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1. A phase II double-blind multicentre, placebo-controlled trial to assess the efficacy and safety of alpelisib (BYL719) in paediatric and adult patients with Megalencephaly-CApillary malformation Polymicrogyria syndrome (MCAP): the SESAM study protocol

Author: Jean-Marc Treluyer, Benedicte Demeer, Laurence Faivre, Marc Bardou, Nathalie Boddaert, Paul Kuentz, Florence Petit, Christine Francannet, Pierre Vabres, Nadia Bahi-Buisson, Estelle Colin, Laurent Guibaud, Romaric Loffroy, Maxime Luu, Caroline Racine, Aurore Garde, Philippe Khau Van Kien, Aurore Curie, Nawale Hadouiri, Aurélie Espitalier, Agnès Maurer, Maud Carpentier, Adélaide Rega, Mouna Chebbi, Julie Charligny, Guillaume Canaud, Camille Fleck, Amelie Cransac, Elise Boucher-Brischoux, Adélaïde Brosseau-Beauvir, Florian Cherik, Alice Phan, Michaela Semeraro, Marion Nys, Charles Joris Roux, Alinoë Lavillaureix, and Isabelle Maruani
Subjects: Medicine
Abstract: Introduction The megalencephaly capillary malformation polymicrogyria (MCAP syndrome) results from mosaic gain-of-function PIK3CA variants. The main clinical features are macrocephaly, somatic overgrowth, neurodevelopmental delay and brain anomalies. Alpelisib (Vijoice) is a recently FDA-approved PI3Kα-specific inhibitor for patients with PIK3CA-related overgrowth spectrum (PROS). During its development, in patients with the MCAP subgroup of PROS, there was no specific, standardised evaluation of the effect on neuro-cognitive functioning. Moreover, it remains unknown if the molecule crosses the blood-brain barrier. Our objective is to evaluate the efficacy of a 24 month treatment with alpelisib on adaptive behaviour in patients with MCAP syndrome.Methods and analysis SESAM is an industry-sponsored two-period multicentre French academic phase II trial, with a 6-month double-blind, placebo-controlled period followed by an open-label period. The primary endpoint is a ≥4-point improvement in the Vineland II Adaptive Behaviour Scale (VABS), 24 months after treatment initiation. Secondary objectives are safety, VABS improvement at 6 months, impact on the quality of life, epilepsy and hypotonia. 20 patients aged 2 to 40 years with an MCAP diagnosis and neurodevelopmental disorders of various degrees, will be followed monthly in local centres, centrally assessed (clinical, biological, neuropsychological and functional evaluation) at baseline and every 6 months. Patients will be evaluated by volumetric MRI at baseline and at 24 months. An optional lumbar puncture will be performed to investigate blood-brain barrier crossing. Inclusions were completed by April 2024, with the end of follow-up in November 2026.Given the efficacy of alpelisib in patients with PROS, if the drug crosses the blood-brain barrier, we can expect a clinical benefit for patients with neurocognitive disorders.Ethics and dissemination Ethical approval was given by CPP Sud-Ouest et Outre-Mer I (reference: 2022-500197-34-01). Findings from this study will be disseminated via publication, reports and conference presentations.Trial registration number NCT05577754
Published: 2024
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2. Analysis of the impact of the SARS-CoV-2 infection on the pediatric population hospitalized during the pandemic in the Greater Paris University Hospitals

Author: Michaela Semeraro, Pierre Pinson, Margaux Populaire, Mourad Dellagi, Mehdi Oualha, Nathanael Beeker, and Hélène Chappuy
Subjects: data warehouse, SARS-CoV-2, children, PIMS, MIS-C multisystem inflammatory syndrome in children, hospitalized child, Pediatrics, RJ1-570
Abstract: BackgroundThe clinical characteristics, disease progression and outcome in children affected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection appear significantly milder compared to older individuals. Nevertheless, the trends in hospitalization and clinical characteristics in the pediatric population seem to be different over time across the different epidemic waves.ObjectiveOur aim was to understand the impact of the different COVID-19 variants in the pediatric population hospitalized in the Pediatric Departments of the Public Hospital in the Greater Paris area by the analysis performed with the Assistance Publique-Hopitaux de Paris (AP-HP) Health Data Warehouse.MethodsThis is a retrospective cohort study including 9,163 patients under 18 years of age, hospitalized from 1 March 2020 to 22 March 2022, in the Paris area, with confirmed infection by SARS-CoV-2. Three mutually exclusive groups with decreasing severity (Pediatric Inflammatory Multisystem Syndrome (PIMS), symptomatic infection, mild or asymptomatic infection) were defined and described regarding demography, medical history, complication of the SARS-CoV-2 infection, and treatment during admission. Temporal evolution was described by defining three successive waves (March–September 2020, October 2020–October 2021, and November 2021–March 2022) corresponding to the emergence of the successive variants.ResultsIn the study period, 9,163 pediatric patients with SARS-CoV-2 infection were hospitalized in 21 AP-HP hospitals. The number of patients with SARS-CoV-2 infection increased over time for each wave of the pandemic (the mean number of patients per month during the first wave was 332, 322 during the 2nd, and 595 during the third wave). In the medical history, the most associated concomitant disease was chronic respiratory disease. Patients hospitalized during the third wave presented a higher incidence of pulmonary involvement (10.2% compared to 7% and 6.5% during the first and second waves, respectively). The highest incidence of PIMS was observed during the first and second waves (4.2% in the first and second waves compared to 2.3% in the 3rd wave).DiscussionThis analysis highlighted the high incidence of hospitalized children in the Greater Paris Area during the third wave of SARS-CoV-2 pandemic corresponding to the Omicron Covid-19 variant, which is probably an expression of a concomitant SARS-CoV-2, while a decreased incidence of PIMS complication was observed during the same period.
Published: 2023
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3. Sustained remission after haploidentical bone marrow transplantation in a child with refractory systemic juvenile idiopathic arthritis

Author: Guillaume Morelle, Martin Castelle, Graziella Pinto, Sylvain Breton, Matthieu Bendavid, Charlotte Boussard, Richard Mouy, Brigitte Bader-Meunier, Michaela Semeraro, Albert Faye, Marina Cavazzana, Bénédicte Neven, Stéphane Blanche, Pierre Quartier, and Despina Moshous
Subjects: Systemic juvenile idiopathic arthritis, Still’s disease, Allogenic hematopoietic stem cell transplantation, Graft versus host disease, Autoimmunity, Pediatrics, RJ1-570, Diseases of the musculoskeletal system, RC925-935
Abstract: Abstract Background Some patients with systemic juvenile idiopathic arthritis (SJIA) and severe, refractory disease achieved remission through intensive immunosuppressive treatment followed by autologous hematopoietic stem cell transplantation (HSCT). However, disease relapsed in most cases. More recently selected SJIA patients received allogenic HSCT from a HLA-identical sibling or a HLA matched unrelated donor. While most transplanted patients achieved sustained SJIA remission off-treatment, the procedure-related morbidity was high. Case report A girl presented SJIA with a severe disease course since the age of 15 months. She was refractory to the combination of methotrexate and steroids to anti-interleukin (IL)-1, then anti-IL-6, tumor necrosis factor alpha inhibitors, and thalidomide. Given the high disease burden and important treatment-related toxicity the indication for a haploidentical HSCT from her mother was validated, as no HLA matched donor was available. The patient received a T replete bone marrow graft at the age of 3.7 years. Conditioning regimen contained Rituximab, Alemtuzumab, Busulfan, and Fludarabine. Cyclophosphamide at D + 3 and + 4 post HSCT was used for graft-versus-host-disease prophylaxis, followed by Cyclosporin A and Mycophenolate Mofetil. Post HSCT complications included severe infections, grade 3 intestinal graft-versus-host-disease, autoimmune thyroiditis, and immune thrombocytopenia. Three years after HSCT, the child is alive and well, notwithstanding persistent hypothyroidy requiring substitution. Immune thrombocytopenia had resolved. Most importantly, SJIA was in complete remission, off immunosuppressive drugs. Conclusion Allogenic HSCT may be a therapeutic option, even with a HLA haplo-identical alternative donor, in patients with inflammatory diseases such as SJIA. Despite increased experience with this treatment, the risk of life-threatening complications restrains its indication to selected patients with severe, refractory disease.
Published: 2021
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4. Autophagy-mediated metabolic effects of aspirin

Author: Francesca Castoldi, Juliette Humeau, Isabelle Martins, Sylvie Lachkar, Damarys Loew, Florent Dingli, Sylvère Durand, David Enot, Noëlie Bossut, Alexis Chery, Fanny Aprahamian, Yohann Demont, Paule Opolon, Nicolas Signolle, Allan Sauvat, Michaela Semeraro, Lucillia Bezu, Elisa Elena Baracco, Erika Vacchelli, Jonathan G. Pol, Sarah Lévesque, Norma Bloy, Valentina Sica, Maria Chiara Maiuri, Guido Kroemer, and Federico Pietrocola
Subjects: Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282, Cytology, QH573-671
Abstract: Abstract Salicylate, the active derivative of aspirin (acetylsalicylate), recapitulates the mode of action of caloric restriction inasmuch as it stimulates autophagy through the inhibition of the acetyltransferase activity of EP300. Here, we directly compared the metabolic effects of aspirin medication with those elicited by 48 h fasting in mice, revealing convergent alterations in the plasma and the heart metabolome. Aspirin caused a transient reduction of general protein acetylation in blood leukocytes, accompanied by the induction of autophagy. However, these effects on global protein acetylation could not be attributed to the mere inhibition of EP300, as determined by epistatic experiments and exploration of the acetyl-proteome from salicylate-treated EP300-deficient cells. Aspirin reduced high-fat diet-induced obesity, diabetes, and hepatosteatosis. These aspirin effects were observed in autophagy-competent mice but not in two different models of genetic (Atg4b −/− or Bcln1 +/−) autophagy-deficiency. Aspirin also improved tumor control by immunogenic chemotherapeutics, and this effect was lost in T cell-deficient mice, as well as upon knockdown of an essential autophagy gene (Atg5) in cancer cells. Hence, the health-improving effects of aspirin depend on autophagy.
Published: 2020
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5. Clinical Validation of a Volumetric Absorptive Micro-Sampling Device for Pharmacokinetic Studies With Tranexamic Acid

Author: Stanislas Grassin-Delyle, Elodie Lamy, Michaela Semeraro, Iléana Runge, Jean-Marc Treluyer, Raoul Mansukhani, Monica Arribas, Ian Roberts, and Haleema Shakur-Still
Subjects: tranexamic acid, volumetric absorptive micro-sampling, pharmacokinetics, whole blood, capillary blood, Therapeutics. Pharmacology, RM1-950
Abstract: We assessed the accuracy of tranexamic acid (TXA) concentrations measured in capillary whole blood using volumetric absorptive micro-sampling (VAMS) devices. Paired venous and VAMS capillary blood samples were collected from 15 healthy volunteers participating in a pharmacokinetic study of alternative routes (oral, IM and IV) of administering TXA. To assess accuracy across a range of concentrations, blood was drawn at different times after TXA administration. We measured TXA concentrations in plasma, whole blood from samples collected by venepuncture and whole blood from venous and capillary samples collected using VAMS devices. TXA was measured using a validated high sensitivity liquid chromatography - mass spectrometry method. We used Bland-Altman plots to describe the agreement between the TXA concentrations obtained with the different methods. In the 42 matched samples, the mean plasma TXA concentration was 14.0 mg/L (range 2.6–36.5 mg/L) whereas the corresponding whole blood TXA concentration was 7.7 mg/L (range 1.6–17.5 mg/L). When comparing TXA concentrations in VAMS samples of venous and capillary whole blood, the average bias was 0.07 mg/L (lower and upper 95% limits of agreement: −2.1 and 2.2 mg/L respectively). When comparing TXA concentrations in venous whole blood and VAMS capillary whole blood, the average bias was 0.7 mg/L (limits of agreement: −2.7 and 4.0 mg/L). Volumetric absorptive micro-sampling devices are sufficiently accurate for use in pharmacokinetic studies of tranexamic acid treatment in the range of plasma concentrations relevant for the assessment of fibrinolysis inhibition.
Published: 2021
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6. Sotatercept, a novel transforming growth factor β ligand trap, improves anemia in β-thalassemia: a phase II, open-label, dose-finding study

Author: Maria Domenica Cappellini, John Porter, Raffaella Origa, Gian Luca Forni, Ersi Voskaridou, Frédéric Galactéros, Ali T. Taher, Jean-Benoît Arlet, Jean-Antoine Ribeil, Maciej Garbowski, Giovanna Graziadei, Chantal Brouzes, Michaela Semeraro, Abderrahmane Laadem, Dimana Miteva, Jun Zou, Victoria Sung, Tatiana Zinger, Kenneth M. Attie, and Olivier Hermine
Subjects: Diseases of the blood and blood-forming organs, RC633-647.5
Abstract: β-thalassemia, a hereditary blood disorder caused by defective synthesis of hemoglobin β globin chains, leads to ineffective erythropoiesis and chronic anemia that may require blood transfusions. Sotatercept (ACE-011) acts as a ligand trap to inhibit negative regulators of late-stage erythropoiesis in the transforming growth factor β superfamily, correcting ineffective erythropoiesis. In this phase II, open-label, dose-finding study, 16 patients with transfusion-dependent β -thalassemia and 30 patients with non-transfusion-dependent β-thalassemia were enrolled at seven centers in four countries between November 2012 and November 2014. Patients were treated with sotatercept at doses of 0.1, 0.3, 0.5, 0.75, or 1.0 mg/kg to determine a safe and effective dose. Doses were administered by subcutaneous injection every 3 weeks. Patients were treated for ≤22 months. Response was assessed as a ≥20% reduction in transfusion burden sustained for 24 weeks in transfusion-dependent β-thalassemia patients, and an increase in hemoglobin level of ≥1.0 g/dL sustained for 12 weeks in non-transfusion-dependent β-thalassemia patients. Sotatercept was well tolerated. After a median treatment duration of 14.4 months (range 0.6-35.9), no severe life-threatening adverse events were observed. Thirteen percent of patients reported serious but manageable adverse events. The active dose of sotatercept was ≥0.3 mg/kg for patients with non-transfusion-dependent β-thalassemia and ≥0.5 mg/kg for those with transfusion-dependent β-thalassemia. Of 30 non-transfusion-dependent β-thalassemia patients treated with ≥0.1 mg/kg sotatercept, 18 (60%) achieved a mean hemoglobin increase ≥1.0 g/dL, and 11 (37%) an increase ≥1.5 g/dL, sustained for ≥12 weeks. Four (100%) transfusion-dependent β-thalassemia patients treated with 1.0 mg/kg sotatercept achieved a transfusion-burden reduction of ≥20%. Sotatercept was effective and well tolerated in patients with β-thalassemia. Most patients with non-transfusion-dependent β-thalassemia treated with higher doses achieved sustained increases in hemoglobin level. Transfusion-dependent β-thalassemia patients treated with higher doses of sotatercept achieved notable reductions in transfusion requirements. This trial was registered at ClinicalTrials.gov with the number NCT01571635.
Published: 2019
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7. Pharmacokinetics of tranexamic acid after intravenous, intramuscular, and oral routes: a prospective, randomised, crossover trial in healthy volunteers

Author: Stanislas Grassin-Delyle, Michaela Semeraro, Elodie Lamy, Saïk Urien, Iléana Runge, Frantz Foissac, Naim Bouazza, Jean-Marc Treluyer, Monica Arribas, Ian Roberts, Haleema Shakur-Still, Infection et inflammation (2I), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Foch [Suresnes], CIC - Mère Enfant Necker Cochin Paris Centre (CIC 1419), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Unité de recherche clinique / Centre d'investigation clinique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), London School of Hygiene and Tropical Medicine (LSHTM), Bill and Melinda Gates Foundation, BMGF: OPP1176150, Wellcome Trust, WT: 208870, Wellcome Trust (208870), Bill & Melinda Gates Foundation (OPP1176150)., and HAL UVSQ, Équipe
Subjects: Adult, Male, Cross-Over Studies, [SDV]Life Sciences [q-bio], Postpartum Hemorrhage, Administration, Oral, Injections, Intramuscular, administration routes, Healthy Volunteers, tranexamic acid, [SDV] Life Sciences [q-bio], Young Adult, Anesthesiology and Pain Medicine, postpartum haemorrhage, Humans, Administration, Intravenous, Female, Prospective Studies, pharmacokinetics, antifibrinolytic agents
Abstract: International audience; Background: In response to the World Health Organization call for research on alternative routes for tranexamic acid (TXA) administration in women with postpartum haemorrhage, we examined the pharmacokinetics of TXA after i.v., i.m., or oral administration. Methods: We conducted a randomised, open-label, crossover trial in 15 healthy volunteers who received i.v. TXA 1 g, i.m. TXA 1 g, or oral TXA solution 2 g. Blood samples were drawn up to 24 h after administration. Tranexamic acid concentration was measured with liquid chromatography–mass spectrometry, and the parameters of the pharmacokinetic models were estimated using population pharmacokinetics. Results: The median time to reach a concentration of 10 mg L−1 was 3.5 min for the i.m. route and 66 min for the oral route, although with the oral route the target concentration was reached in only 11 patients. Median peak concentrations were 57.5, 34.4, and 12.8 mg L−1 for i.v., i.m., and oral routes, respectively. A two-compartment open model with body weight as the main covariate best fitted the data. For a 70 kg volunteer, the population estimates were 10.1 L h−1 for elimination clearance, 15.6 L h−1 for intercompartmental clearance, 7.7 L for the volume of central compartment, and 10.8 L for the volume of the peripheral compartment. Intramuscular and oral bioavailabilities were 1.0 and 0.47, respectively, showing that i.m. absorption is fast and complete. Adverse events were mild and transient, mainly local reactions and low-intensity pain. Conclusions: The i.m. (but not oral) route appears to be an efficient alternative to i.v. tranexamic acid. Studies in pregnant women are needed to examine the impact of pregnancy on the pharmacokinetics. Clinical trial registration: EudraCT 2019-000285-38; NCT 03777488.
Published: 2022
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8. Supplementary Tables 1 - 3, Figures 1 - 2 from Immune Infiltrates Are Prognostic Factors in Localized Gastrointestinal Stromal Tumors

Author: Laurence Zitvogel, Jean-Yves Blay, Axel Le Cesne, Nathalie Chaput, Guido Kroemer, Jean-Michel Coindre, Jean-François Emile, Paule Opolon, Philippe Terrier, Frédéric Commo, Sylvie Bonvalot, Alexander Eggermont, Dirk Jäger, Niels Halama, Caroline Flament, Kariman Chaba, Vichnou Poirier-Colame, Anne Caignard, Isabelle Cremer, Patrice Dubreuil, Valérie Le Brun-Ly, Loic Chaigneau, Nicolas Isambert, Federico Garrido, Angel Concha, Nadège Vimond, Rosa Mendez, Clara Locher, Mélanie Desbois, Matthieu Sarabi, Michaela Semeraro, and Sylvie Rusakiewicz
Abstract: PDF file - 197K, Supplemental Table 1. Characteristics of GIST patients for the immunohistochemistry study. Supplemental Table 2. Characteristics of GIST and STS patients studied in flow cytometry. Supplemental Table 3: Antibodies for flow cytometry and IHC. Supplemental Figure 1. Correlation between T and NK cell infiltrates and the 3-digit Miettinen score. Supplemental Figure 2. GIST TIls are mainly composed of CD4+ T cells.
Published: 2023
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9. Safety and efficacy of once-daily risdiplam in type 2 and non-ambulant type 3 spinal muscular atrophy (SUNFISH part 2): a phase 3, double-blind, randomised, placebo-controlled trial

Author: Eugenio Mercuri, Nicolas Deconinck, Elena S Mazzone, Andres Nascimento, Maryam Oskoui, Kayoko Saito, Carole Vuillerot, Giovanni Baranello, Odile Boespflug-Tanguy, Nathalie Goemans, Janbernd Kirschner, Anna Kostera-Pruszczyk, Laurent Servais, Marianne Gerber, Ksenija Gorni, Omar Khwaja, Heidemarie Kletzl, Renata S Scalco, Hannah Staunton, Wai Yin Yeung, Carmen Martin, Paulo Fontoura, John W Day, Joseph J. Volpe, John Posner, Ulrich Kellner, Rosaline Quinlivan, Aurore Daron, Stéphanie Delstanche, Romain Bruninx, Fabian Dal Farra, Olivier Schneider, Irina Balikova, Patricia Delbeke, Inge Joniau, Valentine Tahon, Sylvia Wittevrongel, Elke De Vos, Ingele Casteels, Liesbeth De Waele, Catherine Cassiman, Lies Prové, David Kinoo, Lisa Vancampenhout, Marleen Van Den Hauwe, Annelies Van Impe, Alexandra Prufer de Queiroz Campos Araujo, Aline Chacon Pereira, Flávia Nardes, Lorena Haefeli, Julia Rossetto, Marcos Ferreira Rebel, Jaqueline Almeida Pereira, Craig Campbell, Sapna Sharan, Wendy McDonald, Cheryl Scholtes, Jean Mah, Maria Sframeli, Angela Chiu, Jane Hagel, Raquel Beneish, Gaela Cariou-Palmer, Connie Pham, Daniela Toffoli, Stephanie Arpin, Sarah Turgeon Desilets, Yi Wang, Chaoping Hu, Jianfeng Huan, Chen Qian, Li Shen, Ying Xiao, Zhenxuan Zhou, Hui Li, Sujuan Wang, Hui Xiong, Xingzhi Chang, Hui Dong, Ying Liu, Tian Sang, Cuijie Wei, Jing Wen, Yiwen Cao, Xingyao Ly, Jingjing Zhao, Wenzhu Li, Lun Qin, Nina Barisic, Martina Galiot Delic, Petra Kristina Ivkic, Nenad Vukojevic, Ivana Kern, Boris Najdanovic, Marin Skugor, Teresa Gidaro, Andreea Seferian, Silvana De Lucia, Emmanuel Barreau, Nabila Mnafek, Marta Milkova Momtchilova, Helene Peche, Carole Valherie, Allison Grange, Charlotte Lilien, Darko Milascevic, Shotaro Tachibana, Claudia Ravelli, Ruxandra Cardas, Jessica Taytard, Guillaume Aubertin, Laure Vanden Brande, Jean-Baptiste Davion, Stephanie Coopman, Ikram Bouacha, Philippe Debruyne, Sabine Defoort, Gilles Derlyn, Florian Leroy, Loïc Danjoux, Julie Guilbaud, Isabelle Desguerre, Christine Barnérias, Michaela Semeraro, Dominique Bremond-Gignac, Lenaic Bruere, Maxence Rateaux, Élodie Deladrière, Virginie Germa, Yann Pereon, Sandra Mercie, Fanny Billaud, Lucie Le Goff, Guy Letellier, Aurélie Portefaix, Camille De-Montferrand, Laure Le-Goff, Stephanie Fontaine, Manel Saidi, Nabil Bouzid, Aurélie Barriere, Marie Tinat, Michelle Dreesbach, Wolf Lagréze, Bettina Michaelis, Fanni Molnar, Dorina Seger, Sibylle Vogt, Enrico Bertini, Adele D'Amico, Sergio Petroni, Anna Maria Bonetti, Adelina Carlesi, Irene Mizzoni, Claudio Bruno, Enrico Priolo, Giuseppe Rao, Simone Morando, Paola Tacchetti, Ambra Zuffi, Giacomo Pietro Comi, Roberta Brusa, Stefania Corti, Velardo Daniele, Alessandra Govoni, Francesca Magri, Valeria Minorini, Silvia Gabriella Osnaghi, Francesca Abbati, Federica Fassini, Michaela Foa, Amaqlia Lopopolo, Megi Meneri, Francesca Zoppas, Valeria Parente, Riccardo Masson, Stefania Bianchi Marzoli, Diletta Santarsiero, Myriam Garcia Sierra, Gemma Tremolada, Maria Teresa Arnoldi, Marta Vigano, Riccardo Zanin, Laura Antonaci, Roberto de Sanctis, Marika Pane, Maria Carmela Pera, Giulia Maria Amorelli, Costanza Barresi, Gugliemo D'Amico, Lorenzo Orazi, Giorgia Coratti, Kazuhiro Haginoya, Atsuko Kato, Yuko Morishita, Ryutaro Kira, Kiyomu Akiyama, Miwako Goto, Yujiro Mori, Misato Okamoto, Saki Tsutsui, Yuta Takatsuji, Aya Tanaka, Hirofumi Komaki, Miina Omori, Ippei Suzuki, Mizuki Takeuchi, Daisuke Todoroki, Seji Watanabe, Tomoko Matsubayashi, Emi Inakazu, Hiroe Nagura, Akira Suzuki, Manami Usui, Nobutsune Ishikawa, Yousuke Harada, Kenishi Fudeyasu, Kazuhiko Hirata, Kana Michiue, Kazuyuki Ueda, Junko Fujitani, Reiko Arakawa, Kozue Takano, Shigeko Yashiro, Maiko Seki, Nozomi Sano, Koji Fukuyama, Yuki Matsumoto, Hirofumi Miyazaki, Minoru Shibata, Kyoko Kobayashi, Yukie Nakamura, Yasuhiro Takeshima, Moe Kuma, Anna Fraczek, Maria Jedrzejowska, Anna Lusakowska, Agnieszka Czeszyk-Piotrowicz, Wojciech Hautz, Klaudia Rakusiewicz, Malgorzata Burlewicz, Zuzanna Gierlak-Wojcicka, Malwina Kepa, Adam Sikorski, Marcin Sobieraj, Maria Mazurkiewicz-Beldzinska, Anna Lemska, Sandra Modrzejewska, Mateusz Koberda, Urszula Stodolska-Koberda, Agnieszka Waskowska, Jagoda Kolendo, Agnieszka Sobierajska-Rek, Barbara Steinborn, Magdalena Dalz, Julia Grabowska, Wojciech Hajduk, Justyna Janasiewicz-Karachitos, Monika Klimas, Marcin Stopa, Ewa Gajewska, Beata Pusz, Dmitry Vlodavets, Evgenia Melnik, Natalya Leppenen, Nataliya Yupatova, Anastasya Monakhova, Yulia Papina, Olga Shidlovsckaia, Vedrana Milic Rasic, Vesna Brankovic, Ana Kosac, Olivera Djokic, Vesna Jakšic, Ana Pepic, Jelena Martinovic, Francina Munell Casadesus, Eduardo Tizzano, Nieves Martín Begué, Charlotte Wolley Dod, Olaia Subira, Bernat Planas Pascual, Esther Toro Tamargo, Marcos Madruga Garrido, José David Medina Romero, Marta Peña Salinas, Andrés Nascimento Osorio, Ana Díaz Cortés, Enrique Jiménez Gañan, Simone Dowon Suh, Julita Medina Cantillo, Obdulia Moya, Nuria Padros, Sandra Roca Urraca, Hugo Gonzalez Valdivia, Samuel Pascual Pascual, Sofía de Manuel, Susana Noval Martin, Paul Burnham, Sandra Espinosa, Mercedes Martinez Moreno, Haluk Topaloglu, Ibrahim Oncel, Nesibe Eroglu Ertugru, Bahadir Konuskan, Bora Eldem, Sibel Kadayifçilar, Ipek Alemdaroglu, Aynur Ayse Karaduman, Oznur Tunca Yilmaz, Neslihan Bilgin, Seher Sari, Claudia Chiriboga, John J. Lee, Donnielle Rome-Martin, John W. Day, Shannon Beres, Tina Duong, Richard Gee, Sally Dunaway Young, Sabine Fuerst-Recktenwald, Anne Marquet, Nicoletta Muelhardt, and Dylan Trundell
Subjects: Adult, Risdiplam, spinal muscular atrophy, Adolescent, Spinal Muscular Atrophies of Childhood, Settore MED/26 - NEUROLOGIA, Young Adult, Pyrimidines, Settore MED/39 - NEUROPSICHIATRIA INFANTILE, Double-Blind Method, Child, Preschool, Humans, Neurology (clinical), Child, Preschool, Azo Compounds, Aged
Abstract: BACKGROUND: Risdiplam is an oral small molecule approved for the treatment of patients with spinal muscular atrophy, with approval for use in patients with type 2 and type 3 spinal muscular atrophy granted on the basis of unpublished data. The drug modifies pre-mRNA splicing of the SMN2 gene to increase production of functional SMN. We aimed to investigate the safety and efficacy of risdiplam in patients with type 2 or non-ambulant type 3 spinal muscular atrophy. METHODS: In this phase 3, randomised, double-blind, placebo-controlled study, patients aged 2-25 years with confirmed 5q autosomal recessive type 2 or type 3 spinal muscular atrophy were recruited from 42 hospitals in 14 countries across Europe, North America, South America, and Asia. Participants were eligible if they were non-ambulant, could sit independently, and had a score of at least 2 in entry item A of the Revised Upper Limb Module. Patients were stratified by age and randomly assigned (2:1) to receive either daily oral risdiplam, at a dose of 5·00 mg (for individuals weighing =20 kg) or 0·25 mg/kg (for individuals weighing
Published: 2022
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10. Late-onset enteric virus infection associated with hepatitis (EVAH) in transplanted SCID patients

Author: Quentin Riller, Jacques Fourgeaud, Julie Bruneau, Suk See De Ravin, Grace Smith, Mathieu Fusaro, Samy Meriem, Aude Magerus, Marine Luka, Ghaith Abdessalem, Ludovic Lhermitte, Anne Jamet, Emmanuelle Six, Alessandra Magnani, Martin Castelle, Romain Lévy, Mathilde M. Lecuit, Benjamin Fournier, Sarah Winter, Michaela Semeraro, Graziella Pinto, Hanène Abid, Nizar Mahlaoui, Nathalie Cheikh, Benoit Florkin, Pierre Frange, Eric Jeziorski, Felipe Suarez, Françoise Sarrot-Reynauld, Dalila Nouar, Dominique Debray, Florence Lacaille, Capucine Picard, Philippe Pérot, Béatrice Regnault, Nicolas Da Rocha, Camille de Cevins, Laure Delage, Brieuc P. Pérot, Angélique Vinit, Francesco Carbone, Camille Brunaud, Manon Marchais, Marie-Claude Stolzenberg, Vahid Asnafi, Thierry Molina, Frédéric Rieux-Laucat, Luigi D. Notarangelo, Stefania Pittaluga, Jean Philippe Jais, Despina Moshous, Stephane Blanche, Harry Malech, Marc Eloit, Marina Cavazzana, Alain Fischer, Mickaël M. Ménager, and Bénédicte Neven
Subjects: Immunology, Immunology and Allergy
Published: 2023
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11. Neurological Outcome of Neonatal Listeriosis: A Prospective Case-Control Study

Author: Caroline Charlier, Jessica Rousseau, Zoe Barrault, Elsa Kermorvant-Duchemin, Candice Meyzer, Michaela Semeraro, Magatte Fall, Gabrielle Coulpier, Alexandre Leclercq, Marie-Aline Charles, Pierre-Yves Ancel, and Marc Lecuit
Published: 2023
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12. Saliva for molecular detection of SARS‐CoV ‐2 in pre‐school and school‐age children

Author: Agnes Delaunay‐Moisan, Tiffany Guilleminot, Michaela Semeraro, Nelly Briand, Brigitte Bader‐Meunier, Romain Berthaud, Guillaume Morelle, Pierre Quartier, Caroline Galeotti, Romain Basmaci, Gregoire Benoist, Vincent Gajdos, Mathie Lorrot, Mahmoud Rifai, Matis Crespin, Zakary M'Sakni, Faheemah Padavia, Catherine Savetier‐Leroy, Michelle Lorenzi, Caroline Maurin, Sylvie Behillil, Loic de Pontual, Narcisse Elenga, Naim Bouazza, Brigitte Moltrecht, Sylvie van der Werf, Marianne Leruez‐Ville, Isabelle Sermet‐Gaudelus, Département Plateforme (PF I2BC), Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CIC - Mère Enfant Necker Cochin Paris Centre (CIC 1419), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Immunogenetics of pediatric autoimmune diseases (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), 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), AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Hôpital Louis Mourier - AP-HP [Colombes], Hôpital Ambroise Paré [AP-HP], AP-HP - Hôpital Antoine Béclère [Clamart], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Ministère de l'Éducation nationale, Centre National de Référence des virus des infections respiratoires (dont la grippe) - National Reference Center Virus Influenzae [Paris] (CNR - laboratoire coordonnateur), Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Biologie des ARN et virus influenza - RNA Biology of Influenza Virus (CNRS-UMR3569), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Hôpital Jean Verdier [AP-HP], Centre Hospitalier Andrée Rosemon [Cayenne, Guyane Française], Unité de recherche clinique / Centre d'investigation clinique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Institut Pasteur [Paris] (IP), Génétique Moléculaire des Virus à ARN - Molecular Genetics of RNA Viruses (GMV-ARN (UMR_3569 / U-Pasteur_2)), Université Paris Cité (UPCité), 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), This study was funded by a research grant from the French Ministry of Health (PHRC) and sponsored by the Assistance Publique – Hôpitaux de Paris (AP-HP) and by delegation: Délégation à la Recherche Clinique et à l'Innovation - DRCI (Clinical Research and Innovation Department)., and The authors thank all the families for their participation and URC-CIC Paris Centre for the implementation, monitoring and data management of the study. The later includes Jean-Marc Treluyer and Caroline Elie, Mathilde Serpinet, Céline Hauw, Amel Bouheraoua, Victor Bruyère, Mégane Ribot, Rosa Salhi, Gael Plastow, Cindy Parent, Sonia Lounis, Insaf Berrazaga, Wafa Atmani, Amélie de Haut de Sigy, Geovanna Meneses and Fabrice Gourmelon. The authors thank Carl Mann for careful reading of the manuscript.
Subjects: Adult, Adolescent, Clinical Laboratory Techniques, SARS-CoV-2, [SDV]Life Sciences [q-bio], COVID-19, Microbiology, COVID-19 Testing, Child, Preschool, Nasopharynx, Humans, Child, Saliva, Ecology, Evolution, Behavior and Systematics
Abstract: International audience; SARS-CoV-2 diagnosis is a cornerstone for the management of coronavirus disease 2019 (COVID-19). Numerous studies have assessed saliva performance over nasopharyngeal sampling (NPS), but data in young children are still rare. We explored saliva performance for SARS-CoV-2 detection by RT-PCR according to the time interval from initial symptoms or patient serological status. We collected 509 NPS and saliva paired samples at initial diagnosis from 166 children under 12 years of age (including 57 children under 6), 106 between 12 and 17, and 237 adults. In children under 12, overall detection rate for SARS-CoV-2 was comparable in saliva and NPS, with an overall agreement of 89.8%. Saliva sensitivity was significantly lower than that of NPS (77.1% compared to 95.8%) in pre-school and school-age children but regained 96% when considering seronegative children only. This pattern was also observed to a lesser degree in adolescents but not in adults. Sensitivity of saliva was independent of symptoms, in contrary to NPS, whose sensitivity decreased significantly in asymptomatic subjects. Performance of saliva is excellent in children under 12 at early stages of infection. This reinforces saliva as a collection method for early and unbiased SARS-CoV-2 detection and a less invasive alternative for young children.
Published: 2022
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13. Pediatric Tumors and Developmental Anomalies: A French Nationwide Cohort Study

Author: Michaela Semeraro, Cyrielle Fouquet, Yoann Vial, Jeanne Amiel, Louise Galmiche, Célia Cretolle, Thomas Blanc, Valérie Jolaine, Nicolas Garcelon, Natacha Entz-Werle, Isabelle Pellier, Cécile Vérité, null SophieTaque, Aurore Coulomb, Arnaud Petit, Nadège Corradini, Naim Bouazza, Brigitte Lacour, Jacqueline Clavel, Laurence Brugières, Franck Bourdeaut, and Sabine Sarnacki
Subjects: Pediatrics, Perinatology and Child Health
Published: 2023
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14. Severe hematopoietic stem cell inflammation compromises chronic granulomatous disease gene therapy

Author: Steicy Sobrino, Alessandra Magnani, Michaela Semeraro, Loredana Martignetti, Akira Cortal, Adeline Denis, Chloé Couzin, Capucine Picard, Jacinta Bustamante, Elisa Magrin, Laure Joseph, Cécile Roudaut, Aurélie Gabrion, Tayebeh Soheili, Corinne Cordier, Olivier Lortholary, François Lefrere, Frédéric Rieux-Laucat, Jean-Laurent Casanova, Sylvain Bodard, Nathalie Boddaert, Adrian J. Thrasher, Fabien Touzot, Sophie Taque, Felipe Suarez, Ambroise Marcais, Agathe Guilloux, Chantal Lagresle-Peyrou, Anne Galy, Antonio Rausell, Stephane Blanche, Marina Cavazzana, and Emmanuelle Six
Subjects: General Biochemistry, Genetics and Molecular Biology
Published: 2023
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15. Long-Term Follow-up Study after Lentiviral Hematopoietic Stem/Progenitor Cell Gene Therapy for Wiskott - Aldrich Syndrome

Author: Salima Hacein-Bey-Abina, Adeline Denis, Alexandre Kauskot, Elizabeth Macintyre, Jin Hua Xu-Bayford, Aurélie Gabrion, Guy Gorochov, Cécile Roudaut, Chantal Lagresle-Peyrou, Aoife M. Doto, Capucine Picard, Frédéric Adam, Felipe Suarez, Alessandra Magnani, Frederic D. Bushman, Alain Fischer, Rachel Petermann, Emma C. Morris, Sarah Abbas, Emmanuel Clave, Marianne Guisset, Chrystelle Abdo, Christine Rivat, Loïc Dupré, Amélie Trinquand, Reem Elfeky, Marina Cavazzana, Elisa Magrin, Despina Moshous, Claire Booth, Anne Galy, Emmanuelle Six, Antoine Toubert, Bobby Gaspar, Adrian J. Thrasher, Mélanie Guiot, Delphine Borgel, Michaela Semeraro, John K. Everett, Makoto Miyara, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Departement Hospitalo- Universitaire - Inflammation, Immunopathologie, Biothérapie [Paris] (DHU - I2B), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), 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), Great Ormond Street Hospital for Children [London] (GOSH), Great Ormond Street Institute of Child Health (UCL), University College of London [London] (UCL), Institut Toulousain des Maladies Infectieuses et Inflammatoires (Infinity), 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), Groupement Hospitalier Universitaire Ouest, Hémostase, Inflammation, Thrombose (HITH - U1176 Inserm - CHU Bicêtre), Institut National de la Santé et de la Recherche Médicale (INSERM)-AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre)-Université Paris-Saclay, Institut de Recherche Saint-Louis - Hématologie Immunologie Oncologie (Département de recherche de l’UFR de médecine, ex- Institut Universitaire Hématologie-IUH) (IRSL), Université Paris Cité (UPCité), Ecotaxie, microenvironnement et développement lymphocytaire (EMily (UMR_S_1160 / U1160)), Hopital Saint-Louis [AP-HP] (AP-HP), Arthrites autoimmunes (AA), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'Immunologie et des Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service d'Immunologie [CHU Pitié-Salpétrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut National de la Transfusion Sanguine [Paris] (INTS), Service d'immuno-hématologie pédiatrique [CHU Necker], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP]
Subjects: business.industry, Wiskott–Aldrich syndrome, Long term follow up, Genetic enhancement, Immunology, Cell Biology, Hematology, medicine.disease, Biochemistry, Haematopoiesis, Cancer research, Medicine, Progenitor cell, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Wiskott Aldrich syndrome (WAS) is a rare X-linked primary immunodeficiency associated with thrombocytopenia, eczema, infectious, autoimmune complications, and lymphomas. Patients lacking an HLA-matched donor may benefit from an alternative therapeutic approach based on the infusion of autologous gene corrected CD34+ cells. We previously reported a non-randomised, open-label, phase 1/2 clinical study applying a lentiviral vector based gene therapy (GT) protocol in 7 paediatric patients with severe WAS (score ≥ 3/5) (S. Hacein-Bey Abina et al, JAMA 2015). One patient died 7 months after GT because of pre-existing severe opportunistic infections, as reported. Two additional patients have been treated since that initial report, with a follow-up of at least 4 years. We here present a comprehensive long-term study on 8 patients with a follow-up from 4 to 9 years (median 7.6). The safety and efficacy of the approach is thoroughly investigated, with a particular focus on the correction of thrombocytopenia and auto-immunity. A stable engraftment of genetically and functionally corrected lymphoid and myeloid cells was reached in all patients, with no serious treatment-associated adverse events or concerning clonal expansion. Corrected lymphoid cells displayed a selective advantage over time with increasing vector copy number (VCN) level. In turn, this led to (i) sustained expression of WAS protein (WASp) in the patients' cells and (ii) clinical resolution of severe eczema and susceptibility to recurrent infections. In line with these results, T-cell function was restored after GT, as shown by the recovery of immune synapse assembly and the normalization of naïve T cell numbers. The T-cell compartment was also reconstituted in the patient treated at the age of 30 years, suggesting that GT for WAS is a treatment option in adult patients. In parallel with the robustness of T-cell reconstitution a normalized B-cell compartment was observed after GT, as shown in particular by increasing levels of WASp + switched memory B cells over time and the age-matched levels of KRECs. Five patients out of 8 were able to discontinue Ig replacement therapy while achieving normal post-vaccination antibody titers. Autoimmune disorders and bleeding episodes were significantly less frequent, despite only partial correction of the platelet compartment. After GT, a few autoimmune manifestations were observed: the persistence of lower extremity vasculitis (P2, very severe prior to GT), the new occurrence of nephrotic syndrome (P9), and the presence of anti-platelet antibodies (P2, P4, P7). The levels of circulating autoantibodies detected before GT (including ANA and vasculitis-related autoantibodies) normalized after treatment. Following GT, platelets were found to express sub-normal levels of WASp and to only partially augment their size. Platelet function studies indicated a partial correction of the platelet compartment achieved by GT, which may be sufficient to prevent occurrence of the hemorrhagic symptoms typical of WAS. Our results suggest that lentiviral GT provides sustained clinical benefits for patients with WAS. Overall clinical remission was observed in our patients despite very severe disease scores before GT. More efficacious and more reliable transduction protocols and conditioning regimen are likely to further improve outcomes, particularly with regard to platelet recovery, where the advantages of intrinsic correction are less apparent. Disclosures Booth: Orchard Therapeutics: Consultancy, Honoraria; SOBI: Consultancy, Honoraria; Takeda: Honoraria; GSK: Honoraria; Rocket Pharmaceuticals, Inc.: Consultancy. Thrasher: Orchard Therapeutics: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Generation bio: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; 4Bio Capital: Consultancy, Membership on an entity's Board of Directors or advisory committees; Rocket Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Cavazzana: Smart Immune: Other: co-founder.
Published: 2021
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16. Tapering Canakinumab Monotherapy in Patients with Systemic Juvenile Idiopathic Arthritis in Clinical Remission: Results from an Open‐label, Randomized Phase IIIb/IV Study

Author: Pierre, Quartier, Ekaterina, Alexeeva, Constantin, Tamàs, Vyacheslav, Chasnyk, Nico, Wulffraat, Karin, Palmblad, Carine, Wouters, Hermine, Brunner, Katherine, Marzan, Rayfel, Schneider, Gerd, Horneff, Martini, Alberto, Jordi, Anton, Xiaoling, Wei, Alan, Slade, Ruperto, Nicolino, Ken, Abrams, Wolfgang, Emminger, Andrea, Ulbrich, Sugarka, Fodor, Lien, Desomer, Bernard, Lauwerys, Bénédicte, Brichard, Cécile, Boulanger, Gabriel, Levy, Laurence, Goffin, Phu Quoc Le, Marcia, Bandeira, Christina Feitosa Pelajo, Sheila Knupp Feitosa, Christianne, Costa, Marta Cristine Felix Rodrigues, Clovis Artur Almeida da Silva, Lucia Maria Mattei de, Katia, Kozu, Ronald, Laxer, Kristin, Houghton, Lori, Tucker, Kimberly, Morishita, Agnes, Mogenet, Richard, Mouy, Brigitte Bader Meunier, Candice, Meyzer, Michaela, Semeraro, Ouafa, Ben‐brahim, Isabelle, Kone‐paut, Caroline, Galeotti, Linda, Rossi, Perrine, Dusser, Bilade, Cherquaoui, Alexandre, Belot, Agnes, Duquesne, Freychet, Caroline, Laurent, Audrey, Marine, Desjonqueres, Ivan, Foeldvari, Antonia, Kienast, Barbara, Willig, Deborah, Barthel, Joachim, Peitz, Stefanie, Wintrich, Tilman Felix Geikowski, Anna Carina Schulz, Markus, Hufnagel, Marc, Hirdes, Rouven, Kubicki, Janbernd, Kirschner, Ales, Janda, Andre, Jacob, Cornelia, Emerich, Anna, Raab, Gonza, Ngoumou, Kirsten, Minden, Mareike, Lieber, Sae‐Lim von Stuckrad, Jasmin Kuemmerle Deschner, Sandra, Hansmann, Tom, Schleich, Ines Maria Magunia, Joachim, Riethmuller, Nicole, Anders, Hartwig, Lehmann, Jan de Laffolie, Thomas, Lutz, Juergen, Grulich‐henn, Johannes, Pfeil, Astrid, Helling‐bakki, Ralf, Trauzeddel, Daniel, Haselbusch, Henryk, Kolbeck, Elisabeth, Weissbarth‐riedel, Anja, Froehlich, Andrea, Ponyi, Diana, Garan, Ilonka, Orban, Krisztina, Sevcic, Yonatan, Butbul, Riva, Brik, Philip, Hashkes, Ori, Toker, Ruby, Haviv, Yosef, Uziel, Rubi, Haviv, Veronica, Moshe, Michal, Rothschild, Liora, Harel, Gil, Amarilyo, Rotem, Tal, Mohamad Hamad Said, Irit, Tirosh, Shiri, Spielman, Maya, Gerstein, Ravelli, Angelo, Schiappapietra, Benedetta, Varnier, GIULIA CAMILLA, Finetti, Martina, Marasini, Maurizio, Caorsi, Roberta, Rosina, Silvia, Federici, Silvia, Irene, Pontikaki, Pier Luigi Meroni, Valeri, Gerloni, Nicola, Ughi, Tania, Ubiali, Maria, Alessio, Roberto Della Casa, Sebastiaan Jozef Vastert, Joost Frans Swart, van Royen‐Kerhof, A., Ellen, Schatorje, Van Iperen‐Schutte, G., Lidia, Rutkowska‐sak, Izabela, Szczygielska, Malgorzata, Kwiatkowska, Maria, Marusak‐banacka, Piotr, Gietka, Kseniya, Isaeva, Rina, Denisova, Ludmila, Snegireva, Margarita, Dubko, Mikhail, Kostik, Natalia, Buchinskaia, Olga, Kalashnikova, Sergey, Avrusin, Vera, Masalova, Esmeralda Nunez Cuadros, Gisela, Diez, Rocio Galindo Zavala, Rosa Bou Torrent, Estibaliz, Iglesias, Joan, Calzada, Violeta, Bittermann, Alina Lucica Boteanu, Maria Luz Gamir, Inmaculada, Calvo, Berta, Lopez, Isabel, Gonzalez, Laura, Fernandez, Daniel Clemente Garulo, Juan Carlos Lopez Robledillo, Rosa, Merino, Rosa, Alcobendas, Agustin, Remesal, Sara, Murias, Magnusson, Bo, Ozgur, Kasapcopur, Kenan, Barut, Amra, Adrovic, Sezgin, Sahin, Muferet, Erguven, Refia Gozdenur Savci, Seza, Ozen, Selcan, Demir, Yelda, Bilginer, Zehra Serap Avci, Ezgi Deriz Batu, Andreas, Reiff, Anusha, Ramanatham, Diana, Brown, Bracha, Shaham, Shirley, Parks, Michal, Cidon, Gloria, Higgins, Charles, Spencer, Jenny, Rossette, Karla, Jones, Sharon Bout Tabaku, Shelli, Farley, Shoghik, Akoghlanian, Quartier, Pierre, Alexeeva, Ekaterina, Tamàs, Constantin, Chasnyk, Vyacheslav, Wulffraat, Nico, Palmblad, Karin, Wouters, Carine, Brunner, Hermine, Marzan, Katherine, Schneider, Rayfel, Horneff, Gerd, Martini, Alberto, Anton, Jordi, Wei, Xiaoling, Slade, Alan, Ruperto, Nicolino, Abrams, Ken, Emminger, Wolfgang, Ulbrich, Andrea, Fodor, Sugarka, Desomer, Lien, Lauwerys, Bernard, Brichard, Bénédicte, Boulanger, Cécile, Levy, Gabriel, Goffin, Laurence, Quoc Le, Phu, Bandeira, Marcia, Feitosa Pelajo, Christina, Knupp Feitosa, Sheila, Costa, Christianne, Cristine Felix Rodrigues, Marta, Artur Almeida da Silva, Clovi, Maria Mattei de, Lucia, Kozu, Katia, Laxer, Ronald, Houghton, Kristin, Tucker, Lori, Morishita, Kimberly, Mogenet, Agne, Mouy, Richard, Bader Meunier, Brigitte, Meyzer, Candice, Semeraro, Michaela, Ben‐brahim, Ouafa, Kone‐paut, Isabelle, Galeotti, Caroline, Rossi, Linda, Dusser, Perrine, Cherquaoui, Bilade, Belot, Alexandre, Duquesne, Agne, Caroline, Freychet, Audrey, Laurent, Desjonqueres, Marine, Foeldvari, Ivan, Kienast, Antonia, Willig, Barbara, Barthel, Deborah, Peitz, Joachim, Wintrich, Stefanie, Felix Geikowski, Tilman, Carina Schulz, Anna, Hufnagel, Marku, Hirdes, Marc, Kubicki, Rouven, Kirschner, Janbernd, Janda, Ale, Jacob, Andre, Emerich, Cornelia, Raab, Anna, Ngoumou, Gonza, Minden, Kirsten, Lieber, Mareike, von Stuckrad, Sae‐lim, Kuemmerle Deschner, Jasmin, Hansmann, Sandra, Schleich, Tom, Maria Magunia, Ine, Riethmuller, Joachim, Anders, Nicole, Lehmann, Hartwig, de Laffolie, Jan, Lutz, Thoma, Grulich‐henn, Juergen, Pfeil, Johanne, Helling‐bakki, Astrid, Trauzeddel, Ralf, Haselbusch, Daniel, Kolbeck, Henryk, Weissbarth‐riedel, Elisabeth, Froehlich, Anja, Ponyi, Andrea, Garan, Diana, Orban, Ilonka, Sevcic, Krisztina, Butbul, Yonatan, Brik, Riva, Hashkes, Philip, Toker, Ori, Haviv, Ruby, Uziel, Yosef, Haviv, Rubi, Moshe, Veronica, Rothschild, Michal, Harel, Liora, Amarilyo, Gil, Tal, Rotem, Hamad Said, Mohamad, Tirosh, Irit, Spielman, Shiri, Gerstein, Maya, Ravelli, Angelo, Schiappapietra, Benedetta, Camilla Varnier, Giulia, Finetti, Martina, Marasini, Maurizio, Caorsi, Roberta, Rosina, Silvia, Federici, Silvia, Pontikaki, Irene, Luigi Meroni, Pier, Gerloni, Valeri, Ughi, Nicola, Ubiali, Tania, Alessio, Maria, DELLA CASA, Roberto, Jozef Vastert, Sebastiaan, Frans Swart, Joost, van Royen‐Kerhof, A., Schatorje, Ellen, Van Iperen‐Schutte, G., Rutkowska‐sak, Lidia, Szczygielska, Izabela, Kwiatkowska, Malgorzata, Marusak‐banacka, Maria, Gietka, Piotr, Isaeva, Kseniya, Denisova, Rina, Snegireva, Ludmila, Dubko, Margarita, Kostik, Mikhail, Buchinskaia, Natalia, Kalashnikova, Olga, Avrusin, Sergey, Masalova, Vera, Nunez Cuadros, Esmeralda, Diez, Gisela, Galindo Zavala, Rocio, Bou Torrent, Rosa, Iglesias, Estibaliz, Calzada, Joan, Bittermann, Violeta, Lucica Boteanu, Alina, Luz Gamir, Maria, Calvo, Inmaculada, Lopez, Berta, Gonzalez, Isabel, Fernandez, Laura, Clemente Garulo, Daniel, Carlos Lopez Robledillo, Juan, Merino, Rosa, Alcobendas, Rosa, Remesal, Agustin, Murias, Sara, Magnusson, Bo, Kasapcopur, Ozgur, Barut, Kenan, Adrovic, Amra, Sahin, Sezgin, Erguven, Muferet, Gozdenur Savci, Refia, Ozen, Seza, Demir, Selcan, Bilginer, Yelda, Serap Avci, Zehra, Deriz Batu, Ezgi, Reiff, Andrea, Ramanatham, Anusha, Brown, Diana, Shaham, Bracha, Parks, Shirley, Cidon, Michal, Higgins, Gloria, Spencer, Charle, Rossette, Jenny, Jones, Karla, Bout Tabaku, Sharon, Farley, Shelli, and Akoghlanian, Shoghik
Published: 2021

17. Long-term outcomes of lentiviral gene therapy for the β-hemoglobinopathies: the HGB-205 trial

Author: Elisa Magrin, Michaela Semeraro, Nicolas Hebert, Laure Joseph, Alessandra Magnani, Anne Chalumeau, Aurélie Gabrion, Cécile Roudaut, Jouda Marouene, Francois Lefrere, Jean-Sebastien Diana, Adeline Denis, Bénédicte Neven, Isabelle Funck-Brentano, Olivier Negre, Sylvain Renolleau, Valentine Brousse, Laurent Kiger, Fabien Touzot, Catherine Poirot, Philippe Bourget, Wassim El Nemer, Stéphane Blanche, Jean-Marc Tréluyer, Mohammed Asmal, Courtney Walls, Yves Beuzard, Manfred Schmidt, Salima Hacein-Bey-Abina, Vahid Asnafi, Isabelle Guichard, Maryline Poirée, Fabrice Monpoux, Philippe Touraine, Chantal Brouzes, Mariane de Montalembert, Emmanuel Payen, Emmanuelle Six, Jean-Antoine Ribeil, Annarita Miccio, Pablo Bartolucci, Philippe Leboulch, and Marina Cavazzana
Subjects: Male, Young Adult, Treatment Outcome, Adolescent, Lentivirus, beta-Thalassemia, Humans, Female, General Medicine, Anemia, Sickle Cell, Genetic Therapy, General Biochemistry, Genetics and Molecular Biology
Abstract: Sickle cell disease (SCD) and transfusion-dependent β-thalassemia (TDT) are the most prevalent monogenic disorders worldwide. Trial HGB-205 ( NCT02151526 ) aimed at evaluating gene therapy by autologous CD34
Published: 2020

18. 23. Immunothérapie en oncologie pédiatrique : l’exemple du neuroblastome et des sarcomes osseux

Author: Véronique Minard-Colin and Michaela Semeraro
Published: 2020
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19. Seletalisib for Activated PI3Kδ Syndromes: Open-Label Phase 1b and Extension Studies

Author: Andrea Martín-Nalda, Maria Juarez, Pere Soler-Palacín, Francesca Conti, Eric Helmer, Caterina Cancrini, Geoffrey I Johnston, Marina Cavazzana, Dionne Cain, Nieves Diaz, Marina Garcia-Prat, Despina Moshous, Maria Elena Maccari, Payne Andrew Charles, Felipe Suarez, Michaela Semeraro, Sven Kracker, Mónica Martínez-Gallo, Daisy Yuill, Silvia Di Cesare, Stephan Ehl, Maximilian Heeg, Joanne Mann, Alessandra Simonetti, Veronica Santilli, and UCB Pharma, Slough SL1 3WE, United Kingdom
Subjects: Adult, Male, medicine.medical_specialty, Adolescent, Class I Phosphatidylinositol 3-Kinases, Pyridines, [SDV]Life Sciences [q-bio], Immunology, Arthritis, CD8-Positive T-Lymphocytes, Gastroenterology, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Humans, Immunology and Allergy, Young adult, Colitis, Child, Adverse effect, Stomatitis, ComputingMilieux_MISCELLANEOUS, business.industry, Precursor Cells, B-Lymphoid, Immunologic Deficiency Syndromes, medicine.disease, 3. Good health, Clinical trial, Settore MED/01, Tolerability, Mutation, aphthous ulcer, Quinolines, Female, business, 030215 immunology
Abstract: Mutations in two genes can result in activated PI3Kδ syndrome (APDS), a rare immunodeficiency disease with limited therapeutic options. Seletalisib, a potent, selective PI3Kδ inhibitor, was evaluated in patients with APDS1 and APDS2. In the phase 1b study (European Clinical Trials Database 2015-002900-10) patients with genetic and clinical confirmation of APDS1 or APDS2 received 15–25 mg/d seletalisib for 12 wk. Patients could enter an extension study (European Clinical Trials Database 2015-005541). Primary endpoints were safety and tolerability, with exploratory efficacy and immunology endpoints. Seven patients (median age 15 years; APDS1 n = 3; APDS2 n = 4) received seletalisib; five completed the phase 1b study. For the extension study, four patients entered, one withdrew consent (week 24), three completed ≥84 wk of treatment. In the phase 1b study, patients had improved peripheral lymphadenopathy (n = 2), lung function (n = 1), thrombocyte counts (n = 1), and chronic enteropathy (n = 1). Overall, effects were maintained in the extension. In the phase 1b study, percentages of transitional B cells decreased, naive B cells increased, and senescent CD8 T cells decreased (human cells); effects were generally maintained in the extension. Seletalisib-related adverse events occurred in four of seven patients (phase 1b study: hepatic enzyme increased, dizziness, aphthous ulcer, arthralgia, arthritis, increased appetite, increased weight, restlessness, tendon disorder, and potential drug-induced liver injury) and one of four patients had adverse events in the extension (aphthous ulcer). Serious adverse events occurred in three of seven patients (phase 1b study: hospitalization, colitis, and potential drug-induced liver injury) and one of four patients had adverse events in the extension (stomatitis). Patients with APDS receiving seletalisib had improvements in variable clinical and immunological features, and a favorable risk–benefit profile was maintained for ≤96 wk.
Published: 2020
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20. Sustained Remission After Haploidentical Bone Marrow Transplantation in a Child With Refractory Systemic Juvenile Idiopathic Arthritis

Author: Sylvain Breton, Pierre Quartier, Bénédicte Neven, Albert Faye, Martin Castelle, Stéphane Blanche, Marina Cavazzana, Matthieu Bendavid, Graziella Pinto, Richard Mouy, Charlotte Boussard, Michaela Semeraro, Brigitte Bader-Meunier, Guillaume Morelle, and Despina Moshous
Subjects: 0301 basic medicine, medicine.medical_specialty, lcsh:Diseases of the musculoskeletal system, Cyclophosphamide, medicine.medical_treatment, Case Report, Autoimmunity, Hematopoietic stem cell transplantation, Graft versus host disease, Gastroenterology, 03 medical and health sciences, 0302 clinical medicine, Rheumatology, Systemic juvenile idiopathic arthritis, Internal medicine, Cyclosporin a, Immunology and Allergy, Medicine, Humans, Bone Marrow Transplantation, 030203 arthritis & rheumatology, business.industry, Still’s disease, Remission Induction, lcsh:RJ1-570, Infant, lcsh:Pediatrics, medicine.disease, Arthritis, Juvenile, Fludarabine, 030104 developmental biology, Graft-versus-host disease, surgical procedures, operative, Pediatrics, Perinatology and Child Health, Alemtuzumab, Allogenic hematopoietic stem cell transplantation, Rituximab, Female, lcsh:RC925-935, business, Busulfan, medicine.drug
Abstract: Background Some patients with systemic juvenile idiopathic arthritis (SJIA) and severe, refractory disease achieved remission through intensive immunosuppressive treatment followed by autologous hematopoietic stem cell transplantation (HSCT). However, disease relapsed in most cases. More recently selected SJIA patients received allogenic HSCT from a HLA-identical sibling or a HLA matched unrelated donor. While most transplanted patients achieved sustained SJIA remission off-treatment, the procedure-related morbidity was high. Case report A girl presented SJIA with a severe disease course since the age of 15 months. She was refractory to the combination of methotrexate and steroids to anti-interleukin (IL)-1, then anti-IL-6, tumor necrosis factor alpha inhibitors, and thalidomide. Given the high disease burden and important treatment-related toxicity the indication for a haploidentical HSCT from her mother was validated, as no HLA matched donor was available. The patient received a T replete bone marrow graft at the age of 3.7 years. Conditioning regimen contained Rituximab, Alemtuzumab, Busulfan, and Fludarabine. Cyclophosphamide at D + 3 and + 4 post HSCT was used for graft-versus-host-disease prophylaxis, followed by Cyclosporin A and Mycophenolate Mofetil. Post HSCT complications included severe infections, grade 3 intestinal graft-versus-host-disease, autoimmune thyroiditis, and immune thrombocytopenia. Three years after HSCT, the child is alive and well, notwithstanding persistent hypothyroidy requiring substitution. Immune thrombocytopenia had resolved. Most importantly, SJIA was in complete remission, off immunosuppressive drugs. Conclusion Allogenic HSCT may be a therapeutic option, even with a HLA haplo-identical alternative donor, in patients with inflammatory diseases such as SJIA. Despite increased experience with this treatment, the risk of life-threatening complications restrains its indication to selected patients with severe, refractory disease.
Published: 2020
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21. Urinary Exosomes of Patients with Cystic Fibrosis Unravel CFTR-Related Renal Disease

Author: Vincent Jung, Alexandre Hinzpeter, Loredana Martignetti, Isabelle Sermet-Gaudelus, Ida Chiara Guerrera, Michaela Semeraro, Sebastien A. Gauthier, Aleksander Edelman, Iwona Pranke, Véronique Stoven, Thao Nguyen-Khoa, Centre de Bioinformatique (CBIO), MINES ParisTech - École nationale supérieure des mines de Paris, and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)
Subjects: 0301 basic medicine, Indoles, Proteome, [SDV]Life Sciences [q-bio], klotho, Aminopyridines, Quinolones, Aminophenols, Exosomes, Cystic fibrosis, cystic fibrosis, lcsh:Chemistry, 0302 clinical medicine, Child, Klotho, lcsh:QH301-705.5, ComputingMilieux_MISCELLANEOUS, Spectroscopy, proteomic, Kidney, biology, General Medicine, Cystic fibrosis transmembrane conductance regulator, 3. Good health, Computer Science Applications, Drug Combinations, medicine.anatomical_structure, Child, Preschool, 030220 oncology & carcinogenesis, Kidney Diseases, medicine.symptom, Adult, kidney, Adolescent, Urinary system, Inflammation, Article, Catalysis, Inorganic Chemistry, Young Adult, 03 medical and health sciences, medicine, Humans, Benzodioxoles, Physical and Theoretical Chemistry, Molecular Biology, business.industry, cystic fibrosis transmembrane conductance regulator, Organic Chemistry, medicine.disease, 030104 developmental biology, lcsh:Biology (General), lcsh:QD1-999, Case-Control Studies, biology.protein, Cancer research, business, Caspase 14, Kidney disease
Abstract: Background: The prevalence of chronic kidney disease is increased in patients with cystic fibrosis (CF). The study of urinary exosomal proteins might provide insight into the pathophysiology of CF kidney disease. Methods: Urine samples were collected from 19 CF patients (among those 7 were treated by cystic fibrosis transmembrane conductance regulator (CFTR) modulators), and 8 healthy subjects. Urine exosomal protein content was determined by high resolution mass spectrometry. Results: A heatmap of the differentially expressed proteins in urinary exosomes showed a clear separation between control and CF patients. Seventeen proteins were upregulated in CF patients (including epidermal growth factor receptor (EGFR), proteasome subunit beta type-6, transglutaminases, caspase 14) and 118 were downregulated (including glutathione S-transferases, superoxide dismutase, klotho, endosomal sorting complex required for transport, and matrisome proteins). Gene set enrichment analysis revealed 20 gene sets upregulated and 74 downregulated. Treatment with CFTR modulators yielded no significant modification of the proteomic content. These results highlight that CF kidney cells adapt to the CFTR defect by upregulating proteasome activity and that autophagy and endosomal targeting are impaired. Increased expression of EGFR and decreased expression of klotho and matrisome might play a central role in this CF kidney signature by inducing oxidation, inflammation, accelerated senescence, and abnormal tissue repair. Conclusions: Our study unravels novel insights into consequences of CFTR dysfunction in the urinary tract, some of which may have clinical and therapeutic implications.
Published: 2020
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22. Modulators of CFTR. Updates on clinical development and future directions

Author: Farouk Berhal, Michaela Semeraro, Alexandre Hinzpeter, Alexandra Pastor, Christine Gravier-Pelletier, Benoit Chevalier, Isabelle Sermet-Gaudelus, Emmanuelle Bardin, Kate Hayes, Guillaume Prestat, Anita Golec, Iwona Pranke, Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques (LCBPT - UMR 8601), and Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)
Subjects: congenital, hereditary, and neonatal diseases and abnormalities, 2019-20 coronavirus outbreak, Indoles, Cystic Fibrosis, [SDV]Life Sciences [q-bio], Aminopyridines, Cystic Fibrosis Transmembrane Conductance Regulator, Quinolones, Bioinformatics, Aminophenols, 01 natural sciences, Cystic fibrosis, Ivacaftor, 03 medical and health sciences, chemistry.chemical_compound, Drug Development, Drug Discovery, medicine, Humans, Pharmacologic therapy, Benzodioxoles, Caucasian population, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Pharmacology, 0303 health sciences, Clinical Trials as Topic, biology, 010405 organic chemistry, Organic Chemistry, Lumacaftor, General Medicine, respiratory system, Potentiator, medicine.disease, digestive system diseases, Cystic fibrosis transmembrane conductance regulator, respiratory tract diseases, 0104 chemical sciences, 3. Good health, chemistry, biology.protein, medicine.drug
Abstract: Cystic fibrosis (CF) is the most frequent life-limiting autosomal recessive disorder in the Caucasian population. It is due to mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. Current symptomatic CF therapies, which treat the downstream consequences of CFTR mutations, have increased survival. Better knowledge of the CFTR protein has enabled pharmacologic therapy aiming to restore mutated CFTR expression and function. These CFTR "modulators" have revolutionised the CF therapeutic landscape, with the potential to transform prognosis for a considerable number of patients. This review provides a brief summary of their mechanism of action and presents a thorough review of the results obtained from clinical trials of CFTR modulators.
Published: 2020
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23. Cell-Cycle Arrest Biomarkers: Usefulness for Cardiac Surgery-Related Acute Kidney Injury in Neonates and Infants

Author: Michaela Semeraro, Marc Froissart, Laurence Piéroni, and Mirela Bojan
Subjects: Adult, medicine.medical_specialty, medicine.medical_treatment, Population, 030204 cardiovascular system & hematology, Critical Care and Intensive Care Medicine, law.invention, 03 medical and health sciences, 0302 clinical medicine, Postoperative Complications, law, medicine, Cardiopulmonary bypass, Humans, Prospective Studies, Cardiac Surgical Procedures, education, Child, Dialysis, Mechanical ventilation, Kidney, education.field_of_study, Tissue Inhibitor of Metalloproteinase-2, business.industry, Incidence (epidemiology), Acute kidney injury, Infant, Newborn, Infant, 030208 emergency & critical care medicine, Cell Cycle Checkpoints, Acute Kidney Injury, medicine.disease, Cardiac surgery, medicine.anatomical_structure, Anesthesia, Pediatrics, Perinatology and Child Health, business, Biomarkers
Abstract: Objectives Cell cycle arrest urine biomarkers have recently been shown to be early indicators of acute kidney injury in various clinical settings in critically ill adults and children. The product of tissue inhibitor metalloproteinase -1 and insulin-like growth factor binding protein-7 concentrations/1,000 (TIMP-1) × (IGFBP-7) provides stratification of acute kidney injury-risk in adults with critical illness. The present study explores the predictive accuracy of (TIMP-1) × (IGFBP-7) measured early after cardiopulmonary bypass for cardiac surgery-related acute kidney injury in neonates and infants, a population in whom such data are not yet available. Design Prospective, observational. Setting A tertiary referral pediatric cardiac ICU. Patients Fifty-seven neonates and 110 infants undergoing surgery with cardiopulmonary bypass. Interventions None. Measurements and main results (TIMP-1) × (IGFBP-7) was measured on the NephroCheck (Astute Medical, San Diego, CA) platform preoperatively, less than 1 hour of cardiopulmonary bypass and 1-3 hours of cardiopulmonary bypass. The incidence of postoperative acute kidney injury, dialysis, and/or death were compared among quintiles of postoperative (TIMP-1) × (IGFBP-7). Multivariable regression was used to assess the added predictive value for renal events of (TIMP-1) × (IGFBP-7) over clinical models. Basal (TIMP-1) × (IGFBP-7) increased with age at surgery (regression coefficient = 0.004 ± 0.001; p = 0.005). (TIMP-1) × (IGFBP-7) increased after cardiopulmonary bypass. Neonates had lower postoperative (TIMP-1) × (IGFBP-7) compared with older infants, despite undergoing longer surgeries and experiencing a higher incidence of postoperative renal events. (TIMP-1) × (IGFBP-7) was not associated with acute kidney injury, dialysis, and/or death and was not a predictor of the aforementioned events when added to a clinical acute kidney injury model including age, duration of cardiopulmonary bypass, and mechanical ventilation prior to surgery. Conclusions These findings question the usefulness of (TIMP-1) × (IGFBP-7) for the prediction of cardiac surgery-related acute kidney injury in neonates and infants when measured within 3 hours of cardiopulmonary bypass.
Published: 2020

24. Tapering Canakinumab Monotherapy in Patients with Systemic Juvenile Idiopathic Arthritis in Clinical Remission: Results from an Open‐label, Randomized Phase IIIb/IV Study

Author: Quartier, P, Alexeeva, E, Tamàs, C, Chasnyk, V, Wulffraat, N, Palmblad, K, Wouters, C, Brunner, H, Marzan, K, Schneider, R, Horneff, G, Martini, A, Anton, J, Wei, X, Slade, A, Ruperto, N, Abrams, K, Emminger, W, Ulbrich, A, Fodor, S, Desomer, L, Lauwerys, B, Brichard, B, Boulanger, C, Levy, G, Goffin, L, Quoc Le, P, Bandeira, M, Feitosa Pelajo, C, Knupp Feitosa, S, Costa, C, Cristine Felix Rodrigues, M, Artur Almeida da Silva, C, Maria Mattei de, L, Kozu, K, Laxer, R, Houghton, K, Tucker, L, Morishita, K, Mogenet, A, Mouy, R, Bader Meunier, B, Meyzer, C, Semeraro, M, Ben‐brahim, O, Kone‐paut, I, Galeotti, C, Rossi, L, Dusser, P, Cherquaoui, B, Belot, A, Duquesne, A, Caroline, F, Audrey, L, Desjonqueres, M, Foeldvari, I, Kienast, A, Willig, B, Barthel, D, Peitz, J, Wintrich, S, Felix Geikowski, T, Carina Schulz, A, Hufnagel, M, Hirdes, M, Kubicki, R, Kirschner, J, Janda, A, Jacob, A, Emerich, C, Raab, A, Ngoumou, G, Minden, K, Lieber, M, von Stuckrad, S, Kuemmerle Deschner, J, Hansmann, S, Schleich, T, Maria Magunia, I, Riethmuller, J, Anders, N, Lehmann, H, de Laffolie, J, Lutz, T, Grulich‐henn, J, Pfeil, J, Helling‐bakki, A, Trauzeddel, R, Haselbusch, D, Kolbeck, H, Weissbarth‐riedel, E, Froehlich, A, Ponyi, A, Garan, D, Orban, I, Sevcic, K, Butbul, Y, Brik, R, Hashkes, P, Toker, O, Haviv, R, Uziel, Y, Moshe, V, Rothschild, M, Harel, L, Amarilyo, G, Tal, R, Hamad Said, M, Tirosh, I, Spielman, S, Gerstein, M, Ravelli, A, Schiappapietra, B, Camilla Varnier, G, Finetti, M, Marasini, M, Caorsi, R, Rosina, S, Federici, S, Pontikaki, I, Luigi Meroni, P, Gerloni, V, Ughi, N, Ubiali, T, Alessio, M, Della Casa, R, Jozef Vastert, S, Frans Swart, J, van Royen‐Kerhof, A, Schatorje, E, Van Iperen‐Schutte, G, Rutkowska‐sak, L, Szczygielska, I, Kwiatkowska, M, Marusak‐banacka, M, Gietka, P, Isaeva, K, Denisova, R, Snegireva, L, Dubko, M, Kostik, M, Buchinskaia, N, Kalashnikova, O, Avrusin, S, Masalova, V, Nunez Cuadros, E, Diez, G, Galindo Zavala, R, Bou Torrent, R, Iglesias, E, Calzada, J, Bittermann, V, Lucica Boteanu, A, Luz Gamir, M, Calvo, I, Lopez, B, Gonzalez, I, Fernandez, L, Clemente Garulo, D, Carlos Lopez Robledillo, J, Merino, R, Alcobendas, R, Remesal, A, Murias, S, Magnusson, B, Kasapcopur, O, Barut, K, Adrovic, A, Sahin, S, Erguven, M, Gozdenur Savci, R, Ozen, S, Demir, S, Bilginer, Y, Serap Avci, Z, Deriz Batu, E, Reiff, A, Ramanatham, A, Brown, D, Shaham, B, Parks, S, Cidon, M, Higgins, G, Spencer, C, Rossette, J, Jones, K, Bout Tabaku, S, Farley, S, Akoghlanian, S, Pierre Quartier, Ekaterina Alexeeva, Constantin Tamàs, Vyacheslav Chasnyk, Nico Wulffraat, Karin Palmblad, Carine Wouters, Hermine Brunner, Katherine Marzan, Rayfel Schneider, Gerd Horneff, Alberto Martini, Jordi Anton, Xiaoling Wei, Alan Slade, Nicolino Ruperto, Ken Abrams, Wolfgang Emminger, Andrea Ulbrich, Sugarka Fodor, Lien Desomer, Bernard Lauwerys, Bénédicte Brichard, Cécile Boulanger, Gabriel Levy, Laurence Goffin, Phu Quoc Le, Marcia Bandeira, Christina Feitosa Pelajo, Sheila Knupp Feitosa, Christianne Costa, Marta Cristine Felix Rodrigues, Clovis Artur Almeida da Silva, Lucia Maria Mattei de, Katia Kozu, Ronald Laxer, Kristin Houghton, Lori Tucker, Kimberly Morishita, Agnes Mogenet, Richard Mouy, Brigitte Bader Meunier, Candice Meyzer, Michaela Semeraro, Ouafa Ben‐Brahim, Isabelle Kone‐Paut, Caroline Galeotti, Linda Rossi, Perrine Dusser, Bilade Cherquaoui, Alexandre Belot, Agnes Duquesne, Freychet Caroline, Laurent Audrey, Marine Desjonqueres, Ivan Foeldvari, Antonia Kienast, Barbara Willig, Deborah Barthel, Joachim Peitz, Stefanie Wintrich, Tilman Felix Geikowski, Anna Carina Schulz, Markus Hufnagel, Marc Hirdes, Rouven Kubicki, Janbernd Kirschner, Ales Janda, Andre Jacob, Cornelia Emerich, Anna Raab, Gonza Ngoumou, Kirsten Minden, Mareike Lieber, Sae‐Lim von Stuckrad, Jasmin Kuemmerle Deschner, Sandra Hansmann, Tom Schleich, Ines Maria Magunia, Joachim Riethmuller, Nicole Anders, Hartwig Lehmann, Jan de Laffolie, Thomas Lutz, Juergen Grulich‐Henn, Johannes Pfeil, Astrid Helling‐Bakki, Ralf Trauzeddel, Daniel Haselbusch, Henryk Kolbeck, Elisabeth Weissbarth‐Riedel, Anja Froehlich, Andrea Ponyi, Diana Garan, Ilonka Orban, Krisztina Sevcic, Yonatan Butbul, Riva Brik, Philip Hashkes, Ori Toker, Ruby Haviv, Yosef Uziel, Rubi Haviv, Veronica Moshe, Michal Rothschild, Liora Harel, Gil Amarilyo, Rotem Tal, Mohamad Hamad Said, Irit Tirosh, Shiri Spielman, Maya Gerstein, Angelo Ravelli, Benedetta Schiappapietra, Giulia Camilla Varnier, Martina Finetti, Maurizio Marasini, Roberta Caorsi, Silvia Rosina, Silvia Federici, Irene Pontikaki, Pier Luigi Meroni, Valeri Gerloni, Nicola Ughi, Tania Ubiali, Maria Alessio, Roberto Della Casa, Sebastiaan Jozef Vastert, Joost Frans Swart, A. van Royen‐Kerhof, Ellen Schatorje, G. Van Iperen‐Schutte, Lidia Rutkowska‐Sak, Izabela Szczygielska, Malgorzata Kwiatkowska, Maria Marusak‐Banacka, Piotr Gietka, Kseniya Isaeva, Rina Denisova, Ludmila Snegireva, Margarita Dubko, Mikhail Kostik, Natalia Buchinskaia, Olga Kalashnikova, Sergey Avrusin, Vera Masalova, Esmeralda Nunez Cuadros, Gisela Diez, Rocio Galindo Zavala, Rosa Bou Torrent, Estibaliz Iglesias, Joan Calzada, Violeta Bittermann, Alina Lucica Boteanu, Maria Luz Gamir, Inmaculada Calvo, Berta Lopez, Isabel Gonzalez, Laura Fernandez, Daniel Clemente Garulo, Juan Carlos Lopez Robledillo, Rosa Merino, Rosa Alcobendas, Agustin Remesal, Sara Murias, Bo Magnusson, Ozgur Kasapcopur, Kenan Barut, Amra Adrovic, Sezgin Sahin, Muferet Erguven, Refia Gozdenur Savci, Seza Ozen, Selcan Demir, Yelda Bilginer, Zehra Serap Avci, Ezgi Deriz Batu, Andreas Reiff, Anusha Ramanatham, Diana Brown, Bracha Shaham, Shirley Parks, Michal Cidon, Gloria Higgins, Charles Spencer, Jenny Rossette, Karla Jones, Sharon Bout Tabaku, Shelli Farley, Shoghik Akoghlanian, Quartier, P, Alexeeva, E, Tamàs, C, Chasnyk, V, Wulffraat, N, Palmblad, K, Wouters, C, Brunner, H, Marzan, K, Schneider, R, Horneff, G, Martini, A, Anton, J, Wei, X, Slade, A, Ruperto, N, Abrams, K, Emminger, W, Ulbrich, A, Fodor, S, Desomer, L, Lauwerys, B, Brichard, B, Boulanger, C, Levy, G, Goffin, L, Quoc Le, P, Bandeira, M, Feitosa Pelajo, C, Knupp Feitosa, S, Costa, C, Cristine Felix Rodrigues, M, Artur Almeida da Silva, C, Maria Mattei de, L, Kozu, K, Laxer, R, Houghton, K, Tucker, L, Morishita, K, Mogenet, A, Mouy, R, Bader Meunier, B, Meyzer, C, Semeraro, M, Ben‐brahim, O, Kone‐paut, I, Galeotti, C, Rossi, L, Dusser, P, Cherquaoui, B, Belot, A, Duquesne, A, Caroline, F, Audrey, L, Desjonqueres, M, Foeldvari, I, Kienast, A, Willig, B, Barthel, D, Peitz, J, Wintrich, S, Felix Geikowski, T, Carina Schulz, A, Hufnagel, M, Hirdes, M, Kubicki, R, Kirschner, J, Janda, A, Jacob, A, Emerich, C, Raab, A, Ngoumou, G, Minden, K, Lieber, M, von Stuckrad, S, Kuemmerle Deschner, J, Hansmann, S, Schleich, T, Maria Magunia, I, Riethmuller, J, Anders, N, Lehmann, H, de Laffolie, J, Lutz, T, Grulich‐henn, J, Pfeil, J, Helling‐bakki, A, Trauzeddel, R, Haselbusch, D, Kolbeck, H, Weissbarth‐riedel, E, Froehlich, A, Ponyi, A, Garan, D, Orban, I, Sevcic, K, Butbul, Y, Brik, R, Hashkes, P, Toker, O, Haviv, R, Uziel, Y, Moshe, V, Rothschild, M, Harel, L, Amarilyo, G, Tal, R, Hamad Said, M, Tirosh, I, Spielman, S, Gerstein, M, Ravelli, A, Schiappapietra, B, Camilla Varnier, G, Finetti, M, Marasini, M, Caorsi, R, Rosina, S, Federici, S, Pontikaki, I, Luigi Meroni, P, Gerloni, V, Ughi, N, Ubiali, T, Alessio, M, Della Casa, R, Jozef Vastert, S, Frans Swart, J, van Royen‐Kerhof, A, Schatorje, E, Van Iperen‐Schutte, G, Rutkowska‐sak, L, Szczygielska, I, Kwiatkowska, M, Marusak‐banacka, M, Gietka, P, Isaeva, K, Denisova, R, Snegireva, L, Dubko, M, Kostik, M, Buchinskaia, N, Kalashnikova, O, Avrusin, S, Masalova, V, Nunez Cuadros, E, Diez, G, Galindo Zavala, R, Bou Torrent, R, Iglesias, E, Calzada, J, Bittermann, V, Lucica Boteanu, A, Luz Gamir, M, Calvo, I, Lopez, B, Gonzalez, I, Fernandez, L, Clemente Garulo, D, Carlos Lopez Robledillo, J, Merino, R, Alcobendas, R, Remesal, A, Murias, S, Magnusson, B, Kasapcopur, O, Barut, K, Adrovic, A, Sahin, S, Erguven, M, Gozdenur Savci, R, Ozen, S, Demir, S, Bilginer, Y, Serap Avci, Z, Deriz Batu, E, Reiff, A, Ramanatham, A, Brown, D, Shaham, B, Parks, S, Cidon, M, Higgins, G, Spencer, C, Rossette, J, Jones, K, Bout Tabaku, S, Farley, S, Akoghlanian, S, Pierre Quartier, Ekaterina Alexeeva, Constantin Tamàs, Vyacheslav Chasnyk, Nico Wulffraat, Karin Palmblad, Carine Wouters, Hermine Brunner, Katherine Marzan, Rayfel Schneider, Gerd Horneff, Alberto Martini, Jordi Anton, Xiaoling Wei, Alan Slade, Nicolino Ruperto, Ken Abrams, Wolfgang Emminger, Andrea Ulbrich, Sugarka Fodor, Lien Desomer, Bernard Lauwerys, Bénédicte Brichard, Cécile Boulanger, Gabriel Levy, Laurence Goffin, Phu Quoc Le, Marcia Bandeira, Christina Feitosa Pelajo, Sheila Knupp Feitosa, Christianne Costa, Marta Cristine Felix Rodrigues, Clovis Artur Almeida da Silva, Lucia Maria Mattei de, Katia Kozu, Ronald Laxer, Kristin Houghton, Lori Tucker, Kimberly Morishita, Agnes Mogenet, Richard Mouy, Brigitte Bader Meunier, Candice Meyzer, Michaela Semeraro, Ouafa Ben‐Brahim, Isabelle Kone‐Paut, Caroline Galeotti, Linda Rossi, Perrine Dusser, Bilade Cherquaoui, Alexandre Belot, Agnes Duquesne, Freychet Caroline, Laurent Audrey, Marine Desjonqueres, Ivan Foeldvari, Antonia Kienast, Barbara Willig, Deborah Barthel, Joachim Peitz, Stefanie Wintrich, Tilman Felix Geikowski, Anna Carina Schulz, Markus Hufnagel, Marc Hirdes, Rouven Kubicki, Janbernd Kirschner, Ales Janda, Andre Jacob, Cornelia Emerich, Anna Raab, Gonza Ngoumou, Kirsten Minden, Mareike Lieber, Sae‐Lim von Stuckrad, Jasmin Kuemmerle Deschner, Sandra Hansmann, Tom Schleich, Ines Maria Magunia, Joachim Riethmuller, Nicole Anders, Hartwig Lehmann, Jan de Laffolie, Thomas Lutz, Juergen Grulich‐Henn, Johannes Pfeil, Astrid Helling‐Bakki, Ralf Trauzeddel, Daniel Haselbusch, Henryk Kolbeck, Elisabeth Weissbarth‐Riedel, Anja Froehlich, Andrea Ponyi, Diana Garan, Ilonka Orban, Krisztina Sevcic, Yonatan Butbul, Riva Brik, Philip Hashkes, Ori Toker, Ruby Haviv, Yosef Uziel, Rubi Haviv, Veronica Moshe, Michal Rothschild, Liora Harel, Gil Amarilyo, Rotem Tal, Mohamad Hamad Said, Irit Tirosh, Shiri Spielman, Maya Gerstein, Angelo Ravelli, Benedetta Schiappapietra, Giulia Camilla Varnier, Martina Finetti, Maurizio Marasini, Roberta Caorsi, Silvia Rosina, Silvia Federici, Irene Pontikaki, Pier Luigi Meroni, Valeri Gerloni, Nicola Ughi, Tania Ubiali, Maria Alessio, Roberto Della Casa, Sebastiaan Jozef Vastert, Joost Frans Swart, A. van Royen‐Kerhof, Ellen Schatorje, G. Van Iperen‐Schutte, Lidia Rutkowska‐Sak, Izabela Szczygielska, Malgorzata Kwiatkowska, Maria Marusak‐Banacka, Piotr Gietka, Kseniya Isaeva, Rina Denisova, Ludmila Snegireva, Margarita Dubko, Mikhail Kostik, Natalia Buchinskaia, Olga Kalashnikova, Sergey Avrusin, Vera Masalova, Esmeralda Nunez Cuadros, Gisela Diez, Rocio Galindo Zavala, Rosa Bou Torrent, Estibaliz Iglesias, Joan Calzada, Violeta Bittermann, Alina Lucica Boteanu, Maria Luz Gamir, Inmaculada Calvo, Berta Lopez, Isabel Gonzalez, Laura Fernandez, Daniel Clemente Garulo, Juan Carlos Lopez Robledillo, Rosa Merino, Rosa Alcobendas, Agustin Remesal, Sara Murias, Bo Magnusson, Ozgur Kasapcopur, Kenan Barut, Amra Adrovic, Sezgin Sahin, Muferet Erguven, Refia Gozdenur Savci, Seza Ozen, Selcan Demir, Yelda Bilginer, Zehra Serap Avci, Ezgi Deriz Batu, Andreas Reiff, Anusha Ramanatham, Diana Brown, Bracha Shaham, Shirley Parks, Michal Cidon, Gloria Higgins, Charles Spencer, Jenny Rossette, Karla Jones, Sharon Bout Tabaku, Shelli Farley, and Shoghik Akoghlanian
Abstract: Objective: To evaluate the efficacy and safety of 2 canakinumab monotherapy tapering regimens in order to maintain complete clinical remission in children with systemic juvenile idiopathic arthritis (JIA). Methods: The study was designed as a 2-part phase IIIb/IV open-label, randomized trial. In the first part, patients received 4 mg/kg of canakinumab subcutaneously every 4 weeks and discontinued glucocorticoids and/or methotrexate as appropriate. Patients in whom clinical remission was achieved (inactive disease for at least 24 weeks) with canakinumab monotherapy were entered into the second part of the trial, in which they were randomized 1:1 into 1 of 2 treatment arms. In arm 1, the dose of canakinumab was reduced from 4 mg/kg to 2 mg/kg and then to 1 mg/kg, followed by discontinuation. In arm 2, the 4 mg/kg dose interval was prolonged from every 4 weeks, to every 8 weeks, and then to every 12 weeks, followed by discontinuation. In both arms, canakinumab exposure could be reduced provided systemic JIA remained in clinical remission for 24 weeks with each step. The primary objective was to assess whether >40% of randomized patients in either arm maintained clinical remission of systemic JIA for 24 weeks in the first part of the study. Results: In part 1 of the study, 182 patients were enrolled, with 75 of those patients randomized before entering part 2 of the trial. Among the 75 randomized patients, clinical remission was maintained for 24 weeks in 27 (71%) of 38 patients in arm 1 (2 mg/kg every 4 weeks) and 31 (84%) of 37 patients in arm 2 (4 mg/kg every 8 weeks) (P ≤ 0.0001 for arm 1 versus arm 2 among those meeting the 40% threshold). Overall, 25 (33%) of 75 patients discontinued canakinumab, and clinical remission was maintained for at least 24 weeks in all 25 of these patients. No new safety signals were identified. Conclusion: Reduction of canakinumab exposure may be feasible in patients who have achieved clinical remission of systemic JIA, but consisten
Published: 2021

25. Clinical Results of the Drepaglobe Trial for Sickle Cell Disease Patients

Author: Laurent Kiger, L. Joseph, Axelle Maulet, Aurélie Gabrion, Annarita Miccio, Ambroise Marçais, Marina Cavazzana, Olivia Leblanc, Anne Chalumeau, Michaela Semeraro, Jean-Marc Tréluyer, Alessandra Magnani, Olivier Hermine, Pablo Bartolucci, Felipe Suarez, Elisa Magrin, Valérie Jolaine, Cécile Roudaut, Nicolas Hebert, Emmanuelle Six, Wassim El Nemer, Jouda Marouene, and Fulvio Mavilio
Subjects: medicine.medical_specialty, medicine.anatomical_structure, business.industry, Internal medicine, Immunology, Cell, Medicine, Cell Biology, Hematology, Disease, business, Biochemistry
Abstract: In sickle cell disease (SCD), the β6 Glu→Val substitution leads to sickle hemoglobin (HbS) polymerization and red blood cell (RBC) sickling. Transplantation of autologous, genetically modified hematopoietic stem/progenitor cells (HSPCs) represents a promising therapeutic option for patients lacking a compatible donor. We previously designed a lentiviral vector (βAS3 LV) expressing a potent anti-sickling βAS3 globin and demonstrated its safety and efficacy in SCD patient cells (Weber et al., 2018). In vitro and in vivo preclinical studies demonstrated the safety and efficacy of a gene therapy (GT) protocol based on the efficient transduction of plerixafor-mobilized SCD HSPCs by βAS3 LV. Based on these results a Phase 1/2 clinical trial (NCT03964792) started in January 2020. Three homozygous SCD patients (P1, P2 and P3) were recruited. Before GT, patients suffered from severe SCD symptoms that were not controlled despite of a strict adherence to the treatment. Plerixafor-mobilized HSPCs were transduced achieving a VCN of 0.9±0.2 in liquid culture, 1.6±0.3 in BFU-E and 0.8±0.2 in CFU-GM. The patients were hypertransfused to reach HbS levels Here, for the 3 patients we report the follow-up of 18 (P1), 10 (P2) and 6 (P3) months. No drug-related severe adverse events were observed. Importantly, no sign of clonal hematopoiesis was detected by NGS sequencing performed on the graft before and after transduction. Despite of the similar VCN in the drug product, gene marking in peripheral blood mononuclear cells was variable and ranged between 0.2 and 0.6, as measured at the last follow-up (0.4 in P1, 0.6 in P2 and 0.2 in P3). These results pinpoint the difficulty to estimate the gene marking, self-renewal and engraftment potential of HSCs in the grafts. P1 and P2 clinically benefit from the GT treatment despite they presented non-severe vaso-occlusive crises (VOCs) not requiring hospitalization (two for P1 at month 6 and 14 and one in P2 at month 8 post-GT). Despite the rapid resolution of these episodes, P1 started hydroxyurea at month 10 and stopped it at month 16. P2 initiated a phlebotomy program to treat liver iron overload and decrease viscosity. Intravascular hemolysis improved in P1 and P2, as shown by a decrease in plasma hemoglobin and heme, and an increase in hemopexin (HPX). Interestingly, in P1 a mild worsening occurred at the time of VOC. In P1 and P2, total bilirubin, a marker of extravascular hemolysis, decreased post-GT. Deformability, measured using osmoscan, improved in P1 and to a lesser extent in P2; however, both still exhibited some degree of dehydration compared to normal RBCs (Fig. 1). Adhesion to thrombospondin decreased after GT with an increase during VOC in P1 or prior the VOC in P2 (Fig. 1). In both patients, markers of inflammation (e.g., C reactive protein) and reticulocyte counts decreased upon GT. An in vitro sickling assays was performed for P1 and showed significant improvement, reaching a frequency of sickling cells similar to SCD heterozygous carriers (from 88% before GT to 45% 6 months post-GT). The GT treatment was not effective in P3 due to the modest intake and rapid decline of gene modified cells. In P1 and P2, who were no longer on transfusions, HbAS3 levels correlated with the VCN (2.1 g/dl for P1 and 3.3 g/dl for P2) and the therapeutic Hb accounted for 21.5%, and 28.7% of the total hemoglobins, respectively. For P3, who remained transfusion-dependent, this frequency was Overall, these clinical data indicate a variable efficacy of the DREPAGLOBE GT treatment, which likely depends on the extent of gene marking achieved in HSCs in vivo and on the engraftment capability of genetically modified HSCs in SCD patients' bone marrow. Single-cell RNA-seq analysis of HSPCs and evaluation of the bone marrow niche in SCD patients will aid to define critical parameters for achieving successful outcomes in GT clinical trials for SCD. Figure 1 Figure 1. Disclosures Joseph: bluebird bio: Consultancy. El Nemer: Hemanext: Consultancy. Bartolucci: INNOVHEM: Other: Co-founder; AGIOS: Consultancy; GBT: Consultancy; Bluebird: Consultancy, Research Funding; Jazz Pharma: Other: Lecture fees; Fabre Foundation: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Lecture fees, Steering committee, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy; Hemanext: Consultancy; Addmedica: Consultancy, Other: Lecture fees, Research Funding; Emmaus: Consultancy. Cavazzana: Smart Immune: Other: co-founder.
Published: 2021
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26. Busulfan–melphalan in high-risk neuroblastoma: the 30-year experience of a single institution

Author: Ellen Benhamou, Proust-Houdemont S, G. Goma, Christelle Dufour, Michaela Semeraro, Marie-Anne Raquin, Dominique Valteau-Couanet, Claudia Pasqualini, Pierre Blanchard, and Olivier Hartmann
Subjects: Male, Oncology, Melphalan, medicine.medical_specialty, Adolescent, medicine.medical_treatment, Cohort Studies, Neuroblastoma, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Internal medicine, medicine, Humans, Child, Busulfan, Survival analysis, Bone Marrow Transplantation, Retrospective Studies, Peripheral Blood Stem Cell Transplantation, Transplantation, Chemotherapy, business.industry, Infant, Induction chemotherapy, Retrospective cohort study, Hematology, Combined Modality Therapy, Survival Analysis, Surgery, medicine.anatomical_structure, Child, Preschool, 030220 oncology & carcinogenesis, Female, Bone marrow, business, 030215 immunology, medicine.drug
Abstract: High-dose chemotherapy (HDC) was investigated in high-risk neuroblastoma (HR-NBL) to reduce the risk of relapse. We report the results of the 30-year experience of a cohort of patients with HR-NBL treated with high-dose (HD) busulfan (Bu)-containing regimens. From 1980 to 2009, 215 patients aged >1 year with stage 4 NBL were treated with HD Bu-containing regimens at Gustave Roussy. These data were prospectively recorded in the Pediatric Transplantation Database. The median age at diagnosis was 40 months (12-218 months). All patients had a stage 4 neuroblastoma. NMYC amplification was displayed in 24% of the tumors. The hematopoietic support consisted of bone marrow or PBSCs in 46% and 49% of patients, respectively. The 5-year event-free survival and overall survival rates of the whole cohort were 35.1% and 40%, respectively. Age at diagnosis, bone marrow involvement and tumor response after induction chemotherapy were significant prognostic factors. Toxicity was manageable and decreased over time, owing to both PBSC administration and better supportive care. Based on this experience, HD Bu-melphalan (Mel) has been implemented in Europe and compared with Carboplatin-Etoposide-Mel in the European SIOP Neuroblastoma (SIOPEN)/HR-NBL randomized protocol. It has now become the standard HDC in the SIOPEN HR strategy.
Published: 2016
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27. Tranexamic acid through intravenous, intramuscular and oral routes: an individual participant data meta-analysis of pharmacokinetic studies in healthy volunteers

Author: Stanislas Grassin-Delyle, Frantz Foissac, Jean-Marc Tréluyer, Michaela Semeraro, Saik Urien, Ian Roberts, Haleema Shakur-Still, and Naïm Bouazza
Subjects: Drug, Antifibrinolytic, medicine.drug_class, media_common.quotation_subject, Population, Administration, Oral, Biological Availability, 030226 pharmacology & pharmacy, Injections, Intramuscular, 03 medical and health sciences, 0302 clinical medicine, Pharmacokinetics, Healthy volunteers, medicine, Humans, Pharmacology (medical), education, Infusions, Intravenous, media_common, Pharmacology, Volume of distribution, education.field_of_study, business.industry, Antifibrinolytic Agents, Healthy Volunteers, Tranexamic Acid, Meta-analysis, Anesthesia, Administration, Intravenous, business, 030217 neurology & neurosurgery, Tranexamic acid, medicine.drug
Abstract: Tranexamic acid (TXA) is an antifibrinolytic drug that reduces surgical blood loss and death due to bleeding after trauma and post-partum haemorrhage. One key issue for treatment success is early administration. While usually given intravenously, oral and intramuscular use would be useful in specific circumstances. Therefore, an understanding of TXA pharmacokinetics when given via different routes is valuable. The aim of this study was to perform an individual participant data meta-analysis of pharmacokinetic studies with TXA given to healthy volunteers via different routes. We searched the following databases: PubMed, Web of Science, Wiley Online Library, Elsevier Science Direct and J-STAGE. Individual subject data were extracted when available, otherwise arithmetic means were used. A population pharmacokinetic model was developed using nonlinear mixed effect modelling. Seven studies were included in the analysis with data from 10 patients for the IV route, six patients for the IM route and 114 patients for the oral route. The pharmacokinetics was ascribed to a two-compartment model, and the main covariate was allometrically scaled bodyweight. Oral and IM bioavailabilities were 46 and 105%, respectively. For a 70 kg bodyweight, the population estimates were 7.6 L/h for clearance, 17.9 L for the volume of the central compartment, 2.5 L/h for the diffusional clearance and 16.6 L for the peripheral volume of distribution. Larger well-designed studies are needed to describe the pharmacokinetics of TXA when given IM or as an oral solution before these can be recommended as alternatives to IV.
Published: 2019

28. Sotatercept, a novel transforming growth factor β ligand trap, improves anemia in β-thalassemia: a phase II, open-label, dose-finding study

Author: Maciej W Garbowski, Raffaella Origa, Gian Luca Forni, Tatiana Zinger, Jun Zou, Kenneth M. Attie, Ersi Voskaridou, Abderrahmane Laadem, Jean Benoît Arlet, Ali T. Taher, Frédéric Galactéros, John B. Porter, Dimana Miteva, Chantal Brouzes, Giovanna Graziadei, Olivier Hermine, Maria Domenica Cappellini, Victoria Sung, Jean Antoine Ribeil, and Michaela Semeraro
Subjects: Ineffective erythropoiesis, Adult, Erythrocyte Indices, Male, medicine.medical_specialty, Blood transfusion, Anemia, medicine.medical_treatment, Thalassemia, Recombinant Fusion Proteins, medicine.disease_cause, Ligands, Gastroenterology, Article, 03 medical and health sciences, Subcutaneous injection, Hemoglobins, 0302 clinical medicine, Transforming Growth Factor beta, Internal medicine, hemic and lymphatic diseases, medicine, Humans, Blood Transfusion, Erythropoiesis, Red Cell Biology & its Disorders, business.industry, beta-Thalassemia, Hematology, Middle Aged, medicine.disease, Effective dose (pharmacology), Combined Modality Therapy, Treatment Outcome, Female, Hemoglobin, business, Biomarkers, 030215 immunology
Abstract: β-thalassemia, a hereditary blood disorder caused by defective synthesis of hemoglobin β globin chains, leads to ineffective erythropoiesis and chronic anemia that may require blood transfusions. Sotatercept (ACE-011) acts as a ligand trap to inhibit negative regulators of late-stage erythropoiesis in the transforming growth factor β superfamily, correcting ineffective erythropoiesis. In this phase II, open-label, dose-finding study, 16 patients with transfusion-dependent β -thalassemia and 30 patients with non-transfusion-dependent β-thalassemia were enrolled at seven centers in four countries between November 2012 and November 2014. Patients were treated with sotatercept at doses of 0.1, 0.3, 0.5, 0.75, or 1.0 mg/kg to determine a safe and effective dose. Doses were administered by subcutaneous injection every 3 weeks. Patients were treated for ≤22 months. Response was assessed as a ≥20% reduction in transfusion burden sustained for 24 weeks in transfusion-dependent β-thalassemia patients, and an increase in hemoglobin level of ≥1.0 g/dL sustained for 12 weeks in non-transfusion-dependent β-thalassemia patients. Sotatercept was well tolerated. After a median treatment duration of 14.4 months (range 0.6-35.9), no severe life-threatening adverse events were observed. Thirteen percent of patients reported serious but manageable adverse events. The active dose of sotatercept was ≥0.3 mg/kg for patients with non-transfusion-dependent β-thalassemia and ≥0.5 mg/kg for those with transfusion-dependent β-thalassemia. Of 30 non-transfusion-dependent β-thalassemia patients treated with ≥0.1 mg/kg sotatercept, 18 (60%) achieved a mean hemoglobin increase ≥1.0 g/dL, and 11 (37%) an increase ≥1.5 g/dL, sustained for ≥12 weeks. Four (100%) transfusion-dependent β-thalassemia patients treated with 1.0 mg/kg sotatercept achieved a transfusion-burden reduction of ≥20%. Sotatercept was effective and well tolerated in patients with β-thalassemia. Most patients with non-transfusion-dependent β-thalassemia treated with higher doses achieved sustained increases in hemoglobin level. Transfusion-dependent β-thalassemia patients treated with higher doses of sotatercept achieved notable reductions in transfusion requirements. This trial was registered at ClinicalTrials.gov with the number NCT01571635.
Published: 2018

29. PF441 RED BLOOD CELLS PROPERTIES IN PATIENTS WITH SICKLE CELL DISEASE TREATED WITH LENTIGLOBIN GENE THERAPY IN THE HGB-205 TRIAL

Author: Annarita Miccio, Valentine Brousse, Chloé Couzin, L. Joseph, Aurélie Gabrion, Cécile Roudaut, Mohammed Asmal, Pablo Bartolucci, W. El Nemer, Nicolas Hebert, Anne Chalumeau, Laurent Kiger, Alessandra Magnani, Olivier Negre, K.-A. Nguyen-Peyre, Michaela Semeraro, Marina Cavazzana, F. Pirenne, Elisa Magrin, Jean-Antoine Ribeil, M. de Montalembert, and J. Marouene
Subjects: medicine.medical_specialty, medicine.anatomical_structure, business.industry, Genetic enhancement, Internal medicine, Cell, Medicine, In patient, Hematology, Disease, business, Gastroenterology
Published: 2019
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30. eIF2α phosphorylation as a biomarker of immunogenic cell death

Author: Heng Zhou, José Manuel Bravo-San Pedro, Laura Senovilla, Xing Huang, Norma Bloy, Guido Kroemer, Oliver Kepp, Aitziber Buqué, Michaela Semeraro, and Lorenzo Galluzzi
Subjects: Cancer Research, Programmed cell death, Eukaryotic Initiation Factor-2, Cell, Antigen-Presenting Cells, Apoptosis, Endoplasmic Reticulum, Epitopes, Mice, medicine, Animals, Humans, Phosphorylation, Endoplasmic Reticulum Chaperone BiP, Heat-Shock Proteins, Cell Death, biology, Endoplasmic reticulum, Cell Membrane, Endoplasmic Reticulum Stress, Acquired immune system, medicine.anatomical_structure, Protein Biosynthesis, Cancer cell, Immunology, Cancer research, biology.protein, Immunogenic cell death, Calreticulin, Biomarkers, Signal Transduction
Abstract: Cancer cells exposed to some forms of chemotherapy and radiotherapy die while eliciting an adaptive immune response. Such a functionally peculiar variant of apoptosis has been dubbed immunogenic cell death (ICD). One of the central events in the course of ICD is the activation of an endoplasmic reticulum (ER) stress response. This is instrumental for cells undergoing ICD to emit all the signals that are required for their demise to be perceived as immunogenic by the host, and culminates with the phosphorylation of eukaryotic translation initiation factor 2α (eIF2α). In particular, eIF2α phosphorylation is required for the pre-apoptotic exposure of the ER chaperone calreticulin (CALR) on the cell surface, which is a central determinant of ICD. Importantly, phosphorylated eIF2α can be quantified in both preclinical and clinical samples by immunoblotting or immunohistochemistry using phosphoneoepitope-specific monoclonal antibodies. Of note, the phosphorylation of eIF2α and CALR exposure do not necessarily correlate with each other, and neither of these parameters is sufficient for cell death to be perceived as immunogenic. Nonetheless, accumulating data indicate that assessing the degree of phosphorylation of eIF2α provides a convenient parameter to monitor ICD. Here, we discuss the role of the ER stress response in ICD and the potential value of eIF2α phosphorylation as a biomarker for this clinically relevant variant of apoptosis.
Published: 2015
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31. Negative prognostic impact of regulatory T cell infiltration in surgically resected esophageal cancer post-radiochemotherapy

Author: Aurélie Perier, Michaela Semeraro, C. Gronnier, Peggy Dartigues, David Enot, Kariman Chaba, Irène Villa, Laurence Zitvogel, Vichnou Poirier Colame, Sylvie Rusakiewicz, Erika Vacchelli, Christophe Mariette, Guido Kroemer, and Diane Goéré
Subjects: Male, Pathology, medicine.medical_specialty, autophagy, Esophageal Neoplasms, Genotype, Colorectal cancer, Regulatory T cell, pattern recognition receptor, ATG16L1, Biology, CD8-Positive T-Lymphocytes, T-Lymphocytes, Regulatory, Cohort Studies, Lymphocytes, Tumor-Infiltrating, immunogenic cell death, medicine, Cytotoxic T cell, Humans, Alleles, apoptosis, FOXP3, Forkhead Transcription Factors, Chemoradiotherapy, Esophageal cancer, medicine.disease, Prognosis, Immunohistochemistry, Immunosurveillance, Gene Expression Regulation, Neoplastic, Toll-Like Receptor 4, medicine.anatomical_structure, Treatment Outcome, Oncology, Cancer research, Female, Receptors, Purinergic P2X7, CD8, Priority Research Paper
Abstract: Ever accumulating evidence indicates that the long-term effects of radiotherapy and chemotherapy largely depend on the induction (or restoration) of an anticancer immune response. Here, we investigated this paradigm in the context of esophageal carcinomas treated by neo-adjuvant radiochemotherapy, in a cohort encompassing 196 patients. We found that the density of the FOXP3+ regulatory T cell (Treg) infiltrate present in the residual tumor (or its scar) correlated with the pathological response (the less Tregs the more pronounced was the histological response) and predicted cancer-specific survival. In contrast, there was no significant clinical impact of the frequency of CD8+ cytotoxic T cells. At difference with breast or colorectal cancer, a loss-of-function allele of toll like receptor 4 (TLR4) improved cancer-specific survival of patients with esophageal cancer. While a loss-of-function allele of purinergic receptor P2X, ligand-gated ion channel, 7 (P2RX7) failed to affect cancer-specific survival, its presence did correlate with an increase in Treg infiltration. Altogether, these results corroborate the notion that the immunosurveillance seals the fate of patients with esophageal carcinomas treated with conventional radiochemotherapy.
Published: 2015

32. Reverse-Transcriptase Inhibitors in the Aicardi–Goutières Syndrome

Author: Diana Rodriguez, Vincent Bondet, Alexandre Belot, Luis Seabra, Claude Cances, Isabelle Desguerre, Virginie Levrat, Diane Doummar, Elodie Henry, Marie Hully, Mathieu P Rodero, Isabelle Melki, Magalie Barth, Alba Llibre, Agathe Roubertie, François-Guillaume Debray, Jean-Marc Tréluyer, Michaela Semeraro, Valérie Jolaine, Nathalie Boddaert, Pierre Meyer, Christine Barnerias, Carolina Uggenti, Jinmi Baek, Gillian I. Rice, Flore Rozenberg, Darragh Duffy, Stéphane Blanche, Marie-Louise Frémond, Florence Renaldo, Naïm Bouazza, Hendy Abdoul, Leo A. H. Zeef, Mame N Sambe, Candice Meyzer, Yanick J. Crow, Marie-Christine Nougues, Alice Lepelley, Naoki Kitabayashi, University of Manchester [Manchester], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Necker - Enfants Malades [AP-HP], Université Paris Descartes - Paris 5 (UPD5), Institut Pasteur [Paris] (IP), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Université de Lyon, Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université de Liège, CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Annecy-Genevois [Saint-Julien-en-Genevois], AP-HP Hôpital universitaire Robert-Debré [Paris], Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Hôpital Robert Debré, Sorbonne Université (SU), University of Edinburgh, Supported by grants from the European Leukodystrophy Association (ELA 2012-008l1), the European Research Council (GA 309449 and 786142-E-T1IFNs), ERA-NET Neuron (MR/M501803/1), and the French National Research Agency (ANR-10-IAHU-01 and CE17001002). Medications were provided by GlaxoSmithKline and ViiV Healthcare., ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), European Project: 309449,EC:FP7:ERC,ERC-2012-StG_20111109,T1-IFN(2013), Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques (LCBPT - UMR 8601), Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Institut Pasteur [Paris], CHU Toulouse [Toulouse], Vougny, Marie-Christine, Instituts Hospitalo-Universitaires - Institut Hospitalo-Universitaire Imagine - - Imagine2010 - ANR-10-IAHU-0001 - IAHU - VALID, and Definition and characterization of type I interferonopathies - T1-IFN - - EC:FP7:ERC2013-03-01 - 2018-02-28 - 309449 - VALID
Subjects: 0301 basic medicine, [SDV]Life Sciences [q-bio], Gene Expression, Pilot Projects, Nervous System Malformations/drug therapy, Medicine, MESH: Interferons, ComputingMilieux_MISCELLANEOUS, Cerebrovascular Circulation/drug effects, MESH: Zidovudine, General Medicine, MESH: Cerebrovascular Circulation, 3. Good health, Drug Combinations, MESH: Dideoxynucleosides, Lamivudine, Cerebrovascular Circulation, Autoimmune Diseases of the Nervous System/drug therapy, Reverse Transcriptase Inhibitors, [SDV.IMM]Life Sciences [q-bio]/Immunology, France, Zidovudine, MESH: Lamivudine, Interferons/genetics, Reverse Transcriptase Inhibitors/therapeutic use, MESH: Gene Expression, [SDV.IMM] Life Sciences [q-bio]/Immunology, Zidovudine/therapeutic use, Encephalopathy, Gene Expression/drug effects, Nervous System Malformations, MESH: Nervous System Malformations, 03 medical and health sciences, Autoimmune Diseases of the Nervous System, Humans, Lamivudine/therapeutic use, MESH: Drug Combinations, MESH: Humans, business.industry, Dideoxynucleosides/therapeutic use, medicine.disease, MESH: Pilot Projects, Virology, Dideoxynucleosides, Reverse transcriptase, MESH: Autoimmune Diseases of the Nervous System, MESH: France, 030104 developmental biology, Nucleic acid, Aicardi–Goutières syndrome, Interferons, MESH: Reverse Transcriptase Inhibitors, business
Abstract: International audience; To the Editor:The Aicardi–Goutières syndrome is a genetic encephalopathy that is associated with childhood illness and death. The syndrome is hypothesized to be due to misidentification of self-derived nucleic acids as nonself and the subsequent induction of a type I interferon–mediated response that simulates an antiviral reaction.1 Endogenous retroelements, mobile genetic elements that can be transcribed to RNA and then to DNA by reverse transcription, constitute 40% of the human genome and represent a potential source of immunostimulatory nucleic acid in patients with this syndrome.2
Published: 2018
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33. Gene Therapy in Patients with Transfusion-Dependent beta-Thalassemia

Author: Stany Chrétien, Jean-Sebastien Diana, Mariane de Montalembert, Olivier Hermine, Alexandria Petrusich, Janet L. Kwiatkowski, Catherine Poirot, Sandeep Soni, Christof von Kalle, Felipe Suarez, Laure Caccavelli, David Davidson, Olivier Negre, Thibaud Lefebvre, Emmanuel Payen, Elliott Vichinsky, David T. Teachey, Philippe Leboulch, Jean-Antoine Ribeil, Marina Cavazzana, Fabrice Monpoux, Suradej Hongeng, Gabor Istvan Veres, Mark C. Walters, John E.J. Rasko, Despina Moshous, Philippe Bourget, Michaela Semeraro, Stéphane Blanche, Salima Hacein-Bey-Abina, Alessandra Magnani, Chantal Brouzes, François Lefrère, Corinne Pondarré, Jean-François Meritet, P. Joy Ho, Laura Sandler, Robert W. Ross, Mohammed Asmal, Alexis A. Thompson, Morris Kletzel, Valentine Brousse, Yves Beuzard, Hervé Puy, Usanarat Anurathapan, Elisa Magrin, Gary J. Schiller, Unité de Technologies Chimiques et Biologiques pour la Santé (UTCBS - UM 4 (UMR 8258 / U1022)), Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)
Subjects: 0301 basic medicine, Oncology, Male, [SDV.BIO]Life Sciences [q-bio]/Biotechnology, Genetic enhancement, Thalassemia, Antigens, CD34, beta-Globins, Medical and Health Sciences, DISEASE, Hemoglobins, Stem Cell Research - Nonembryonic - Human, Child, biology, Cooley's Anemia, Gene Transfer Techniques, General Medicine, Gene Therapy, Hematology, 3. Good health, Blood, Lentivirus, LentiGlobin BB305, Stem Cell Research - Nonembryonic - Non-Human, Female, Development of treatments and therapeutic interventions, Erythrocyte Transfusion, BURDEN, Autologous, medicine.drug, Biotechnology, Adult, medicine.medical_specialty, Adolescent, Genetic Vectors, VECTOR, Transplantation, Autologous, GLOBIN GENE, 03 medical and health sciences, Young Adult, Rare Diseases, CONDITIONING REGIMEN, Clinical Research, Internal medicine, General & Internal Medicine, medicine, Genetics, Humans, Antigens, Adverse effect, Transplantation, 5.2 Cellular and gene therapies, business.industry, beta-Thalassemia, STEM-CELL TRANSPLANTATION, Genetic Therapy, biology.organism_classification, medicine.disease, Stem Cell Research, EFFICACY, BONE-MARROW-TRANSPLANTATION, HEMOGLOBINOPATHIES, 030104 developmental biology, Mutation, CD34, ERYTHROPOIESIS, business, Busulfan, Ex vivo
Abstract: International audience; BACKGROUND Donor availability and transplantation-related risks limit the broad use of allogeneic hematopoietic-cell transplantation in patients with transfusion-dependent beta-thalassemia. After previously establishing that lentiviral transfer of a marked beta-globin (beta(A-T87Q)) gene could substitute for long-term red-cell transfusions in a patient with beta-thalassemia, we wanted to evaluate the safety and efficacy of such gene therapy in patients with transfusion-dependent beta-thalassemia. METHODS In two phase 1-2 studies, we obtained mobilized autologous CD34+ cells from 22 patients (12 to 35 years of age) with transfusion-dependent beta-thalassemia and transduced the cells ex vivo with LentiGlobin BB305 vector, which encodes adult hemoglobin (HbA) with a T87Q amino acid substitution (HbA(T87Q)). The cells were then reinfused after the patients had undergone myeloablative busulfan conditioning. We subsequently monitored adverse events, vector integration, and levels of replication-competent lentivirus. Efficacy assessments included levels of total hemoglobin and HbA(T87Q), transfusion requirements, and average vector copy number. RESULTS At a median of 26 months (range, 15 to 42) after infusion of the gene-modified cells, all but 1 of the 13 patients who had a non-beta(0)/beta(0) genotype had stopped receiving red-cell transfusions; the levels of HbA(T87Q) ranged from 3.4 to 10.0 g per deciliter, and the levels of total hemoglobin ranged from 8.2 to 13.7 g per deciliter. Correction of biologic markers of dyserythropoiesis was achieved in evaluated patients with hemoglobin levels near normal ranges. In 9 patients with a beta(0)/beta(0) genotype or two copies of the IVS1-110 mutation, the median annualized transfusion volume was decreased by 73%, and red-cell transfusions were discontinued in 3 patients. Treatment-related adverse events were typical of those associated with autologous stem-cell transplantation. No clonal dominance related to vector integration was observed. CONCLUSIONS Gene therapy with autologous CD34+ cells transduced with the BB305 vector reduced or eliminated the need for long-term red-cell transfusions in 22 patients with severe beta-thalassemia without serious adverse events related to the drug product. (Funded by Bluebird Bio and others; HGB-204 and HGB-205 ClinicalTrials. gov numbers, NCT01745120 and NCT02151526.)
Published: 2018
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34. Immune Biomarkers in Paediatric Malignancies

Author: Claudia Pasqualini, Michaela Semeraro, and Nathalie Chaput
Subjects: Immune system, business.industry, Personalized treatment, Medicine, Cancer, In patient, Pediatric Tumor, Molecular Profile, business, medicine.disease, Bioinformatics, Immune checkpoint, Predictive biomarker
Abstract: During the last decade, biomarkers have played an increasingly important role in the development of novel targeted cancer therapies. Since such treatments are rarely effective in all patients, predictive biomarkers to identify those most likely to benefit from a specific therapy are useful. Identification of biomarkers may also improve our understanding of how treatments work, as well as resistance mechanisms, and thus be used not only to anticipate clinical benefit but also the toxicity of a candidate drug. This applies similarly to the identification of immunological biomarkers associated with immunotherapies. The objective of such immunomonitoring is to identify prognostic but also predictive immune biomarkers in patients. Today, reliable identification of biomarkers is a necessary step to personalized treatment for cancer patients. An evaluation of the immune profile and/or the molecular profile of the tumor is expected to optimize the treatment for a better chance of therapeutic benefit. This can also apply to pediatric tumors. Here we will describe the main immunological biomarkers that have been described in patients with pediatric tumor.
Published: 2017
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35. Gene Therapy in a Patient with Sickle Cell Disease

Author: Bénédicte Neven, Emmanuel Payen, Olivier Negre, Yves Beuzard, Mariane de Montalembert, Pablo Bartolucci, Laure Caccavelli, Thibaud Lefebvre, Robert W. Ross, Laura Sandler, Philippe Leboulch, Stany Chrétien, Michaela Semeraro, Sandeep Soni, Hervé Puy, Salima Hacein-Bey-Abina, Stéphane Blanche, Gabor Istvan Veres, Jean-Antoine Ribeil, Wassim El Nemer, David Grevent, Jean-François Meritet, Philippe Bourget, Alessandra Magnani, Marina Cavazzana, Elisa Magrin, Leslie Weber, Département de Biothérapie [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5), Centre d’Investigation Clinique en Biothérapies [CHU Pitié-Salpêtrière] (CIC-BT), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Unité de Technologies Chimiques et Biologiques pour la Santé (UTCBS - UM 4 (UMR 8258 / U1022)), Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Laboratoire d'Immunologie [AP-HP Hôpital Kremlin-Bicêtre] (GHU Paris-Sud), AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Institut des Maladies Emergentes et des Thérapies Innovantes (IMETI), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Commission de l'Energie Atomique et Alternative [Fontenay-aux-Roses], Université Paris-Sud - Paris 11 (UP11), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), CIC - Mère Enfant Necker Cochin Paris Centre (CIC 1419), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Université des Antilles (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'Excellence : Biogenèse et pathologies du globule rouge (Labex Gr-Ex), Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), Centre de Référence des Syndromes Drépanocytaires Majeurs [AP-HP 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), GR-Ex, Laboratoire d'Excellence, GR-Ex, Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), Hôpital Cochin [AP-HP], Bluebird bio, Inc, Service de pédiatrie générale [CHU Necker], Brigham & Women’s Hospital [Boston] (BWH), Harvard Medical School [Boston] (HMS), Ramathibodi Hospital [Bangkok, Thailand] (Mahidol University), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [AP-HP], Centre d'investigation clinique Biothérapie [CHU Pitié-Salpêtrière] (CIC-BTi), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA), Université Paris Diderot - Paris 7 (UPD7)-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, Payen, Emmanuel, Centre d'investigation clinique pluridisciplinaire [CHU Pitié Salpêtrière] (CIC-P 1421), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP]
Subjects: [SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, 0301 basic medicine, Oncology, medicine.medical_specialty, Pathology, [SDV.BIO]Life Sciences [q-bio]/Biotechnology, Anemia, Genetic enhancement, 03 medical and health sciences, hemic and lymphatic diseases, Internal medicine, medicine, Bluebird Bio, Missense mutation, Adverse effect, ComputingMilieux_MISCELLANEOUS, business.industry, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, General Medicine, medicine.disease, [SDV.BIO] Life Sciences [q-bio]/Biotechnology, 3. Good health, Haematopoiesis, 030104 developmental biology, Stem cell, business, Busulfan, medicine.drug
Abstract: Sickle cell disease results from a homozygous missense mutation in the ß-globin gene that causes polymerization of hemoglobin S. Gene therapy for patients with this disorder is complicated by the complex cellular abnormalities and challenges in achieving effective, persistent inhibition of polymerization of hemoglobin S. We describe our first patient treated with lentiviral vector-mediated addition of an antisickling ß-globin gene into autologous hematopoietic stem cells. Adverse events were consistent with busulfan conditioning. Fifteen months after treatment, the level of therapeutic antisickling ß-globin remained high (approximately 50% of ß-like-globin chains) without recurrence of sickle crises and with correction of the biologic hallmarks of the disease. (Funded by Bluebird Bio and others; HGB-205 ClinicalTrials.gov number, NCT02151526 .).
Published: 2017
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36. Results from the Completed Hgb-205 Trial of Lentiglobin for β-Thalassemia and Lentiglobin for Sickle Cell Disease Gene Therapy

Author: Mariane de Montalembert, Elisa Magrin, Despina Moshous, Pablo Bartolucci, Marilyne Poirée, Fabrice Monpoux, Nicolas Hebert, David Grévent, Hervé Puy, Jean-François Meritet, Marina Cavazzana, Thibaud Lefebvre, Annarita Miccio, Isabelle Guichard, Catherine Poirot, Michaela Semeraro, Olivier Hermine, Erin Whitney, Felipe Suarez, Jean-Antoine Ribeil, Isabelle Funck-Brentano, Wassim El Nemer, Alessandra Magnani, Laure Joseph, François Lefrère, Valentine Brousse, Mohammed Asmal, Jean-Sebastien Diana, Bénédicte Neven, Philippe Bourget, Marisa Gayron, and Wenmei Huang
Subjects: medicine.medical_specialty, Blood transfusion, business.industry, Thalassemia, medicine.medical_treatment, Immunology, Cell Biology, Hematology, medicine.disease, Biochemistry, Sickle cell anemia, Hemoglobin A, Internal medicine, medicine, Bluebird Bio, Packed red blood cells, Adverse effect, business, Busulfan, medicine.drug
Abstract: Background LentiGlobin gene therapy contains autologous CD34+ hematopoietic stem cells (HSCs) transduced with the BB305 lentiviral vector (LVV), encoding human β-globin with a T87Q substitution. This substitution confers anti-sickling properties to the gene therapy-derived hemoglobin (HbAT87Q) and allows for its quantification in transduced HSCs. The proof of concept for LentiGlobin gene therapy in patients with transfusion-dependent β-thalassemia (TDT) and sickle cell disease (SCD) was established in the recently completed HGB-205 study (NCT02151526). Herein, we provide the safety and efficacy outcomes and long-term follow-up data for all 7 treated patients, 4 with TDT and 3 with SCD. Methods Patients 5−35 years old with TDT (≥ 100 mL/kg of packed red blood cells [pRBCs]/year) or severe SCD (e.g., ≥ 2 acute chest syndromes [ACS] or ≥ 2 vaso-occlusive crises in the preceding year or the year before regular transfusions) were enrolled. CD34+ HSCs were obtained by mobilization and apheresis in patients with TDT or by bone marrow harvest in patients with SCD. Following collection, cells were transduced with the BB305 LVV. Patients underwent busulfan myeloablative conditioning and were infused with transduced cells. Patients were monitored for engraftment, adverse events (AEs), HbAT87Q levels, and other hematologic and clinical parameters. After 2 years in HGB-205, patients transitioned into the long-term follow-up study, LTF-303 (NCT02633943). Summary statistics are shown as median (min-max). Results As of June 2019, patients with TDT (n=4) and SCD (n=3) had a median follow-up of 49.6 (40.5-60.6) and 28.5 (25.5-52.5) months, respectively. Table 1 shows patient and drug product characteristics and several key efficacy outcomes. All patients achieved HSC engraftment. LentiGlobin safety profile was consistent with busulfan myeloablative conditioning and, in case of SCD, with the underlying disease state. The most common non-hematologic Grade ≥ 3 AEs post-LentiGlobin gene therapy (≥ 2 patients) for patients with TDT were stomatitis (n=4) and increased aspartate aminotransferase (n=2), and for patients with SCD were ACS (n=2) and vaso-occlusive pain (n=2). In all 4 patients with TDT, total Hb and HbAT87Q levels remained generally stable up to 5 years post-LentiGlobin infusion. Three of 4 patients achieved transfusion independence (TI; defined as weighted average Hb ≥ 9g/dL without pRBC transfusions for ≥ 12 months), for an ongoing duration of 56.3 (38.2-57.6) months. Weighted average total Hb during TI was 11.4 (10.5-13.0) g/dL. One patient has been off transfusions for 37.5 months and had total Hb of 7.7 g/dL, which was below the ≥ 9 g/dL requirement to meet the protocol definition of TI. At last visit, HbAT87Q levels in these 4 patients ranged from 6.2-11.2 g/dL, which contributed 73.8-86.8% of the total Hb. The first patient treated with LentiGlobin for SCD experienced one vaso-occlusive pain episode, which developed at 30 months after LentiGlobin gene therapy following a case of acute gastroenteritis with fever and dehydration. The second SCD patient had 2 serious AEs (SAEs) of ACS approximately 6 and 8 months after LentiGlobin gene therapy. The patient resumed chronic pRBC transfusions and hydroxyurea treatment and subsequently experienced 2 SAEs of vaso-occlusive pain; no additional SAEs of vaso-occlusive pain or ACS were reported during the last 16 months of follow-up after LentiGlobin infusion. The third SCD patient had no episodes of vaso-occlusive pain or ACS during 25.5 months of follow-up post-LentiGlobin gene therapy as of the data cut-off. Two patients with SCD who have been off chronic pRBC transfusions, showed improvement in hemolysis markers post-LentiGlobin treatment and stabilization of HbAT87Q expression at approximately 6 months post-LentiGlobin infusion. Total Hb levels for patients with SCD at last visit were 13.0 g/dL (patient 1), 9.4 g/dL (patient 2), and 9.8 g/dL (patient 3), with corresponding HbAT87Q contributions of 47.9%, 7.9%, and 25.8%, respectively. Summary With up to 5 years of follow-up, treatment with LentiGlobin gene therapy was well tolerated and resulted in improvement in hematologic parameters and disease-related symptoms. Further results from the completed study will be presented. Disclosures Hermine: Celgene: Research Funding; Novartis: Research Funding; AB science: Consultancy, Equity Ownership, Honoraria, Research Funding. Brousse:bluebird bio, Inc: Consultancy; AddMedica: Consultancy. El Nemer:Hemanext: Other: Other. Bartolucci:Novartis: Membership on an entity's Board of Directors or advisory committees; AddMedica: Honoraria, Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; HEMANEXT: Membership on an entity's Board of Directors or advisory committees. Asmal:bluebird bio, Inc: Employment, Equity Ownership. Whitney:bluebird bio, Inc: Employment, Equity Ownership. Gayron:bluebird bio, Inc: Employment, Equity Ownership. Huang:bluebird bio, Inc.: Employment, Equity Ownership. de Montalembert:AddMedica: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; bluebird bio, Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Ribeil:bluebird bio, Inc: Employment, Equity Ownership. Cavazzana:SmartImmune: Other: Founder.
Published: 2019
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37. Metabolic effects of fasting on human and mouse blood in vivo

Author: Guido Kroemer, Didier Métivier, Frank Madeo, Michaela Semeraro, Francesca Castoldi, Chloé Bordenave, David Enot, Sylvère Durand, Federico Pietrocola, M. Chiara Maiuri, Yohann Demont, Alexis Chery, Juliette Humeau, Sarah Levesque, Jonathan Pol, Elisa E. Baracco, José Manuel Bravo-San Pedro, Pietrocola, Federico, Demont, Yohann, Castoldi, Francesca, Enot, David, Durand, Sylvère, Semeraro, Michaela, Baracco, Elisa Elena, Pol, Jonathan, Bravo San Pedro, Jose Manuel, Bordenave, Chloé, Levesque, Sarah, Humeau, Juliette, Chery, Alexi, Métivier, Didier, Madeo, Frank, Maiuri, MARIA CHIARA, and Kroemer, Guido
Subjects: 0301 basic medicine, Adult, Male, medicine.medical_specialty, Basic Research Papers, Neutrophils, Cell, Biology, Immunofluorescence, 03 medical and health sciences, chemistry.chemical_compound, Young Adult, longevity, In vivo, Internal medicine, medicine, Metabolome, Autophagy, Animals, Humans, Metabolomics, Molecular Biology, Cells, Cultured, medicine.diagnostic_test, Lysine, IGF1, p62, Leupeptin, protein acetylation, Acetylation, Cell Biology, Fasting, Middle Aged, Mice, Inbred C57BL, 030104 developmental biology, Endocrinology, medicine.anatomical_structure, chemistry, Cytoplasm, Starvation, Female, caloric restriction, leukocyte, Intracellular
Abstract: Starvation is a strong physiological stimulus of macroautophagy/autophagy. In this study, we addressed the question as to whether it would be possible to measure autophagy in blood cells after nutrient deprivation. Fasting of mice for 48 h (which causes ∼20% weight loss) or starvation of human volunteers for up to 4 d (which causes
Published: 2017

38. NKp30 isoforms and NKp30 ligands are predictive biomarkers of response to imatinib mesylate in metastatic GIST patients

Author: Serge Leyvraz, Katrin S. Reiners, Christos Christidis, Jean-Yves Blay, Jonathan M. Pitt, Marion Lambert, Aurélien Marabelle, Frédéric Vély, Alexandre Ivagnes, Jean-François Emile, Christian Auclair, Benedita Rocha, Axel Le Cesne, Loic Chaigneau, Christelle Piperoglou, Kariman Chaba, Philippe Terrier, Eric Vivier, Nicolas Isambert, Julien Adam, Sylvie Rusakiewicz, Pierre Validire, Bruno Landi, Thierry Perniceni, Laurence Zitvogel, Sarah Jegou, Sylvie Bonvalot, Michaela Semeraro, Sophie Caillat-Zucman, David Enot, Sandrine Aspeslagh, Aurélie Perier, Christophe Borg, Vichnou Poirier-Colame, Anne Berger, Alexander M.M. Eggermont, Antoine Toubert, Niels Halama, Joachim Koch, Elke Pogge von Strandmann, Olivier Mir, Julien Domont, Anne Caignard, Jean-Michel Coindre, Immunologie des tumeurs et immunothérapie (UMR 1015), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Necker - Enfants Malades [AP-HP], Institut Gustave Roussy (IGR), Université Paris-Sud 11 - Faculté de médecine (UP11 UFR Médecine), Université Paris-Saclay, Département d’Innovation Thérapeutique et essais précoces [Gustave Roussy] (DITEP), Laboratoire d'Immunologie [Hôpital de la Conception - APHM], Assistance Publique - Hôpitaux de Marseille (APHM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital de la Conception [CHU - APHM] (LA CONCEPTION )-Centre National de la Recherche Scientifique (CNRS), 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), Service d'Immunologie [AP-HM], Hôpital de la Conception [CHU - APHM] (LA CONCEPTION ), Microorganismes, Molécules Bioactives et Physiopathologie Intestinale (LBM-E4), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de rhumatologie, inflammation-immunopathologie- biothérapie [CHU Saint-Antoine] (DHU i2B ), CHU Saint-Antoine [APHP]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Service d'oncologie Médicale, Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Hôpital Jean Minjoz, Departement d'Anatomopathologie, Institut Mutualiste de Montsouris (IMM), Hellenic Open University [Patras], Département de chirurgie digestive, Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Laboratoire d'Excellence : Lipoprotéines et Santé : prévention et Traitement des maladies Inflammatoires et du Cancer (LabEx LipSTIC), Institut National de la Recherche Agronomique (INRA)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Paris-Sud - Paris 11 (UP11)-École pratique des hautes études (EPHE)-Institut Gustave Roussy (IGR)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc (CRLCC - CGFL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Fédération Francophone de la Cancérologie Digestive, FFCD-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-France-Comté] (EFS [Bourgogne-France-Comté])-Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Université de Franche-Comté (UFC)-Université de Montpellier (UM), Département d'oncologie médicale [Centre Georges-François Leclerc], Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc (CRLCC - CGFL), Centre Jean-bernard, Département de biologie et pathologie médicales [Gustave Roussy], Biomarqueurs prédictifs et nouvelles stratégies moléculaires en thérapeutique anticancéreuse (U981), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Service de Pathologie, Institut Bergonié, Service de pathologie [CHU Ambroise Paré], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Ambroise Paré, Immunologie et Cancérologie Intégratives (CRC - Inserm U1138), Centre de Recherche des Cordeliers (CRC), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Différenciation et physiologie des lymphocytes T (U1020), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), Alloimmunité-Autoimmunité-Transplantation (A2T), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7), Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7), Plateforme de métabolomique, Direction de la recherche [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Virologie et Immunologie Moléculaires, Université Francois Rabelais [Tours], Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'immunologie, AP-HP Hôpital universitaire Robert-Debré [Paris], Laboratoire de Biologie et de Pharmacologie Appliquée (LBPA), École normale supérieure - Cachan (ENS Cachan)-Centre National de la Recherche Scientifique (CNRS), Service d'Oncologie Médicale [CHRU Besançon], Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Université de Franche-Comté (UFC), Equipe 11, Centre de Recherche en Cancérologie de Lyon (CRCL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Département de médecine oncologique [Gustave Roussy], AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Centre d'Investigation Clinique en Biotherapie des cancers (CIC 1428 , CBT 507 ), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Immunologie des tumeurs et immunothérapie ( UMR 1015 ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut Gustave Roussy ( IGR ), Université Paris-Sud 11 - Faculté de médecine ( UP11 UFR Médecine ), Département d’Innovation Thérapeutique et essais précoces [Gustave Roussy] ( DITEP ), Assistance Publique - Hôpitaux de Marseille ( APHM ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Hôpital de la Conception [CHU - APHM] ( LA CONCEPTION ) -Centre National de la Recherche Scientifique ( CNRS ), Centre d'Immunologie de Marseille - Luminy ( CIML ), Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Hôpital de la Conception [CHU - APHM] ( LA CONCEPTION ), Microorganismes, Molécules Bioactives et Physiopathologie Intestinale ( LBM-E4 ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service de rhumatologie, inflammation-immunopathologie- biothérapie [CHU Saint-Antoine] ( DHU i2B ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Saint-Antoine [APHP], Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Hôpital Jean Minjoz, Institut Mutualiste de Montsouris ( IMM ), Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Laboratoire d'Excellence : Lipoprotéines et Santé : prévention et Traitement des maladies Inflammatoires et du Cancer ( LabEx LipSTIC ), Institut National de la Recherche Agronomique ( INRA ) -Université Montpellier 2 - Sciences et Techniques ( UM2 ) -Université Paris-Sud - Paris 11 ( UP11 ) -École pratique des hautes études ( EPHE ) -Institut Gustave Roussy ( IGR ) -Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ) -Université de Bourgogne ( UB ) -Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ) -Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Fédération Francophone de la Cancérologie Digestive, FFCD-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-France-Comté] ( EFS [Bourgogne-France-Comté] ) -Centre National de la Recherche Scientifique ( CNRS ) -Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Université de Franche-Comté ( UFC ), 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 ), Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ), Biomarqueurs prédictifs et nouvelles stratégies moléculaires en thérapeutique anticancéreuse ( U981 ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Ambroise Paré, Immunologie et Cancérologie Intégratives ( CRC - Inserm U1138 ), Centre de Recherche des Cordeliers ( CRC ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -École pratique des hautes études ( EPHE ) -Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -École pratique des hautes études ( EPHE ) -Université Paris Diderot - Paris 7 ( UPD7 ), Différenciation et physiologie des lymphocytes T ( U1020 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), 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 ), Alloimmunité-Autoimmunité-Transplantation ( A2T ), Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut Universitaire d'Hématologie ( IUH ), Université Paris Diderot - Paris 7 ( UPD7 ), Institut Gustave Roussy ( IGR ) -Institut Gustave Roussy ( IGR ), Centre de recherche sur l'Inflammation ( CRI ), Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Laboratoire de Biologie et de Pharmacologie Appliquée ( LBPA ), École normale supérieure - Cachan ( ENS Cachan ) -Centre National de la Recherche Scientifique ( CNRS ), Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Université de Franche-Comté ( UFC ), Centre de Recherche en Cancérologie de Lyon ( CRCL ), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -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 ), Centre d'Investigation Clinique en Biotherapie des cancers ( CIC 1428 , CBT 507 ), Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris-Sud - Paris 11 - Faculté de médecine (UP11 UFR Médecine), Université Paris-Sud - Paris 11 (UP11), Assistance Publique - Hôpitaux de Marseille (APHM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital de la Conception [CHU - APHM] (LA CONCEPTION)-Centre National de la Recherche Scientifique (CNRS), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), Service de rhumatologie [CHU Saint-Antoine], CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Institut National de la Recherche Agronomique (INRA)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Paris-Sud - Paris 11 (UP11)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Gustave Roussy (IGR)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM)-Fédération Francophone de la Cancérologie Digestive, FFCD-Université de Montpellier (UM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER, Institut Bergonié [Bordeaux], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Ambroise Paré [AP-HP], Université Pierre et Marie Curie - Paris 6 (UPMC)-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)-Université Pierre et Marie Curie - Paris 6 (UPMC)-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), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), University Medical Centre of the Johannes Gutenberg University Mainz, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), 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), Institut Gustave Roussy (IGR)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Gustave Roussy (IGR)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM)-Fédération Francophone de la Cancérologie Digestive, FFCD-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université de Montpellier (UM), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Cachan (ENS Cachan), Medical Oncology, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut National de la Recherche Agronomique (INRA)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Paris-Sud - Paris 11 (UP11)-École Pratique des Hautes Études (EPHE), UNICANCER-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM)-Fédération Francophone de la Cancérologie Digestive, FFCD-Université de Montpellier (UM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS BFC)-Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Université Pierre et Marie Curie - Paris 6 (UPMC)-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)-Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), and Johannes Gutenberg - Universität Mainz = Johannes Gutenberg University (JGU)
Subjects: 0301 basic medicine, medicine.medical_treatment, Immunology, PDGFRA, Targeted therapy, 03 medical and health sciences, 0302 clinical medicine, medicine, Immunology and Allergy, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, neoplasms, Original Research, Tumor microenvironment, GiST, business.industry, Cancer, medicine.disease, digestive system diseases, 3. Good health, Immunosurveillance, 030104 developmental biology, Imatinib mesylate, Oncology, 030220 oncology & carcinogenesis, Cancer research, [SDV.IMM]Life Sciences [q-bio]/Immunology, business, Tyrosine kinase
Abstract: International audience; Despite effective targeted therapy acting on KIT and PDGFRA tyrosine kinases, gastrointestinal stromal tumors (GIST) escape treatment by acquiring mutations conveying resistance to imatinib mesylate (IM). Following the identification of NKp30-based immunosurveillance of GIST and the off-target effects of IM on NK cell functions, we investigated the predictive value of NKp30 isoforms and NKp30 soluble ligands in blood for the clinical response to IM. The relative expression and the proportions of NKp30 isoforms markedly impacted both event-free and overall survival, in two independent cohorts of metastatic GIST. Phenotypes based on disbalanced NKp30B/NKp30C ratio (Delta BClow) and low expression levels of NKp30A were identified in one third of patients with dismal prognosis across molecular subtypes. This Delta BClow blood phenotype was associated with a pro-inflammatory and immunosuppressive tumor microenvironment. In addition, detectable levels of the NKp30 ligand sB7-H6 predicted a worse prognosis in metastatic GIST. Soluble BAG6, an alternate ligand for NKp30 was associated with low NKp30 transcription and had additional predictive value in GIST patients with high NKp30 expression. Such GIST microenvironments could be rescued by therapy based on rIFN-alpha and anti-TRAIL mAb which reinstated innate immunity.
Published: 2017
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39. Immune Infiltrates Are Prognostic Factors in Localized Gastrointestinal Stromal Tumors

Author: Jean-François Emile, Frédéric Commo, Nadege Vimond, Guido Kroemer, Axel Le Cesne, Dirk Jäger, Sylvie Rusakiewicz, Philippe Terrier, Federico Garrido, Laurence Zitvogel, Alexander M.M. Eggermont, Jean-Yves Blay, Paule Opolon, Nicolas Isambert, Valérie Le Brun-Ly, Mélanie Desbois, Patrice Dubreuil, Vichnou Poirier-Colame, Isabelle Cremer, Nathalie Chaput, Michaela Semeraro, Niels Halama, Rosa Mendez, Loic Chaigneau, Kariman Chaba, Caroline Flament, Clara Locher, Ángel Concha, Sylvie Bonvalot, Jean-Michel Coindre, Matthieu Sarabi, and Anne Caignard
Subjects: Adult, Male, Cancer Research, Stromal cell, CD3 Complex, Gastrointestinal Stromal Tumors, T-Lymphocytes, Kaplan-Meier Estimate, Biology, Piperazines, Cohort Studies, 03 medical and health sciences, Lymphocytes, Tumor-Infiltrating, 0302 clinical medicine, Immune system, medicine, Humans, Protein Kinase Inhibitors, neoplasms, Aged, 030304 developmental biology, Aged, 80 and over, 0303 health sciences, GiST, Natural Cytotoxicity Triggering Receptor 1, FOXP3, Cancer, Forkhead Transcription Factors, Middle Aged, Flow Cytometry, Prognosis, medicine.disease, Immunohistochemistry, CD56 Antigen, 3. Good health, Killer Cells, Natural, Immunosurveillance, Pyrimidines, Treatment Outcome, Imatinib mesylate, Oncology, 030220 oncology & carcinogenesis, Benzamides, Multivariate Analysis, Immunology, Imatinib Mesylate, Cancer research, Female, CD8
Abstract: Cancer immunosurveillance relies on effector/memory tumor-infiltrating CD8+ T cells with a T-helper cell 1 (TH1) profile. Evidence for a natural killer (NK) cell-based control of human malignancies is still largely missing. The KIT tyrosine kinase inhibitor imatinib mesylate markedly prolongs the survival of patients with gastrointestinal stromal tumors (GIST) by direct effects on tumor cells as well as by indirect immunostimulatory effects on T and NK cells. Here, we investigated the prognostic value of tumor-infiltrating lymphocytes (TIL) expressing CD3, Foxp3, or NKp46 (NCR1) in a cohort of patients with localized GIST. We found that CD3+ TIL were highly activated in GIST and were especially enriched in areas of the tumor that conserve class I MHC expression despite imatinib mesylate treatment. High densities of CD3+ TIL predicted progression-free survival (PFS) in multivariate analyses. Moreover, GIST were infiltrated by a homogeneous subset of cytokine-secreting CD56bright (NCAM1) NK cells that accumulated in tumor foci after imatinib mesylate treatment. The density of the NK infiltrate independently predicted PFS and added prognostic information to the Miettinen score, as well as to the KIT mutational status. NK and T lymphocytes preferentially distributed to distinct areas of tumor sections and probably contributed independently to GIST immunosurveillance. These findings encourage the prospective validation of immune biomarkers for optimal risk stratification of patients with GIST. Cancer Res; 73(12); 3499–510. ©2013 AACR.
Published: 2013
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40. The ratio of CD8

Author: Michaela, Semeraro, Julien, Adam, Gautier, Stoll, Emilie, Louvet, Kariman, Chaba, Vichnou, Poirier-Colame, Allan, Sauvat, Laura, Senovilla, Erika, Vacchelli, Norma, Bloy, Juliette, Humeau, Aitziber, Buque, Oliver, Kepp, Laurence, Zitvogel, Fabrice, André, Marie-Christine, Mathieu, Suzette, Delaloge, and Guido, Kroemer
Subjects: Original Research
Abstract: In a series of 248 tumor samples obtained from image-guided biopsies from patients diagnosed with ductal carcinoma in situ of the breast, we attempted to identify biomarkers that predict microinfiltration at definitive surgery or relapse during follow-up. For this, we used immunohistochemical methods, followed by automated image analyses, to measure the mean diameter of nuclei (which correlates with ploidy), the phosphorylation of eukaryotic initiation factor 2α (eIF2α, which reflects endoplasmic reticulum stress) as well as the density and ratio of CD8+ cytotoxic T lymphocytes and FOXP3+ regulatory T cells. The median nuclear diameter of malignant cells correlated with eIF2α phosphorylation (in cancerous tissue), which in turn correlated with the density of the CD8+ infiltrate and the CD8+/FOXP3 ratio (both in cancerous and the adjacent non-cancerous parenchyma). Neither microinfiltration nor lymph node involvement was associated with the probability of relapse. Both correlated positively with the CD8+/FOXP3 ratio in the malignant area. In contrast, relapse was associated with a paucity of the CD8+ infiltrate as well as an unfavorable CD8+/FOXP3 ratio, both in malignant and non-malignant parenchyma. The combined analysis of the CD8+/FOXP3 ratio in cancerous and non-cancerous tissues revealed a significant impact of their interaction on the probability of relapse, but not on the presence of microinfiltration or lymph node metastasis. Altogether, these results support the idea of an immunosurveillance system that determines the risk of relapse in ductal carcinoma in situ of the breast.
Published: 2016

41. End of life care in adolescents and young adults with cancer: Experience of the adolescent unit of the Institut Gustave Roussy

Author: Nathalie Gaspar, G. Marioni, Sarah Cohen-Gogo, Christelle Dufour, Dominique Valteau-Couanet, Sophie Laurent, Martine Gabolde, Laurence Brugières, and Michaela Semeraro
Subjects: Adult, Male, Cancer Research, Pediatrics, medicine.medical_specialty, Time Factors, Palliative care, Adolescent, Conscious Sedation, Young Adult, Institut Gustave Roussy, Neoplasms, medicine, Humans, Young adult, Retrospective Studies, Cause of death, Terminal Care, business.industry, Retrospective cohort study, medicine.disease, Pain, Intractable, Hospitalization, Clinical trial, Oncology, Female, business, End-of-life care, Progressive disease
Abstract: Background Cancer is the third leading cause of death in adolescents and young adults (AYA). Little is known, however, about how end-of-life unfolds for those who die of progressive disease. In order to better evaluate the specific needs of these patients, we performed this study providing baseline information about end-of-life care patterns for AYA in our department. Patients A standardised form was used to collect data concerning all 45 patients treated for a malignancy in the Paediatric and Adolescent Oncology Department at the Gustave Roussy Institute, and who had died of progressive disease above 13 years of age, over a two-year period. Results The main diagnoses were sarcomas and brain tumours. Previous cancer-directed treatment included a median of 3 different chemotherapy regimens, high-dose chemotherapy with haematopoietic stem cell support for 13% and radiotherapy for 40%. One in every four patients had been enrolled in a clinical trial at diagnosis. Median survival was 18 months after the diagnosis and 7 months after the first relapse/progression. During the last week of life, the median number of physical symptoms was 4, mostly pain and dyspnoea. Frequent psychological symptoms were sadness, anxiety, fear and guilt. End-of-life care included transfusions, artificial nutrition, corticosteroids, pain control, sedation but also palliative chemotherapy. The median time spent in hospital during the last month of life was 16 days. Most patients had died in hospital. Conclusions The terminally ill adolescent displays notable challenges to care providers and requires a holistic approach with the help of a multidisciplinary team.
Published: 2011
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42. GDF15 and Erythroferrone Mark Erythropoietic Response to ACE-011 (Sotatercept) in Thalassemia

Author: Jean Benoît Arlet, Jun Zou, Ersi Voskaridou, Chantal Brouzes, Olivier Hermine, Maciej W Garbowski, Patricia Evans, Raffaella Origa, Tatiana Zinger, Abderrahmane Laadem, Victoria Sung, Jean-Antoine Ribeil, Ali T. Taher, Gian Luca Forni, Giovanna Graziadei, Frédéric Galactéros, Maria Domenica Cappellini, Dimana Miteva, Michaela Semeraro, Martin Schwickart, and John B. Porter
Subjects: Ineffective erythropoiesis, Oncology, medicine.medical_specialty, biology, business.industry, Transferrin saturation, Thalassemia, Immunology, Cell Biology, Hematology, Erythroferrone, medicine.disease_cause, medicine.disease, Biochemistry, Hepcidin, Internal medicine, biology.protein, Medicine, Erythropoiesis, GDF15, business, Soluble transferrin receptor
Abstract: Background The hemoglobin (Hb) response to the activin receptor type IIA ligand trap ACE-011 (Sotatercept) in non-transfusion-dependent thalassemia (NTDT), and the transfusion requirement response in TDT are described, but the mechanisms of action, clinical predictors and markers of response, are unclear. In principle, ACE-011 may act on early and/or late erythroblasts to decrease ineffective erythropoiesis (IE), both in healthy subjects and in thalassemia. As erythropoiesis intimately links to iron metabolism, changes in markers of iron metabolism relative to those of erythropoiesis may inform the mechanisms and developmental stage at which ACE-011 acts. Methods Markers of IE and iron metabolism in 46 thalassemia patients (30 NTDT, 16 TDT) were taken before and during a median follow up of 722.5 days, (IQR 830.5, range 152-1427) of escalating doses of ACE-011 (3-weekly 0.1 to 1.0 mg/kg s.c. injections), depending on the protocol, as part of the approved study (Cappellini, et al. 2018 under review). Markers of erythropoiesis included Hb, Reticulocytes (Ret), soluble transferrin receptor 1 (sTfR), growth differentiation factor 11 and 15 (GDF11, GDF15), erythroferrone (ERFE). Markers of iron metabolism included plasma hepcidin, serum ferritin (SF), transferrin saturation (TSAT), and non-transferrin-bound iron (NTBI). Data were analyzed using longitudinal multilevel model for change (LMMC) on STATA (Version 14) as generalized linear mixed model with random and fixed effects to account for repeated measures and highly complex temporal data structure. Final LMMCs were built to explain the change in Hb from baseline and the behavior of key biomarkers. Independent variables were entered into the models based on the study design (predictors from design) and theoretical background (predictors of interest and control variables). P value Results Predictors of response. In NTDT, Hb response associated positively with dose and duration of exposure (both at p Biomarker changes with time In NTDT, significant changes with time on study were increases in Hb, sTfR, ERFE and Ret and decreases in hepcidin, bilirubin, and NTBI. GDF15 showed no change. In TDT, GDF15, sTfR and ERFE increased, whereas hepcidin decreased. The Hb change was insignificant in TDT (as expected per protocol) and was dose-independent, however the mean 41% reduction in transfusion iron load rate (ILR) was dose dependent, implying an equivalent net production of Hb in TDT (Table 1). Other significant relationships Absolute hepcidin level in NTDT and TDT was negatively predicted by ERFE (p Interpretation and conclusions NTDT patients allow a cleaner interpretation of biomarker changes as these are confounded in TDT by increased bone marrow stress from less transfusion. In NTDT, sTfR and ERFE (total erythropoiesis) increase on study while GDF15 (IE) and EPO do not. Thus Hb gain may result from increased effectiveness of late stage erythropoiesis (sTfR+ and ERFE+) possibly from decreased apoptosis and more rapid maturation (Carrancio et al, BJH 2014) in this compartment. We speculate that increased survival of those erythroid progenitor cells expressing TfR (and hence sTfR) and ERFE (hence increased ERFE) also explains the observed hepcidin reduction. Despite exposure to lower hepcidin, there is no iron loading: NTBI falls against stable SF in NTDT, consistent with shunting of iron into the sink of effective erythropoiesis. The reduction in GDF11 in vivo, not previously reported for ACE-011, is also consistent with increased apoptosis of the early progenitor pool and with improved erythroblast differentiation relative to proliferation as suggested in murine β-thalassemia treated with ACE-011 (Dussiot, et al. Nat Med 2014). Disclosures Garbowski: Vifor: Consultancy. Hermine:Erythec: Research Funding; AB Science: Consultancy, Equity Ownership, Honoraria, Research Funding; Celgene Corporation: Research Funding; Hybrigenics: Research Funding; Novartis: Research Funding. Cappellini:Sanofi/Genzyme: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Vifor: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees. Origa:Bluebird Bio: Consultancy; Novartis: Honoraria; Cerus Corporation: Research Funding; Apopharma: Honoraria. Forni:Celgene: Research Funding; Novartis: Other: travel expenses, Research Funding; Shire: Research Funding; Roche: Consultancy; Apopharma: Other: DSM Board. Voskaridou:Acceleron: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene Corp: Membership on an entity's Board of Directors or advisory committees, Research Funding. Galactéros:Addmedica: Other: grant; Novartis: Other: grant. Taher:Novartis: Consultancy, Honoraria, Research Funding; La Jolla Pharmaceutical: Research Funding; Protagonist Therapeutics: Consultancy; Celgene Corp.: Research Funding; Ionis Pharmaceuticals: Consultancy. Ribeil:bluebird bio: Consultancy; Vitalaire: Other: grant; Addmedica: Other: grant; Cydan: Consultancy; Novartis: Consultancy. Laadem:Celgene: Employment, Equity Ownership. Miteva:Celgene Corporation: Employment, Other: grants. Zou:Celgene Corporation: Employment, Equity Ownership. Zinger:Celgene Corporation: Employment. Schwickart:Celgene Corporation: Employment, Equity Ownership. Sung:Celgene Corporation: Employment, Equity Ownership. Porter:Novartis: Consultancy; Cerus: Honoraria; Agios: Honoraria.
Published: 2018
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43. A predictor of unfavourable outcome in neutropenic paediatric patients presenting with fever of unknown origin

Author: Loredana Amoroso, Caroline Thomee, Olivier Hartmann, Michaela Semeraro, Marie-Cécile Le Deley, Marie Dubrel, Estelle Rolland, Frédéric Troalen, and David D. Rosselini
Subjects: medicine.medical_specialty, business.industry, Cancer, Hematology, medicine.disease, Outcome (game theory), Procalcitonin, Oncology, Quality of life, Internal medicine, Pediatrics, Perinatology and Child Health, medicine, Fever of unknown origin, Intensive care medicine, business, Prospective cohort study, Febrile neutropenia, Paediatric patients
Abstract: Background No sensitive, specific marker able to discriminate favourable or unfavourable outcome of fever of unknown origin (FUO) at diagnosis has been identified. Procalcitonin, a recently assessed infection marker, may be useful in predicting the outcome of FUO. Methods We conducted a prospective study examining the following variables: age 0.5–22 years; solid tumour diagnosis; chemotherapy-related grade-4 febrile neutropenia (FN). A complete clinical, bacteriological and biological evaluation was performed at hospital admission (H0). Other investigations depended on clinical status. FUO was considered to be of unfavourable outcome if the fever was persistent or re-appeared at day 3 (or later), or if secondary clinical or microbiological infection occurred. To validate the results of the analysis the data set was randomly split into a training set and a validation set. Results Out of 172 episodes of FN, 136 episodes were classified as FUO (80%). Seventy-two (53%) were included in this study. PCT values were significantly higher in episodes of unfavourable outcome (P
Published: 2009
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44. Immunophenotyping of Stage III Melanoma Reveals Parameters Associated with Patient Prognosis

Author: Lieping Chen, François Aubin, Sylvie Rusakiewicz, Laurence Zitvogel, Guido Kroemer, Sarah Jegou, Alexander M.M. Eggermont, Nicolas Jacquelot, Maria Paula Roberti, Aurélien Marabelle, Benjamin Weide, Maha Ayyoub, Holbrook E Kohrt, Byoung S. Kwon, David Enot, Stéphane Dalle, Camila Flores, Andrea Cavalcanti, Christophe Borg, Michaela Semeraro, HAL UPMC, Gestionnaire, Immunologie des tumeurs et immunothérapie (UMR 1015), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris-Saclay, Centre d'Investigation Clinique en Biotherapie des cancers (CIC 1428 , CBT 507 ), Institut Gustave Roussy (IGR)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Plateforme de métabolomique, Direction de la recherche [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Pierre et Marie Curie - Paris 6 (UPMC), Yale University [New Haven], National Cancer Center Korea, Tulane University, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), 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), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen, Hospices Civils de Lyon (HCL), Stanford School of Medicine [Stanford], Stanford Medicine, Stanford University-Stanford University, Centre de Recherche des Cordeliers (CRC), Université Pierre et Marie Curie - Paris 6 (UPMC)-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), Apoptose, cancer et immunité (Equipe labellisée Ligue contre le cancer - CRC - Inserm U1138), Institut Gustave Roussy (IGR)-Centre de Recherche des Cordeliers (CRC), 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)-Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Université Paris Descartes - Paris 5 (UPD5), 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), Institut Gustave Roussy (IGR), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-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]), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Immunologie des tumeurs et immunothérapie ( UMR 1015 ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre d'Investigation Clinique en Biotherapie des cancers ( CIC 1428 , CBT 507 ), Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut Gustave Roussy ( IGR ) -Institut Gustave Roussy ( IGR ), Université Pierre et Marie Curie - Paris 6 ( UPMC ), Tulane University - New Orleans, LA, Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ), Centre d'Investigation Clinique de Besançon ( CICB ), Etablissement Français du Sang Bourgogne Franche-Comté-Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Franche-Comté ( UFC ), Eberhard Karls Universität Tübingen, Hospices Civils de Lyon ( HCL ), Stanford University School of Medicine [Stanford], Stanford University [Stanford], Centre de Recherche des Cordeliers ( CRC ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -École pratique des hautes études ( EPHE ) -Université Paris Diderot - Paris 7 ( UPD7 ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Apoptose, cancer et immunité ( Equipe labellisée Ligue contre le cancer - CRC - Inserm U1138 ), Institut Gustave Roussy ( IGR ) -Centre de Recherche des Cordeliers ( CRC ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -École pratique des hautes études ( EPHE ) -Université Paris Diderot - Paris 7 ( UPD7 ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -École pratique des hautes études ( EPHE ) -Université Paris Diderot - Paris 7 ( UPD7 ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Paris Descartes - Paris 5 ( UPD5 ), Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Institut Gustave Roussy ( IGR ), 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 Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), and 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)-Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE)
Subjects: 0301 basic medicine, Oncology, Male, Skin Neoplasms, medicine.medical_treatment, Lymphocyte, Biochemistry, Cohort Studies, 0302 clinical medicine, Immunophenotyping, Prospective Studies, Lymph node, Melanoma, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Middle Aged, Prognosis, Combined Modality Therapy, Neoadjuvant Therapy, 3. Good health, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Female, Immunotherapy, Adult, medicine.medical_specialty, Dermatology, Risk Assessment, Disease-Free Survival, Article, 03 medical and health sciences, Internal medicine, [ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology, medicine, Humans, Clinical significance, Neoplasm Invasiveness, Progression-free survival, Molecular Biology, Survival analysis, business.industry, Cell Biology, medicine.disease, Survival Analysis, 030104 developmental biology, Immunology, Lymph Nodes, Neoplasm Recurrence, Local, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; Stage III metastatic melanomas require adequate adjuvant immunotherapy to prevent relapses. Prognostic factors are awaited to optimize the clinical management of these patients. The magnitude of metastatic lymph node invasion and the BRAF V600 activating mutation have clinical significance. Based on a comprehensive immunophenotyping of 252 parameters per patient in paired blood and metastatic lymph nodes performed in 39 metastatic melanomas, we found that blood markers were as contributive as tumor-infiltrated lymphocyte immunotypes, and parameters associated with lymphocyte exhaustion/suppression showed higher clinical significance than those related to activation or lineage. High frequencies of CD45RA þ CD4 þ and CD3 e CD56 e tumor-infiltrated lymphocytes appear to be independent prognostic factors of short progression-free survival. High NKG2D expression on CD8 þ tumor-infiltrated lymphocytes, low level of regulatory T-cell tumor-infiltrated lymphocytes, and low PD-L1 expression on circulating T cells were retained in the multivariate Cox analysis model to predict prolonged overall survival. Prospective studies are needed to determine whether such immunological markers may guide adjuvant therapies in stage III metastatic melanomas.
Published: 2016
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45. The presence of LC3B puncta and HMGB1 expression in malignant cells correlate with the immune infiltrate in breast cancer

Author: Laura Senovilla, Marie Laure Poillot, Guido Kroemer, Marie Chaix, Patrick Arveux, Fabrice Andre, Laurent Arnould, Vichnou Poirier-Colame, Laurence Zitvogel, Sylvain Ladoire, David Enot, Suzette Delaloge, François Ghiringhelli, Frédérique Penault-Llorca, Kariman Chaba, Michaela Semeraro, Immunologie des tumeurs et immunothérapie (UMR 1015), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Lipides - Nutrition - Cancer (U866) (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-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Plateforme de métabolomique, Direction de la recherche [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Institut Gustave Roussy (IGR), Immunologie et Cancérologie Intégratives (CRC - Inserm U1138), Centre de Recherche des Cordeliers (CRC), Université Pierre et Marie Curie - Paris 6 (UPMC)-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)-Université Pierre et Marie Curie - Paris 6 (UPMC)-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), Centre d'Investigation Clinique en Biotherapie des cancers (CIC 1428 , CBT 507 ), Institut Gustave Roussy (IGR)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Equipe de recherche sur les traitements individualisés des cancers (ERTICa), Université d'Auvergne - Clermont-Ferrand I (UdA), Centre d'épidémiologie des populations (CEP), Université de Bourgogne (UB)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER, Département de médecine oncologique [Gustave Roussy], Karolinska University Hospital [Stockholm], Service de biologie [CHU HEGP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Immunologie des tumeurs et immunothérapie ( UMR 1015 ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ), Lipides - Nutrition - Cancer (U866) ( 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-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), Institut Gustave Roussy ( IGR ) -Institut Gustave Roussy ( IGR ), Institut Gustave Roussy ( IGR ), Immunologie et Cancérologie Intégratives ( CRC - Inserm U1138 ), Centre de Recherche des Cordeliers ( CRC ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -École pratique des hautes études ( EPHE ) -Université Paris Diderot - Paris 7 ( UPD7 ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -École pratique des hautes études ( EPHE ) -Université Paris Diderot - Paris 7 ( UPD7 ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre d'Investigation Clinique en Biotherapie des cancers ( CIC 1428 , CBT 507 ), Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Equipe de recherche sur les traitements individualisés des cancers ( ERTICa ), Université d'Auvergne - Clermont-Ferrand I ( UdA ), Centre d'épidémiologie des populations ( CEP ), Université de Bourgogne ( UB ) -Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -École pratique des hautes études ( EPHE ) -Université Paris Diderot - Paris 7 ( UPD7 ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Hôpital Européen Georges Pompidou [APHP] ( HEGP ) -Assistance publique - Hôpitaux de Paris (AP-HP), Université Paris Diderot - Paris 7 ( UPD7 ) -École pratique des hautes études ( EPHE ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Diderot - Paris 7 ( UPD7 ) -École pratique des hautes études ( EPHE ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Paris Diderot - Paris 7 ( UPD7 ) -École pratique des hautes études ( EPHE ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), and 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)-Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE)
Subjects: 0301 basic medicine, Pathological Complete Response, 0302 clinical medicine, Pathology, Cytotoxic T cell, Lymphocytes, HMGB1 Protein, FOXP3, Forkhead Transcription Factors, Mammary Tumorigenesis, 3. Good health, Immunosurveillance, Death, 030220 oncology & carcinogenesis, Female, Beclin-1, Microtubule-Associated Proteins, Infiltration (medical), Histology, Predictive-Value, Breast Neoplasms, chemical and pharmacologic phenomena, Cd8, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Prognostic, 03 medical and health sciences, Immune system, Breast Cancer, medicine, Autophagy, Humans, Prognostic Value, Treg Cells, Molecular Biology, Hmgb1, Anticancer Chemotherapy, [ SDV.BC ] Life Sciences [q-bio]/Cellular Biology, Macrophages, Neoadjuvant Chemotherapy, Cell Biology, medicine.disease, 030104 developmental biology, Tumor progression, Cancer cell, Immunology, Cancer research, Lc3, Clinical Research Paper, CD8, T-Lymphocytes, Cytotoxic
Abstract: International audience; Several cell-intrinsic alterations have poor prognostic features in human breast cancer, as exemplified by the absence of MAP1LC3B/LC3B (microtubule-associated protein 1 light chain 3 )-positive puncta in the cytoplasm (which indicates reduced autophagic flux) or the loss of nuclear HMGB1 expression by malignant cells. It is well established that breast cancer is under strong immunosurveillance, as reflected by the fact that scarce infiltration of the malignant lesion by CD8(+) cytotoxic T lymphocytes or comparatively dense infiltration by immunosuppressive cell types (such as FOXP3(+) regulatory T cells or CD68(+) tumor-associated macrophages), resulting in low CD8(+):FOXP3(+) or CD8(+):CD68(+) ratios, has a negative prognostic impact. Here, we reveal the surprising finding that cell-intrinsic features may influence the composition of the immune infiltrate in human breast cancer. Thus, the absence of LC3B puncta is correlated with intratumoral (but not peritumoral) infiltration by fewer CD8(+) cells and more FOXP3(+) or CD68(+) cells, resulting in a major drop in the CD8(+):FOXP3(+) or CD8(+):CD68(+) ratios. Moreover, absence of HMGB1 expression in nuclei correlated with a general drop in all immune effectors, in particular FOXP3(+) and CD68(+) cells, both within the tumor and close to it. Combined analysis of LC3B puncta and HMGB1 expression allowed for improved stratification of patients with respect to the characteristics of their immune infiltrate as well as overall and metastasis-free survival. It can be speculated that blocked autophagy in, or HMGB1 loss from, cancer cells may favor tumor progression due to their negative impact on anticancer immunosurveillance.
Published: 2016
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46. Melanoma and immunotherapy bridge 2015 : Naples, Italy. 1-5 December 2015

Author: Erik Wennerberg, Gabriele Madonna, Gennaro Ciliberto, Michele Minopoli, Caroline Dutriaux, Matthew Wongchenko, Elisabetta Gambale, David F. Stroncek, Céleste Lebbé, Ani S. Balmanoukian, Gianluca Di Monta, Vincenzo Ingangi, Soldano Ferrone, Ivan Marquez-Rodas, Giuseppe Masucci, Janis M. Taube, Simona Mastroeni, Gerardo Bott, Franck Pagès, Jonathan M. Pitt, Judit Olasz, Elisabetta Panza, Paola Michelozzi, Daniil Stoyakovskiy, Stéphane Dalle, Mario Sznol, John M. Kirkwood, Keith T. Flaherty, Maria Capuano, Amalia Azzariti, Edward Cha, Peter Boasberg, Maria Godeny, Angela Gismondi, Ornella Franzese, Giusy Gentilcore, Jean-Jacques Grob, Olivier Michielin, Adina Elena Stanciu, Giuseppe Cirino, Julien Fourcade, Nelofer Syed, Giuseppe Ercolano, Caroline Robert, Ascierto Paolo Antonio, Christine K. Gause, Silviu Voinea, Adeeb Rahman, Anne Caignard, Camila Flores, Cristina Fortes, Yuya Yoshimoto, Angela Sandru, Andras Szollar, Monica Cantile, Frederic Lehmann, Maria Libera Ascierto, Sacha Gnjatic, Marco Tucci, Rosa Russo, Giuseppina Liguori, Valeria De Biasio, David Ross Kaufman, Mary Ruisi, Ewa Kalinka-Warzocha, Phillip Wong, Rosaria Falcon, Vincenzo Faiola, Nicole Richie, Lars Ny, Miri Blank, Paola De Cicco, Anna Passarelli, Jean-François Baurain, Guido Kroemer, Claudio Jommi, Francesca Capone, Maria Teresa Fierro, Tracee L. McMiller, Lev V. Demidov, Alessandro Testori, Omid Hamid, Marone Ugo, Annamaria Anniciello, Andrew J. Park, Fara De Murtas, RuthAnn Gordan, Emil Farkas, David Hogg, Alessandra Di Paolo, Mark Maurer, Yangyang Wang, Mario Mandalà, Rodabe N. Amaria, Massimiliano Di Marzo, Stefania Guida, Luigi Fattore, Veronica Huber, Ludmila Danilova, Luigi Aurisicchio, Gabriella Aquino, Domenico Mallardo, Catriona M. McNeil, Stephanie Anne Kronenberg, Consiglia Carella, Theresa S. Pritchard, Katia Bifulco, Michaela Semeraro, Carlo M. Croce, David P. Enot, Laurence Zitvogel, Marcella Occelli, Benjamin Weide, Magdalena Thurin, Margherita Cerrone, Naiyer A. Rizvi, Blessing Agunwamba, Stella D'Oronzo, Sarah Jegou, Stucci Stefania, Drew M. Pardoll, Vito Michele Garrisi, Haidong Tang, Szabolcs Horvath, Hong Wang, Benjamin Brady, Antonio Doronzo, Claudia Marino, Xian He, Michael A. Davies, Hexiao Wang, Isabelle Rooney, Orsolya Csuka, Maurizio Nudo, Lance Leopold, Jeffrey S. Wasser, Sabino Strippoli, Silvia Ch Formenti, MariaLaura Foddai, Michael A. Postow, Robert H.I. Andtbacka, Paul Lorigan, Tommy Andersson, Naoko Imai, Ari VanderWalde, Mariaelena Capone, Ilsung Chang, Laura Lattanzio, Carmen Loquai, Arantxa Sancho, Christine Horak, Federica Sallusto, Timea Balatoni, Maha Ayyoub, Angela Santoni, Alessio Caggiati, Anna Lisa De Presbiteris, Henrik Schmidt, Paola Savoia, Pontus Berglund, Igor Puzanov, Aurélien Marabelle, Ana Carrizossa Anderson, Hassane M. Zarour, Maria Wolodarski, Patrick Hwu, Joel Jiang, Pio Zeppa, Jeffrey A. Sosman, Eugenio Fernandez, Susan Costantini, Marcus Ballinger, Luc Thomas, Leslie Cope, Rolf Kiessling, Christophe Borg, Francesca Platini, Florian Stratica, Tilman T. Rau, Craig L. Slingluff, Paolo A. Ascierto, Angela Ianaro, Harriet M. Kluger, Stephen Hodi, Tara C. Gangadhar, Claire Vanpouille-Box, Caroline Flament, Hearn J. Cho, Mannavola Francesco, Takahiro Yamazaki, Charles G. Drake, Jason J. Luke, Miklos Kasler, Linda Pan, Caracò Corrado, Alfonso Berrocal, Angel Rivera, Vera Hirsh, Eduardo J. Patriarca, Giovanni Di Giulio, Antonello Pessi, Helena Stabile, Helene Hardy, Tucci Marco, Ralph Venhaus, Maria Luisa Di Cecilia, Catherine A. Harwood, Jonathan Cebon, Anna Maria Anniciello, Grant A. McArthur, Carlo Baldi, Ahmad A. Tarhini, Shelley Coleman, Gil Bar-Sela, Axel Hauschild, Byoung S. Kwon, Maria Paula Roberti, Sabin Cinca, Tiziana Cocco, Valeria Sorrentino, Jeffrey Wallin, Rosa Camerlingo, Sandra Demaria, Jedd D. Wolchok, Isabel Poschke, Alessandro Lugli, Michael B. Atkins, Andrea Cavalcanti, Laura Marra, Rosamaria Pinto, Adam D. Cohen, Michele Maio, Weiyi Peng, Rosario Guarrasi, David Enot, Antoni Ribas, Oscar Alabiso, Chiara Armogida, Silvestris Franco, Jessica C. Hassel, Rita Mancini, Michele Guida, Silvia C. Formenti, Andrea P. Sponghini, Imma Maida, Alba Zappalà, Charlotte M. Proby, Alan J. Korman, Yibing Yan, Matias Chacon, Haiying Xu, Carolin Blattner, Maria-Paula Roberti, Lisa Chen, James Larkin, Ryan J. Sullivan, Madonna Gabriele, Nadege Vimond, Cosmo Di Donna, Farnaz Moradi, Manish R. Patel, Sylvie Rusakiewicz, Francesca Passarelli, Luis de la Cruz-Merino, Nicolas Jacquelot, Roberta Miceli, Viktor Umansky, Akos Savolt, David Rondonotti, Gabriella Liszkay, Jianda Yuan, Stefani Spranger, Yufan Zhao, Yehuda Shoenfeld, Todd M. Bauer, Claus Garbe, Joe-Marc Chauvin, Achim A. Jungbluth, Cristiana Lo Nigro, Alexander M. Lesokhin, Gabriella Guida, Brigitte Dréno, Cindy Sanders, Jeffrey S. Weber, Janet Maleski, Chris Cheadle, Romain Daillère, Isabella Sperduti, Michaele Maio, Claudia Felici, Parneet K. Cheema, Concetta Ragone, Johan Hansson, Klara Eles, Victoria Atkinson, Speiser Daniel, Daniel O. Koralek, Zhaojun Sun, Debora Malpicci, Elena Marra, Rickard Linnskog, Jeffrey Chou, Yang Wang, Eugenia Panaitescu, F. Stephen Hodi, Anthony J. Olszanski, Chiara Botti, Nicola Mozzillo, Anna Ferretta, Paul B. Chapman, Michaë la Semeraro, Belinda Palermo, Francesco Sabbatino, Neil H. Segal, Yago Pico de Coaña, Tseng-hui Timothy Chen, Ornella Pagliano, John B. A. G. Haanen, Huibin Yue, Emilia Caputo, Alan E. Berger, Simona De Summa, Nikoletta Lendvai, Paola Queirolo, Francesco Mannavola, Thomas F. Gajewski, Michele De Tursi, Paola Nisticò, Karen Briscoe, Karmele Mujika Eizmendi, Maria Vincenza Carrier, Passarelli Anna, Laurent Mortier, Crescenzo D'Alterio, Jorge Camarero, Licia Rivoltini, Pietro Quaglino, Davide Quaresmini, Marie Vétizou, Anna Maria Di Giacomo, Chandra Prakash Prasad, Riccardo Bono, Vichnou Poirier-Colame, David Smith, Capone Mariaelena, Giosuè Scognamiglio, Margaret K. Callahan, Vashisht Gopal Yennu Nanda, Fabiola Gilda Cordaro, George J. Netto, Madalina Bolovan, Federica Fratangelo, Josep Malvehy, Robert A. Anders, Karsten A. Pilones, Vincenzo C. Battarra, Karin Leandersson, Maria Letizia Motti, Yang Xin Fu, Tim Crook, Sarah Nataraj, Alastair M. Thompson, Franco Silvestris, Carolina Cauchi, Georgina V. Long, Holbrook E Kohrt, Giuseppe Pirozzi, Celeste Fusciello, Marco Carlo Merlano, François Aubin, Mozzillo Nicola, Giuseppe Cirin, Stefania Scala, Suzanne L. Topalian, Alexander M.M. Eggermont, Antonio Marra, Jinshui Fan, Reinhard Dummer, Federica Zito Marino, Amanda Ralabate, Matthew M. Burke, Piotr Rutkowski, Gerardo Botti, Stefano Pepe, Ivor Caro, and Stefania Tommasi
Subjects: 0301 basic medicine, business.industry, MEDLINE, General Medicine, medicine.disease, Bridge (interpersonal), General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, 030220 oncology & carcinogenesis, Medicine, Medical emergency, business
Published: 2016

47. Chemotherapy-induced antitumor immunity requires formyl peptide receptor 1

Author: Guido Kroemer, Oliver Kepp, Fabrice Andre, Patrick Günther, José Manuel Bravo-San Pedro, Thomas Ulas, Sandy Adjemian, Elisa E. Baracco, Adele De Ninno, Gwenola Manic, Luca Businaro, Ilio Vitale, Valeria Lucarini, Monica Lucattelli, Federico Pietrocola, Suzette Delaloge, Laurence Zitvogel, Yuting Ma, Joachim L. Schultze, Michaela Semeraro, Giovanna Schiavoni, Celine Lefebvre, Heng Yang, Kariman Chaba, Lionel Apetoh, Antonella Sistigu, Sylvain Ladoire, Gautier Stoll, Christophe Borg, David Enot, Valérie Boige, Michel Ducreux, Francesca Castoldi, Francesca Peschiaroli, Fabrizio Mattei, Sylvie Rusakiewicz, Erika Vacchelli, Cécile Delarasse, Michele Signore, Annamaria Gerardino, Claire Mulot, and Pierre Laurent-Puig
Subjects: Anthracycline, Colorectal cancer, medicine.medical_treatment, T-Lymphocytes, Breast Neoplasms, microfluidic chip, chemotherapy, Polymorphism, Single Nucleotide, Formyl peptide receptor 1, immune response, Mice, Immune system, Immunity, Cell Line, Tumor, Neoplasms, medicine, Leukocytes, Animals, Humans, Anthracyclines, Alleles, Annexin A1, Chemotherapy, Multidisciplinary, business.industry, Dendritic Cells, medicine.disease, Receptors, Formyl Peptide, Immunity, Innate, Chemotherapy, Adjuvant, Cancer cell, Immunology, Cancer research, Female, business, Colorectal Neoplasms, Adjuvant, FPR1 microfluidic
Abstract: How dying tumor cells get noticed Besides killing tumor cells directly, some chemotherapies, such as anthracyclines, also activate the immune system to kill tumors. Vacchelli et al. discovered that in mice, anthracycline-induced antitumor immunity requires immune cells to express the protein formyl peptide receptor 1 (FPR1). Dendritic cells (DCs) near tumors expressed especially high amounts of FPR1. DCs normally capture fragments of dying tumor cells and use them to activate nearby T cells to kill tumors, but DCs lacking FPR1 failed to do this effectively. Individuals with breast or colon cancer expressing a variant of FPR1 and treated with anthracyclines showed poor metastasis-free and overall survival. Thus, FPR1 may affect anti-tumor immunity in people, too. Science , this issue p. 972
Published: 2015
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48. Natural killer cell mediated immunosurveillance of pediatric neuroblastoma

Author: Michaela Semeraro, Sylvie Rusakiewicz, Laurence Zitvogel, and Guido Kroemer
Subjects: Lymphokine-activated killer cell, Stromal cell, business.industry, Immunology, medicine.disease, Pediatric cancer, Natural killer cell, Immunosurveillance, Interleukin 21, medicine.anatomical_structure, Oncology, Neuroblastoma, Interleukin 12, Immunology and Allergy, Medicine, business, Author's View
Abstract: Until recently, the pathophysiological impact of natural killer (NK) lymphocytes has been largely elusive. Capitalizing on our previous discovery that NK cells mediate immunosurveillance against gastrointestinal stromal tumors (GISTs), we have now investigated the potential influence of immunostimulatory and immunosuppressive isoforms of the NK receptor NKp30 on the fate of infants with neuroblastoma. In three independent cohorts of high-risk neuroblastoma, we observed a similar prognostic impact of the ratio of immunostimulatory vs. immunosuppressive NKp30 isoforms. Patients with high-risk neuroblastoma that are in remission after induction chemotherapy have a higher risk of relapse if their circulating and bone marrow NK cells express the preponderantly immunosuppressive NKp30 C isoform, as determined by a robust RT-PCR-based assay. We also found that neuroblastoma cells express the NKp30 ligand B7-H6, which can be shed from the tumor cells. Elevated soluble B7-H6 levels contained in patient sera inhibited NK functions in vitro and correlated with downregulation of NK-p30 on NK cells, as well as with bone marrow metastasis and chemoresistance. Altogether, these results support the contention that NK cells play a decisive role in the immunosurveillance of neuroblastoma. In light of these results, efforts should be undertaken to investigate NK cell functions in all major cancer types, with the obvious expectation of identifying additional NK cell-related prognostic or predictive biomarkers and improving NK cell based immunotherapeutic strategies against cancer.
Published: 2015

49. Clinical impact of the NKp30/B7-H6 axis in high-risk neuroblastoma patients

Author: Guido Kroemer, Andrei Tchirkov, Frédéric Commo, Vichnou Poirier-Colame, Sophie Cotteret, Nicole Prada, Dominique Valteau-Couanet, Sylvie Rusakiewicz, Benjamin Papoular, Laurence Zitvogel, Jessica Matta, Nathalie Chaput, David Enot, Tala Shekarian, Aurélien Marabelle, Laurence Brugières, Brigitte Bressac, Michaela Semeraro, Valérie Lapierre, Mirco Ponzoni, Frédéric Vély, Christelle Piperoglou, Patrizia Perri, Françoise Farace, Nicolas F. Delahaye, Sandrine Valsesia-Wittmann, and Véronique Minard-Colin
Subjects: Adult, B7 Antigens, Adolescent, Antineoplastic Agents, Biology, Ligands, Jurkat cells, Disease-Free Survival, Jurkat Cells, Neuroblastoma, Young Adult, Risk Factors, Cell Line, Tumor, Antineoplastic Combined Chemotherapy Protocols, medicine, Biomarkers, Tumor, Humans, Prospective Studies, Neoplasm Metastasis, Child, Natural Cytotoxicity Triggering Receptor 3, Brain Neoplasms, Induction chemotherapy, Infant, General Medicine, medicine.disease, Prognosis, Transplantation, Immunosurveillance, Gene Expression Regulation, Neoplastic, medicine.anatomical_structure, Phenotype, Cell culture, Child, Preschool, Immunology, Bone marrow, Stem cell, Protein Binding
Abstract: The immunosurveillance mechanisms governing high-risk neuroblastoma (HR-NB), a major pediatric malignancy, have been elusive. We identify a potential role for natural killer (NK) cells, in particular the interaction between the NK receptor NKp30 and its ligand, B7-H6, in the metastatic progression and survival of HR-NB after myeloablative multimodal chemotherapy and stem cell transplantation. NB cells expressing the NKp30 ligand B7-H6 stimulated NK cells in an NKp30-dependent manner. Serum concentration of soluble B7-H6 correlated with the down-regulation of NKp30, bone marrow metastases, and chemoresistance, and soluble B7-H6 contained in the serum of HR-NB patients inhibited NK cell functions in vitro. The expression of distinct NKp30 isoforms affecting the polarization of NK cell functions correlated with 10-year event-free survival in three independent cohorts of HR-NB in remission from metastases after induction chemotherapy (n = 196, P0.001), adding prognostic value to known risk factors such as N-Myc amplification and age18 months. We conclude that the interaction between NKp30 and B7-H6 may contribute to the fate of NB patients and that both the expression of NKp30 isoforms on circulating NK cells and the concentration of soluble B7-H6 in the serum may be clinically useful as biomarkers for risk stratification.
Published: 2015

50. 279. Clinical Outcomes of Gene Therapy with BB305 Lentiviral Vector for Sickle Cell Disease and β-Thalassemia

Author: Pablo Bartolucci, Michaela Semeraro, Stany Chrétien, Stéphane Blanche, Fabien Touzot, Laura Sandler, Mariane de Montalembert, Manfred G. Schmidt, Salima Hacein-Bey-Abina, Sandeep Soni, Olivier Hermine, Bénédicte Neven, Philippe Bourget, Christof von Kalle, Marina Cavazzana, François Lefrère, Yves Beuzard, Felipe Suarez, Wassim El Nemer, Corinne Pondarré, Elisa Magrin, Emmanuel Payen, Philippe Leboulch, Jean-Antoine Ribeil, and Fabrice Monpoux
Subjects: 0301 basic medicine, Pharmacology, business.industry, Genetic enhancement, Thalassemia, Cell, Disease, medicine.disease, Viral vector, 03 medical and health sciences, 030104 developmental biology, medicine.anatomical_structure, Drug Discovery, Immunology, Genetics, Molecular Medicine, Medicine, business, Molecular Biology
Published: 2016
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