42 results on '"Le Garff-Tavernier M"'
Search Results
2. Gain in the short arm of chromosome 2 (2p+) induces gene overexpression and drug resistance in chronic lymphocytic leukemia: analysis of the central role of XPO1
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Cosson, A, Chapiro, E, Bougacha, N, Lambert, J, Herbi, L, Cung, H-A, Algrin, C, Keren, B, Damm, F, Gabillaud, C, Brunelle-Navas, M-N, Davi, F, Merle-Béral, H, Le Garff-Tavernier, M, Roos-Weil, D, Choquet, S, Uzunov, M, Morel, V, Leblond, V, Maloum, K, Lepretre, S, Feugier, P, Lesty, C, Lejeune, J, Sutton, L, Landesman, Y, Susin, S A, and Nguyen-Khac, F
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- 2017
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3. P11.09.B Chemotherapy is an efficient treatment in primary CNS MALT lymphoma
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Desjardins, C, primary, Larrieu-Ciron, D, additional, Choquet, S, additional, Mokhtari, K, additional, Charlotte, F, additional, Nichelli, L, additional, Mathon, B, additional, Ahle, G, additional, Le Garff-Tavernier, M, additional, Dehais, C, additional, Hoang-Xuan, K, additional, and Houillier, C, additional
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- 2022
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4. Antibody-dependent cellular cytotoxicity of the optimized anti-CD20 monoclonal antibody ublituximab on chronic lymphocytic leukemia cells with the 17p deletion
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Le Garff-Tavernier, M, Herbi, L, de Romeuf, C, Nguyen-Khac, F, Davi, F, Grelier, A, Boudjoghra, M, Maloum, K, Choquet, S, Urbain, R, Vieillard, V, and Merle-Béral, H
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- 2014
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5. Analysis of CD16+CD56dim NK cells from CLL patients: evidence supporting a therapeutic strategy with optimized anti-CD20 monoclonal antibodies
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Le Garff-Tavernier, M, Decocq, J, de Romeuf, C, Parizot, C, Dutertre, C A, Chapiro, E, Davi, F, Debré, P, Prost, J F, Teillaud, J L, Merle-Beral, H, and Vieillard, V
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- 2011
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6. P14.49 Primary central nervous system lymphoma presenting as dementia: do not forget IL10 in CSF analysis
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Blain, A, primary, Brinet, A, additional, Berthel, M, additional, Camoyret, A, additional, Gaultier, C, additional, Droy-Dupré, L, additional, Oesterlé, H, additional, Hurstel, R, additional, Debliquis, A, additional, Costopoulos, M, additional, Le Garff-Tavernier, M, additional, Sellal, F, additional, and Ahle, G, additional
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- 2019
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7. P14.90 Interleukin 6 is a useful marker for pseudotumoral inflammatory CNS lesions suspicious of lymphoma
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Ungureanu, A, primary, Costopoulos, M, additional, Parratte, T, additional, Brinet, A, additional, Durand, H, additional, Gaultier, C, additional, Postert, T, additional, Hurstel, R, additional, Alamome, I, additional, Sellal, F, additional, Le Garff-Tavernier, M, additional, and Ahle, G, additional
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- 2019
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8. PB1868 B-CELL PROLYMPHOCYTIC LEUKEMIA (B-PLL) AND PROLYMPHOCYTOID MANTLE CELL LYMPHOMA (PMCL) (MORE THAN 55% OF PROLYMPHOCYTES) ARE CLOSED BUT DISTINCT ENTITIES. ON BEHALF GFCH AND FILO GROUPS
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Chapiro, E., primary, Diop, K., additional, Dessen, P., additional, Roos-Weil, D., additional, Gabillaud, C., additional, Pramil, E., additional, Maloum, K., additional, Settegrana, C., additional, Baseggio, L., additional, Davi, F., additional, Le Garff-Tavernier, M., additional, Droin, N., additional, Algrin, C., additional, Leblond, V., additional, Eclache, V., additional, Gaillard, B., additional, Callet-Bauchu, E., additional, Muller, M., additional, Lefebvre, C., additional, Nadal, N., additional, Ittel, A., additional, Struski, S., additional, Collonge-Rame, M.-A., additional, Quilichini, B., additional, Fert-Ferrer, S., additional, Auger, N., additional, Radford-Weiss, I., additional, Susin, S., additional, Bernard, O., additional, and Nguyen-Khac, F., additional
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- 2019
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9. Guideline for the diagnosis, treatment and response criteria for Bing-Neel syndrome
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Minnema, M.C. Kimby, E. D’Sa, S. Fornecker, L.-M. Poulain, S. Snijders, T.J. Kastritis, E. Kremer, S. Fitsiori, A. Simon, L. Davi, F. Lunn, M. Castillo, J.J. Patterson, C.J. Le Garff-Tavernier, M. Costopoulos, M. Leblond, V. Kersten, M.-J. Dimopoulos, M.A. Treon, S.P.
- Abstract
Bing Neel syndrome is a rare disease manifestation of Waldenström’s macroglobulinemia that results from infiltration of the central nervous system by malignant lymphoplasmacytic cells. In this guideline we describe the clinical symptoms, as well as the appropriate laboratory and radiological studies, that can aid in the diagnosis. The presentation of Bing Neel syndrome may be very diverse, and includes headaches, cognitive deficits, paresis, and psychiatric symptoms. The syndrome can present in patients with known Waldenström’s macroglobulinemia, even in the absence of systemic progression, but also in previously undiagnosed patients. Diagnostic work-up should include cerebral spinal fluid analysis with multiparameter flow cytometry to establish B-cell clonality, protein electrophoresis and immunofixation for the detection and classification of a monoclonal protein as well as molecular diagnostic testing for immunoglobulin gene rearrangement and mutated MYD88. MRI of the brain and spinal cord is also essential. The second challenge is to expand our knowledge of prognosis and treatment outcome. Prospective clinical trials on Bing Neel syndrome patients that employ uniform treatment along with appropriate laboratory cerebral spinal fluid assessments and standardized MRI protocols will be invaluable, constituting a significant step forward in delineating treatment outcome for this intriguing disease manifestation. © 2017 Ferrata Storti Foundation.
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- 2017
10. The optimized anti-CD20 monoclonal antibody ublituximab bypasses natural killer phenotypic features in Waldenstrom macroglobulinemia
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Le Garff-Tavernier, M., primary, Herbi, L., additional, de Romeuf, C., additional, Azar, N., additional, Roos-Weil, D., additional, Bonnemye, P., additional, Urbain, R., additional, Leblond, V., additional, Merle-Beral, H., additional, and Vieillard, V., additional
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- 2014
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11. Antibody-dependent cellular cytotoxicity of the optimized anti-CD20 monoclonal antibody ublituximab on chronic lymphocytic leukemia cells with the 17p deletion
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Le Garff-Tavernier, M, primary, Herbi, L, additional, de Romeuf, C, additional, Nguyen-Khac, F, additional, Davi, F, additional, Grelier, A, additional, Boudjoghra, M, additional, Maloum, K, additional, Choquet, S, additional, Urbain, R, additional, Vieillard, V, additional, and Merle-Béral, H, additional
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- 2013
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12. Functional assessment of p53 in chronic lymphocytic leukemia
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Le Garff-Tavernier, M, primary, Blons, H, additional, Nguyen-Khac, F, additional, Pannetier, M, additional, Brissard, M, additional, Gueguen, S, additional, Jacob, F, additional, Ysebaert, L, additional, Susin, S A, additional, and Merle-Béral, H, additional
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- 2011
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13. Analysis of CD16+CD56dim NK cells from CLL patients: evidence supporting a therapeutic strategy with optimized anti-CD20 monoclonal antibodies
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Le Garff-Tavernier, M, primary, Decocq, J, additional, de Romeuf, C, additional, Parizot, C, additional, Dutertre, C A, additional, Chapiro, E, additional, Davi, F, additional, Debré, P, additional, Prost, J F, additional, Teillaud, J L, additional, Merle-Beral, H, additional, and Vieillard, V, additional
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- 2010
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14. Serum-free light chain elevation is associated with a shorter time to treatment in Waldenstrom's macroglobulinemia
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Itzykson, R., primary, Le Garff-Tavernier, M., additional, Katsahian, S., additional, Diemert, M.-C., additional, Musset, L., additional, and Leblond, V., additional
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- 2008
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15. Analysis of CD16+CD56dim NK cells from CLL patients: evidence supporting a therapeutic strategy with optimized anti-CD20 monoclonal antibodies.
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Le Garff-Tavernier, M., Decocq, J., de Romeuf, C., Parizot, C., Dutertre, C. A., Chapiro, E., Davi, F., Debré, P., Prost, J. F., Teillaud, J. L., Merle-Beral, H., and Vieillard, V.
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MONOCLONAL antibodies , *CHRONIC lymphocytic leukemia , *ANTINEOPLASTIC antibiotics , *KILLER cells , *CELL receptors , *DISEASE progression , *CELL-mediated cytotoxicity - Abstract
Although anti-CD20 monoclonal antibodies (mAbs) show promise for the treatment of chronic lymphocytic leukemia (CLL), the success of the anti-CD20 mAb rituximab in CLL treatment has been limited. Novel anti-CD20 mAbs with more potent cytotoxic activity have recently been engineered, but so far most have only been tested in vitro with natural killer (NK) cells from healthy donors. Because it is still unclear whether these optimized cytotoxic mAbs will improve NK-cell killing of tumor cells in CLL patients, we characterized the relevant phenotypic and functional features of NK cells from CLL patients in detail. Expression of inhibitory and activating NK-cell receptors and of Fc gamma receptor IIIA (FcγRIIIA) is well preserved in CD16+CD56dim cytotoxic NK cells from these patients, independently of disease progression. These cells are fully functional following cytokine stimulation. In addition, the FcγRIIIA-optimized LFB-R603 anti-CD20 mAb mediates 100 times greater antibody-dependent cell-mediated cytotoxicity by NK cells from CLL patients and healthy donors than rituximab. Enhanced degranulation against autologous B-CLL cells is observed at lower concentrations of LFB-R603 than rituximab, regardless of CLL prognostic factors. These findings strongly justify further clinical development of anti-CD20 mAbs optimized for FcγR engagement in CLL patients. [ABSTRACT FROM AUTHOR]
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- 2011
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16. How should we diagnose and treat blastic plasmacytoid dendritic cell neoplasm patients?
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Xavier Cahu, Maxime Desmarets, Thibaut Leguay, Philippe Saas, Victoria Raggueneau, Delphine Binda, Maria Alessandra Rosenthal, Chrystelle Vidal, Olivier Adotevi, Fanny Angelot-Delettre, Françoise Solly, Anne-Cécile Galoisy, Alice Garnier, Sylvie Daliphard, Estelle Guérin, Marie-Pierre Gourin, Karim Maloum, Véronique Harrivel, Edouard Cornet, Felipe Suarez, Jacques Vargaftig, Fabrice Jardin, Caroline Mayeur-Rousse, Sylvain Thepot, Maïder Pagadoy, Thorsten Braun, Bernard Drenou, Yuriy Drebit, Marc Maynadié, Caroline Basle, Zehaira Benseddik, Frédéric Féger, Jean Feuillard, Christian Recher, Etienne Lengliné, Catherine Cordonnier, Rémi Letestu, Mathieu Puyade, Isabelle Arnoux, Remy Gressin, Nathalie Contentin, Jerome Tamburini, Pascale Saussoy, Mary Callanan, Elodie Dindinaud, Pierre-Simon Rohrlich, Julien Guy, Hind Bennani, Tony Petrella, Vincent Foissaud, Johann Rose, Natacha Maillard, Lucile Baseggio, Magali Le Garff-Tavernier, Vincent Barlogis, Denis Guyotat, Yohan Desbrosses, Caroline Bonmati, Damien Roos-Weil, Michel Ticchioni, Sandrine Puyraimond, Norbert Vey, Adriana Plesa, Blandine Guffroy, Daniel Lusina, Bérengère Gruson, Anne Roggy, Véronique Salaun, Eric Deconinck, Jean-Yves Cahn, Nathalie Jacques, Caroline Bret, Florian Renosi, Marie-Christine Béné, Alice Eischen, Stefan Wickenhauser, Benjamin Papoular, Francine Garnache-Ottou, François-Xavier Gros, Vahid Asnafi, Celia Salanoubat, Blandine Bénet, Elisabeth Macintyre, Lou Soret, Orianne Wagner-Ballon, Mohamad Mohty, Elsa Bera, Nicolas Freynet, Ludovic Lhermitte, Franck Trimoreau, Claude Preudhomme, Christophe Roumier, Sébastien Maury, Sabrina Bouyer, Eve Poret, Mikael Roussel, Romaric Lacroix, Christine Arnoulet, Françoise Schillinger, Patricia Okamba, Christine Lefebvre, Didier Blaise, Nicolas Lechevalier, Sabine Brechignac, Christophe Ferrand, Estelle Seilles, Richard Veyrat-Masson, Giorgia Battipaglia, Denis Caillot, Véronique Latger-Cannard, Bruno Quesnel, Didier Bouscary, Sophie Brun, Agathe Debliquis, Marie Loosveld, Franck Geneviève, Carinne Lafon, Lydia Campos, Thierry Fest, Ouda Ghoual, Marie-Christine Jacob, Pierre Peterlin, Valérie Bardet, Anne Arnaud, Véronique Dorvaux, Sabeha Biichle, Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (RIGHT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Centre d'Investigation Clinique de Besançon (Inserm CIC 1431), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), 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), Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Microenvironment, Cell Differentiation, Immunology and Cancer (MICMAC), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Pontchaillou [Rennes], 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), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), 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, Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), ANR-11-LABX-0024,ParaFrap,Alliance française contre les maladies parasitaires(2011), European Project: IC18CT980373, Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté]), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Université de 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), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS BFC)-Université de Franche-Comté (UFC), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS BFC)-Université de Franche-Comté (UFC), 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 ), 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), UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Service de biologie hématologique, Garnache-Ottou, F., Vidal, C., Biichle, S., Renosi, F., Poret, E., Pagadoy, M., Desmarets, M., Roggy, A., Seilles, E., Soret, L., Schillinger, F., Puyraimond, S., Petrella, T., Preudhomme, C., Roumier, C., Macintyre, E. A., Harrivel, V., Desbrosses, Y., Gruson, B., Genevieve, F., Thepot, S., Drebit, Y., Leguay, T., Gros, F. -X., Lechevalier, N., Saussoy, P., Salaun, V., Cornet, E., Benseddik, Z., Veyrat-Masson, R., Wagner-Ballon, O., Salanoubat, C., Maynadie, M., Guy, J., Caillot, D., Jacob, M. -C., Cahn, J. -Y., Gressin, R., Rose, J., Quesnel, B., Guerin, E., Trimoreau, F., Feuillard, J., Gourin, M. -P., Plesa, A., Baseggio, L., Arnoux, I., Vey, N., Blaise, D., Lacroix, R., Arnoulet, C., Benet, B., Dorvaux, V., Bret, C., Drenou, B., Debliquis, A., Latger-Cannard, V., Bonmati, C., Bene, M. -C., Peterlin, P., Ticchioni, M., Rohrlich, P. -S., Arnaud, A., Wickenhauser, S., Bardet, V., Brechignac, S., Papoular, B., Raggueneau, V., Vargaftig, J., Letestu, R., Lusina, D., Braun, T., Foissaud, V., Tamburini, J., Bennani, H., Freynet, N., Cordonnier, C., Le Garff-Tavernier, M., Jacques, N., Maloum, K., Roos-Weil, D., Bouscary, D., Asnafi, V., Lhermitte, L., Suarez, F., Lengline, E., Feger, F., Battipaglia, G., Mohty, M., Bouyer, S., Ghoual, O., Dindinaud, E., Basle, C., Puyade, M., Lafon, C., Fest, T., Roussel, M., Cahu, X., Bera, E., Daliphard, S., Jardin, F., Campos, L., Solly, F., Guyotat, D., Galoisy, A. -C., Eischen, A., Mayeur-Rousse, C., Guffroy, B., Recher, C., Loosveld, M., Garnier, A., Barlogis, V., Rosenthal, M. A., Brun, S., Contentin, N., Maury, S., Callanan, M., Lefebvre, C., Maillard, N., Okamba, P., Ferrand, C., Adotevi, O., Saas, P., Angelot-Delettre, F., Binda, D., and Deconinck, E.
- Subjects
Oncology ,Vincristine ,medicine.medical_specialty ,Myeloid ,Cyclophosphamide ,Clinical Trials and Observations ,medicine.medical_treatment ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Hematopoietic stem cell transplantation ,Plasmacytoid dendritic cell ,Immunophenotyping ,Clonal Evolution ,03 medical and health sciences ,0302 clinical medicine ,Bone Marrow ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Humans ,Neoplasm Metastasis ,Neoplasm Staging ,030304 developmental biology ,Chromosome Aberrations ,0303 health sciences ,Leukemia ,business.industry ,Hematopoietic Stem Cell Transplantation ,Disease Management ,Myeloid leukemia ,Dendritic Cells ,Hematology ,Prognosis ,medicine.disease ,Blood Cell Count ,3. Good health ,Transplantation ,Treatment Outcome ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Acute Disease ,business ,Biomarkers ,medicine.drug - Abstract
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive leukemia for which we developed a nationwide network to collect data from new cases diagnosed in France. In a retrospective, observational study of 86 patients (2000-2013), we described clinical and biological data focusing on morphologies and immunophenotype. We found expression of markers associated with plasmacytoid dendritic cell origin (HLA-DRhigh, CD303+, CD304+, and cTCL1+) plus CD4 and CD56 and frequent expression of isolated markers from the myeloid, B-, and T-lymphoid lineages, whereas specific markers (myeloperoxidase, CD14, cCD3, CD19, and cCD22) were not expressed. Fifty-one percent of cytogenetic abnormalities impact chromosomes 13, 12, 9, and 15. Myelemia was associated with an adverse prognosis. We categorized chemotherapeutic regimens into 5 groups: acute myeloid leukemia (AML)–like, acute lymphoid leukemia (ALL)–like, lymphoma (cyclophosphamide, doxorubicin, vincristine, and prednisone [CHOP])–like, high-dose methotrexate with asparaginase (Aspa-MTX) chemotherapies, and not otherwise specified (NOS) treatments. Thirty patients received allogeneic hematopoietic cell transplantation (allo-HCT), and 4 patients received autologous hematopoietic cell transplantation. There was no difference in survival between patients receiving AML-like, ALL-like, or Aspa-MTX regimens; survival was longer in patients who received AML-like, ALL-like, or Aspa-MTX regimens than in those who received CHOP-like regimens or NOS. Eleven patients are in persistent complete remission after allo-HCT with a median survival of 49 months vs 8 for other patients. Our series confirms a high response rate with a lower toxicity profile with the Aspa-MTX regimen, offering the best chance of access to hematopoietic cell transplantation and a possible cure.
- Published
- 2019
17. Evaluation of ZAP-70 expression by flow cytometry in chronic lymphocytic leukemia: A multicentric international harmonization process
- Author
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Magali Le Garff-Tavernier, Medhat Shehata, Ian Mockridge, Clare Walker, Laura Z. Rassenti, Neus Villamor, Anton W. Langerak, Nancy Boeckx Leuven, Piotr Smolewski, Paolo Ghia, Andy C. Rawstron, Peter Staib, Alison Morilla, Rachel Ibbotson, Ruth Padmore, Matthias Ritgen, Florence Ajchenbaum-Cymbalista, Michel Ticchioni, Sebastian Boettcher, Rémi Letestu, Anne Mette Buhl, Jan Duerig, Alexander Kroeber, Letestu, R, Rawstron, A, Ghia, PAOLO PROSPERO, Villamor, N, Boeckx, N, Boettcher, S, Buhl, Am, Duerig, J, Ibbotson, R, Kroeber, A, Langerak, A, Le Garff Tavernier, M, Mockridge, I, Morilla, A, Padmore, R, Rassenti, L, Ritgen, M, Shehata, M, Smolewski, P, Staib, P, Ticchioni, M, Walker, C, and Ajchenbaum Cymbalista, F.
- Subjects
Histology ,Consensus ,Chronic lymphocytic leukemia ,International Cooperation ,T-Lymphocytes ,Immunoglobulin Variable Region ,CD19 ,Pathology and Forensic Medicine ,Flow cytometry ,Antigen-Antibody Reactions ,Immunophenotyping ,Antibody Specificity ,Biomarkers, Tumor ,Medicine ,Humans ,ZAP-70 Protein-Tyrosine Kinase ,biology ,medicine.diagnostic_test ,business.industry ,Antibodies, Monoclonal ,Anticoagulants ,Reproducibility of Results ,Cell Biology ,medicine.disease ,Flow Cytometry ,Isotype ,Leukemia, Lymphocytic, Chronic, B-Cell ,Killer Cells, Natural ,Leukemia ,Immunology ,Mutation ,biology.protein ,Antibody ,business ,Clone (B-cell biology) ,Immunoglobulin Heavy Chains - Abstract
The clinical course of patients with chronic lymphocytic leukemia (CLL) is heterogeneous with some patients requiring early therapy whereas others will not be treated for years. The evaluation of an individual CLL patient's prognosis remains a problematic issue. The presence or absence of somatic mutations in the IgVH genes is currently the gold-standard prognostic factor, but this technique is labor intensive and costly. Genomic studies uncovered that 70 kDa zeta-associated protein (ZAP-70) expression was associated with unmutated IgVH genes and ZAP-70 protein expression was proposed as a surrogate for somatic mutational status. Among the available techniques for ZAP-70 detection, flow cytometry is most preferable as it allows the simultaneous quantification of ZAP-70 protein expression levels in CLL cells and residual normal lymphocyte subsets. However, several factors introduce variability in the results reported from different laboratories; these factors include the anti-ZAP-70 antibody clone and conjugate, the staining procedure, the gating strategy, and the method of reporting the results. The need for standardization of the approach led to the organization of an international working group focused on harmonizing all aspects of the technique. During this workshop, a technical consensus was reached on the methods for cell permeabilization and immunophenotyping procedures. An assay was then designed that allowed comparison of two clones of anti-ZAP-70 antibody and the identification of the expression of this molecule in B, T, and NK cells identified in a four multicolor analysis. This procedure was applied to three stabilized blood samples, provided by the UK NEQAS group to all participating members of this study, in order to minimize variability caused by sample storage and shipment. Analysis was performed in 20 laboratories providing interpretable data from 14 centers. Various gating strategies were used and the ZAP-70 levels were expressed as percentage positive (POS) relative to isotype control or normal B-cells or normal T-cells; in addition the levels were reported as a ratio of expression in CLL cells relative to T-cells. The reported level of ZAP-70 expression varied greatly depending on the antibody and the method used to express the results. The CLL/T-cell ZAP-70 expression ratio showed a much lower interlaboratory variation than other reporting strategies and is recommended for multicenter studies. Stabilization results in decreased expression of CD19 making gating more difficult and therefore stabilized samples are not optimal for multicentric analysis of ZAP-70 expression. We assessed the variation of ZAP-70 expression levels in fresh cells according to storage time, which demonstrated that ZAP-70 is labile but sufficiently stable to allow comparison using fresh samples distributed between labs in Europe. These studies have demonstrated progress toward a consensus reporting procedure, and further work is underway to harmonize the preparation and analysis procedures. ispartof: Cytometry Part B: Clinical Cytometry vol:70 issue:4 pages:309-314 ispartof: location:United States status: published
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- 2006
18. CAR T-cell therapy induces a high rate of prolonged remission in relapsed primary CNS lymphoma: Real-life results of the LOC network.
- Author
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Choquet S, Soussain C, Azar N, Morel V, Metz C, Ursu R, Waultier-Rascalou A, di Blasi R, Houot R, Souchet L, Roos-Weil D, Uzunov M, Quoc SN, Jacque N, Boussen I, Gauthier N, Ouzegdouh M, Blonski M, Campidelli A, Ahle G, Guffroy B, Willems L, Corvilain E, Barrie M, Alcantara M, le Garff-Tavernier M, Psimaras D, Weiss N, Baron M, Bravetti C, Hoang-Xuan K, Davi F, Shor N, Alentorn A, and Houillier C
- Subjects
- Humans, Male, Female, Middle Aged, Aged, Retrospective Studies, Leukapheresis, Remission Induction, Adult, Aged, 80 and over, Receptors, Chimeric Antigen, Immunotherapy, Adoptive adverse effects, Immunotherapy, Adoptive methods, Central Nervous System Neoplasms therapy, Central Nervous System Neoplasms mortality
- Abstract
The prognosis of relapsed primary central nervous system lymphoma (PCNSL) remains dismal. CAR T-cells are a major contributor to systemic lymphomas, but their use in PCNSL is limited. From the LOC network database, we retrospectively selected PCNSL who had leukapheresis for CAR-T cells from the third line of treatment, and, as controls, PCNSL treated with any treatment, at least in the third line and considered not eligible for ASCT. Twenty-seven patients (median age: 68, median of three previous lines, including ASCT in 14/27) had leukapheresis, of whom 25 received CAR T-cells (tisa-cel: N = 16, axi-cel: N = 9) between 2020 and 2023. All but one received a bridging therapy. The median follow-up after leukapheresis was 20.8 months. The best response after CAR-T cells was complete response in 16 patients (64%). One-year progression-free survival from leukapheresis was 43% with a plateau afterward. One-year relapse-free survival was 79% for patients in complete or partial response at CAR T-cell infusion. The median overall survival was 21.2 months. Twenty-three patients experienced a cytokine release syndrome and 17/25 patients (68%) a neurotoxicity (five grade ≥3). The efficacy endpoints were significantly better in the CAR T-cell group than in the control group (N = 247) (median PFS: 3 months; median OS: 4.7 months; p < 0.001). This series represents the largest cohort of PCNSL treated with CAR T-cells reported worldwide. CAR T-cells are effective in relapsed PCNSL, with a high rate of long-term remission and a reassuring tolerance profile. The results seem clearly superior to those usually observed in this setting., (© 2024 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.)
- Published
- 2024
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19. CAR T-cell therapy for central nervous system lymphomas: blood and cerebrospinal fluid biology, and outcomes.
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Lacan C, Caron J, Tarantino N, Fouquet B, Cherai M, Parizot C, Morel V, Souchet L, Uzunov M, Gorochov G, Nguyen-Quoc S, Sourdeau E, Vieillard V, Miyara M, Vinit A, Solorzano S, Soussain C, Houillier C, Metz C, Autran B, Litvinova E, Le Garff-Tavernier M, Norol F, Roos-Weil D, Choquet S, Guihot A, and Baron M
- Subjects
- Humans, Immunotherapy, Adoptive adverse effects, Central Nervous System, Biology, Cerebrospinal Fluid, Lymphoma, Non-Hodgkin, Central Nervous System Neoplasms therapy
- Published
- 2023
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20. A fixed-duration immunochemotherapy approach in CLL: 5.5-year results from the phase 2 ICLL-07 FILO trial.
- Author
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Michallet AS, Letestu R, Le Garff-Tavernier M, Campos L, Ticchioni M, Dilhuydy MS, Morisset S, Rouille V, Mahé B, Laribi K, Villemagne B, Ferrant E, Tournilhac O, Delmer A, Molina L, Leblond V, Tomowiak C, de Guibert S, Orsini-Piocelle F, Banos A, Carassou P, Cartron G, Fornecker LM, Ysebaert L, Dartigeas C, Truchan-Graczyk M, Vilque JP, Schleinitz TA, Cymbalista F, Leprêtre S, Lévy V, Nguyen-Khac F, and Feugier P
- Subjects
- Humans, Rituximab therapeutic use, Cyclophosphamide, Bone Marrow, Remission Induction, Neoplasm, Residual drug therapy, Leukemia, Lymphocytic, Chronic, B-Cell diagnosis, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy
- Abstract
In previously untreated, medically fit patients with chronic lymphocytic leukemia (CLL), research is focused on developing fixed-duration strategies to improve long-term outcomes while sparing patients from serious toxicities. The ICLL-07 trial evaluated a fixed-duration (15-month) immunochemotherapy approach in which after obinutuzumab-ibrutinib induction for 9 months, patients (n = 10) in complete remission (CR) with bone marrow (BM) measurable residual disease (MRD) <0.01% continued only ibrutinib 420 mg/day for 6 additional months (I arm), whereas the majority (n = 115) received up to 4 cycles of fludarabine/cyclophosphamide-obinutuzumab 1000 mg alongside the ibrutinib (I-FCG arm). Primary analysis at month 16 showed that 84 of 135 (62.2%) patients enrolled achieved CR with a BM MRD <0.01%. Here, we report follow-up at median 63 months. Peripheral blood (PB) MRD was assessed 6 monthly beyond the end of treatment using a highly sensitive (10-6) flow cytometry technique. In the I-FCG arm, the PB MRD <0.01% rate (low-level positive <0.01% or undetectable with limit of detection ≤10-4) in evaluable patients was still 92.5% (74/80) at month 40 and 80.6% (50/62) at month 64. No differences in the PB MRD status were apparent per to the IGHV mutational status. In the overall population, 4-year progression-free and overall survival rates were 95.5% and 96.2%, respectively. Twelve deaths occurred overall. Fourteen serious adverse events occurred beyond the end of treatment. Thus, our fixed-duration immunochemotherapy approach produced deep and sustained PB MRD responses, high survival rates, and low long-term toxicity. A randomized trial is needed to compare our immunochemotherapy approach with a chemotherapy-free strategy. This trial was registered at www.clinicaltrials.gov as #NCT02666898., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
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- 2023
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21. Prevalence of IGLV3-21R110 among familial CLL: a retrospective study of 45 cases.
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Armand M, Verrier P, Theves F, Bravetti C, Le Garff-Tavernier M, Choquet S, and Davi F
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- Humans, Prevalence, Retrospective Studies, Leukemia, Lymphocytic, Chronic, B-Cell epidemiology, Leukemia, Lymphocytic, Chronic, B-Cell genetics
- Published
- 2022
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22. CAR T-cell therapy in primary central nervous system lymphoma: the clinical experience of the French LOC network.
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Alcantara M, Houillier C, Blonski M, Rubio MT, Willems L, Rascalou AW, Le Garff-Tavernier M, Maloum K, Bravetti C, Souchet L, Roos-Weil D, Morel V, Uzunov M, Metz C, Dhib-Charfi M, Nguyen S, Shor N, Psimaras D, Weiss N, Jacque N, Solorzano S, Gauthier N, Le Cann M, Norol F, Soussain C, and Choquet S
- Subjects
- Aged, Central Nervous System pathology, Central Nervous System Neoplasms epidemiology, Central Nervous System Neoplasms pathology, Cohort Studies, Female, France epidemiology, Humans, Lymphoma, Large B-Cell, Diffuse epidemiology, Lymphoma, Large B-Cell, Diffuse pathology, Male, Middle Aged, Survival Analysis, Central Nervous System Neoplasms therapy, Immunotherapy, Adoptive, Lymphoma, Large B-Cell, Diffuse therapy
- Published
- 2022
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23. Plasmacytoid dendritic cells proliferation associated with acute myeloid leukemia: phenotype profile and mutation landscape
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Zalmaï L, Viailly PJ, Biichle S, Cheok M, Soret L, Angelot-Delettre F, Petrella T, Collonge-Rame MA, Seilles E, Geffroy S, Deconinck E, Daguindau E, Bouyer S, Dindinaud E, Baunin V, Le Garff-Tavernier M, Roos-Weil D, Wagner-Ballon O, Salaun V, Feuillard J, Brun S, Drenou B, Mayeur-Rousse C, Okamba P, Dorvaux V, Tichionni M, Rose J, Rubio MT, Jacob MC, Raggueneau V, Preudhomme C, Saas P, Ferrand C, Adotevi O, Roumier C, Jardin F, Garnache-Ottou F, and Renosi F
- Subjects
- Cell Proliferation, Humans, Mutation, Phenotype, Dendritic Cells, Leukemia, Myeloid, Acute genetics
- Abstract
Neoplasms involving plasmacytoid Dendritic Cells (pDCs) include Blastic pDC Neoplasms (BPDCN) and other pDC proliferations, where pDCs are associated with myeloid malignancies: most frequently Chronic MyeloMonocytic Leukemia (CMML) but also Acute Myeloid Leukemia (AML), hereafter named pDC-AML. We aimed to determine the reactive or neoplastic origin of pDCs in pDC-AML, and their link with the CD34+ blasts, monocytes or conventional DCs (cDCs) associated in the same sample, by phenotypic and molecular analyses (targeted NGS, 70 genes). We compared 15 pDC-AML at diagnosis with 21 BPDCN and 11 normal pDCs from healthy donors. CD45low CD34+ blasts were found in all cases (10-80% of medullar cells), associated with pDCs (4-36%), monocytes in 14 cases (1-10%) and cDCs (2 cases, 4.8-19%). pDCs in pDC-AML harbor a clearly different phenotype from BPDCN: CD4+ CD56- in 100% of cases, most frequently CD303+, CD304+ and CD34+; lower expression of cTCL1 and CD123 with isolated lymphoid markers (CD22/CD7/CD5) in some cases, suggesting a pre-pDC stage. In all cases, pDCs, monocytes and cDC are neoplastic since they harbor the same mutations as CD34+ blasts. RUNX1 is the most commonly mutated gene: detected in all AML with minimal differentiation (M0-AML) but not in the other cases. Despite low number of cases, the systematic association between M0-AML, RUNX1 mutations and an excess of pDC is puzzling. Further evaluation in a larger cohort is required to confirm RUNX1 mutations in pDC-AML with minimal differentiation and to investigate whether it represents a proliferation of blasts with macrophage and DC progenitor potential.
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- 2021
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24. Intravenous high-dose methotrexate based systemic therapy in the treatment of isolated primary vitreoretinal lymphoma: An LOC network study.
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Lam M, Touitou V, Choquet S, Cassoux N, Ghesquières H, Kodjikian L, Schmitt A, Gattoussi S, Tabouret É, Sampo M, Blonski M, Angioi-Duprez K, Houot R, Mouriaux F, Gyan E, Le Lez ML, Moles MP, Croisé F, Chauchet A, Schwartz C, Ahle G, Meyer L, Gressin R, Chiquet C, Oberic L, Ollé P, Marolleau JP, Jany B, Tempescul A, Cochener B, Damaj G, Quintyn JC, Moluçon-Chabrot C, Rousseau E, Franciane P, Schneider C, Massé H, Tamburini-Bonnefoy J, Brézin A, Fornecker LM, Ballonzoli L, Le Garff-Tavernier M, Hoang-Xuan K, Bodaghi B, Soussain C, and Houillier C
- Subjects
- Administration, Intravenous, Adult, Aged, Aged, 80 and over, Antimetabolites, Antineoplastic administration & dosage, Antimetabolites, Antineoplastic adverse effects, Female, Humans, Intraocular Lymphoma diagnosis, Male, Methotrexate administration & dosage, Methotrexate adverse effects, Middle Aged, Prognosis, Retinal Neoplasms diagnosis, Treatment Outcome, Antimetabolites, Antineoplastic therapeutic use, Intraocular Lymphoma drug therapy, Methotrexate therapeutic use, Retinal Neoplasms drug therapy
- Abstract
The treatment of primary vitreoretinal lymphoma (PVRL) remains controversial regarding the use of local, systemic, or combined treatments. The aim of this study was to analyze the efficacy and toxicity of intravenous high-dose methotrexate (IV HD-MTX) based systemic therapy in a uniformly treated population of PVRL patients. From a nationwide French database, we retrospectively selected 59 patients (median age: 70 years, median Karnofsky Performance Status: 90%) with isolated PVRL at diagnosis who received first-line treatment with HD-MTX between 2011 and 2018. 8/59 patients also received a local treatment. No deaths or premature discontinuations of MTX due to toxicity were reported. A complete response was obtained in 40/57 patients after chemotherapy. Before treatment, IL-10 was elevated in the aqueous humor (AH) or in the vitreous in 89% of patients. After treatment, AH IL-10 was undetectable in 87% of patients with a CR/uCR/PR and detectable in 92% of patients with PD/SD. After a median follow-up of 61 months, 42/59 (71%) patients had relapsed, including 29 isolated ocular relapses as the first relapse and a total of 22 brain relapses. The median overall survival, progression-free survival, ocular-free survival and brain-free survival were 75, 18, 29 and 73 months, respectively. IV HD-MTX based systemic therapy as a first-line treatment for isolated PVRL is feasible, with acceptable toxicity, even in an elderly population. This strategy seems efficient to prevent brain relapse with prolonged overall survival. However, the ocular relapse rate remains high. New approaches are needed to improve local control of this disease, and ocular assessment could be completed by monitoring AH IL-10., (© 2021 Wiley Periodicals LLC.)
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- 2021
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25. Efficacy of minimal residual disease driven immune-intervention after allogeneic hematopoietic stem cell transplantation for high-risk chronic lymphocytic leukemia: results of a prospective multicenter trial.
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Tournilhac O, Le Garff-Tavernier M, Nguyen Quoc S, Forcade E, Chevallier P, Legrand-Izadifar F, Laurent Damaj G, Michonneau D, Tomowiak C, Borel C, Orvain C, Turlure P, Redjou R, Guillerm G, Vincent L, Simand C, Lemal R, Quiney C, Combes P, Pereira B, Calvet L, Cabrespine A, Bay JO, Leblond V, Dhédin N, Organization Filo FIL, and De Moelle Et de Thérapie Cellulaire Sfgm-Tc SFG
- Subjects
- Humans, Neoplasm, Residual, Prospective Studies, Retrospective Studies, Transplantation Conditioning, Graft vs Host Disease etiology, Hematopoietic Stem Cell Transplantation adverse effects, Leukemia, Lymphocytic, Chronic, B-Cell diagnosis, Leukemia, Lymphocytic, Chronic, B-Cell therapy
- Abstract
Allogeneic hematopoietic stem cell transplantation (HSCT) remains a potentially curative and useful strategy in high-risk relapsing CLL. Minimal Residual Disease (MRD) assessment at 12 months post-HSCT is predictive of relapse. This phase 2 study aimed to achieve M12 MRD negativity (MRDneg) using MRD-driven immune-intervention (Md-PII) algorithm based on serial flow-cytometry blood MRD, involving cyclosporine tapering followed if failure by donor lymphocytes infusions. Patients had high-risk CLL according to 2006 EBMT consensus, in complete or partial response with lymphadenopathy < 5 cm and comorbidity score ≤ 2. Donors were HLA-matched sibling or matched unrelated (10/10). Forty-two enrolled patients with either 17p deletion (front-line, n=11; relapse n=16) or other high-risk relapse (n=15) received reduced intensity-conditioning regimen before HSCT and were submitted to Md-PII. M12-MRDneg status was achieved in 64% versus 14.2% before HSCT. With a median follow-up of 36 months (range, 19-53), 3-year overall survival, non-relapse mortality and cumulative incidence of relapse are 86.9% (95%CI, 70.8-94.4), 9.5% (95%CI, 3.7-23.4) and 29.6% (95%CI, 17.3-47.7). Incidence of 2-year limited and extensive chronic graft versus host disease (cGVHD) is 38% (95%CI, 23-53) and 23% (95%CI, 10-36) including 2 cases post Md-PII. Fifteen patients converted to MRDneg either after CsA withdrawal (n=12) or after cGVHD (n=3). As a time-dependent variable, MRDneg achievement at any time-point correlates with reduced relapse (HR=0.14 [0.04-0.53], p=0.004) and improvement of both progression free (HR=0.18 [0.06-0.6], p<0.005) and overall (HR: 0.18 [0.03-0.98], p=0.047) survival. These data highlight the value of MRD-driven immune-intervention to induce prompt MRD clearance in the therapy of CLL.
- Published
- 2021
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26. A fixed-duration, measurable residual disease-guided approach in CLL: follow-up data from the phase 2 ICLL-07 FILO trial.
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Michallet AS, Letestu R, Le Garff-Tavernier M, Aanei C, Ticchioni M, Dilhuydy MS, Subtil F, Rouille V, Mahe B, Laribi K, Villemagne B, Salles G, Tournilhac O, Delmer A, Portois C, Pegourie B, Leblond V, Tomowiak C, De Guibert S, Orsini Piocelle F, Banos A, Carassou P, Cartron G, Fornecker LM, Ysebaert L, Dartigeas C, Truchan-Graczyk M, Vilque JP, Aurran T, Cymbalista F, Lepretre S, Levy V, Nguyen-Khac F, and Feugier P
- Subjects
- Adenine administration & dosage, Adenine adverse effects, Adenine therapeutic use, Antibodies, Monoclonal, Humanized administration & dosage, Antibodies, Monoclonal, Humanized adverse effects, Antineoplastic Agents, Immunological administration & dosage, Antineoplastic Agents, Immunological adverse effects, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Antineoplastic Combined Chemotherapy Protocols adverse effects, Cyclophosphamide administration & dosage, Cyclophosphamide adverse effects, Cyclophosphamide therapeutic use, Follow-Up Studies, Humans, Leukemia, Lymphocytic, Chronic, B-Cell diagnosis, Neoplasm, Residual diagnosis, Neoplasm, Residual drug therapy, Piperidines administration & dosage, Piperidines adverse effects, Remission Induction, Treatment Outcome, Vidarabine administration & dosage, Vidarabine adverse effects, Vidarabine therapeutic use, Adenine analogs & derivatives, Antibodies, Monoclonal, Humanized therapeutic use, Antineoplastic Agents, Immunological therapeutic use, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Piperidines therapeutic use
- Abstract
Trials assessing first-line, fixed-duration approaches in chronic lymphocytic leukemia (CLL) are yielding promising activity, but few long-term data are available. We report follow-up data from a phase 2 trial (ICLL07 FILO) in previously untreated, medically fit patients (N = 135). Patients underwent obinutuzumab-ibrutinib induction for 9 months; then, following evaluation (N = 130 evaluable), those in complete remission and with bone marrow measurable residual disease (BM MRD) <0.01% (n = 10) received ibrutinib for 6 additional months; those in partial remission and/or with BM MRD ≥0.01%, the majority (n = 120), also received 4 cycles of immunochemotherapy (fludarabine/cyclophosphamide-obinutuzumab). Beyond end of treatment, responses were assessed every 3 month and peripheral blood MRD every 6 months. At median follow-up 36.7 months from treatment start, progression-free and overall survival rates (95% confidence interval) at 3 years were 95.7% (92.0% to 99.5%) and 98% (95.1% to 100%), respectively. Peripheral blood MRD <0.01% rates were 97%, 96%, 90%, 84%, and 89% at months 16, 22, 28, 34, and 40, respectively. No new treatment-related or serious adverse event occurred beyond end of treatment. Thus, in previously untreated, medically fit patients with CLL, a fixed-duration (15 months), MRD-guided approach achieved high survival rates, a persistent MRD benefit beyond the end of treatment, and low long-term toxicity. This trial was registered at www.clinicaltrials.gov as #NCT02666898., (© 2021 by The American Society of Hematology.)
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- 2021
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27. Identification of 2 DNA methylation subtypes of Waldenström macroglobulinemia with plasma and memory B-cell features.
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Roos-Weil D, Giacopelli B, Armand M, Della-Valle V, Ghamlouch H, Decaudin C, Metzner M, Lu J, Le Garff-Tavernier M, Leblond V, Vyas P, Zenz T, Nguyen-Khac F, Bernard OA, and Oakes CC
- Subjects
- Humans, Waldenstrom Macroglobulinemia classification, B-Lymphocyte Subsets immunology, DNA Methylation genetics, Plasma Cells immunology, Waldenstrom Macroglobulinemia genetics, Waldenstrom Macroglobulinemia immunology
- Abstract
Epigenetic changes during B-cell differentiation generate distinct DNA methylation signatures specific for B-cell subsets, including memory B cells (MBCs) and plasma cells (PCs). Waldenström macroglobulinemia (WM) is a B-cell malignancy uniquely comprising a mixture of lymphocytic and plasmacytic phenotypes. Here, we integrated genome-wide DNA methylation, transcriptome, mutation, and phenotypic features of tumor cells from 35 MYD88-mutated WM patients in relation to normal plasma and B-cell subsets. Patients naturally segregate into 2 groups according to DNA methylation patterns, related to normal MBC and PC profiles, and reminiscent of other memory and PC-derived malignancies. Concurrent analysis of DNA methylation changes in normal and WM development captured tumor-specific events, highlighting a selective reprogramming of enhancer regions in MBC-like WM and repressed and heterochromatic regions in PC-like WM. MBC-like WM hypomethylation was enriched in motifs belonging to PU.1, TCF3, and OCT2 transcription factors and involved elevated MYD88/TLR pathway activity. PC-like WM displayed marked global hypomethylation and selective overexpression of histone genes. Finally, WM subtypes exhibited differential genetic, phenotypic, and clinical features. MBC-like WM harbored significantly more clonal CXCR4 mutations (P = .015), deletion 13q (P = .006), splenomegaly (P = .02), and thrombocytopenia (P = .004), whereas PC-like WM harbored more deletion 6q (P = .012), gain 6p (P = .033), had increased frequencies of IGHV3 genes (P = .002), CD38 expression (P = 4.1e-5), and plasmacytic differentiation features (P = .008). Together, our findings illustrate a novel approach to subclassify WM patients using DNA methylation and reveal divergent molecular signatures among WM patients., (© 2020 by The American Society of Hematology.)
- Published
- 2020
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28. Temozolomide is effective and well tolerated in patients with primary vitreoretinal lymphoma.
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Baron M, Belin L, Cassoux N, Fardeau C, Blaizeau M, Soussain C, Houillier C, Hoang-Xuan K, Gyan E, Le Lez ML, Lavaud A, Soubeyran P, Bodaghi B, Costopoulos M, Leblond V, Touitou V, Maloum K, Errera MH, Roos-Weil D, Le Garff-Tavernier M, and Choquet S
- Subjects
- Adult, Aged, Aged, 80 and over, Drug-Related Side Effects and Adverse Reactions epidemiology, Eye Neoplasms epidemiology, Eye Neoplasms pathology, Female, Humans, Lymphoma epidemiology, Lymphoma pathology, Male, Middle Aged, Retinal Neoplasms epidemiology, Retinal Neoplasms pathology, Retrospective Studies, Treatment Outcome, Vitreous Body pathology, Eye Neoplasms drug therapy, Lymphoma drug therapy, Retinal Neoplasms drug therapy, Temozolomide therapeutic use
- Published
- 2020
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29. How should we diagnose and treat blastic plasmacytoid dendritic cell neoplasm patients?
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Garnache-Ottou F, Vidal C, Biichlé S, Renosi F, Poret E, Pagadoy M, Desmarets M, Roggy A, Seilles E, Soret L, Schillinger F, Puyraimond S, Petrella T, Preudhomme C, Roumier C, MacIntyre EA, Harrivel V, Desbrosses Y, Gruson B, Geneviève F, Thepot S, Drebit Y, Leguay T, Gros FX, Lechevalier N, Saussoy P, Salaun V, Cornet E, Benseddik Z, Veyrat-Masson R, Wagner-Ballon O, Salanoubat C, Maynadié M, Guy J, Caillot D, Jacob MC, Cahn JY, Gressin R, Rose J, Quesnel B, Guerin E, Trimoreau F, Feuillard J, Gourin MP, Plesa A, Baseggio L, Arnoux I, Vey N, Blaise D, Lacroix R, Arnoulet C, Benet B, Dorvaux V, Bret C, Drenou B, Debliquis A, Latger-Cannard V, Bonmati C, Bene MC, Peterlin P, Ticchioni M, Rohrlich PS, Arnaud A, Wickenhauser S, Bardet V, Brechignac S, Papoular B, Raggueneau V, Vargaftig J, Letestu R, Lusina D, Braun T, Foissaud V, Tamburini J, Bennani H, Freynet N, Cordonnier C, Le Garff-Tavernier M, Jacques N, Maloum K, Roos-Weil D, Bouscary D, Asnafi V, Lhermitte L, Suarez F, Lengline E, Féger F, Battipaglia G, Mohty M, Bouyer S, Ghoual O, Dindinaud E, Basle C, Puyade M, Lafon C, Fest T, Roussel M, Cahu X, Bera E, Daliphard S, Jardin F, Campos L, Solly F, Guyotat D, Galoisy AC, Eischen A, Mayeur-Rousse C, Guffroy B, Recher C, Loosveld M, Garnier A, Barlogis V, Rosenthal MA, Brun S, Contentin N, Maury S, Callanan M, Lefebvre C, Maillard N, Okamba P, Ferrand C, Adotevi O, Saas P, Angelot-Delettre F, Binda D, and Deconinck E
- Subjects
- Acute Disease, Biomarkers, Blood Cell Count, Bone Marrow pathology, Chromosome Aberrations, Clonal Evolution genetics, Dendritic Cells metabolism, Disease Management, Hematopoietic Stem Cell Transplantation, Humans, Immunophenotyping, Leukemia etiology, Leukemia metabolism, Neoplasm Metastasis, Neoplasm Staging, Prognosis, Treatment Outcome, Dendritic Cells pathology, Leukemia diagnosis, Leukemia therapy
- Abstract
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive leukemia for which we developed a nationwide network to collect data from new cases diagnosed in France. In a retrospective, observational study of 86 patients (2000-2013), we described clinical and biological data focusing on morphologies and immunophenotype. We found expression of markers associated with plasmacytoid dendritic cell origin (HLA-DRhigh, CD303+, CD304+, and cTCL1+) plus CD4 and CD56 and frequent expression of isolated markers from the myeloid, B-, and T-lymphoid lineages, whereas specific markers (myeloperoxidase, CD14, cCD3, CD19, and cCD22) were not expressed. Fifty-one percent of cytogenetic abnormalities impact chromosomes 13, 12, 9, and 15. Myelemia was associated with an adverse prognosis. We categorized chemotherapeutic regimens into 5 groups: acute myeloid leukemia (AML)-like, acute lymphoid leukemia (ALL)-like, lymphoma (cyclophosphamide, doxorubicin, vincristine, and prednisone [CHOP])-like, high-dose methotrexate with asparaginase (Aspa-MTX) chemotherapies, and not otherwise specified (NOS) treatments. Thirty patients received allogeneic hematopoietic cell transplantation (allo-HCT), and 4 patients received autologous hematopoietic cell transplantation. There was no difference in survival between patients receiving AML-like, ALL-like, or Aspa-MTX regimens; survival was longer in patients who received AML-like, ALL-like, or Aspa-MTX regimens than in those who received CHOP-like regimens or NOS. Eleven patients are in persistent complete remission after allo-HCT with a median survival of 49 months vs 8 for other patients. Our series confirms a high response rate with a lower toxicity profile with the Aspa-MTX regimen, offering the best chance of access to hematopoietic cell transplantation and a possible cure., (© 2019 by The American Society of Hematology.)
- Published
- 2019
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30. Genetic characterization of B-cell prolymphocytic leukemia: a prognostic model involving MYC and TP53.
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Chapiro E, Pramil E, Diop M, Roos-Weil D, Dillard C, Gabillaud C, Maloum K, Settegrana C, Baseggio L, Lesesve JF, Yon M, Jondreville L, Lesty C, Davi F, Le Garff-Tavernier M, Droin N, Dessen P, Algrin C, Leblond V, Gabarre J, Bouzy S, Eclache V, Gaillard B, Callet-Bauchu E, Muller M, Lefebvre C, Nadal N, Ittel A, Struski S, Collonge-Rame MA, Quilichini B, Fert-Ferrer S, Auger N, Radford-Weiss I, Wagner L, Scheinost S, Zenz T, Susin SA, Bernard OA, and Nguyen-Khac F
- Subjects
- Aged, Aged, 80 and over, Chromosome Aberrations, Cytogenetic Analysis, Female, Humans, Male, Middle Aged, Prognosis, Leukemia, Prolymphocytic, B-Cell genetics, Proto-Oncogene Proteins c-myc genetics, Tumor Suppressor Protein p53 genetics
- Abstract
B-cell prolymphocytic leukemia (B-PLL) is a rare hematological disorder whose underlying oncogenic mechanisms are poorly understood. Our cytogenetic and molecular assessments of 34 patients with B-PLL revealed several disease-specific features and potential therapeutic targets. The karyotype was complex (≥3 abnormalities) in 73% of the patients and highly complex (≥5 abnormalities) in 45%. The most frequent chromosomal aberrations were translocations involving MYC [t(MYC)] (62%), deletion (del)17p (38%), trisomy (tri)18 (30%), del13q (29%), tri3 (24%), tri12 (24%), and del8p (23%). Twenty-six (76%) of the 34 patients exhibited an MYC aberration, resulting from mutually exclusive translocations or gains. Whole-exome sequencing revealed frequent mutations in TP53, MYD88, BCOR, MYC, SF3B1, SETD2, CHD2, CXCR4, and BCLAF1. The majority of B-PLL used the IGHV3 or IGHV4 subgroups (89%) and displayed significantly mutated IGHV genes (79%). We identified 3 distinct cytogenetic risk groups: low risk (no MYC aberration), intermediate risk (MYC aberration but no del17p), and high risk (MYC aberration and del17p) (P = .0006). In vitro drug response profiling revealed that the combination of a B-cell receptor or BCL2 inhibitor with OTX015 (a bromodomain and extra-terminal motif inhibitor targeting MYC) was associated with significantly lower viability of B-PLL cells harboring a t(MYC). We concluded that cytogenetic analysis is a useful diagnostic and prognostic tool in B-PLL. Targeting MYC may be a useful treatment option in this disease., (© 2019 by The American Society of Hematology.)
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- 2019
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31. Targeting chronic lymphocytic leukemia with N-methylated thrombospondin-1-derived peptides overcomes drug resistance.
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Pramil E, Herbi Bastian L, Denèfle T, Nemati F, Xiao M, Lardé E, Maloum K, Roos-Weil D, Chapiro E, Le Garff-Tavernier M, Davi F, Decaudin D, Sarfati M, Nguyen-Khac F, Merle-Béral H, Karoyan P, and Susin SA
- Subjects
- Animals, Apoptosis drug effects, Caspases metabolism, Cell Cycle Checkpoints drug effects, Cell Death drug effects, Cell Line, Tumor, Cyclic AMP metabolism, Cyclic AMP-Dependent Protein Kinases metabolism, Disease Models, Animal, Female, Humans, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Leukemia, Lymphocytic, Chronic, B-Cell metabolism, Leukemia, Lymphocytic, Chronic, B-Cell pathology, Mice, Mitochondria drug effects, Mitochondria metabolism, Models, Molecular, Molecular Mimicry, Peptides chemistry, Signal Transduction drug effects, Xenograft Model Antitumor Assays, Antineoplastic Agents pharmacology, Drug Resistance, Neoplasm drug effects, Peptides pharmacology, Thrombospondin 1 chemistry
- Abstract
Chronic lymphocytic leukemia (CLL), the most common adulthood leukemia in Western countries, is a very heterogeneous disease characterized by a peripheral accumulation of abnormal CD5+ B lymphocytes in the immune system. Despite new therapeutic developments, there remains an unmet medical need for CLL. Here, we demonstrate that the use of N-methylated thrombospondin-1 (TSP-1)-derived peptides is an efficient way to kill the malignant CLL cells, including those from high-risk individuals with poor clinical prognosis, del11q, del17p, 2p gain, or complex karyotype. PKT16, our hit N-methylated peptide, triggers the elimination of the leukemic cells, sparing the nontumor cells, including the hematopoietic precursors, and reduces the in vivo tumor burden of a CLL-xenograft mice model. A complementary analysis underscores the improved cytotoxic efficiency of PKT16 compared with the previously described TSP-1-derived probes, such as PKHB1. PKT16 elicits an original caspase-independent programmed necrotic mode of cell death, different from necroptosis or ferroptosis, implicating an intracellular Ca2+ deregulation that provokes mitochondrial damage, cell cycle arrest, and the specific death of the malignant CLL cells. The activation of the Gαi proteins and the subsequent drop of cyclic adenosine monophosphate levels and protein kinase A activity regulate this cytotoxic cascade. Remarkably, PKT16 induces the molecular hallmarks of immunogenic cell death, as defined by the calreticulin plasma membrane exposure and the release of adenosine triphosphate and high-mobility group box 1 protein from the dying CLL cells. Thus, PKT16 appears to be able to stimulate an anticancer in vivo immune response. Collectively, our results pave the way toward the development of an efficient strategy against CLL., (© 2019 by The American Society of Hematology.)
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- 2019
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32. Optimization of CSF biological investigations for CNS lymphoma diagnosis.
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Armand M, Costopoulos M, Osman J, Tarfi S, Houillier C, Choquet S, Agnelo H, Bonnemye P, Ronez E, Settegrana C, Soussain C, Hoang-Xuan K, Le Garff-Tavernier M, and Davi F
- Subjects
- Algorithms, Central Nervous System Diseases cerebrospinal fluid, Central Nervous System Neoplasms diagnosis, Central Nervous System Neoplasms pathology, Cerebrospinal Fluid cytology, Clone Cells, Cytokines cerebrospinal fluid, Early Detection of Cancer, False Negative Reactions, False Positive Reactions, Flow Cytometry, Gene Rearrangement, B-Lymphocyte, Genes, Immunoglobulin, Humans, Lymphoma, Non-Hodgkin diagnosis, Lymphoma, Non-Hodgkin pathology, Meninges pathology, Multiplex Polymerase Chain Reaction, Neoplasm Invasiveness, Somatic Hypermutation, Immunoglobulin, Staining and Labeling methods, Central Nervous System Neoplasms cerebrospinal fluid, Lymphoma, Non-Hodgkin cerebrospinal fluid
- Abstract
Diagnosis of lymphoma leptomeningeal dissemination is challenging and relies on a wide array of methods. So far, no consensus biological guidelines are available. This increases the chance of intra- and interpractice variations, despite the shared concern to perform the minimum amount of tests while preserving clinically relevant results.We evaluated a training cohort of 371 cerebrospinal fluid (CSF) samples from patients with putative lymphomatous central nervous system (CNS) localization using conventional cytology (CC), flow cytometry (FCM), molecular clonality assesment by PCR and cytokine quantification (CQ). This led us to propose a biological algorithm, which was then verified on a validation cohort of 197 samples. The samples were classified according to the clinical context and the results of each technique were compared. Using all four techniques was not useful for exclusion diagnosis of CNS lymphoma (CNSL), but they proved complementary for cases with suspected CNSL. This was particularly true for CQ in primary CNSL. Overall, diagnosis can be obtained with a two-step approach. The first step comprises CC and FCM, as results are available quickly and FCM is a sensitive method. Both PCR and CQ can be postponed and performed in a second step, depending on the results from the first step and the clinical context.The proposed algorithm missed none of the CNSL samples of the validation cohort. Moreover, applying this algorithm would have spared 30% of PCR tests and 20% of CQ over a one-year period, without compromising clinical management., (© 2019 Wiley Periodicals, Inc.)
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- 2019
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33. Gain of the short arm of chromosome 2 (2p gain) has a significant role in drug-resistant chronic lymphocytic leukemia.
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Kostopoulou F, Gabillaud C, Chapiro E, Grange B, Tran J, Bouzy S, Degaud M, Ghamlouch H, Le Garff-Tavernier M, Maloum K, Choquet S, Leblond V, Gabarre J, Lavaud A, Morel V, Roos-Weil D, Uzunov M, Guieze R, Bernard OA, Susin SA, Tournilhac O, and Nguyen-Khac F
- Subjects
- Adult, Aged, Antineoplastic Agents therapeutic use, Antineoplastic Combined Chemotherapy Protocols adverse effects, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Chromosome Aberrations, Female, Humans, Immunoglobulin Variable Region genetics, Immunophenotyping, In Situ Hybridization, Fluorescence, Karyotyping, Leukemia, Lymphocytic, Chronic, B-Cell diagnosis, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Leukemia, Lymphocytic, Chronic, B-Cell mortality, Longitudinal Studies, Male, Middle Aged, Mutation, Polymorphism, Single Nucleotide, Prognosis, Protein Kinase Inhibitors pharmacology, Protein Kinase Inhibitors therapeutic use, Recurrence, Time-to-Treatment, Treatment Outcome, Antineoplastic Agents pharmacology, Chromosome Duplication, Chromosomes, Human, Pair 2, Drug Resistance, Neoplasm genetics, Leukemia, Lymphocytic, Chronic, B-Cell genetics
- Abstract
The different types of drug resistance encountered in chronic lymphocytic leukemia (CLL) cannot be fully accounted for by the 17p deletion (and/or TP53 mutation), a complex karyotype (CK), immunoglobulin heavy-chain variable region genes (IGHV) status and gene mutations. Hence, we sought to assess the associations between recurrent genomic abnormalities in CLL and the disease's development and outcome. To this end, we analyzed 64 samples from patients with CLL and gain of the short arm of chromosome 2 (2p+), which is frequent in late-stage and relapsed/refractory CLL. We found that fludarabine/cyclophosphamide/rituximab (a common first-line treatment in CLL) is not effective in removing the 2p+ clone - even in samples lacking a CK, the 17p deletion or unmutated IGHV. Our results suggest strongly that patients with CLL should be screened for 2p+ (using karyotyping and fluorescence in situ hybridization) before a treatment option is chosen. Longer follow-up is now required to evaluate bendamustine-rituximab, ibrutinib, and idelalisib-rituximab treatments., (© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)
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- 2019
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34. "Double-hit" chronic lymphocytic leukemia: An aggressive subgroup with 17p deletion and 8q24 gain.
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Chapiro E, Lesty C, Gabillaud C, Durot E, Bouzy S, Armand M, Le Garff-Tavernier M, Bougacha N, Struski S, Bidet A, Laharanne E, Barin C, Veronese L, Prié N, Eclache V, Gaillard B, Michaux L, Lefebvre C, Gaillard JB, Terré C, Penther D, Bastard C, Nadal N, Fert-Ferrer S, Auger N, Godon C, Sutton L, Tournilhac O, Susin SA, and Nguyen-Khac F
- Subjects
- Abnormal Karyotype, Adult, Aged, Aged, 80 and over, Disease-Free Survival, Female, Genes, p53, Humans, In Situ Hybridization, Fluorescence, Kaplan-Meier Estimate, Leukemia, Lymphocytic, Chronic, B-Cell mortality, Leukemia, Lymphocytic, Chronic, B-Cell pathology, Male, Middle Aged, Neoplasm Invasiveness genetics, Prognosis, Retrospective Studies, Chromosome Deletion, Chromosomes, Human, Pair 17 ultrastructure, Chromosomes, Human, Pair 8 ultrastructure, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Translocation, Genetic, Trisomy
- Abstract
Chronic lymphocytic leukemia (CLL) with 17p deletion (17p-) is associated with a lack of response to standard treatment and thus the worst possible clinical outcome. Various chromosomal abnormalities (including unbalanced translocations, deletions, ring chromosomes and isochromosomes) result in the loss of 17p and one copy of the TP53 gene. The objective of the present study was to determine whether the type of chromosomal abnormality leading to 17p- and the additional aberrations influenced the prognosis in a series of 195 patients with 17p-CLL. Loss of 17p resulted primarily from an unbalanced translocation (70%) with several chromosome partners (the most frequent being chromosome 18q), followed by deletion 17p (23%), monosomy 17 (8%), isochromosome 17q [i(17q)] (5%) and a ring chromosome 17 (2%). In a univariate analysis, monosomy 17, a highly complex karyotype (≥5 abnormalities), and 8q24 gain were associated with poor treatment-free survival, and i(17q) (P = .04), unbalanced translocations (P = .03) and 8q24 gain (P = .001) were significantly associated with poor overall survival. In a multivariate analysis, 8q24 gain remained a significant predictor of poor overall survival. We conclude that 17p deletion and 8q24 gain have a synergistic impact on outcome, and so patients with this "double-hit" CLL have a particularly poor prognosis. Systematic, targeting screening for 8q24 gain should therefore be considered in cases of 17p- CLL., (© 2017 Wiley Periodicals, Inc.)
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- 2018
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35. Direct-Acting Antiviral Therapy Restores Immune Tolerance to Patients With Hepatitis C Virus-Induced Cryoglobulinemia Vasculitis.
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Comarmond C, Garrido M, Pol S, Desbois AC, Costopoulos M, Le Garff-Tavernier M, Si Ahmed SN, Alric L, Fontaine H, Bellier B, Maciejewski A, Rosenzwajg M, Klatzmann D, Musset L, Poynard T, Cacoub P, and Saadoun D
- Subjects
- Aged, Antiviral Agents adverse effects, B-Lymphocyte Subsets immunology, B-Lymphocyte Subsets metabolism, B-Lymphocyte Subsets virology, Biomarkers blood, Carbamates, Case-Control Studies, Cryoglobulinemia diagnosis, Cryoglobulinemia immunology, Cryoglobulinemia virology, Cytokines blood, Drug Therapy, Combination, Female, Hepatitis C complications, Hepatitis C diagnosis, Hepatitis C immunology, Hepatitis Viruses immunology, Humans, Imidazoles adverse effects, Male, Middle Aged, Phenotype, Prospective Studies, Pyrrolidines, Ribavirin adverse effects, Simeprevir adverse effects, Sofosbuvir adverse effects, T-Lymphocyte Subsets immunology, T-Lymphocyte Subsets metabolism, T-Lymphocyte Subsets virology, Time Factors, Treatment Outcome, Valine analogs & derivatives, Vasculitis diagnosis, Vasculitis immunology, Vasculitis virology, Viral Load, Antiviral Agents therapeutic use, B-Lymphocyte Subsets drug effects, Cryoglobulinemia drug therapy, Hepatitis C drug therapy, Hepatitis Viruses drug effects, Imidazoles therapeutic use, Immune Tolerance drug effects, Immunity, Cellular drug effects, Ribavirin therapeutic use, Simeprevir therapeutic use, Sofosbuvir therapeutic use, T-Lymphocyte Subsets drug effects, Vasculitis drug therapy
- Abstract
Background & Aims: Interferon-free direct-acting antiviral (DAA) therapies are effective in patients with hepatitis C virus-induced cryoglobulinemia vasculitis (HCV-CV). We analyzed blood samples from patients with HCV-CV before and after DAA therapy to determine mechanisms of these drugs and their effects on cellular immunity., Methods: We performed a prospective study of 27 consecutive patients with HCV-CV (median age, 59 y) treated with DAA therapy (21 patients received sofosbuvir plus ribavirin for 24 weeks, 4 patients received sofosbuvir plus daclatasvir for 12 weeks, and 2 patients received sofosbuvir plus simeprevir for 12 weeks) in Paris, France. Blood samples were collected from these patients before and after DAA therapy, and also from 12 healthy donors and 12 individuals with HCV infection without CV. HCV load, cryoglobulins, and cytokines were quantified by flow cytometry, cytokine multiplex assays, and enzyme-linked immunosorbent assay., Results: Twenty-four patients (88.9%) had a complete clinical response of CV to DAA therapy at week 24, defined by improvement of all the affected organs and the absence of relapse. Compared with healthy donors and patients with HCV infection without CV, patients with HCV-CV, before DAA therapy, had a lower percentage of CD4+CD25hiFoxP3+ regulatory T cells (P < .01), but higher proportions of IgM+CD21-/low memory B cells (P < .05), CD4+IFNγ+ cells (P < .01), CD4+IL17A+ cells (P < .01), and CD4+CXCR5+interleukin 21+ follicular T-helper (Tfh) cells (P < .01). In patients with HCV-CV, there was a negative correlation between numbers of IgM+CD21-/low memory B cells and T-regulatory cells (P = .03), and positive correlations with numbers of Tfh cells (P = .03) and serum levels of cryoglobulin (P = .01). DAA therapy increased patients' numbers of T-regulatory cells (1.5% ± 0.18% before therapy vs 2.1% ± 0.18% after therapy), decreased percentages of IgM+CD21-/low memory B cells (35.7% ± 6.1% before therapy vs 14.9% ± 3.8% after therapy), and decreased numbers of Tfh cells (12% ± 1.3% before therapy vs 8% ± 0.9% after therapy). Expression levels of B lymphocyte stimulator receptor 3 and programmed cell death 1 on B cells increased in patients with HCV-CV after DAA-based therapy (mean fluorescence units, 37 ± 2.4 before therapy vs 47 ± 2.6 after therapy, P < .01; and 29 ± 7.3 before therapy vs 48 ± 9.3 after therapy, P < .05, respectively)., Conclusions: In a prospective clinical trial of patients with HCV-CV, DAA-based therapy restored disturbances in peripheral B- and T-cell homeostasis., (Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.)
- Published
- 2017
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36. Guideline for the diagnosis, treatment and response criteria for Bing-Neel syndrome.
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Minnema MC, Kimby E, D'Sa S, Fornecker LM, Poulain S, Snijders TJ, Kastritis E, Kremer S, Fitsiori A, Simon L, Davi F, Lunn M, Castillo JJ, Patterson CJ, Le Garff-Tavernier M, Costopoulos M, Leblond V, Kersten MJ, Dimopoulos MA, and Treon SP
- Subjects
- Algorithms, Combined Modality Therapy adverse effects, Combined Modality Therapy methods, Diagnosis, Differential, Diagnostic Tests, Routine, Disease Management, Humans, Magnetic Resonance Imaging methods, Molecular Diagnostic Techniques, Syndrome, Treatment Outcome, Waldenstrom Macroglobulinemia epidemiology, Waldenstrom Macroglobulinemia etiology, Phenotype, Waldenstrom Macroglobulinemia diagnosis, Waldenstrom Macroglobulinemia therapy
- Abstract
Bing Neel syndrome is a rare disease manifestation of Waldenström's macroglobulinemia that results from infiltration of the central nervous system by malignant lymphoplasmacytic cells. In this guideline we describe the clinical symptoms, as well as the appropriate laboratory and radiological studies, that can aid in the diagnosis. The presentation of Bing Neel syndrome may be very diverse, and includes headaches, cognitive deficits, paresis, and psychiatric symptoms. The syndrome can present in patients with known Waldenström's macroglobulinemia, even in the absence of systemic progression, but also in previously undiagnosed patients. Diagnostic work-up should include cerebral spinal fluid analysis with multiparameter flow cytometry to establish B-cell clonality, protein electrophoresis and immunofixation for the detection and classification of a monoclonal protein as well as molecular diagnostic testing for immunoglobulin gene rearrangement and mutated MYD88. MRI of the brain and spinal cord is also essential. The second challenge is to expand our knowledge of prognosis and treatment outcome. Prospective clinical trials on Bing Neel syndrome patients that employ uniform treatment along with appropriate laboratory cerebral spinal fluid assessments and standardized MRI protocols will be invaluable, constituting a significant step forward in delineating treatment outcome for this intriguing disease manifestation., (Copyright© Ferrata Storti Foundation.)
- Published
- 2017
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37. CD1d-restricted peripheral T cell lymphoma in mice and humans.
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Bachy E, Urb M, Chandra S, Robinot R, Bricard G, de Bernard S, Traverse-Glehen A, Gazzo S, Blond O, Khurana A, Baseggio L, Heavican T, Ffrench M, Crispatzu G, Mondière P, Schrader A, Taillardet M, Thaunat O, Martin N, Dalle S, Le Garff-Tavernier M, Salles G, Lachuer J, Hermine O, Asnafi V, Roussel M, Lamy T, Herling M, Iqbal J, Buffat L, Marche PN, Gaulard P, Kronenberg M, Defrance T, and Genestier L
- Subjects
- Animals, Antigens, CD1d genetics, Antigens, Ly genetics, Antigens, Ly immunology, Female, Humans, Lymphoma, T-Cell, Peripheral genetics, Lymphoma, T-Cell, Peripheral pathology, Male, Mice, Mice, Knockout, NK Cell Lectin-Like Receptor Subfamily B genetics, NK Cell Lectin-Like Receptor Subfamily B immunology, Receptors, Antigen, T-Cell genetics, Receptors, Antigen, T-Cell immunology, Signal Transduction genetics, Streptococcus pneumoniae immunology, Tumor Suppressor Protein p53 genetics, Tumor Suppressor Protein p53 immunology, Antigens, CD1d immunology, Lymphoma, T-Cell, Peripheral immunology, Signal Transduction immunology
- Abstract
Peripheral T cell lymphomas (PTCLs) are a heterogeneous entity of neoplasms with poor prognosis, lack of effective therapies, and a largely unknown pathophysiology. Identifying the mechanism of lymphomagenesis and cell-of-origin from which PTCLs arise is crucial for the development of efficient treatment strategies. In addition to the well-described thymic lymphomas, we found that p53-deficient mice also developed mature PTCLs that did not originate from conventional T cells but from CD1d-restricted NKT cells. PTCLs showed phenotypic features of activated NKT cells, such as PD-1 up-regulation and loss of NK1.1 expression. Injections of heat-killed Streptococcus pneumonia, known to express glycolipid antigens activating NKT cells, increased the incidence of these PTCLs, whereas Escherichia coli injection did not. Gene expression profile analyses indicated a significant down-regulation of genes in the TCR signaling pathway in PTCL, a common feature of chronically activated T cells. Targeting TCR signaling pathway in lymphoma cells, either with cyclosporine A or anti-CD1d blocking antibody, prolonged mice survival. Importantly, we identified human CD1d-restricted lymphoma cells within Vδ1 TCR-expressing PTCL. These results define a new subtype of PTCL and pave the way for the development of blocking anti-CD1d antibody for therapeutic purposes in humans., (© 2016 Bachy et al.)
- Published
- 2016
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38. Presence of multiple recurrent mutations confers poor trial outcome of relapsed/refractory CLL.
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Guièze R, Robbe P, Clifford R, de Guibert S, Pereira B, Timbs A, Dilhuydy MS, Cabes M, Ysebaert L, Burns A, Nguyen-Khac F, Davi F, Véronèse L, Combes P, Le Garff-Tavernier M, Leblond V, Merle-Béral H, Alsolami R, Hamblin A, Mason J, Pettitt A, Hillmen P, Taylor J, Knight SJ, Tournilhac O, and Schuh A
- Subjects
- Ataxia Telangiectasia Mutated Proteins genetics, High-Throughput Nucleotide Sequencing, Humans, Kaplan-Meier Estimate, Leukemia, Lymphocytic, Chronic, B-Cell diagnosis, Neoplasm Recurrence, Local diagnosis, Phosphoproteins genetics, Prognosis, Prospective Studies, RNA Splicing Factors, Ribonucleoprotein, U2 Small Nuclear genetics, Treatment Outcome, Tumor Suppressor Protein p53 genetics, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Leukemia, Lymphocytic, Chronic, B-Cell therapy, Mutation, Neoplasm Recurrence, Local genetics, Salvage Therapy methods
- Abstract
Although TP53, NOTCH1, and SF3B1 mutations may impair prognosis of patients with chronic lymphocytic leukemia (CLL) receiving frontline therapy, the impact of these mutations or any other, alone or in combination, remains unclear at relapse. The genome of 114 relapsed/refractory patients included in prospective trials was screened using targeted next-generation sequencing of the TP53, SF3B1, ATM, NOTCH1, XPO1, SAMHD1, MED12, BIRC3, and MYD88 genes. We performed clustering according to both number and combinations of recurrent gene mutations. The number of genes affected by mutation was ≥ 2, 1, and 0 in 43 (38%), 49 (43%), and 22 (19%) respectively. Recurrent combinations of ≥ 2 mutations of TP53, SF3B1, and ATM were found in 22 (19%) patients. This multiple-hit profile was associated with a median progression-free survival of 12 months compared with 22.5 months in the remaining patients (P = .003). Concurrent gene mutations are frequent in patients with relapsed/refractory CLL and are associated with worse outcome., (© 2015 by The American Society of Hematology.)
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- 2015
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39. The optimized anti-CD20 monoclonal antibody ublituximab bypasses natural killer phenotypic features in Waldenström macroglobulinemia.
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Le Garff-Tavernier M, Herbi L, de Romeuf C, Azar N, Roos-Weil D, Bonnemye P, Urbain R, Leblond V, Merle-Beral H, and Vieillard V
- Subjects
- Antibodies, Monoclonal, Murine-Derived pharmacology, Antigens, CD20 metabolism, Antineoplastic Agents pharmacology, Cytotoxicity, Immunologic, Humans, Immunologic Factors pharmacology, Killer Cells, Natural metabolism, Lymphocyte Subsets drug effects, Lymphocyte Subsets immunology, Lymphocyte Subsets metabolism, Rituximab, Antibodies, Monoclonal, Murine-Derived therapeutic use, Antineoplastic Agents therapeutic use, Immunologic Factors therapeutic use, Killer Cells, Natural drug effects, Killer Cells, Natural immunology, Waldenstrom Macroglobulinemia drug therapy, Waldenstrom Macroglobulinemia immunology
- Published
- 2015
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40. CD47 agonist peptides induce programmed cell death in refractory chronic lymphocytic leukemia B cells via PLCγ1 activation: evidence from mice and humans.
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Martinez-Torres AC, Quiney C, Attout T, Boullet H, Herbi L, Vela L, Barbier S, Chateau D, Chapiro E, Nguyen-Khac F, Davi F, Le Garff-Tavernier M, Moumné R, Sarfati M, Karoyan P, Merle-Béral H, Launay P, and Susin SA
- Subjects
- Aged, Aged, 80 and over, Animals, Female, Humans, Leukemia, Lymphocytic, Chronic, B-Cell blood, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Male, Mice, Mice, Inbred NOD, Middle Aged, Peptides therapeutic use, Thrombospondin 1 therapeutic use, Apoptosis drug effects, B-Lymphocytes metabolism, CD47 Antigen metabolism, Drug Resistance, Neoplasm, Leukemia, Lymphocytic, Chronic, B-Cell metabolism, Peptides pharmacology, Phospholipase C gamma metabolism
- Abstract
Background: Chronic lymphocytic leukemia (CLL), the most common adulthood leukemia, is characterized by the accumulation of abnormal CD5+ B lymphocytes, which results in a progressive failure of the immune system. Despite intense research efforts, drug resistance remains a major cause of treatment failure in CLL, particularly in patients with dysfunctional TP53. The objective of our work was to identify potential approaches that might overcome CLL drug refractoriness by examining the pro-apoptotic potential of targeting the cell surface receptor CD47 with serum-stable agonist peptides., Methods and Findings: In peripheral blood samples collected from 80 patients with CLL with positive and adverse prognostic features, we performed in vitro genetic and molecular analyses that demonstrate that the targeting of CD47 with peptides derived from the C-terminal domain of thrombospondin-1 efficiently kills the malignant CLL B cells, including those from high-risk individuals with a dysfunctional TP53 gene, while sparing the normal T and B lymphocytes from the CLL patients. Further studies reveal that the differential response of normal B lymphocytes, collected from 20 healthy donors, and leukemic B cells to CD47 peptide targeting results from the sustained activation in CLL B cells of phospholipase C gamma-1 (PLCγ1), a protein that is significantly over-expressed in CLL. Once phosphorylated at tyrosine 783, PLCγ1 enables a Ca2+-mediated, caspase-independent programmed cell death (PCD) pathway that is not down-modulated by the lymphocyte microenvironment. Accordingly, down-regulation of PLCγ1 or pharmacological inhibition of PLCγ1 phosphorylation abolishes CD47-mediated killing. Additionally, in a CLL-xenograft model developed in NOD/scid gamma mice, we demonstrate that the injection of CD47 agonist peptides reduces tumor burden without inducing anemia or toxicity in blood, liver, or kidney. The limitations of our study are mainly linked to the affinity of the peptides targeting CD47, which might be improved to reach the standard requirements in drug development, and the lack of a CLL animal model that fully mimics the human disease., Conclusions: Our work provides substantial progress in (i) the development of serum-stable CD47 agonist peptides that are highly effective at inducing PCD in CLL, (ii) the understanding of the molecular events regulating a novel PCD pathway that overcomes CLL apoptotic avoidance, (iii) the identification of PLCγ1 as an over-expressed protein in CLL B cells, and (iv) the description of a novel peptide-based strategy against CLL.
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- 2015
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41. Cytokine profile in human eyes: contribution of a new cytokine combination for differential diagnosis between intraocular lymphoma or uveitis.
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Fisson S, Ouakrim H, Touitou V, Baudet S, Ben Abdelwahed R, Donnou S, Miloudi A, Galand C, Bodaghi B, Lehoang P, Brissard M, Le Garff-Tavernier M, Fridman WH, Sautès-Fridman C, Cassoux N, and Merle-Béral H
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Aqueous Humor immunology, Aqueous Humor metabolism, Child, Cytokines immunology, Diagnosis, Differential, Eye Neoplasms immunology, Female, Humans, Interferon-gamma immunology, Interferon-gamma metabolism, Interleukins immunology, Interleukins metabolism, Lymphoma immunology, Male, Middle Aged, T-Lymphocytes, Helper-Inducer immunology, T-Lymphocytes, Helper-Inducer metabolism, Th1 Cells immunology, Th1 Cells metabolism, Th2 Cells immunology, Th2 Cells metabolism, Tumor Necrosis Factor-alpha immunology, Tumor Necrosis Factor-alpha metabolism, Uveitis immunology, Young Adult, Cytokines metabolism, Eye Neoplasms diagnosis, Eye Neoplasms metabolism, Lymphoma diagnosis, Lymphoma metabolism, Uveitis diagnosis, Uveitis metabolism
- Abstract
Primary intraocular lymphoma (PIOL), also called primary vitreoretinal lymphomas, often masquerades as uveitis. This misdiagnosis can result in subsequent brain involvement and oculocerebral lymphoma (OCL). In this study, we sought to characterize the helper T-cell type 1 (Th1)/Th2 cytokine profile in vitreous samples from patients with PIOL, OCL, uveitis and controls with non-inflammatory disease. Vitreous and aqueous humor samples from 87 patients with PIOL (n = 30), OCL (n = 12), uveitis (n = 34), and retinal detachment (RD) without hemorrhage (n = 11) were analyzed and their concentrations of interleukin (IL)-2, IL-4, IL-6, IL-10, interferon (IFN)-γ, and tumor necrosis factor (TNF)-α were determined by flow cytometric bead arrays (CBA). The IL-10 levels determined by CBA were compared with those by ELISA. IL-10 concentrations measured by CBA and ELISA were highly correlated. IL-2, IL-4, and TNFα were not detected in any sample. The only cytokine detected at a significant level in samples from RD vitreous was IL-6. The IL-10/IL-6 ratio, as previously reported, was slightly higher in PIOL than in uveitis samples, but not for all patients. Cytokine profiles from PIOL and OCL samples did not differ. The combination of the IL-10/IL-6 and IL-10/IFNγ ratios was highly informative for discriminating PIOL/OCL from uveitis samples and for therapeutic follow up of PIOL. This strategy might be very helpful as an initial screening to rule out PIOL in patients thought to have uveitis.
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- 2013
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42. Human NK cells display major phenotypic and functional changes over the life span.
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Le Garff-Tavernier M, Béziat V, Decocq J, Siguret V, Gandjbakhch F, Pautas E, Debré P, Merle-Beral H, and Vieillard V
- Subjects
- Adult, Aged, Aged, 80 and over, Cell Membrane metabolism, Cytotoxicity, Immunologic, Humans, Interferon-gamma biosynthesis, Lymphocyte Subsets cytology, Lymphocyte Subsets metabolism, Middle Aged, Phenotype, Receptors, Natural Killer Cell metabolism, Killer Cells, Natural cytology, Killer Cells, Natural metabolism, Longevity physiology
- Abstract
Aging is generally associated with an increased predisposition to infectious diseases and cancers, related in part to the development of immune senescence, a process that affects all cell compartments of the immune system. Although many studies have investigated the effects of age on natural killer (NK) cells, their conclusions remain controversial because the diverse health status of study subjects resulted in discordant findings. To clarify this situation, we conducted the first extensive phenotypic and functional analysis of NK cells from healthy subjects, comparing NK cells derived from newborn (cord blood), middle-aged (18-60 years), old (60-80 years), and very old (80-100 years) subjects. We found that NK cells in cord blood displayed specific features associated with immaturity, including poor expression of KIR and LIR-1/ILT-2 and high expression of both NKG2A and IFN-gamma. NK cells from older subjects, on the other hand, preserved their major phenotypic and functional characteristics, but with their mature features accentuated. These include a profound decline of the CD56(bright) subset, a specific increase in LIR-1/ILT-2, and a perfect recovering of NK-cell function following IL2-activation in very old subjects. We conclude that the preservation of NK cell features until very advanced age may contribute to longevity and successful aging.
- Published
- 2010
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