Sclérose Latérale Amyotrophique et autres maladies du motoneurone [CHU Limoges] (SLA CHU Limoges), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)

Subjects
Adult, medicine.medical_specialty, Neoplasm, Residual, Adolescent, [SDV]Life Sciences [q-bio], Lymphoma, Mantle-Cell, Neutropenia, Antibodies, Monoclonal, Humanized, Gastroenterology, Transplantation, Autologous, Dexamethasone, 03 medical and health sciences, chemistry.chemical_compound, Young Adult, 0302 clinical medicine, Maintenance therapy, Obinutuzumab, Bone Marrow, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, Prospective Studies, business.industry, Cytarabine, Hematopoietic Stem Cell Transplantation, Induction chemotherapy, Anemia, Hematology, Minimal Residual Disease Negativity, Middle Aged, medicine.disease, Minimal residual disease, 3. Good health, Transplantation, [SDV] Life Sciences [q-bio], Treatment Outcome, chemistry, ROC Curve, 030220 oncology & carcinogenesis, Area Under Curve, Mantle cell lymphoma, business, 030215 immunology
Abstract

International audience; BACKGROUND: Obinutuzumab monotherapy has shown promising efficacy in mantle cell lymphoma. We aimed to investigate the activity of obinutuzumab plus DHAP (dexamethasone, high-dose cytarabine, and cisplatin), measured by minimal residual disease quantitative (q)PCR status in the bone marrow after four cycles. METHODS: LyMa-101 was a prospective, open-label, single-arm, phase 2 trial. Participants were enrolled from 28 hospitals in France. Newly diagnosed patients with mantle cell lymphoma (aged 18 to

Published
2020

22. Lenalidomide/rituximab induces high molecular response in untreated follicular lymphoma: LYSA ancillary RELEVANCE study

Author

Hervé Tilly, Thierry Fest, Loic Ysebaert, Sylvie Glaisner, Guillaume Cartron, Rene-Olivier Casasnovas, Steven Le Gouill, Jean-Claude Eisenmann, Roch Houot, Marie-Hélène Delfau-Larue, Marie-Laure Boulland, Gilles Salles, Gian Matteo Pica, Franck Morschhauser, Asma Beldi-Ferchiou, François Lemonnier, Pierre Feugier, Luc Xerri, Pascal Godmer, Vincent Ribrag, Hervé Maisonneuve, 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), CHU Pontchaillou [Rennes], Service d'Hématologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre Hospitalier Départemental - Hôpital de La Roche-sur-Yon (CHD Vendée), CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), CHU Henri Mondor, Centre Hospitalier Métropole Savoie [Chambéry], Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Emile Muller [Mulhouse] (CH E.Muller Mulhouse), Groupe Hospitalier de Territoire Haute Alsace (GHTHA), Regulation of Bcl2 and p53 Networks in Multiple Myeloma and Mantle Cell Lymphoma (CRCINA-ÉQUIPE 10), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Institut Gustave Roussy (IGR), Département d'hématologie [Gustave Roussy], Centre hospitalier Bretagne Atlantique (Morbihan) (CHBA), CRLCC René Huguenin, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut de Génétique Moléculaire de Montpellier (IGMM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Recherche translationelle relations hôte-pathogènes, Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre Hospitalier Départemental - Hôpital de La Roche-sur-Yon, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), CHU Montpellier, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Bernardo, Elizabeth, CHU Henri Mondor [Créteil], and Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Oncology, medicine.medical_specialty, medicine.medical_treatment, Follicular lymphoma, [SDV.CAN]Life Sciences [q-bio]/Cancer, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, hemic and lymphatic diseases, Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, Lenalidomide, Lymphoma, Follicular, 030304 developmental biology, 0303 health sciences, Chemotherapy, Lymphoid Neoplasia, business.industry, Hematology, medicine.disease, Prognosis, Minimal residual disease, 3. Good health, Lymphoma, Regimen, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Rituximab, Bone marrow, business, medicine.drug
Abstract

Complete molecular response (CMR) after first-line immunochemotherapy reflects treatment efficacy and may predict prognosis in patients with follicular lymphoma (FL). RELEVANCE is the first phase 3 trial comparing the chemotherapy-free regimen lenalidomide/rituximab (R2) vs rituximab/chemotherapy (R-Chemo) in previously untreated FL patients (ClinicalTrials.gov identifier: NCT01650701). The objective of the minimal residual disease (MRD) analysis was to determine the ability of a chemotherapy-free regimen to induce CMR. Of 440 French patients participating in the Lymphoma Study Association (LYSA) RELEVANCE MRD study, all 222 patients with a BIOMED-2–detectable BCL2-JH translocation at diagnosis were analyzed. MRD was quantified by droplet digital polymerase chain reaction with a sensitivity ≤10−4. At week 24 (end of induction treatment), 98% and 78% of patients achieved CMR in peripheral blood (PB) and bone marrow (BM), respectively. Achievement of CMR (in PB and/or BM) had a significant impact on progression-free survival (PFS), with 3-year PFS of 84% and 55% for patients with CMR and detectable MRD, respectively (P = .015). CMR at week 24 was reached more frequently in the R2 arm (105/117; 90%) than in the R-Chemo arm (70/90; 77%) (P = .022). The poor prognostic value in terms of PFS for the persistence of molecular disease was observed irrespective of treatment arm (interaction test, P = .31). In agreement with the clinical results of the RELEVANCE trial, our results show that R2 immunomodulatory treatment in first-line FL can achieve high rates of CMR.

Published
2020

23. Circulating plasmablasts and high level of BAFF are hallmarks of minimal change nephrotic syndrome in adults

Author

Matthieu Mahevas, Julie Oniszczuk, Dil Sahali, Carole Hénique, Marie-Hélène Delfau-Larue, Mohamad Zaidan, Etienne Audureau, Vincent Frontera, Anissa Moktefi, Mario Ollero, Valérie Molinier-Frenkel, Khalil El Karoui, Alexandre Karras, Asma Beldi-Ferchiou, Vincent Audard, Imane Azzaoui, Evangeline Pillebout, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, IMRB - 'Transfusion et Maladies du Globule Rouge' [Créteil] (U955 Inserm - UPEC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, Hôpital Henri Mondor, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service de santé publique [Mondor], 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), service Anatomie et Cytologie Pathologique, Hôpital Henri Mondor, Assistance Publique - Hôpitaux de Paris (AP-HP), Service de rhumatologie, CHU Bordeaux [Bordeaux], Néphrologie [CHU Bicêtre], AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Université Paris Est Créteil, Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), IMRB - PGD/'Pathophysiology of Glomerular Diseases' [Créteil] (U955 Inserm - UPEC), and Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)

Subjects
0301 basic medicine, Adult, Male, medicine.medical_specialty, Nephrotic Syndrome, [SDV]Life Sciences [q-bio], Plasma Cells, 030232 urology & nephrology, Serum albumin, Gastroenterology, Glomerulonephritis, Membranous, Pathogenesis, 03 medical and health sciences, 0302 clinical medicine, Recurrence, Internal medicine, B-Cell Activating Factor, Medicine, Humans, B-cell activating factor, Interleukin 6, ComputingMilieux_MISCELLANEOUS, Transplantation, Proteinuria, biology, business.industry, Nephrosis, Lipoid, Interleukin, Gamma globulin, Middle Aged, 3. Good health, 030104 developmental biology, Nephrology, Immunoglobulin M, Case-Control Studies, biology.protein, Female, medicine.symptom, business
Abstract

Background The recent success achieved with the use of B cell-depleting agents in some patients with minimal change nephrotic syndrome (MCNS) suggests an unexpected role for B lymphocytes in the pathogenesis of this immune-mediated glomerular disease. Nevertheless, no extensive B-cell phenotyping analysis has ever been performed in untreated adult patients soon after MCNS diagnosis. Methods We investigated the distribution of the different B-cell subpopulations in 22 untreated adult patients with biopsy-proven MCNS [MCNS relapse (MCNS-Rel)]. We compared these data with those for 24 healthy controls, 13 MCNS patients in remission (with no specific treatment) and 19 patients with idiopathic membranous nephropathy (IMN). Results Patients with MCNS-Rel or IMN had higher proteinuria and lower serum albumin and gammaglobulin levels (P Conclusions An increase in the proportion of circulating plasmablasts seems to be a hallmark of untreated MCNS in adult patients. Further studies are required to more precisely determine the phenotype and functions of these cells.

Published
2020

24. High effector-memory CD8

Author

Asma, Beldi-Ferchiou, Abir, Wahab, Matthieu, Duchmann, Jérôme, Hodel, Ivania, Patry, Marie-Hélène, Delfau-Larue, Valérie, Molinier-Frenkel, and Alain, Créange

Subjects
Multiple Sclerosis, T-Lymphocyte Subsets, Natalizumab, Leukoencephalopathy, Progressive Multifocal, Humans, CD8-Positive T-Lymphocytes
Abstract

Progressive multifocal leukoencephalopathy (PML) is a severe complication of natalizumab (NTZ) treatment in multiple sclerosis (MS) patients. Based on the analysis of cryopreserved cells, several reports have showed that CD62L+ CD4+ T-cells percentage drops before PML onset.To analyze CD62L and CD45RA expression on fresh-blood CD4+ and CD8+ T-cells from NTZ-treated patients, according to their estimated PML risk.We prospectively enrolled 74 MS patients, including 62 NTZ-treated, and stratified them into low, intermediate and high PML risk groups. Circulating naïve and memory T-cell subsets were analyzed by flow cytometry.We found no correlation between the percentage of CD62L+ CD4+ T-cells and PML risk. In contrast, the repartition of CD8+ T-cells subpopulations was altered in the high risk group: both the percentage and absolute count of CD8+ CD62L- CD45RA- effector memory T- cells (TOur results suggest that CD8+ T

Published
2020

25. Impaired TGF-β signaling in patients with active systemic lupus erythematosus is associated with an overexpression of IL-22

Author

Imen Zamali, Monia Khanfir, Houman Mh, Mohamed-Ridha Barbouche, Skander Mrad, Soumaya Marzouki, Raja Rekik, Asma Beldi-Ferchiou, Melika Ben Ahmed, S. Hamzaoui, T. Larbi, Ons Kammoun, Laboratoire de Transmission, Contrôle et Immunobiologie des Infections - Laboratory of Transmission, Control and Immunobiology of Infection (LR11IPT02), Institut Pasteur de Tunis, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Hôpital La Rabta [Tunis], Université de Tunis El Manar (UTM), Centre Hospitalier Universitaire Mongi Slim [La Marsa], Laboratoire d'immunologie clinique [Institut Pasteur de Tunis], Hôpital Henri Mondor, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), and This work was supported by the Tunisian Ministry of Higher Education and Research.

Subjects
Adult, 0301 basic medicine, Tunisia, T-Lymphocytes, CD3, Immunology, Smad3 pathway, Gene Expression, Smad2 Protein, Biochemistry, Immune tolerance, Transforming Growth Factor beta1, Pathogenesis, Interleukin 22, Young Adult, 03 medical and health sciences, Systemic lupus erythematosus, Immune system, TGF-β1, Immune Tolerance, IL-22, Humans, Lupus Erythematosus, Systemic, Immunology and Allergy, Medicine, Phosphorylation, skin and connective tissue diseases, Molecular Biology, Aged, Interleukin-15, biology, business.industry, Interleukins, Interleukin, Hematology, Middle Aged, 3. Good health, 030104 developmental biology, IL-15, Interleukin 15, Cancer research, biology.protein, Female, Signal transduction, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Signal Transduction
Abstract

International audience; The mechanisms leading to the disruption of self-tolerance in systemic lupus erythematosus (SLE) remain elusive. Herein, we aimed to decipher the molecular basis of the impaired response of mononuclear cells to TGF-β1. The Smad3-pathway was explored on CD3+ lymphocytes in either active or non active SLE patients. An impaired transcription of TGF-β1 target genes was demonstrated in the CD3+ lymphocytes of active SLE patients confirming that the defect involves T cells and pointing to its extrinsic nature. We further demonstrate that the defect did not result from an impaired TGF-βRII expression or Smad2/3 phosphorylation suggesting that the mechanism lies downstream Smad2/3 translocation. Interestingly, the TGF-1 signaling defect did not correlate with an increased expression of soluble or membrane-bound IL-15. However, it was associated with an overexpression of IL-22. This suggests that an excessive activation of AhR pathway (through UV radiations, infections, etc.) could lead to the inhibition of immunosuppressive actions of TGF-β thus disrupting immune homeostasis in SLE. Collectively, our data suggest that the impaired response to TGF-β in SLE patients is associated with disease activity and provide new insights into the pathogenesis of SLE since it could establish the link between the environmental factors and the aberrancies of the immune system usually described in SLE.

Published
2018

26. Gene alterations in epigenetic modifiers and JAK-STAT signaling are frequent in breast implant-associated ALCL

Author

Luc Xerri, Alina Nicolae, Reda Bouabdallah, Joan Somja, Marie-Pierre Chenard, François-Xavier Frenois, Fabien Reyal, Catherine Chassagne-Clément, Lénaïg Mescam, Marie-Hélène Delfau-Larue, Frédéric Escudié, Anne Moreau, Corinne Haioun, Philippe Gaulard, Lucie Oberic, Nadia Amara, Asma Beldi-Ferchiou, Laetitia Lacroix, Alexandra Traverse-Glehen, François Lemonnier, Jean-Marc Schiano, Bruno Tesson, Virginie Fataccioli, Marie Bannier, Daniel Birnbaum, Cécile Laurent, Nadine Martin, P. Brousset, Fabien Le Bras, José Adélaïde, Marc André, Naïs Prade, Camille Laurent, Arnaud Guille, Anne-Sophie Hamy, Centre de Recherche en Cancérologie de Marseille (CRCM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), Bidaut, Ghislain, Laboratoire Jacques-Louis Lions (LJLL), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Rt2 Lab, Institut Curie [Paris], CHU Henri Mondor, 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), 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), Islamic University of Gaza (IUG - IU Gaza), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Institut Carnot Lymphome (CALYM), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'Anatomie Pathologique Générale, CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], Centre hospitalier universitaire de Nantes (CHU Nantes), Département d'anatomopathologie, biopathologie, Centre Léon Bérard [Lyon], Groupe de Recherche d'Histoire (GRHis), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut de Recherche Interdisciplinaire Homme et Société (IRIHS), Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Centre d'Études des Phénomènes Aléatoires et Géophysiques (CEPHAG), École Nationale Supérieure d'Ingénieurs Électriciens de Grenoble (ENSIEG)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Centre des maladies du sein, 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), Surgery Department, CRLCC Paul Strauss, 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), Hôpital Henri Mondor, Service d'Hématologie, Centre de Recherches en Cancérologie de Toulouse (CRCT), 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), IUCT Oncopole - Institut Universitaire du Cancer de Toulouse, UCL - (MGD) Service d'hématologie, UCL - SSS/IREC/MIRO - Pôle d'imagerie moléculaire, radiothérapie et oncologie, Service d'Hématologie [CHU Toulouse], CHU Toulouse [Toulouse], Laboratoire d'Hématologie [Purpan], CHU Henri Mondor [Créteil], École Pratique des Hautes Études (EPHE), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, Institut Carnot CALYM [Pierre-Benite], Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Hématologie [IUCT Toulouse], Université Fédérale Toulouse Midi-Pyrénées-Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse]

Subjects
Adult, 0301 basic medicine, DNA Copy Number Variations, Breast Implants, [SDV]Life Sciences [q-bio], Immunology, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, medicine.disease_cause, Biochemistry, Germline, Epigenesis, Genetic, 03 medical and health sciences, 0302 clinical medicine, medicine, Humans, Epigenetics, SOCS3, STAT3, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Anaplastic large-cell lymphoma, PI3K/AKT/mTOR pathway, ComputingMilieux_MISCELLANEOUS, Aged, Janus Kinases, Aged, 80 and over, Mutation, Lymphoid Neoplasia, Genome, Human, JAK-STAT signaling pathway, Cell Biology, Hematology, Middle Aged, medicine.disease, [SDV] Life Sciences [q-bio], STAT Transcription Factors, 030104 developmental biology, Cancer research, biology.protein, Lymphoma, Large-Cell, Anaplastic, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Signal Transduction, 030215 immunology
Abstract

The oncogenic events involved in breast implant-associated anaplastic large cell lymphoma (BI-ALCL) remain elusive. To clarify this point, we have characterized the genomic landscape of 34 BI-ALCLs (15 tumor and 19 in situ subtypes) collected from 54 BI-ALCL patients diagnosed through the French Lymphopath network. Whole-exome sequencing (n = 22, with paired tumor/germline DNA) and/or targeted deep sequencing (n = 24) showed recurrent mutations of epigenetic modifiers in 74% of cases, involving notably KMT2C (26%), KMT2D (9%), CHD2 (15%), and CREBBP (15%). KMT2D and KMT2C mutations correlated with a loss of H3K4 mono- and trimethylation by immunohistochemistry. Twenty cases (59%) showed mutations in ≥1 member of the JAK/STAT pathway, including STAT3 (38%), JAK1 (18%), and STAT5B (3%), and in negative regulators, including SOCS3 (6%), SOCS1 (3%), and PTPN1 (3%). These mutations were more frequent in tumor-type samples than in situ samples (P = .038). All BI-ALCLs expressed pSTAT3, regardless of the mutational status of genes in the JAK/STAT pathway. Mutations in the EOMES gene (12%) involved in lymphocyte development, PI3K-AKT/mTOR (6%), and loss-of-function mutations in TP53 (12%) were also identified. Copy-number aberration (CNA) analysis identified recurrent alterations, including gains on chromosomes 2, 9p, 12p, and 21 and losses on 4q, 8p, 15, 16, and 20. Regions of CNA encompassed genes involved in the JAK/STAT pathway and epigenetic regulators. Our results show that the BI-ALCL genomic landscape is characterized by not only JAK/STAT activating mutations but also loss-of-function alterations of epigenetic modifiers.

Published
2019

27. Combination lenalidomide-rituximab immunotherapy activates anti-tumour immunity and induces tumour cell death by complementary mechanisms of action in follicular lymphoma

Author

Marie-Hélène Delfau-Larue, Anita Gandhi, Preeti Trisal, Despoina Papazoglou, Asma Beldi-Ferchiou, Carla Guarinos, Karin Tarte, Patrick Hagner, Franck Morschhauser, Alan G. Ramsay, Soraya Carrancio, Chad C. Bjorklund, Hsiling Chiu, Estela G. Toraño, Celgene Corporation, School of Cancer and Pharmaceutical Sciences [London, UK] (Faculty of Life Sciences & Medicine), King‘s College London, Département d'immunobiologie et d'hématobiologie [CHU Henri Mondor], CHU Henri Mondor [Créteil], Microenvironment, Cell Differentiation, Immunology and Cancer (MICMAC), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Hôpital Claude Huriez [Lille], CHU Lille, Celgene, CHU Henri Mondor, 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 ), Jonchère, Laurent, Université de Lille, Groupe de Recherche sur les formes Injectables et les Technologies Associées (GRITA) - EA 7365, Hôpital Henri Mondor, Centre Hospitalier Universitaire [Rennes], AP-HP, Hôpital Henri-Mondor Albert-Chenevier, Service d'Immunologie Clinique et Maladies Infectieuses 94000 Créteil, France, Groupe de Recherche sur les formes Injectables et les Technologies Associées - ULR 7365 [GRITA], Celgene Corporation [San Diego, CA, USA], Celgene Institute for Translational Research Europe [Seville, Spain], and Hôpital Claude Huriez

Subjects
[SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, Myeloid, Immunological Synapses, Neutrophils, medicine.medical_treatment, Follicular lymphoma, CD8-Positive T-Lymphocytes, Lymphocyte Activation, immunomodulation, antibody‐dependent cell‐mediated cytotoxicity, 0302 clinical medicine, Immunophenotyping, non-Hodgkin lymphoma, antibody-dependent cell-mediated cytotoxicity, lenalidomide, follicular lymphoma, Antineoplastic Combined Chemotherapy Protocols, Tumor Cells, Cultured, Cytotoxic T cell, non‐Hodgkin lymphoma, Lymphoma, Follicular, Antibody-dependent cell-mediated cytotoxicity, B-Lymphocytes, Haematological Malignancy, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Hematology, 3. Good health, Killer Cells, Natural, medicine.anatomical_structure, Vincristine, 030220 oncology & carcinogenesis, Cytokines, Rituximab, Immunotherapy, [SDV.IMM.IMM] Life Sciences [q-bio]/Immunology/Immunotherapy, Research Paper, medicine.drug, [SDV.CAN]Life Sciences [q-bio]/Cancer, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, medicine, Humans, Lymphocyte Count, Cyclophosphamide, Cell Proliferation, Lenalidomide, business.industry, Antibody-Dependent Cell Cytotoxicity, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, medicine.disease, Doxorubicin, Drug Resistance, Neoplasm, Cancer research, Prednisone, business, 030215 immunology
Abstract

International audience; Chemotherapy plus rituximab has been the mainstay of treatment for follicular lymphoma (FL) for two decades but is associated with immunosuppression and relapse. In phase 2 studies, lenalidomide combined with rituximab (R 2 ) has shown clinical synergy in front-line and relapsed/refractory FL. Here, we show that lenalidomide reactivated dysfunctional T and Natural Killer (NK) cells ex vivo from FL patients by enhancing proliferative capacity and T-helper cell type 1 (Th1) cytokine release. In combination with rituximab, lenalidomide improved antibody-dependent cellular cytotoxicity in sensitive and chemo-resistant FL cells, via a cereblon-dependent mechanism. While single-agent lenalidomide and rituximab increased formation of lytic NK cell immunological synapses with primary FL tumour cells, the combination was superior and correlated with enhanced cytotoxicity. Immunophenotyping of FL patient samples from a phase 3 trial revealed that R 2 treatment increased circulating T- and NK-cell counts, while R-chemotherapy was associated with reduced cell numbers. Finally, using an in vitro model of myeloid differentiation, we demonstrated that lenalidomide caused a reversible arrest in neutrophil maturation that was distinct from a cytotoxic chemotherapeutic agent, which may help explain the lower rates of neutropenia observed with R 2 versus R-chemotherapy. Taken together, we believe these data support a paradigm shift in the treatment of FL – moving from combination immunochemotherapy to chemotherapy-free immunotherapy. © 2019 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley and Sons Ltd.

Published
2019

28. Total metabolic tumor volume, circulating tumor cells, cell-free DNA: distinct prognostic value in follicular lymphoma

Author

Axel Van Der Gucht, Jehan Dupuis, E. Itti, René-Olivier Casasnovas, Philippine Robert, Alina Berriolo-Riedinger, Salma Hamdane, Jean-Philippe Jais, Asma Beldi-Ferchiou, Gaelle Laboure, Christiane Copie-Bergman, Benjamin Verret, Marie-Hélène Delfau-Larue, Ichrafe Benmaad, Isabelle Nel, Corinne Haioun, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, The lymphoma study association (LYSA), CHU Henri Mondor, Service de Médecine Nucléaire, Centre Georges-François Leclerc [Dijon] (CGFL), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER, Service d'Hématologie Clinique (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de médecine nucléaire [Créteil], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), and Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement

Subjects
Adult, Male, 0301 basic medicine, Oncology, endocrine system, medicine.medical_specialty, Follicular lymphoma, [SDV.CAN]Life Sciences [q-bio]/Cancer, Polymerase Chain Reaction, Circulating Tumor DNA, law.invention, 03 medical and health sciences, 0302 clinical medicine, Circulating tumor cell, immune system diseases, Predictive Value of Tests, law, hemic and lymphatic diseases, Internal medicine, medicine, Humans, Digital polymerase chain reaction, Lymphoma, Follicular, Polymerase chain reaction, Survival analysis, Aged, Retrospective Studies, Lymphoid Neoplasia, business.industry, Hematology, Middle Aged, Neoplastic Cells, Circulating, Prognosis, medicine.disease, Survival Analysis, Tumor Burden, 3. Good health, Lymphoma, 030104 developmental biology, Cell-free fetal DNA, 030220 oncology & carcinogenesis, Predictive value of tests, Female, business
Abstract

International audience; Outcomes for follicular lymphoma (FL) have greatly improved, but most patients will ultimately relapse. High total metabolic tumor volume (TMTV), computed from baseline 18F-fluorodeoxyglucose-positron emission tomography (PET), is associated with shorter progression-free survival (PFS), but circulating tumor cells (CTCs) and cell-free DNA (cfDNA) may also reflect tumor burden and be of prognostic value. The aim of our study was to correlate CTCs and cfDNA with TMTV in FL at diagnosis and to determine their prognostic values. We retrospectively analyzed 133 patients (with previously untreated FL and a baseline PET) from 2 cohorts with either a baseline plasma sample (n = 61) or a bcl2-JH-informative peripheral blood (PB) sample (n = 68). Quantification of circulating bcl2-JH+ cells and cfDNA was performed by droplet digital polymerase chain reaction. A significant correlation was found between TMTV and both CTCs (P < .0001) and cfDNA (P < .0001). With a median 48-month follow-up, 4-year PFS was lower in patients with TMTV > 510 cm3 (P = .0004), CTCs >0.0018 PB cells (P = .03), or cfDNA >2550 equivalent-genome/mL (P = .04). In comparison with TMTV alone, no additional prognostic information was obtained by measuring CTCs. In contrast, Cox multivariate analysis, including cfDNA and TMTV, showed that both cfDNA and TMTV remained predictive of outcome. In conclusion, CTCs and cfDNA correlate with TMTV in FL, and all 3 influence patient outcome. PFS was shorter for patients with high cfDNA and TMTV, suggesting that these parameters provide relevant information for tumor-tailored therapy.

Published
2018

29. OBINUTUZUMAB PLUS DHAP FOLLOWED BY AUTOLOGOUS STEM CELL TRANSPLANTATION (ASCT) PLUS OBINUTUZUMAB MAINTENANCE PROVIDES A HIGH MRD RESPONSE RATE IN UNTREATED MCL PATIENTS. RESULTS OF LYMA-101 TRIAL, A LYSA GROUP STUDY

Author

Lucie Oberic, Catherine Thieblemont, Olivier Hermine, T. Lamy de la Chapelle, Gilles Salles, Vincent Delwail, Caroline Bodet-Milin, Danielle Canioni, H. Maisonneuve, Kamal Bouabdallah, S. Le Gouill, Vincent Ribrag, Asma Beldi-Ferchiou, Elisabeth Macintyre, Victoria Cacheux, Marion Alcantara, M.H. Delfau-Larue, and Thomas Gastinne

Subjects
Oncology, Cancer Research, medicine.medical_specialty, MRD Response, Group study, business.industry, Hematology, General Medicine, chemistry.chemical_compound, Autologous stem-cell transplantation, chemistry, Obinutuzumab, DHAP, Internal medicine, medicine, business
Published
2019

30. Abnormal repression of SHP-1, SHP-2 and SOCS-1 transcription sustains the activation of the JAK/STAT3 pathway and the progression of the disease in multiple myeloma

Author

Saloua Ladeb, Nour Skouri, Ines Safra, Abderrahman Abdelkefi, Tarek Ben Othman, Melika Ben Ahmed, Karima Mrad, Cyrine Ben Ali, Asma Beldi-Ferchiou, Laboratoire d'immunologie clinique [Institut Pasteur de Tunis], Institut Pasteur de Tunis, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Faculté de Médecine de Tunis, Université de Tunis El Manar (UTM), Laboratoire d'Hématologie, Institut Pasteur de Tunis, Centre National de Greffe de la Moëlle osseuse Tunis (CNGMO), and Institut Salah Azaiez de Cancer

Subjects
0301 basic medicine, Male, Physiology, Cancer Treatment, Gene Expression, lcsh:Medicine, Protein Tyrosine Phosphatase, Non-Receptor Type 11, Stat3 Signaling Pathway, Plasma Cell Disorders, Suppressor Genes, Hematologic Cancers and Related Disorders, White Blood Cells, 0302 clinical medicine, Animal Cells, Bone Marrow, Immune Physiology, Medicine and Health Sciences, Prospective Studies, STAT3, lcsh:Science, Regulation of gene expression, Multidisciplinary, biology, Protein Tyrosine Phosphatase, Non-Receptor Type 6, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Hematology, Middle Aged, Immunohistochemistry, 3. Good health, Myelomas, medicine.anatomical_structure, Treatment Outcome, Oncology, 030220 oncology & carcinogenesis, DNA methylation, Disease Progression, Female, Cellular Types, Multiple Myeloma, Research Article, Signal Transduction, STAT3 Transcription Factor, Immune Cells, Plasma Cells, Immunology, Bone Marrow Cells, [SDV.CAN]Life Sciences [q-bio]/Cancer, Real-Time Polymerase Chain Reaction, stat, 03 medical and health sciences, Suppressor of Cytokine Signaling 1 Protein, Gene Types, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], medicine, Genetics, Gene silencing, Humans, Gene Regulation, Myelomas and Lymphoproliferative Diseases, RNA, Messenger, Blood Cells, lcsh:R, Biology and Life Sciences, Cancers and Neoplasms, Cell Biology, 030104 developmental biology, Immune System, Cancer research, biology.protein, lcsh:Q, Bone marrow, Whole Bone Marrow
Abstract

cited By 1; International audience; Sustained activation of JAK/STAT3 signaling pathway is classically described in Multiple Myeloma (MM). One explanation could be the silencing of the JAK/STAT suppressor genes, through the hypermethylation of SHP-1 and SOCS-1, previously demonstrated in MM cell lines or in whole bone marrow aspirates. The link between such suppressor gene silencing and the degree of bone marrow invasion or the treatment response has not been evaluated in depth. Using real-time RT-PCR, we studied the expression profile of three JAK/STAT suppressor genes: SHP-1, SHP-2 and SOCS-1 in plasma cells freshly isolated from the bone marrows of MM patients and healthy controls. Our data demonstrated an abnormal repression of such genes in malignant plasma cells and revealed a significant correlation between such defects and the sustained activation of the JAK/STAT3 pathway during MM. The repressed expression of SHP-1 and SHP-2 correlated significantly with a high initial degree of bone marrow infiltration but was, unexpectedly, associated with a better response to the induction therapy. Collectively, our data provide new evidences that substantiate the contribution of JAK/STAT suppressor genes in the pathogenesis of MM. They also highlight the possibility that the decreased gene expression of SHP-1 and SHP-2 could be of interest as a new predictive factor of a favorable treatment response, and suggest new potential mechanisms of action of the therapeutic molecules. Whether such defect helps the progression of the disease from monoclonal gammopathy of unknown significance to MM remains, however, to be determined.

Published
2017

31. Clinical, Immunophenotypic and Genetic Characteristics of Aggressive (non-Burkitt) B-Cell Lymphoma in a Real Life Cohort

Author

Sébastien Mulé, Alina Nicolae, Jehan Dupuis, Marie Helene Delfau Larue, Corinne Haioun, Cyrielle Robe, Karim Belhadj, Mohammad Hammoud, Jean-Philippe Jais, Louise Roulin, François Lemonnier, Fabien Le Bras, Asma Beldi-Ferchiou, Elsa Poullot, Taoufik El Gnaoui, Christiane Copie, Elodie Scherman, Emmanuel Itti, Philippe Gaulard, and Alizée Maarek

Subjects
Idiopathic guttate hypomelanosis, business.industry, Immunology, Cell Biology, Hematology, medicine.disease, Biochemistry, Chemotherapy regimen, Lymphoma, hemic and lymphatic diseases, medicine, Cancer research, Methotrexate, Rituximab, B-cell lymphoma, business, Burkitt's lymphoma, Diffuse large B-cell lymphoma, medicine.drug
Abstract

Introduction: Diffuse large B-cell lymphoma (DLBCL) is an aggressive and heterogeneous disease characterized by recurrent genetic alterations. Several adverse prognostic factors are well known as International Prognostic Index (IPI) parameters or MYC and BCL2 and/or BCL6 gene rearrangements (High-Grade B-cell Lymphoma double/triple hit, HGBL-DH/TH, according to the 2016 WHO classification). Other factors are controversial as previous history of indolent lymphoma, cell of origin (COO), co-expression of MYC and BCL2 proteins (double expressor (DE) status), MYC partner gene if rearranged. The aim of this study is to describe a « real life » cohort of patients treated in our institution for aggressive (non-Burkitt) B-cell lymphoma and to evaluate the prognostic impact of phenotypic and genetic alterations. Methods: We collected clinical and histological characteristics of patients uniformly treated between January 2009 and June 2017 with rituximab R-CHOP/CHOP-like chemotherapy. Treatment was reinforced with high dose methotrexate in case of central nervous system (CNS) localization or HGBL subtype. All tumor samples were analysed for MYC and BCL2 protein expression by immunohistochemistry. BCL2, BCL6 and MYC break were analysed by Interphase Fluorescence In Situ Hybridization (FISH) with breakapart probes. When MYC was rearranged MYC partner gene was analysed with double fusion probes (MYC/IgH, MYC/IgL, MYC/IgK). Positron Emission Tomography (PET scanner) was performed with maximal Standardized Uptake Value (SUV max) at baseline in all patients except 7. Results: 242 patients were studied. Baseline characteristics were: median age: 61 y (18-88), IPI 3-5: 49.6%, CNS localization: 6.6%. With a median follow-up of 4.4 years, 5y-overall survival (OS) and 5y-progression free survival (PFS) were 72% (66.0-78.5) and 65% (58.5-71.3), respectively. SUV max at baseline was 17,1 (minimum value 2,4 - maximal value 39,3).Histological diagnoses were DLBCL-not otherwise specified (NOS): 57%, transformed DLBCL: 26%, HGBL: 7.9%, primary mediastinal B-cell lymphoma (PMBL): 4.1% and others: 5%. Using Hans algorithm, 48.8% were classified as germinal center (GC), 47.9% as non-GC, 3.3% could not be evaluated and 38% were DE. MYC rearrangement was detected in 36 cases (14.9%) with an immunoglobulin partner gene (IgH, IgL or IgK) in 24 (77.4%) of 31 evaluable cases. BCL2 and BCL6 rearrangement were observed in 45 cases (18.6%) and 62 (25.6%) cases respectively. Fifteen cases were HGBL DH/TH including 7 DH MYC/BCL2, 5 DH MYC/BCL6 and 3 TH MYC/BCL2/BCL6. Four cases were HGBL-NOS. IPI score 3-5 (p Conclusions: This monocentric study in a large cohort of aggressive B-cell lymphoma patients treated in real life conditions confirms previous reports on the negative prognostic impact of DE status, MYC and BCL2 translocations and HGBL subtype. These genetic and immuno-histological characteristics should have implications in the design and interpretation of future clinical trials. Disclosures Le Bras: Takeda: Research Funding; Pfizer: Other: Travel grant; Jansen: Other: Travel grant. Belhadj:Celgene: Other: personal fees from Celgene, personal fees from Amgen, personal fees from Takeda, personal fees from Janssen, outside the submitted work. Haioun:servier: Honoraria; amgen: Honoraria; janssen cilag: Consultancy; takeda: Consultancy; gilead: Consultancy; novartis: Honoraria; celgene: Honoraria; roche: Consultancy; celgene: Consultancy.

Published
2019

32. Étude des sous-populations lymphocytaires B au sein du SNILGM

Author

Carole Hénique, Asma Beldi-Ferchiou, Julie Oniszczuk, Vincent Audard, Anissa Moktefi, Matthieu Mahevas, Evangeline Pillebout, A. Karras, Imane Azzaoui, and Dil Sahali

Subjects
Nephrology
Abstract

Introduction La physiopathologie du syndrome nephrotique a lesions glomerulaires minimes (SNLGM) reste incompletement elucidee, mais des arguments cliniques et experimentaux, suggerent que les lymphocytes B (LB) puissent jouer un role majeur dans la pathogenie de cette glomerulopathie. Methodes L’objectif de ce travail est de decrire les sous-populations de LB chez des patients atteints de SNLGM naifs de tout traitement corticoide ou immunosuppresseur. Cette etude prospective, multicentrique, porte sur 21 malades atteints de SNLGM en premiere poussee ou en rechute a plus de 6 mois de toute prise d’immunosuppresseurs (P), compares a 16 patients en remission (R) sans immunosuppresseurs depuis plus de 6 mois, 20 patients atteints de glomerulonephrite extra-membraneuse idiopathique (G) et 25 temoins sains (TS). Le phenotype B a ete analyse en cytometrie en flux avant traitement par differents marqueurs de surface : CD45, CD3, CD19, CD21, IgD, IgM, CD38, CD24, CD27. BAFF a ete mesure dans le plasma par ELISA. Resultats obtenus ou attendus Les patients des groupes P et G presentent une intensite de maladie identique (proteinurie, hypoalbuminemie et hypogammaglobulinemie). Parmi les populations analysees, nous observons uniquement une augmentation significative du pourcentage de plasmablastes (CD38+ CD24−) chez les patients P par rapport aux patients R (p = 0,01), aux patients G (p = 0,03) et aux TS (p Fig. 1 ). Conclusion Les plasmablastes et BAFF sont significativement augmentes chez les patients en pousssee de SNLGM suggerant une anomalie intrinseque des LB chez les patients P naifs de tout traitement.

Published
2019

33. S103 OBINUTUZUMAB PLUS DHAP FOLLOWED BY AUTOLOGOUS STEM CELL TRANSPLANTATION PLUS OBINUTUZUMAB MAINTENANCE PROVIDES A HIGH MRD RESPONSE RATE IN UNTREATED MCL PATIENTS, LYMA-101 TRIAL - A LYSA TRIAL

Author

Danielle Canioni, C. thieblemont, Marion Alcantara, O. Hermine, Marie-Pierre Moles, M. H. Delfau-Larue, C. Bodet-Milin, Vincent Delwail, G. Damaj, Victoria Cacheux, V. Ribrag, Asma Beldi-Ferchiou, N. Daguindau, G. Salles, E. Macintyre, Steven Legouill, Arnaud Jaccard, and T. Gastinne

Subjects
Oncology, medicine.medical_specialty, chemistry.chemical_compound, Autologous stem-cell transplantation, MRD Response, chemistry, Obinutuzumab, business.industry, DHAP, Internal medicine, medicine, Hematology, business
Published
2019

34. PD-1 mediates functional exhaustion of activated NK cells in patients with Kaposi sarcoma

Author

Daniel Olive, Damien Sène, Stéphanie Dogniaux, Céleste Lebbé, Asma Beldi-Ferchiou, Frank Levasseur, Claire Hivroz, Sophie Caillat-Zucman, Frédéric Vély, Marion Lambert, Eric Vivier, David Zucman, Stéphanie Dupuy, Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris Diderot, Sorbonne Paris Cité, Paris, France, Université Paris Diderot - Paris 7 (UPD7), Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'Immunologie de Marseille - Luminy (CIML), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), Centre de Recherche en Cancérologie de Marseille (CRCM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), Hôpital Foch [Suresnes], 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), Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hopital Saint-Louis [AP-HP] (AP-HP), ANR-13-BSV2-0018,NeuroImmunoSynapse,Trafic vésiculaire, formation et maintien des synapses neuronales et immunologiques(2013), European Project: 268537,EC:FP7:ERC,ERC-2010-AdG_20100317,THINK(2011), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), VAFFIDES, Chantal, Blanc 2013 - Trafic vésiculaire, formation et maintien des synapses neuronales et immunologiques - - NeuroImmunoSynapse2013 - ANR-13-BSV2-0018 - Blanc 2013 - VALID, and The Immune function of NK cells - THINK - - EC:FP7:ERC2011-07-01 - 2016-12-31 - 268537 - VALID

Subjects
0301 basic medicine, Functional impairment, [SDV.IMM] Life Sciences [q-bio]/Immunology, T cell, Programmed Cell Death 1 Receptor, Tumor escape, Gene Expression, HIV Infections, NK cells, Lymphocyte Activation, Immunomodulation, 03 medical and health sciences, 0302 clinical medicine, Healthy control, PD-1, Humans, Medicine, In patient, Sarcoma, Kaposi, Activating receptors, Coinfection, business.industry, Kaposi sarcoma, Herpesviridae Infections, Flow Cytometry, medicine.disease, Hepatitis C, Immunohistochemistry, Immune surveillance, Immune checkpoint, 3. Good health, Killer Cells, Natural, Phenotype, 030104 developmental biology, medicine.anatomical_structure, Oncology, Case-Control Studies, 030220 oncology & carcinogenesis, Herpesvirus 8, Human, Immunology, Cytokines, [SDV.IMM]Life Sciences [q-bio]/Immunology, Sarcoma, business, Biomarkers, Research Paper
Abstract

// Asma Beldi-Ferchiou 1, 2, 11 , Marion Lambert 1, 2 , Stephanie Dogniaux 3 , Frederic Vely 4, 5 , Eric Vivier 4, 5 , Daniel Olive 6 , Stephanie Dupuy 1 , Frank Levasseur 1 , David Zucman 7 , Celeste Lebbe 8 , Damien Sene 1, 2, 9 , Claire Hivroz 4 , Sophie Caillat-Zucman 1, 2, 10 1 Institut National de Recherche Medicale (INSERM) UMR1149, Centre de Recherche Sur l’Inflammation, Equipe Immunite Innee Chez l’enfant, Hopital Robert Debre, Paris, France 2 Universite Paris Diderot, Sorbonne Paris Cite, Paris, France 3 Institut Curie, Centre de Recherche, PSL Research University, INSERM U932 Immunite et Cancer, Paris, France 4 Centre d’Immunologie de Marseille-Luminy, Aix-Marseille Universite UM2, INSERM U1104, CNRS UMR7280, Marseille, France 5 Immunologie, Hopital de la Conception, Assistance Publique- Hopitaux de Marseille, Marseille, France 6 Centre de Cancerologie de Marseille, INSERM U1068, Equipe Immunite et Cancer, Institut Paoli-Calmettes, Aix-Marseille Universite, CNRS, UMR7258, Marseille, France 7 Hopital Foch, Service de Medecine Interne, Suresnes, France 8 Assistance Publique-Hopitaux de Paris (AP-HP), Hopital Saint-Louis, Departement de Dermatologie, INSERM U976, Universite Paris Diderot, Paris, France 9 Assistance Publique-Hopitaux de Paris (AP-HP), Hopital Lariboisiere, Departement de Medecine Interne, Paris, France 10 Assistance Publique-Hopitaux de Paris (AP-HP), Hopital Saint-Louis, Laboratoire d’Immunologie, Paris, France 11 Present address: Assistance Publique-Hopitaux de Paris (AP-HP), Hopital Henri Mondor, Laboratoire d’Immunologie, Creteil, France Correspondence to: Sophie Caillat-Zucman, email: sophie.caillat@inserm.fr Keywords: NK cells, Kaposi sarcoma, PD-1, immune checkpoint, tumor escape Received: March 31, 2016 Accepted: September 13, 2016 Published: September 20, 2016 ABSTRACT Programmed Death-1 (PD-1), an inhibitory receptor expressed by activated lymphocytes, is involved in regulating T- and B-cell responses. PD-1 and its ligands are exploited by a variety of cancers to facilitate tumor escape through PD-1-mediated functional exhaustion of effector T cells. Here, we report that PD-1 is upregulated on Natural Killer (NK) cells from patients with Kaposi sarcoma (KS). PD-1 was expressed in a sub-population of activated, mature CD56 dim CD16 pos NK cells with otherwise normal expression of NK surface receptors. PD-1 pos NK cells from KS patients were hyporesponsive ex vivo following direct triggering of NKp30, NKp46 or CD16 activating receptors, or short stimulation with NK cell targets. PD-1 pos NK cells failed to degranulate and release IFNγ, but exogenous IL-2 or IL-15 restored this defect. That PD-1 contributed to NK cell functional impairment and was not simply a marker of dysfunctional NK cells was confirmed in PD-1-transduced NKL cells. In vitro , PD-1 was induced at the surface of healthy control NK cells upon prolonged contact with cells expressing activating ligands, i.e. a condition mimicking persistent stimulation by tumor cells. Thus, PD-1 appears to plays a critical role in mediating NK cell exhaustion. The existence of this negative checkpoint fine-tuning NK activation highlights the possibility that manipulation of the PD-1 pathway may be a strategy for circumventing tumor escape not only from the T cell-, but also the NK-cell mediated immune surveillance.

Published
2016

35. LOW NK CELL COUNT AT DIAGNOSIS IS ASSOCIATED WITH SHORTER PFS IN ELDERLY PATIENTS WITH DLBCL TREATED WITH RCHOP AND RANDOMIZED FOR LENALIDOMIDE MAINTENANCE: a LYSA STUDY

Author

R. Bouabdallah, M.H. Delfau-Larue, Hervé Tilly, N. Godard, Asma Beldi-Ferchiou, Corinne Haioun, Josette Briere, Julien Lazarovici, Bertrand Coiffier, F. Morschhauser, H. Gonzalez, Gilles Salles, Jean-Philippe Jais, Catherine Sebban, P. Gaulard, Catherine Thieblemont, René-Olivier Casasnovas, B. Corront, Lucie Oberic, Christophe Fruchart, and A. Perrot

Subjects
Oncology, Cancer Research, medicine.medical_specialty, business.industry, Cell, Hematology, General Medicine, Surgery, medicine.anatomical_structure, Internal medicine, medicine, business, Lenalidomide, medicine.drug
Published
2017

36. High effector-memory CD8 + T-cell levels correlate with high PML risk in natalizumab-treated patients.

Author

Beldi-Ferchiou A, Wahab A, Duchmann M, Hodel J, Patry I, Delfau-Larue MH, Molinier-Frenkel V, and Créange A

Subjects
CD8-Positive T-Lymphocytes, Humans, Natalizumab adverse effects, T-Lymphocyte Subsets, Leukoencephalopathy, Progressive Multifocal chemically induced, Multiple Sclerosis drug therapy
Abstract

Background: Progressive multifocal leukoencephalopathy (PML) is a severe complication of natalizumab (NTZ) treatment in multiple sclerosis (MS) patients. Based on the analysis of cryopreserved cells, several reports have showed that CD62L+ CD4+ T-cells percentage drops before PML onset., Objective: To analyze CD62L and CD45RA expression on fresh-blood CD4+ and CD8+ T-cells from NTZ-treated patients, according to their estimated PML risk., Methods: We prospectively enrolled 74 MS patients, including 62 NTZ-treated, and stratified them into low, intermediate and high PML risk groups. Circulating naïve and memory T-cell subsets were analyzed by flow cytometry., Results: We found no correlation between the percentage of CD62L+ CD4+ T-cells and PML risk. In contrast, the repartition of CD8+ T-cells subpopulations was altered in the high risk group: both the percentage and absolute count of CD8+ CD62L- CD45RA- effector memory T- cells (T EM ) was significantly higher compared to patients at lower risk despite similar CD3+ and CD8+ T-cell counts. One high-risk patient with elevated CD8+ T EM and CD62L+ CD4+ T-cell levels developed PML six months after sampling., Conclusion: Our results suggest that CD8+ T EM cells should be evaluated in larger studies as a potential surrogate marker of PML risk in NTZ-treated patients., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Published
2020
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