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1. Genomic Instability and Protumoral Inflammation Are Associated with Primary Resistance to Anti–PD-1 + Antiangiogenesis in Malignant Pleural Mesothelioma

Author: François-Xavier Danlos, Matthieu Texier, Bastien Job, Severine Mouraud, Lydie Cassard, Capucine Baldini, Andrea Varga, Andrey A. Yurchenko, Audrey Rabeau, Stéphane Champiat, Diane Letourneur, Delphine Bredel, Sandrine Susini, Yuna Blum, Aurelien Parpaleix, Cedric Parlavecchio, Lambros Tselikas, Jean-Eudes Fahrner, Anne-Gaelle Goubet, Mathieu Rouanne, Saloomeh Rafie, Alae Abbassi, Ines Kasraoui, Marie Breckler, Siham Farhane, Samy Ammari, Salim Laghouati, Anas Gazzah, Ludovic Lacroix, Benjamin Besse, Nathalie Droin, Marc Deloger, Sophie Cotteret, Julien Adam, Laurence Zitvogel, Sergey I. Nikolaev, Nathalie Chaput, Christophe Massard, Jean-Charles Soria, Carlos Gomez-Roca, Gerard Zalcman, David Planchard, Aurelien Marabelle, Institut Gustave Roussy (IGR), Immunologie anti-tumorale et immunothérapie des cancers (ITIC), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, École normale supérieure de Lyon (ENS de Lyon), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Département d'imagerie médicale [Gustave Roussy], Département de biologie et pathologie médicales [Gustave Roussy], Département de médecine oncologique, CRLCC Paul Strauss, Dynamique moléculaire de la transformation hématopoïétique (Dynamo), Département de médecine oncologique [Gustave Roussy], Prédicteurs moléculaires et nouvelles cibles en oncologie (PMNCO), Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse (AMMICa), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Département d’Innovation Thérapeutique et essais précoces [Gustave Roussy] (DITEP), and Institut Claudius Regaud
Subjects: Oncology, [SDV.CAN]Life Sciences [q-bio]/Cancer
Abstract: Cancer immunotherapy combinations have recently been shown to improve the overall survival of advanced mesotheliomas, especially for patients responding to those treatments. We aimed to characterize the biological correlates of malignant pleural mesotheliomas’ primary resistance to immunotherapy and antiangiogenics by testing the combination of pembrolizumab, an anti–PD-1 antibody, and nintedanib, a pan-antiangiogenic tyrosine kinase inhibitor, in the multicenter PEMBIB trial (NCT02856425). Thirty patients with advanced malignant pleural mesothelioma were treated and explored. Unexpectedly, we found that refractory patients were actively recruiting CD3+CD8+ cytotoxic T cells in their tumors through CXCL9 tumor release upon treatment. However, these patients displayed high levels of somatic copy-number alterations in their tumors that correlated with high blood and tumor levels of IL6 and CXCL8. Those proinflammatory cytokines resulted in higher tumor secretion of VEGF and tumor enrichment in regulatory T cells. Advanced mesothelioma should further benefit from stratified combination therapies adapted to their tumor biology. Significance: Sequential explorations of fresh tumor biopsies demonstrated that mesothelioma resistance to anti–PD-1 + antiangiogenics is not due to a lack of tumor T-cell infiltration but rather due to adaptive immunosuppressive pathways by tumors, involving molecules (e.g., IL6, CXCL8, VEGF, and CTLA4) that are amenable to targeted therapies. This article is highlighted in the In This Issue feature, p. 799
Published: 2023

2. Prevalence and characteristics of gonadoblastoma in a retrospective multi-center study with follow-up investigations of 70 patients with Turner syndrome and a 45,X/46,XY karyotype

Author: Daphné Karila, Bruno Donadille, Juliane Léger, Claire Bouvattier, Anne Bachelot, Veronique Kerlan, Sophie Catteau-Jonard, Sylvie Salenave, Frédérique Albarel, Claire Briet, Regis Coutant, Aude Brac De La Perriere, Alexander Valent, Jean-Pierre Siffroi, Sophie Christin-Maitre, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Saint-Antoine [AP-HP], Service d'endocrinologie diabétologie pédiatrique [CHU Debré], AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), National Reference Network DSD DevGen, Service d'endocrinologie pédiatrique [CHU Bicêtre], Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), CHU Lille, Université de Lille, AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Endocrinologie, diabète, maladies métaboliques (CHU Marseille, AP-HM), Assistance Publique - Hôpitaux de Marseille (APHM), Centre de référence des maladies rares de l'hypophyse (HYPO), Service d'Endocrinologie, Diabète et Maladies Métaboliques, Endocrinologie pédiatrique[CHU Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Hôpital Louis Pradel [CHU - HCL], Hospices Civils de Lyon (HCL), Département de biologie et pathologie médicales [Gustave Roussy], Institut Gustave Roussy (IGR), Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse (AMMICa), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Maladies génétiques d'expression pédiatrique (U933), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Trousseau [APHP], Centre de référence des Maladies Endocriniennes Rares de la Croissance [CHU Saint-Antoine AP-HP] (CRMERC), Service d'Endocrinologie, diabétologie et endocrinologie de la reproduction [CHU Saint-Antoine], Centre de référence des maladies endocriniennes rares de la croissance et du développement [CHU Pitié-Salpêtrière], Service d'Endocrinologie et Médecine de la Reproduction [CHU Pitié-Salpêtrière], Maladies génétiques d'expression pédiatrique [CHU Trousseau] (Inserm U933), UF de Génétique chromosomique [CHU Trousseau], and Couvet, Sandrine
Subjects: Adult, Ovarian Neoplasms, Adolescent, Mosaicism, [SDV]Life Sciences [q-bio], Endocrinology, Diabetes and Metabolism, Karyotype, Turner Syndrome, General Medicine, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, [SDV] Life Sciences [q-bio], Young Adult, Endocrinology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Prevalence, Humans, Female, Gonadoblastoma, Child, Follow-Up Studies
Abstract: Introduction A gonadectomy is currently recommended in patients with Turner syndrome (TS) and a 45,X/46,XY karyotype, due to a potential risk of gonadoblastoma (GB). However, the quality of evidence behind this recommendation is low. Objective This study aimed to evaluate the prevalence of GB, its characteristics, as well as its risk factors, according to the type of Y chromosomal material in the karyotype. Methods Our study within French rare disease centers included patients with TS and a 45,X/46,XY karyotype, without ambiguity of external genitalia. Clinical characteristics of the patients, their age at gonadectomy, and gonadal histology were recorded. The regions of the Y chromosome, the presence of TSPY regions, and the percentage of 45,X/46,XY mosaicism were evaluated. Results A total of 70 patients were recruited, with a median age of 29.5 years (21.0–36.0) at the end of follow-up. Fifty-eight patients had a gonadectomy, at a mean age of 15 ± 8 years. GB was present in nine cases. Two were malignant, which were discovered at the age of 14 and 32 years, without metastases. Neither the percentage of XY cells within the 45,X/46,XY mosaicism nor the number of TSPY copies was statistically different in patients with or without GB (P = 0.37). However, the entire Y chromosome was frequent in patients with GB (6/9). Conclusions In our study, including a large number of patients with 45,X/46,XY TS, the prevalence of gonadoblastoma is 12.8%. An entire Y chromosome appears as the main risk factor of GB and should favor early gonadectomy. Significant statement About 10% of patients with TS have a karyotype containing Y chromosomal material: 45,X/46,XY. Its presence is related to the risk of GB. Therefore, a prophylactic gonadectomy is currently recommended in such patients. However, the quality of evidence is low. Our objective was to evaluate the prevalence of GB according to the type of Y-chromosomal material. We found a prevalence of GB of 12.8% in a cohort of 70 TS patients. No sign of hyperandrogenism was observed. The entire Y chromosome was the most frequent type of Y-material in patients with GB. As the prognosis of these tumors was good, a delay of surgery might be discussed.
Published: 2022

3. Lanreotide as maintenance therapy after first-line treatment in patients with non-resectable duodeno-pancreatic neuroendocrine tumours: An international double-blind, placebo-controlled randomised phase II trial – Prodige 31 REMINET: An FFCD study

Author: Côme Lepage, Jean-Marc Phelip, Astrid Lievre, Karine Le-Malicot, Laetitia Dahan, David Tougeron, Christos Toumpanakis, Frédéric Di-Fiore, Catherine Lombard-Bohas, Ivan Borbath, Romain Coriat, Thierry Lecomte, Rosine Guimbaud, Caroline Petorin, Jean-Louis Legoux, Pierre Michel, Jean-Yves Scoazec, Denis Smith, Thomas Walter, Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Agro Dijon, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Oncogenesis, Stress, Signaling (OSS), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pontchaillou [Rennes], Hôpital de la Timone [CHU - APHM] (TIMONE), Centre hospitalier universitaire de Poitiers (CHU Poitiers), Royal Free Hospital [London, UK], Communications Cellulaires et Différenciation (CCD), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), Hospices Civils de Lyon (HCL), Cliniques Universitaires Saint-Luc [Bruxelles], AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Trousseau [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Institut Gustave Roussy (IGR), Département de biologie et pathologie médicales [Gustave Roussy], Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], Amgen, Bristol-Myers Squibb, BMS, Bayer, Merck, Novartis, Roche, Celgene, Sandoz, Advanced Accelerator Applications, AAA, Agence Nationale de la Recherche, ANR: ANR-11-LABX-0021, Ligue Contre le Cancer, Servier, Ipsen, and ANR-11-LABX-0021,Lipstic,Lipoprotéines et santé : prévention et traitement des maladies inflammatoires non vasculaires et du cancer(2011)
Subjects: Pancreatic Neoplasms, Clinical trial, Neuroendocrine Tumors, Cancer Research, Neuroendocrine tumours, Oncology, Duodeno-pancreatic, Maintenance, Non-resectable, Humans, [SDV.CAN]Life Sciences [q-bio]/Cancer, Somatostatin, Peptides, Cyclic
Abstract: International audience; Background: Following European guidelines, patients with aggressive metastatic or locally advanced, non-resectable, duodeno-pancreatic (DP) neuroendocrine tumours (NETs) should receive systemic combination chemotherapy until progression. Aggressive disease is defined as progressive and/or symptomatic metastases with or without significant hepatic invasion (>30–50%), and/or bone metastases. Methods: This academic randomised, double-blind, placebo-controlled phase II study aims to evaluate lanreotide autogel 120 mg (LAN) as maintenance treatment after at least 2 months of first-line treatment (L1) in aggressive G1-G2 DP-NET. Patients were randomly assigned in a 1:1 ratio to receive LAN or placebo (PBO), every 28 days, until progression or toxicity. The primary end-point was progression-free survival (PFS) at 6 months. Results: Among the 118 planned patients, 53 were included. Of these, 81.1% had a G2 tumour, and 90.6% had metastatic disease. L1 therapy consisted of chemotherapy (96.8%). Median duration of L1 was 4.6 months (range: 2.0–7.7). At the time of randomisation, 81.1% of patients had stable disease. Median follow-up was 27.0 months (95% CI: 19.5; 31.2). PFS at 6 months was 73.1% (90% CI: 55.3; 86.6) in LAN versus 54.2% (90% CI: 35.8; 71.8) in PBO. Median PFS was 19.4 months (95% CI: 7.6; 32.6) and 7.6 months (95% CI: 3.0; 9.0), respectively. Median overall survival was 41.9 months in PBO and was not reached in LAN. The toxicity profile was mainly grade 1–2 expected toxicities. Conclusions: The encouraging results of lanreotide autogel 120 mg as a maintenance treatment after L1 in aggressive G1/2 DP-NET should be confirmed. Trial registration: NCT02288377 (clinicaltrials.gov). © 2022 The Authors
Published: 2022

4. The European MAPPYACTS Trial: Precision Medicine Program in Pediatric and Adolescent Patients with Recurrent Malignancies

Author: Pablo Berlanga, Gaelle Pierron, Ludovic Lacroix, Mathieu Chicard, Tiphaine Adam de Beaumais, Antonin Marchais, Anne C. Harttrampf, Yasmine Iddir, Alicia Larive, Aroa Soriano Fernandez, Imene Hezam, Cecile Chevassus, Virginie Bernard, Sophie Cotteret, Jean-Yves Scoazec, Arnaud Gauthier, Samuel Abbou, Nadege Corradini, Nicolas André, Isabelle Aerts, Estelle Thebaud, Michela Casanova, Cormac Owens, Raquel Hladun-Alvaro, Stefan Michiels, Olivier Delattre, Gilles Vassal, Gudrun Schleiermacher, Birgit Geoerger, Institut Català de la Salut, [Berlanga P] Department of Pediatric and Adolescent Oncology, Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif, France. [Pierron G] Unité de Génétique Somatique, Service de Génétique, Hospital Group, Institut Curie, Paris, France. [Lacroix L] Department of Pathology and Laboratory Medicine, Translational Research Laboratory and Biobank, AMMICA, INSERM US23/CNRS UMS3655, Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif, France. [Chicard M] INSERM U830, Laboratoire de Génétique et Biologie des Cancers, Research Center, PSL Research University, Institut Curie, Paris, France. [Adam de Beaumais T] Clinical Research Direction, Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif, France. [Marchais A] INSERM U1015, Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif, France. [Soriano Fernandez A] Grup de Recerca Translacional en Càncer en la Infància i l’Adolescència, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. [Hladun-Alvaro R] Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Servei d’Oncologia i Hematologia Pediàtriques, Vall d’Hebron Hospital Universitari, Barcelona, Spain, Vall d'Hebron Barcelona Hospital Campus, Institut Gustave Roussy (IGR), Département de cancérologie de l'enfant et de l'adolescent [Gustave Roussy], Institut Curie [Paris], Department of Medical Oncology, Département de médecine oncologique [Gustave Roussy], Unité de génétique et biologie des cancers (U830), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Plateforme de Bioinformatique [Gustave Roussy], Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse (AMMICa), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Immunologie anti-tumorale et immunothérapie des cancers (ITIC), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), 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 Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Service de biostatistique et d'épidémiologie (SBE), Direction de la recherche clinique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Centre de Recherche et de Documentation sur l'Océanie (CREDO), École des hautes études en sciences sociales (EHESS)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Biomarqueurs prédictifs et nouvelles stratégies moléculaires en thérapeutique anticancéreuse (U981), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'Excellence en Recherche sur le Médicament et l'Innovation Thérapeutique [Châtenay-Malabry] (LabEx LERMIT), Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de biologie et pathologie médicales [Gustave Roussy], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Prédicteurs moléculaires et nouvelles cibles en oncologie (PMNCO), Centre Léon Bérard [Lyon], Institut d'hématologie et d'oncologie pédiatrique [CHU - HCL] (IHOPe), Biologie Cellulaire et Cancer, Institut Curie [Paris]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre hospitalier universitaire de Nantes (CHU Nantes), Istituto di Ricovero e Cura a Carattere Scientifico, Ospedale Casa Sollievo della Sofferenza [San Giovanni Rotondo] (IRCCS), Oncostat (U1018 (Équipe 2)), Institut Gustave Roussy (IGR)-Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Immunologie des tumeurs et immunothérapie (UMR 1015), Vectorologie et thérapeutiques anti-cancéreuses [Villejuif] (UMR 8203), and Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS)
Subjects: neoplasias::procesos neoplásicos::recurrencia neoplásica local [ENFERMEDADES], Pediatria, Adolescent, [SDV]Life Sciences [q-bio], Carcinoma, High-Throughput Nucleotide Sequencing, Neoplasms [DISEASES], neoplasias [ENFERMEDADES], Càncer - Recaiguda, terapéutica::medicina de precisión [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], Oncology, Mutation, Biomarkers, Tumor, Neoplasms::Neoplastic Processes::Neoplasm Recurrence, Local [DISEASES], Humans, Prospective Studies, Medicina personalitzada, Neoplasm Recurrence, Local, Precision Medicine, Child, Therapeutics::Precision Medicine [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], Cell-Free Nucleic Acids
Abstract: Abstract MAPPYACTS (NCT02613962) is an international prospective precision medicine trial aiming to define tumor molecular profiles in pediatric patients with recurrent/refractory malignancies in order to suggest the most adapted salvage treatment. From February 2016 to July 2020, 787 patients were included in France, Italy, Ireland, and Spain. At least one genetic alteration leading to a targeted treatment suggestion was identified in 436 patients (69%) with successful sequencing; 10% of these alterations were considered “ready for routine use.” Of 356 patients with follow-up beyond 12 months, 107 (30%) received one or more matched targeted therapies—56% of them within early clinical trials—mainly in the AcSé-ESMART platform trial (NCT02813135). Overall, matched treatment resulted in a 17% objective response rate, and of those patients with ready for routine use alterations, it was 38%. In patients with extracerebral tumors, 76% of actionable alterations detected in tumor tissue were also identified in circulating cell-free DNA (cfDNA). Significance: MAPPYACTS underlines the feasibility of molecular profiling at cancer recurrence in children on a multicenter, international level and demonstrates benefit for patients with selected key drivers. The use of cfDNA deserves validation in prospective studies. Our study highlights the need for innovative therapeutic proof-of-concept trials that address the underlying cancer complexity. This article is highlighted in the In This Issue feature, p. 1171
Published: 2022

5. Reduced Venetoclax Exposition to Seven Days of Azacitidine Is Efficient in Treatment-Naïve Patients with Acute Myeloid Leukemia

Author: Christophe Willekens, Samy Chraibi, Justine Decroocq, Benjamin Carpentier, Delphine Lebon, Sarah Bonnet, Nicolas Gauthier, Arnaud Pagès, Matteo Dragani, Sabine Khalife-Hachem, Jean-Baptiste Micol, Florence Pasquier, Stefan Wickenhauser, Véronique Saada, Véronique Vergé, Ahmadreza Arbab, Christophe Marzac, Laurent Pascal, Damien Roos-Weil, Eric Jourdan, Didier Bouscary, Stéphane de Botton, Cellules souches hématopoïétiques et développement des hémopathies myéloïdes (CSHMyelo), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Amiens-Picardie, HEMATIM - Hématopoïèse et immunologie - UR UPJV 4666 (HEMATIM), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Commissariat à l'énergie atomique et aux énergies alternatives - Laboratoire d'Electronique et de Technologie de l'Information (CEA-LETI), Direction de Recherche Technologique (CEA) (DRT (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Epidémiologie et analyses en santé publique : risques, maladies chroniques et handicaps (LEASP), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), INSERM UMR 1287 Département d'hématologie, Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Dynamique moléculaire de la transformation hématopoïétique (Dynamo), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Institut Gustave Roussy (IGR), Département de biologie et pathologie médicales [Gustave Roussy], Université Grenoble Alpes - UFR Médecine (UGA UFRM), Université Grenoble Alpes (UGA), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU), and Université de Montpellier (UM)
Subjects: Immunology, Cell Biology, Hematology, Biochemistry, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience
Published: 2022

6. Myeloid malignancies with translocation t(4;12)(q11‐13;p13): molecular landscape, clonal hierarchy and clinical outcomes

Author: François Lifermann, Jean-Alain Martignoles, Anne Quinquenel, Vincent Parinet, Christine Lefebvre, Pierre Hirsch, Mélanie Martin, Sabine Defasque, Florence Nguyen-Khac, Matthieu Decamp, Laurence Simon, Dominique Penther, Nadia Ali-Ammar, Elise Chapiro, Odile Maarek, Chrystele Bilhou-Nabera, Baptiste Gaillard, Agathe Maillon, Jean-Baptiste Micol, Marine Baron, Nathalie Auger, Stéphanie Struski, Damien Roos-Weil, Sylvie Tondeur, Marie-Joelle Mozziconacci, Audrey Bidet, Service d'Hématologie clinique [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], Hôpital Robert Debré, Service d'Hémato-oncologie [CHU Saint-Louis], Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Universitaire [Grenoble] (CHU), Laboratoire CERBA [Saint Ouen l'Aumône], Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Centre Hospitalier Universitaire de Reims (CHU Reims), Service de Génétique [CHU Caen], CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Université de Caen Normandie (UNICAEN), Normandie Université (NU), Centre Hospitalier de Dax, Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département d'hématologie [Gustave Roussy], Institut Gustave Roussy (IGR), Génétique (Biologie pathologie), Département de biologie et pathologie médicales [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Service d'immunologie et hématologies biologiques [CHU Saint-Antoine], Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), HAL-SU, Gestionnaire, École Pratique des Hautes Études (EPHE), and Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Male, Oncology, Myeloid, [SDV]Life Sciences [q-bio], Chromosomal translocation, Translocation, Genetic, chemistry.chemical_compound, 0302 clinical medicine, hemic and lymphatic diseases, 12), In Situ Hybridization, Fluorescence, Aged, 80 and over, CHIC2, Middle Aged, Immunohistochemistry, 3. Good health, [SDV] Life Sciences [q-bio], Leukemia, Myeloid, Acute, medicine.anatomical_structure, RUNX1, 030220 oncology & carcinogenesis, Cytogenetic Analysis, Cohort, Molecular Medicine, Female, Original Article, Chromosomes, Human, Pair 4, medicine.medical_specialty, IDH1, 03 medical and health sciences, Internal medicine, Biomarkers, Tumor, medicine, Humans, Genetic Predisposition to Disease, acute myeloid leukaemia, Genetic Association Studies, Aged, Chromosome Aberrations, Chromosomes, Human, Pair 12, Myeloproliferative Disorders, business.industry, Myelodysplastic syndromes, Original Articles, ETV6, Cell Biology, medicine.disease, myelodysplastic syndrome, t(4, chemistry, Fusion transcript, Myelodysplastic Syndromes, prognosis, business, 030215 immunology
Abstract: International audience; Translocation t(4;12)(q11-13;p13) is a recurrent but very rare chromosomal aberration in acute myeloid leukaemia (AML) resulting in the non-constant expression of a CHIC2/ETV6 fusion transcript. We report clinico-biological features, molecular characteristics and outcomes of 21 cases of t(4;12) including 19 AML and two myelodysplastic syndromes (MDS). Median age at the time of t(4;12) was 78 years (range, 56–88). Multilineage dysplasia was described in 10 of 19 (53%) AML cases and CD7 and/or CD56 expression in 90%. FISH analyses identified ETV6 and CHIC2 region rearrangements in respectively 18 of 18 and 15 of 17 studied cases. The t(4;12) was the sole cytogenetic abnormality in 48% of cases. The most frequent associated mutated genes were ASXL1 (n = 8/16, 50%), IDH1/2 (n = 7/16, 44%), SRSF2 (n = 5/16, 31%) and RUNX1 (n = 4/16, 25%). Interestingly, concurrent FISH and molecular analyses showed that t(4;12) can be, but not always, a founding oncogenic event. Median OS was 7.8 months for the entire cohort. In the 16 of 21 patients (76%) who received antitumoral treatment, overall response and first complete remission rates were 37% and 31%, respectively. Median progression-free survival in responders was 13.7 months. Finally, t(4;12) cases harboured many characteristics of AML with myelodysplasia-related changes (multilineage dysplasia, MDS-related cytogenetic abnormalities, frequent ASXL1 mutations) and a poor prognosis.
Published: 2021

7. Cell clusters adopt a collective amoeboid mode of migration in confined nonadhesive environments

Author: Diane-Laure Pagès, Emmanuel Dornier, Jean de Seze, Emilie Gontran, Ananyo Maitra, Aurore Maciejewski, Li Wang, Rui Luan, Jérôme Cartry, Charlotte Canet-Jourdan, Joël Raingeaud, Grégoire Lemahieu, Marceline Lebel, Michel Ducreux, Maximiliano Gelli, Jean-Yves Scoazec, Mathieu Coppey, Raphaël Voituriez, Matthieu Piel, Fanny Jaulin, Dynamique des cellules tumorales (UMR1279), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Université Paris-Saclay, Laboratoire Physico-Chimie Curie [Institut Curie] (PCC), Institut Curie [Paris]-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Jean Perrin (LJP), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Biologie Cellulaire et Cancer, Institut Curie [Paris]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut Pierre-Gilles de Gennes pour la Microfluidique, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR), Département de chirurgie viscérale [Gustave Roussy], Département de biologie et pathologie médicales [Gustave Roussy], Laboratoire de Physique Théorique de la Matière Condensée (LPTMC), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and raingeaud, joel
Subjects: [SDV] Life Sciences [q-bio], Multidisciplinary, [SDV]Life Sciences [q-bio]
Abstract: International audience; Cell migration is essential to living organisms and deregulated in cancer. Single cell’s migration ranges from traction-dependent mesenchymal motility to contractility-driven propulsive amoeboid locomotion, but collective cell migration has only been described as a focal adhesion–dependent and traction-dependent process. Here, we show that cancer cell clusters, from patients and cell lines, migrate without focal adhesions when confined into nonadhesive microfabricated channels. Clusters coordinate and behave like giant super cells, mobilizing their actomyosin contractility at the rear to power their migration. This polarized cortex does not sustain persistent retrograde flows, of cells or actin, like in the other modes of migration but rather harnesses fluctuating cell deformations, or jiggling. Theoretical physical modeling shows this is sufficient to create a gradient of friction forces and trigger directed cluster motion. This collective amoeboid mode of migration could foster metastatic spread by enabling cells to cross a wide spectrum of environments.
Published: 2022

8. Automatic diagnosis and biopsy classification with dynamic Full-Field OCT and machine learning

Author: Jean-Christophe Olivo-Marin, Marie Darche, Emilie Benoit a la Guillaume, Claude Boccara, Kate Grieve, Diana Mandache, Aïcha Ben Lakhdar, Tual Monfort, Marie Christine Mathieu, Olivier Thouvenin, Vannary Meas Yedid, Jules Scholler, Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL), Analyse d'images biologiques - Biological Image Analysis (BIA), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), LLTech SAS Paris, Département de biologie et pathologie médicales [Gustave Roussy], Institut Gustave Roussy (IGR), Institut de la Vision, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)
Subjects: medicine.diagnostic_test, Computer science, business.industry, [SDV]Life Sciences [q-bio], Full field, Machine learning, computer.software_genre, Text mining, Biopsy, medicine, [INFO]Computer Science [cs], Artificial intelligence, business, computer
Abstract: The adoption of emerging imaging technologies in the medical community is often hampered if they provide a new unfamiliar contrast that requires experience to be interpreted. Here, in order to facilitate such integration, we developed two complementary machine learning approaches, respectively based on feature engineering and on convolutional neural networks (CNN), to perform automatic diagnosis of breast biopsies using dynamic full field optical coherence tomography (D-FF-OCT) microscopy. This new technique provides fast, high resolution images of biopsies with a contrast similar to H&E histology, but without any tissue preparation and alteration. We conducted a pilot study on 51 breast biopsies, and more than 1,000 individual images, and performed standard histology to obtain each biopsy diagnosis. Using our automatic diagnosis algorithms, we obtained an accuracy above 88% at the image level, and above 96% at the biopsy level. Finally, we proposed different strategies to narrow down the spatial scale of the automatic segmentation in order to be able to draw the tumor margins by drawing attention maps with the CNN approach, or by performing high resolution precise annotation of the datasets. Altogether, these results demonstrate the high potential of D-FF-OCT coupled to machine learning to provide a rapid, automatic, and accurate histopathology diagnosis.
Published: 2022

9. Upfront surgery or definitive radiotherapy for p16+ oropharyngeal cancer. A GETTEC multicentric study

Author: Laure Santini, Agnès Dupret-Bories, Haitham Mirghani, Aicha Ben Lakdar, Pascal Roger, Guillaume Chambon, Olivier Dassonville, Françoise Chapel, Emmanuel Chamorey, Julien Viotti, Sébastien Vergez, Thibault Galissier, Karen Benezery, Valérie Coste, Benjamin Lallemant, Stéphane Temam, D. Culié, Alexandre Bozec, Nicolas Fakhry, Bruno Guelfucci, Frederic Peyrade, Anne Sophie Ramay, Anne Sudaka, Florence Jourdan-Soulier, P. Gorphe, Alain Bizeau, Gilles Poissonnet, Joanne Guerlain, Renaud Garrel, Esma Saada-Bouzid, A. Modesto, Renaud Schiappa, Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Intercommunal Toulon-La Seyne sur Mer - Hôpital Sainte-Musse, Assistance Publique - Hôpitaux de Marseille (APHM), Laboratoire Parole et Langage (LPL), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Pathogénèse et contrôle des infections chroniques (PCCI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre Hospitalier Universitaire de Montpellier (CHU Montpellier ), Institut Gustave Roussy (IGR), Pathologie morphologique, Département de biologie et pathologie médicales [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Département de cancérologie cervico-faciale [Gustave Roussy] (CCF), 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), Université de Montpellier (UM), Université Côte d'Azur (UCA)-UNICANCER, CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Male, medicine.medical_specialty, Multivariate analysis, Survival, medicine.medical_treatment, Oropharynx, Cetuximab, [SDV.CAN]Life Sciences [q-bio]/Cancer, Human papilloma virus, [SDV.MHEP.CHI]Life Sciences [q-bio]/Human health and pathology/Surgery, 03 medical and health sciences, Antineoplastic Agents, Immunological, 0302 clinical medicine, Humans, Medicine, In patient, 030223 otorhinolaryngology, Definitive radiotherapy, Cyclin-Dependent Kinase Inhibitor p16, Cancer, Aged, Neoplasm Staging, Retrospective Studies, Chemotherapy, Radiotherapy, business.industry, Papillomavirus Infections, Univariate, Chemoradiotherapy, Adjuvant, Induction Chemotherapy, General Medicine, Middle Aged, medicine.disease, 3. Good health, Surgery, Survival Rate, Radiation therapy, Oropharyngeal Neoplasms, Oncology, 030220 oncology & carcinogenesis, Propensity score matching, Female, Radiotherapy, Adjuvant, Cisplatin, Neoplasm Recurrence, Local, business
Abstract: International audience; Background: The aim of this study was to assess the impact of the initial therapeutic strategy on oncologic outcomes in patients with HPV-positive OPSCC.Methods: All p16-positive OPSCCs treated from 2009 to 2014 in 7 centers were retrospectively included and classified according to the therapeutic strategy: surgical strategy (surgery ± adjuvant radiotherapy and chemotherapy) vs. non-surgical strategy (definitive radiotherapy ± chemotherapy). Univariate, multivariate propensity score matching analyses were performed to compare overall (OS), disease-specific (DSS) and recurrence-free survival (RFS).Results: 382 patients were included (surgical group: 144; non-surgical group: 238). Five-year OS, DSS and RFS were 89.2, 96.8 and 83.9% in the surgical group and 84.2, 87.1 and 70.4% in the non-surgical group, respectively. These differences were statistically significant for DSS and RFS after multivariate analysis, but only for RFS after propensity score matching analysis.Conclusion: In p16+ OPSCC patients, upfront surgery results in higher RFS than definitive radiotherapy ± chemotherapy but does not impact OS.
Published: 2021

10. Bamlanivimab + etesevimab therapy induces SARS-CoV-2 immune escape mutations and secondary clinical deterioration in COVID-19 patients with B-cell malignancies

Author: Sophie Bockel, J. Colomba, C. Bigenwald, Aude Jary, S. Marot, Pierre Tiberghien, Thomas Hueso, A. Laparra, Frank Griscelli, Fanny Pommeret, Emeline Colomba, Arnaud Bayle, J-M. Michot, Fabrice Barlesi, Karine Lacombe, Laurence Albiges, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR), Département d'hématologie [Gustave Roussy], Department of Radiotherapy, Département d’Innovation Thérapeutique et essais précoces [Gustave Roussy] (DITEP), Oncologie génito-urinaire, Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (RIGHT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS BFC)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), CHU Saint-Antoine [AP-HP], Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Microbiologie, and Département de biologie et pathologie médicales [Gustave Roussy]
Subjects: B-Lymphocytes, Mutation, 2019-20 coronavirus outbreak, Clinical Deterioration, Coronavirus disease 2019 (COVID-19), SARS-CoV-2, business.industry, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Immune escape, COVID-19, Hematology, medicine.disease_cause, Virology, medicine.anatomical_structure, Oncology, Neoplasms, Humans, Medicine, business, Letter to the Editor, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, B cell
Abstract: International audience
Published: 2021

11. Neuropilin-1 cooperates with PD-1 in CD8+ T cells predicting outcomes in melanoma patients treated with anti-PD1

Author: Julien Rossignol, Zakia Belaid, Guillemette Fouquet, Flavia Guillem, Rachel Rignault, Pierre Milpied, Amédée Renand, Tereza Coman, Maud D’Aveni, Michael Dussiot, Elia Colin, Jonathan Levy, Caroline Carvalho, Nicolas Goudin, Nicolas Cagnard, Francine Côté, Joel Babdor, Kanit Bhukhai, Laura Polivka, Amélie E. Bigorgne, Héloise Halse, Aurélien Marabelle, Séverine Mouraud, Yves Lepelletier, Thiago T. Maciel, Marie-Thérèse Rubio, Delphine Heron, Caroline Robert, Isabelle Girault, Doris Lebeherec, Jean-Yves Scoazec, Ivan Moura, Louise Condon, Mirjana Weimershaus, Franck Pages, Jean Davoust, David Gross, Olivier Hermine, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), 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), 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), Département de génétique [Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP Hôpital universitaire Robert-Debré [Paris], Structure Fédérative de Recherche Necker (SFR Necker - UMS 3633 / US24), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Plate Forme Paris Descartes de Bioinformatique (BIP-D), Université Paris Cité (UPCité), Département d’Innovation Thérapeutique et essais précoces [Gustave Roussy] (DITEP), Institut Gustave Roussy (IGR), Service de Génétique médicale [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de dermatologie, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Département de biologie et pathologie médicales [Gustave Roussy], Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-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), AP-HP Hôpital universitaire Robert-Debré [Paris], This work was supported (Research Grants) by 'fondation BMS ' and 'Sauvez la vie, appel à projet Université Paris Descartes ' (16FND998UPDE), Côté, Francine, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and École Pratique des Hautes Études (EPHE)
Subjects: [SDV] Life Sciences [q-bio], Multidisciplinary, [SDV]Life Sciences [q-bio], Immunology, Cancer
Abstract: International audience; Targeting immune checkpoints, such as Programmed cell Death 1 (PD1), has improved survival in cancer patients by restoring antitumor immune responses. Most patients, however, relapse or are refractory to immune checkpoint blocking therapies. Neuropilin-1 (NRP1) is a transmembrane glycoprotein required for nervous system and angiogenesis embryonic development, also expressed in immune cells. We hypothesized that NRP1 could be an immune checkpoint co-receptor modulating CD8+ T cells activity in the context of the antitumor immune response. Here, we show that NRP1 is recruited in the cytolytic synapse of PD1+CD8+ T cells, cooperates and enhances PD-1 activity. In mice, CD8+ T cells specific deletion of Nrp1 improves anti-PD1 antibody antitumor immune responses. Likewise, in human metastatic melanoma, the expression of NRP1 in tumor infiltrating CD8+ T cells predicts poor outcome of patients treated with anti-PD1. NRP1 is a promising target to overcome resistance to anti-PD1 therapies.
Published: 2022

12. Sympathetic axonal sprouting induces changes in macrophage populations and protects against pancreatic cancer

Author: Jérémy Guillot, Chloé Dominici, Adrien Lucchesi, Huyen Thi Trang Nguyen, Angélique Puget, Mélanie Hocine, Martha M. Rangel-Sosa, Milesa Simic, Jérémy Nigri, Fabienne Guillaumond, Martin Bigonnet, Nelson Dusetti, Jimmy Perrot, Jonathan Lopez, Anders Etzerodt, Toby Lawrence, Pierre Pudlo, Florence Hubert, Jean-Yves Scoazec, Serge A. van de Pavert, Richard Tomasini, Sophie Chauvet, Fanny Mann, Institut de Biologie du Développement de Marseille (IBDM), Aix Marseille Université (AMU)-Collège de France (CdF (institution))-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), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hospices Civils de Lyon (HCL), 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 de Mathématiques de Marseille (I2M), Aix Marseille Université (AMU)-École Centrale de Marseille (ECM)-Centre National de la Recherche Scientifique (CNRS), Institut Gustave Roussy (IGR), Département de biologie et pathologie médicales [Gustave Roussy], ANR-17-EURE-0029,nEURo*AMU,Marseille NeuroSchool, une formation d'excellence(2017), and DUMENIL, Anita
Subjects: Cancer microenvironment, Sympathetic Nervous System, [SDV]Life Sciences [q-bio], REDUCES SURVIVAL, General Physics and Astronomy, DUCTAL ADENOCARCINOMA, PROGRESSION, General Biochemistry, Genetics and Molecular Biology, Mice, INITIATION, COOPERATE, Sympathetic Nervous System/physiology, Tumor Microenvironment, Autonomic nervous system, Animals, NEURONS, INNERVATION, Multidisciplinary, Macrophages, TUMOR-GROWTH, PAIN, General Chemistry, Pancreatic cancer, SENSATION, [SDV] Life Sciences [q-bio], Pancreatic Neoplasms, Carcinoma, Pancreatic Ductal
Abstract: Neuronal nerve processes in the tumor microenvironment were highlighted recently. However, the origin of intra-tumoral nerves remains poorly known, in part because of technical difficulties in tracing nerve fibers via conventional histological preparations. Here, we employ three-dimensional (3D) imaging of cleared tissues for a comprehensive analysis of sympathetic innervation in a murine model of pancreatic ductal adenocarcinoma (PDAC). Our results support two independent, but coexisting, mechanisms: passive engulfment of pre-existing sympathetic nerves within tumors plus an active, localized sprouting of axon terminals into non-neoplastic lesions and tumor periphery. Ablation of the innervating sympathetic nerves increases tumor growth and spread. This effect is explained by the observation that sympathectomy increases intratumoral CD163+ macrophage numbers, which contribute to the worse outcome. Altogether, our findings provide insights into the mechanisms by which the sympathetic nervous system exerts cancer-protective properties in a mouse model of PDAC.
Published: 2022

13. Integrating deep learning CT-scan model, biological and clinical variables to predict severity of COVID-19 patients

Author: Paul Trichelair, Kathryn Schutte, Etienne Bendjebbar, Thomas Clozel, Nathalie Lassau, Sagar Verma, Gilles Wainrib, Simon Jégou, Remy Dubois, Frank Chemouni, Gabriel Garcia, Yingping Li, Annabelle Stoclin, Samer Soliman, Imad Bousaid, Paul Jehanno, Fabien Brulport, Hugo Gortais, Olivier Meyrignac, Jocelyn Dachary, Marie-Pauline Talabard, Emilie Chouzenoux, Ana Neacsu, Matthieu Terris, Fabrice Barlesi, Matthieu Devilder, Mikael Azoulay, Hugues Talbot, Kavya Gupta, Paul Herent, Olivier Dehaene, Franck Griscelli, Jean-Baptiste Schiratti, Michael G. B. Blum, Adrian Gonzalez, Jean-Christophe Pesquet, Nicolas Tetelboum, Corinne Balleyguier, Nicolas Loiseau, Marie-France Bellin, Samy Ammari, Elodie Pronier, Tasnim Dardouri, Emmanuel Planchet, Yannick Boursin, Meriem Sefta, Jean-Philippe Lamarque, Mansouria Merad, Unité BioMaps (BIOMAPS), Service Hospitalier Frédéric Joliot (SHFJ), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Département d'imagerie médicale [Gustave Roussy], Institut Gustave Roussy (IGR), OPtimisation Imagerie et Santé (OPIS), Inria Saclay - Ile de France, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre de vision numérique (CVN), Institut National de Recherche en Informatique et en Automatique (Inria)-CentraleSupélec-Université Paris-Saclay-CentraleSupélec-Université Paris-Saclay, Département de Radiologie [AP-HP Hôpital Bicêtre], AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Owkin, Inc. [New York, NY, États-Unis], Département interdisciplinaire d’organisation des parcours patients (DIOPP), Département de biologie et pathologie médicales [Gustave Roussy], Centre de vision numérique (CVN), Institut National de Recherche en Informatique et en Automatique (Inria)-CentraleSupélec-Université Paris-Saclay, Heriot-Watt University [Edinburgh] (HWU), Direction de la Transformation Numérique et des Systèmes d’Information, Owkin France, Département de médecine oncologique [Gustave Roussy], LaBoratoire d'Imagerie biOmédicale MultimodAle Paris-Saclay (BIOMAPS), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: medicine.medical_specialty, Multivariate analysis, Clinical variables, Coronavirus disease 2019 (COVID-19), Science, MEDLINE, General Physics and Astronomy, macromolecular substances, Models, Biological, Severity of Illness Index, Article, General Biochemistry, Genetics and Molecular Biology, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, Deep Learning, 0302 clinical medicine, Text mining, Artificial Intelligence, Intensive care, Radiologists, Machine learning, Severity of illness, Humans, Medicine, 030212 general & internal medicine, Multidisciplinary, business.industry, Deep learning, COVID-19, General Chemistry, Prognosis, 3. Good health, Risk factors, Viral infection, Multivariate Analysis, Emergency medicine, Neural Networks, Computer, Artificial intelligence, Tomography, X-Ray Computed, business, [SPI.SIGNAL]Engineering Sciences [physics]/Signal and Image processing
Abstract: The SARS-COV-2 pandemic has put pressure on intensive care units, so that identifying predictors of disease severity is a priority. We collect 58 clinical and biological variables, and chest CT scan data, from 1003 coronavirus-infected patients from two French hospitals. We train a deep learning model based on CT scans to predict severity. We then construct the multimodal AI-severity score that includes 5 clinical and biological variables (age, sex, oxygenation, urea, platelet) in addition to the deep learning model. We show that neural network analysis of CT-scans brings unique prognosis information, although it is correlated with other markers of severity (oxygenation, LDH, and CRP) explaining the measurable but limited 0.03 increase of AUC obtained when adding CT-scan information to clinical variables. Here, we show that when comparing AI-severity with 11 existing severity scores, we find significantly improved prognosis performance; AI-severity can therefore rapidly become a reference scoring approach., The SARS-COV-2 pandemic has put pressure on intensive care units, so that predicting severe deterioration early is a priority. Here, the authors develop a multimodal severity score including clinical and imaging features that has significantly improved prognostic performance in two validation datasets compared to previous scores.
Published: 2021

14. Escherichia coli-Specific CXCL13-Producing TFH Are Associated with Clinical Efficacy of Neoadjuvant PD-1 Blockade against Muscle-Invasive Bladder Cancer

Author: Anne-Gaëlle Goubet, Leonardo Lordello, Carolina Alves Costa Silva, Isabelle Peguillet, Marianne Gazzano, Maxime Descartes Mbogning-Fonkou, Cassandra Thelemaque, Cédric Lebacle, Constance Thibault, François Audenet, Géraldine Pignot, Gwenaelle Gravis, Carole Helissey, Luca Campedel, Morgan Roupret, Evanguelos Xylinas, Idir Ouzaid, Agathe Dubuisson, Marine Mazzenga, Caroline Flament, Pierre Ly, Virginie Marty, Nicolas Signolle, Allan Sauvat, Thomas Sbarrato, Mounia Filahi, Caroline Davin, Gabriel Haddad, Jacques Bou Khalil, Camille Bleriot, François-Xavier Danlos, Garett Dunsmore, Kevin Mulder, Aymeric Silvin, Thibault Raoult, Baptiste Archambaud, Shaima Belhechmi, Ivo Gomperts Boneca, Nadège Cayet, Maryse Moya-Nilges, Adeline Mallet, Romain Daillere, Etienne Rouleau, Camelia Radulescu, Yves Allory, Jacques Fieschi, Mathieu Rouanne, Florent Ginhoux, Gwénaël Le Teuff, Lisa Derosa, Aurélien Marabelle, Jeroen Van Dorp, Nick Van Dijk, Michiel S. Van Der Heijden, Benjamin Besse, Fabrice Andre, Miriam Merad, Guido Kroemer, Jean-Yves Scoazec, Laurence Zitvogel, Yohann Loriot, Université Paris-Saclay, Institut Gustave Roussy (IGR), Immunologie anti-tumorale et immunothérapie des cancers (ITIC), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, NF-kappaB, Différenciation et Cancer (OncokappaB (URP_7324)), Université Paris Cité (UPCité), Immunologie intégrative des tumeurs et immunothérapie des cancers (INTIM), Institut Curie [Paris], 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), Petites Molécules de neuroprotection, neurorégénération et remyélinisation, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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 Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hôpital d'Instruction des Armées Begin, Service de Santé des Armées, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), 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 de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Microbes évolution phylogénie et infections (MEPHI), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Institut Hospitalier Universitaire Méditerranée Infection (IHU Marseille), Département d’Innovation Thérapeutique et essais précoces [Gustave Roussy] (DITEP), Direction de la recherche clinique [Gustave Roussy], Service de biostatistique et d'épidémiologie (SBE), Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Département de médecine oncologique [Gustave Roussy], Département de biologie et pathologie médicales [Gustave Roussy], Oncologie gynécologique, ANR-16-RHUS-0008, ANR-21-RHUS-0017, Bristol-Myers Squibb, BMS, Pfizer, Astellas Pharma US, APUS, AstraZeneca, Genentech, Merck, Roche, Gilead Sciences, Meso Scale Diagnostics, MSD, Janssen Pharmaceuticals, Merck Sharp and Dohme, MSD, Horizon 2020 Framework Programme, H2020: 19-CE15-0029-01, 825410, Clovis Oncology, Seerave Foundation, Fondation Philanthropia, Advanced Accelerator Applications, AAA, Agence Nationale de la Recherche, ANR: ANR-10-LABX-62-IBEID, Fondation pour la Recherche Médicale, FRM, Daiichi-Sankyo, Fondation ARC pour la Recherche sur le Cancer, ARC, Ligue Contre le Cancer, Institut Universitaire de France, IUF, Institut National Du Cancer, INCa, Cancéropôle Ile de France, Association Française d'Urologie, AFU, Labex Immuno-Oncology, The trial was conducted by the French Genitourinary Group (GETUG) and funded by MSD, which provided the drug. This study was approved by the ethics committee CPP Est-III in December 2017 and the French National Agency for the Safety of Medicines and Health Products (ANSM) in November 2017, and was conducted in accordance with the protocols and Good Clinical Practice Guidelines defined by the International Conference for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use and the principles of the Declaration of Helsinki., C. Alves Costa Silva reports grants from MSD Avenir Foundation during the conduct of the study. C. Thibault reports personal fees and nonfinancial support from Pfizer, Merck, MSD, Janssen, and Ipsen, grants, personal fees, and nonfinancial support from AstraZeneca, We thank pathologists, nurses, and clinical research associates from Hôpital Européenn George Pompidou, Hôpital Begin, Institut Paoli-Calmettes, Hôpital Bichat, and Hôpital Pitié-Salpétrière for their participation in the PANDORE clinical trial. We are thankful to the flow and mass cytometry facility team of Gustave Roussy (Philippe Rameau and Cyril Catelain). We thank Fluidigm for their support. We are grateful for support for equipment from the French Government Programme Investissements d’Avenir France BioImag-ing (FBI, No. ANR-10-INSB-04-01) and the French Government (Agence Nationale de la Recherche) Investissement d’Avenir program, Laboratoire d’Excellence 'Integrative Biology of Emerging Infectious Diseases' (ANR-10-LABX-62-IBEID). A.-G. Goubet was supported by Fondation pour la Recherche Médicale. C. Alves Costa Silva was supported by MSD Avenir. F.-X. Danlos was supported by Fondation Philantropia. M. Roupret was supported by Fondation Foch and the Association Française d’Urologie (AFU). L. Zitvogel was funded by the RHU Torino Lumière (ANR-16-RHUS-0008). L. Zitvogel and L. Derosa were supported by RHU5 'ANR-21-RHUS-0017' IMMUNOLIFE, SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE), as well as the SIGN’IT ARC foundation. L. Zitvogel was supported by European Union’s Horizon 2020 research and innovation programme under grant agreement number 825410 [project acronym: ONCOBIOME, project title: Gut OncoMicrobiome Signatures (GOMS) associated with cancer incidence, prognosis, and prediction of treatment response]. L. Zitvogel also received an ANR grant–French-German Ileobiome 19-CE15-0029-01. L. Zitvogel and G. Kroemer received a donation from the Seerave Foundation. L. Zitvogel and G. Kroemer were supported by the Ligue contre le Cancer (équipe labelisée), ANR projets blancs, Cancéropôle Ile-de-France, Fondation pour la Recherche Médicale (FRM), a donation by Elior, Institut National du Cancer (INCa), Inserm (HTE), Institut Universitaire de France, the LabEx Immuno-Oncology, and FHU CARE, Dassault, and Badinter Philantropia. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact., Bristol Myers Squibb, and Sanofi, and personal fees from Astellas and AAA during the conduct of the study, as well as personal fees and nonfinancial support from Pfizer, Merck, MSD, Janssen, and Ipsen, grants, personal fees, and nonfinancial support from AstraZeneca, Bristol Myers Squibb, and Sanofi, and personal fees from Astellas and AAA outside the submitted work. F. Audenet reports personal fees from Astellas, Urodiag, Vitadx, and Bristol Myers Squibb, and nonfinancial support from Ipsen outside the submitted work. G. Gravis reports grants from Bristol Myers Squibb, and other support from MSD, Bristol Myers Squibb, and Merck–Pfizer alliance outside the submitted work. C. Helissey reports personal fees from Janssen-Cilag, Roche, Bayer, AstraZeneca, and Astellas outside the submitted work. L. Cam-pedel reports personal fees from MSD, Pfizer, Bristol Myers Squibb, and Bayer outside the submitted work. T. Sbarrato reports personal fees from Veracyte during the conduct of the study. T. Raoult reports grants, personal fees, and nonfinancial support from Merck Sharp & Dohme during the conduct of the study. E. Rouleau reports grants from AstraZeneca, Roche, Clovis, Bristol Myers Squibb, and MSD outside the submitted work. Y. Allory reports other support from Astra-Zeneca, MSD, and Bristol Myers Squibb outside the submitted work. J. Fieschi reports personal fees from Veracyte during the conduct of the study. A. Marabelle reports grants, personal fees, nonfinancial support, and other support from MSD, Bristol Myers Squibb, and AstraZeneca, and personal fees, nonfinancial support, and other support from Roche/Genentech and Pfizer outside the submitted work. J. Van Dorp reports other support from Bristol Myers Squibb during the conduct of the study. M.S. van der Heijden reports grants from Bristol Myers Squibb during the conduct of the study, as well as grants and personal fees from Bristol Myers Squibb, Roche, and AstraZeneca, grants from 4SC, and personal fees from MSD/Merck, Janssen, Pfizer, and Seagen outside the submitted work. B. Besse reports grants from 4D Pharma, AbbVie, Amgen, Aptitude Health, AstraZeneca, BeiGene, Blueprint Medicines, Boehringer Ingelheim, Celgene, Cergentis, Chu-gai Pharmaceutical, Cristal Therapeutics, Daiichi Sankyo, Eli Lilly, Eisai, Genzyme Corporation, GSK, Inivata, Ipsen, Janssen, Onxeo, OSE Immunotherapeutics, Pfizer, Roche/Genentech, Sanofi, Takeda, Tolero Pharmaceuticals, and Turning Point Therapeutics during the conduct of the study. F. Andre reports grants and other support from AstraZeneca and Daiichi Sankyo, grants from Lilly and Sanofi, and other support from Novartis and Relay outside the submitted work. M. Merad reports grants and personal fees from Regeneron, personal fees from Compugen, Morphic Therapeutics, Myeloid Therapeutics, Nirogy, DrenBio, Oncoresponse, Asherbio, Pionyr, Owkin, and Larkspur, other support from Innate Pharma, Genenta, DBV, and OSE Immunotherapeutics, and grants from Boehringer outside the submitted work. G. Kroemer reports grants from Daiichi Sankyo, Eleor, Kaleido, Lytix Pharma, PharmaMar, Osasuna Therapeutics, Samsara Therapeutics, Sanofi, Sotio, Tollys, Vascage, and Vasculox/Tioma, and personal fees from Reithera outside the submitted work, is on the Board of Directors for Bristol Myers Squibb Foundation France, and is a scientific cofounder of EverImmune, Osasuna Therapeutics, Samsara Therapeutics, and Therafast Bio. L. Zitvogel reports grants and personal fees from EverImmune, and grants from 9 Meters and Pileje during the conduct of the study, grants from Daiichi Sankyo outside the submitted work, and a patent for B220028EPA pending. Y. Loriot reports grants from MSD and personal fees from MSD during the conduct of the study, personal fees from Bristol Myers Squibb, Pfizer, Merck Serono, AstraZeneca, Seattle Genetics, Gilead, Taiho, and Astel-las, grants and personal fees from Janssen, and grants from Roche and Celsius outside the submitted work, and a patent for EP2305181.4 pending. No disclosures were reported by the other authors., and FHU CARE, Dassault, and Badinter Philantropia., ANR-16-RHUS-0008,LUMIERE,LUMIERE(2016), and ANR-21-RHUS-0017,IMMUNOLIFE,Microbiota-centered interventions to solve antibiotics-induced primary resistance to immune checkpoint inhibitors(2021)
Subjects: [SDV]Life Sciences [q-bio], Muscles, Programmed Cell Death 1 Receptor, T-Lymphocytes, Helper-Inducer, Chemokine CXCL13, B7-H1 Antigen, Neoadjuvant Therapy, Treatment Outcome, Oncology, Urinary Bladder Neoplasms, Immunoglobulin G, Escherichia coli, Humans, Immune Checkpoint Inhibitors
Abstract: Biomarkers guiding the neoadjuvant use of immune-checkpoint blockers (ICB) are needed for patients with localized muscle-invasive bladder cancers (MIBC). Profiling tumor and blood samples, we found that follicular helper CD4+ T cells (TFH) are among the best therapeutic targets of pembrolizumab correlating with progression-free survival. TFH were associated with tumoral CD8 and PD-L1 expression at baseline and the induction of tertiary lymphoid structures after pembrolizumab. Blood central memory TFH accumulated in tumors where they produce CXCL13, a chemokine found in the plasma of responders only. IgG4+CD38+ TFH residing in bladder tissues correlated with clinical benefit. Finally, TFH and IgG directed against urothelium-invasive Escherichia coli dictated clinical responses to pembrolizumab in three independent cohorts. The links between tumor infection and success of ICB immunomodulation should be prospectively assessed at a larger scale. Significance: In patients with bladder cancer treated with neoadjuvant pembrolizumab, E. coli–specific CXCL13 producing TFH and IgG constitute biomarkers that predict clinical benefit. Beyond its role as a biomarker, such immune responses against E. coli might be harnessed for future therapeutic strategies. This article is highlighted in the In This Issue feature, p. 2221
Published: 2022

15. Genetic landscape of a large cohort of Primary Ovarian Insufficiency: New genes and pathways and implications for personalized medicine

Author: Abdelkader Heddar, Cagri Ogur, Sabrina Da Costa, Inès Braham, Line Billaud-Rist, Necati Findikli, Claire Beneteau, Rachel Reynaud, Khaled Mahmoud, Stéphanie Legrand, Maud Marchand, Isabelle Cedrin-Durnerin, Adèle Cantalloube, Maeliss Peigne, Marion Bretault, Benedicte Dagher-Hayeck, Sandrine Perol, Celine Droumaguet, Sabri Cavkaytar, Carole Nicolas-Bonne, Hanen Elloumi, Mohamed Khrouf, Charlotte Rougier-LeMasle, Melanie Fradin, Elsa Le Boette, Perrine Luigi, Anne-Marie Guerrot, Emmanuelle Ginglinger, Amandine Zampa, Anais Fauconnier, Nathalie Auger, Françoise Paris, Elise Brischoux-Boucher, Christelle Cabrol, Aurore Brun, Laura Guyon, Melanie Berard, Axelle Riviere, Nicolas Gruchy, Sylvie Odent, Brigitte Gilbert-Dussardier, Bertrand Isidor, Juliette Piard, Laetitia Lambert, Samir Hamamah, Anne Marie Guedj, Aude Brac de la Perriere, Hervé Fernandez, Marie-Laure Raffin-Sanson, Michel Polak, Hélène Letur, Sylvie Epelboin, Genevieve Plu-Bureau, Sławomir Wołczyński, Sylvie Hieronimus, Kristiina Aittomaki, Sophie Catteau-Jonard, Micheline Misrahi, Medicum, Research Programs Unit, Kristiina Aittomäki / Principal Investigator, HUSLAB, Department of Medical and Clinical Genetics, University of Helsinki, Physiopathologie et traitement des maladies du foie, Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Universitaire de Nice (CHU Nice), Hôpital Cochin [AP-HP], Centre hospitalier universitaire de Nantes (CHU Nantes), Hôpital de la Timone [CHU - APHM] (TIMONE), Hôpital Jean Verdier [AP-HP], Service d’endocrinologie et nutrition [AP-HP Ambroise-Paré], Hôpital Ambroise Paré [AP-HP], Unité de Gynécologie Médicale, AP-HP, Hôpital Port-Royal, Université de Paris, Service de médecine interne [Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service d'endocrinologie [CHU Nice], CHU Pontchaillou [Rennes], Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU de Saint-Brieuc, Centre Hospitalier Antibes - Juan-les-Pins, Cancer and Brain Genomics (CBG), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-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), CHU Rouen, Normandie Université (NU), Centre Hospitalier de Mulhouse, site du Hasenrain (Mulhouse), CIC Saint Etienne, Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne)-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Nord (Saint Etienne), Institut Gustave Roussy (IGR), Génétique (Biologie pathologie), Département de biologie et pathologie médicales [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Développement Embryonnaire, Fertilité et Environnement (DEFE), 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)-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Service de génétique clinique [Poitiers], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Service de Génétique Clinique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Biologie, génétique et thérapies ostéoarticulaires et respiratoires (BIOTARGEN), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU), Centre de génétique humaine [CHRU Besançon], Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Hôpital Foch [Suresnes], Centre hospitalier de Pau, CHU Lille, This study was supported by Université Paris Sud-Paris Saclay, Hôpitaux Universitaires Paris Saclay (AH, MM), the Institut National de la Santé et de la Recherche Médicale-INSERM (AH, MM), and by the Agence Nationale de Biomédecine (AH, MM)., Hôpital Bicêtre, Hôpital Paul Brousse, Yildiz Technical University (YTU), Aix Marseille Université (AMU), CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU), Üsküdar university, Centre Hospitalier Alpes Léman (CHAL), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Hôpital Arnaud de Villeneuve [CHRU Montpellier], Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC), Université de Poitiers, CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Université de Montpellier (UM), Hôpital Louis Pradel [CHU - HCL], Hospices Civils de Lyon (HCL), Polyclinique de Navarre, Partenaires INRAE, Medical University of Białystok (MUB), Helsingin yliopisto = Helsingfors universitet = University of Helsinki, and Université de Lille
Subjects: [SDV.GEN]Life Sciences [q-bio]/Genetics, Post-translational regulation, DNA repair genes, Mitophagy, 1184 Genetics, developmental biology, physiology, NF-kappa B, General Medicine, Nf-kb, Primary Ovarian Insufficiency, Personalized medicine, General Biochemistry, Genetics and Molecular Biology, Mitomycins, Meiosis, Molecular pathophysiology, Genetic, Infertility, Humans, Female, 3111 Biomedicine, Precision Medicine
Abstract: Background Primary Ovarian Insufficiency (POI), a public health problem, affects 1-3.7% of women under 40 yield-ing infertility and a shorter lifespan. Most causes are unknown. Recently, genetic causes were identified, mostly in single families. We studied an unprecedented large cohort of POI to unravel its molecular pathophysiology.Methods 375 patients with 70 families were studied using targeted (88 genes) or whole exome sequencing with pathogenic/likely-pathogenic variant selection. Mitomycin-induced chromosome breakages were studied in patients' lymphocytes if necessary. Findings A high-yield of 29.3% supports a clinical genetic diagnosis of POI. In addition, we found strong evidence of pathogenicity for nine genes not previously related to a Mendelian phenotype or POI: ELAVL2, NLRP11, CENPE, SPATA33, CCDC150, CCDC185, including DNA repair genes: C17orf53(HROB), HELQ, SWI5 yielding high chromo-somal fragility. We confirmed the causal role of BRCA2, FANCM, BNC1, ERCC6, MSH4, BMPR1A, BMPR1B, BMPR2, ESR2, CAV1, SPIDR, RCBTB1 and ATG7 previously reported in isolated patients/families. In 8.5% of cases, POI is the only symptom of a multi-organ genetic disease. New pathways were identified: NF-kB, post-translational regulation, and mitophagy (mitochondrial autophagy), providing future therapeutic targets. Three new genes have been shown to affect the age of natural menopause supporting a genetic link.Interpretation We have developed high-performance genetic diagnostic of POI, dissecting the molecular pathogene-sis of POI and enabling personalized medicine to i) prevent/cure comorbidities for tumour/cancer susceptibility genes that could affect life-expectancy (37.4% of cases), or for genetically-revealed syndromic POI (8.5% of cases), ii) predict residual ovarian reserve (60.5% of cases). Genetic diagnosis could help to identify patients who may benefit from the promising in vitro activation-IVA technique in the near future, greatly improving its success in treating infertility.Funding Universite? Paris Saclay, Agence Nationale de Biome?decine.Copyright (c) 2022 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)
Published: 2022

16. Antimicrobial resistance in enterobacterales recovered from urinary tract infections in France

Author: Eric, Farfour, Laurent, Dortet, Thomas, Guillard, Nicolas, Chatelain, Agathe, Poisson, Assaf, Mizrahi, Damien, Fournier, Rémy A, Bonnin, Nicolas, Degand, Philippe, Morand, Frédéric, Janvier, Vincent, Fihman, Stéphane, Corvec, Lauranne, Broutin, Cécile, Le Brun, Nicolas, Yin, Geneviève, Héry-Arnaud, Antoine, Grillon, Emmanuelle, Bille, Hélène, Jean-Pierre, Marlène, Amara, Francoise, Jaureguy, Christophe, Isnard, Vincent, Cattoir, Tristan, Diedrich, Emilie, Flevin, Audrey, Merens, Hervé, Jacquier, Marc, Vasse, On Behalf Of The Gmc Study Group, Hôpital Foch [Suresnes], Immunologie des maladies virales, auto-immunes, hématologiques et bactériennes (IMVA-HB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Pathologies Pulmonaires et Plasticité Cellulaire - UMR-S 1250 (P3CELL), Université de Reims Champagne-Ardenne (URCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Reims (CHU Reims), BIOPATH Laboratoires, BIO ARD’AISNE, MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), AgroParisTech-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Centre Hospitalier Antibes - Juan-les-Pins, AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hopital d'instruction des armées Sainte-Anne [Toulon] (HIA), CHU Henri Mondor [Créteil], Centre hospitalier universitaire de Nantes (CHU Nantes), Centre hospitalier universitaire de Poitiers (CHU Poitiers), CHU Trousseau [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Université libre de Bruxelles (ULB), Institut Gustave Roussy (IGR), Microbiologie, Département de biologie et pathologie médicales [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Virulence bactérienne précoce : fonctions cellulaires et contrôle de l'infection aiguë et subaiguë, Université de Strasbourg (UNISTRA), CHU Necker - Enfants Malades [AP-HP], Maladies infectieuses et vecteurs : écologie, génétique, évolution et contrôle (MIVEGEC), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud])-Université de Montpellier (UM), Centre Hospitalier de Versailles André Mignot (CHV), Hôpital Avicenne [AP-HP], CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), CHU Pontchaillou [Rennes], ARN régulateurs bactériens et médecine (BRM), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre hospitalier [Valenciennes, Nord], Centre hospitalier de Dieppe, Hôpital d'Instruction des Armées Begin, Service de Santé des Armées, Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], CHU Henri Mondor, and Jonchère, Laurent
Subjects: Enterobacterales, ESBL, urinary tract infection (UTI), fosfomycin, carbapenem, temocillin, nitrofurantoin, pivmecillinam, Microbiology (medical), General Immunology and Microbiology, [SDV]Life Sciences [q-bio], biochemical phenomena, metabolism, and nutrition, bacterial infections and mycoses, [SDV] Life Sciences [q-bio], Infectious Diseases, Immunology and Allergy, Molecular Biology
Abstract: International audience; In the context of increasing antimicrobial resistance in Enterobacterales, the management of these UTIs has become challenging. We retrospectively assess the prevalence of antimicrobial resistance in Enterobacterales isolates recovered from urinary tract samples in France, between 1 September 2017, to 31 August 2018. Twenty-six French clinical laboratories provided the susceptibility of 134,162 Enterobacterales isolates to 17 antimicrobials. The most frequent species were $E.\ coli$ (72.0%), $Klebsiella\ pneumoniae$ (9.7%), $Proteus\ mirabilis$ (5.8%), and $Enterobacter\ cloacae$ complex (2.9%). The overall rate of ESBL-producing Enterobacterales was 6.7%, and ranged from 1.0% in $P.\ mirabilis$ to 19.5% in $K.\ pneumoniae$, and from 3.1% in outpatients to 13.6% in long-term care facilities. Overall, 4.1%, 9.3% and 10.5% of the isolates were resistant to cefoxitin, temocillin and pivmecillinam. Cotrimoxazole was the less active compound with 23.4% resistance. Conversely, 4.4%, 12.9%, and 14.3% of the strains were resistant to fosfomycin, nitrofurantoin, and ciprofloxacin. However, less than 1% of E. coli was resistant to fosfomycin and nitrofurantoin. We identified several trends in antibiotics resistances among Enterobacterales isolates recovered from the urinary tract samples in France. Carbapenem-sparing drugs, such as temocillin, mecillinam, fosfomycin, cefoxitin, and nitrofurantoin, remained highly active, including towards ESBL-E.
Published: 2022

17. Second-Line Treatment and Prognostic Factors in Neuroendocrine Carcinoma

Author: Hadoux, Julien, Walter, Thomas, Kanaan, Christina, Hescot, Segolene, Hautefeuille, Vincent, Perrier, Marine, Tauveron, Igor, Laboureau, Sandrine, Do Cao, Christine, Pétorin, Caroline, Blanchet, Odile, Faron, Matthieu, Leteurtre, Emmanuelle, Rousselet, Marie-Christine, Joubert Zakeyh, Juliette, Marchal, Aude, Chatelain, Denis, Beaulaton, Clement, Hervieu, Valerie, Lombard-Bohas, Catherine, Ducreux, Michel, Scoazec, Jean Yves, Baudin, Eric, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR), Centre de Bioinformatique (CBIO), Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris sciences et lettres (PSL), Institut Curie [Paris], CHU Amiens-Picardie, CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), Génétique, Reproduction et Développement (GReD), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne (UCA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), CHU Lille, Service de Chirurgie Digestive et Hépatobiliaire [CHU Clermont-Ferrand], CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Centre de Ressources Biologiques [CHU Angers], PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 (CANTHER), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Hôpital universitaire Robert Debré [Reims], CHirurgie, IMagerie et REgénération tissulaire de l’extrémité céphalique - Caractérisation morphologique et fonctionnelle - UR UPJV 7516 (CHIMERE), Université de Picardie Jules Verne (UPJV), Hospices Civils de Lyon (HCL), Hôpital Edouard Herriot [CHU - HCL], UNICANCER, and Département de biologie et pathologie médicales [Gustave Roussy]
Subjects: [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; Neuroendocrine carcinomas (NEC) are aggressive malignant diseases. Etoposide-based rechallenge (EBR) and the prognostic role of Rb status in second-line chemotherapy (2L) have not been studied. The objectives of this study were to report the results of 2L including EBR as well as prognostic factors in a national retrospective multicenter study. NEC patients treated in 2L and further, with tissue samples available were included. Rb status and morphological classification were reviewed centrally. Among the 121 NEC patients (40% female, median age 61) included, there were 73 small cell NEC (60%), 34 large cell NEC (28%) and 14 NEC (not otherwise specified, 12%). Primary sites were lung (39%), gastro-enteropancreatic (36%), other (13%) and unknown (12%). Median Ki-67 index was 80%. Median progression-free survival (PFS) and overall survival (OS) under 2L were 2.1 and 6.2 months, respectively. No difference was observed between patients who received an "Adenocarcinoma-like" or a "Neuroendocrine-like" 2L or according to the Rb status. Thoracic primary was the only adverse prognostic factor for OS. EBR, administered to 31 patients, resulted in a 62% disease control rate with a median PFS and OS of 3.2 and 11.7 months respectively. In the 94 patients with a relapse-free interval ≥q 3 months after first-line platinum-etoposide, median OS was 12 months in patients who received EBR as compared to 5.9 months in patients who did not (p=0.043). EBR could be the best 2L option for patient with initial response to first line platinum-etoposide lasting at least 3 months. Rb status does not provide prognostic information in this setting.
Published: 2022

18. Management of Pathogenic CDH1 Variant Carriers Within the FREGAT Network

Author: Bres, Capucine, Voron, Thibault, Benhaim, Leonor, Bergeat, Damien, Parc, Yann, Karoui, Mehdi, Genser, Laurent, Péré, Guillaume, Demma, Jonathan, Bacoeur-Ouzillou, Ophélie, Lebreton, Gil, Thereaux, Jeremie, Gronnier, Caroline, Dartigues, Peggy, Svrcek, Magali, Bouzillé, Guillaume, Bardier, Armelle, Brunac, Anne, Roche, Brigitte, Darcha, Claude, Bazille, Celine, Doucet, Laurent, Belleannee, Genevieve, Lejeune, Sophie, Buisine, Marie, Renaud, Florence, Nuytens, Frederiek, Benusiglio, Patrick, Veziant, Julie, Eveno, Clarisse, Piessen, Guillaume, CHU Lille, CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut Gustave Roussy (IGR), Département de chirurgie viscérale [Gustave Roussy], CHU Pontchaillou [Rennes], 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), Nutrition et obésités: approches systémiques (UMR-S 1269) (Nutriomics), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Département de biologie et pathologie médicales [Gustave Roussy], Laboratoire Traitement du Signal et de l'Image (LTSI), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pitié-Salpêtrière [AP-HP], Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 (CANTHER), Institut Pasteur de Lille, and Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS)
Subjects: prophylactic surgery, [SDV]Life Sciences [q-bio], CDH1 mutation, morbidity, [SDV.MHEP.CHI]Life Sciences [q-bio]/Human health and pathology/Surgery, gastrectomy
Abstract: International audience; Objective: To describe the management of pathogenic CDH1 variant carriers (pCDH1vc) within the FREGAT (FRench Eso-GAsTric tumor) network. Primary objective focused on clinical outcomes and pathological findings, Secondary objective was to identify risk factor predicting postoperative morbidity (POM).Background: Prophylactic total gastrectomy (PTG) remains the recommended option for gastric cancer risk management in pCDH1vc with, however, endoscopic surveillance as an alternative.Methods: A retrospective observational multicenter study was carried out between 2003 and 2021. Data were reported as median (interquartile range) or as counts (proportion). Usual tests were used for univariate analysis. Risk factors of overall and severe POM (ie, Clavien-Dindo grade 3 or more) were identified with a binary logistic regression.Results: A total of 99 patients including 14 index cases were reported from 11 centers. Median survival among index cases was 12.0 (7.6-16.4) months with most of them having peritoneal carcinomatosis at diagnosis (71.4%). Among the remaining 85 patients, 77 underwent a PTG [median age=34.6 (23.7-46.2), American Society of Anesthesiologists score 1: 75%] mostly via a minimally invasive approach (51.9%). POM rate was 37.7% including 20.8% of severe POM, with age 40 years and above and low-volume centers as predictors ( P =0.030 and 0.038). After PTG, the cancer rate on specimen was 54.5% (n=42, all pT1a) of which 59.5% had no cancer detected on preoperative endoscopy (n=25).Conclusions: Among pCDH1vc, index cases carry a dismal prognosis. The risk of cancer among patients undergoing PTG remained high and unpredictable and has to be balanced with the morbidity and functional consequence of PTG.
Published: 2022

19. Patient-derived organoids identify an apico-basolateral polarity switch associated with survival in colorectal cancer

Author: Charlotte Canet-Jourdan, Diane-Laure Pagès, Clémence Nguyen-Vigouroux, Jérôme Cartry, Olivier Zajac, Christophe Desterke, Jean-Baptiste Lopez, Emie Gutierrez-Mateyron, Nicolas Signolle, Julien Adam, Joel Raingeaud, Mélanie Polrot, Patrick Gonin, Jacques R. R. Mathieu, Sylvie Souquere, Gerard Pierron, Maximiliano Gelli, Peggy Dartigues, Michel Ducreux, Valeria Barresi, Fanny Jaulin, Dynamique des cellules tumorales (UMR1279), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Biologie Cellulaire et Cancer, Institut Curie [Paris]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre Hépato-Biliaire [Hôpital Paul Brousse] (CHB), Hôpital Paul Brousse-Assistance Publique - Hôpitaux de Paris, Institut National de la Santé et de la Recherche Médicale (INSERM), Radiothérapie Moléculaire et Innovation Thérapeutique (RaMo-IT), Institut Gustave Roussy (IGR), Biomarqueurs prédictifs et nouvelles stratégies moléculaires en thérapeutique anticancéreuse (U981), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse (AMMICa), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Physiologie et physiopathologie des rétrovirus endogènes et infectieux (RETRO-ENDO), Institut Gustave Roussy (IGR)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Département de chirurgie viscérale [Gustave Roussy], Département de biologie et pathologie médicales [Gustave Roussy], Département de médecine oncologique [Gustave Roussy], Università degli studi di Verona = University of Verona (UNIVR), Prédicteurs moléculaires et nouvelles cibles en oncologie (PMNCO), and raingeaud, joel
Subjects: Integrins, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Cell Biology, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Colorectal cancer, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Organoids, Apicobasolateral polarity, [SDV.CAN] Life Sciences [q-bio]/Cancer, TGFbeta, Transforming Growth Factor beta, Cell Adhesion, [SDV.BC.BC] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Humans, Colorectal Neoplasms, Signal Transduction
Abstract: The metastatic progression of cancer remains a major issue in patient treatment. However, the molecular and cellular mechanisms underlying this process remain unclear. Here, we use primary explants and organoids from patients harboring mucinous colorectal carcinoma (MUC CRC), a poor-prognosis histological form of digestive cancer, to study the architecture, invasive behavior and chemoresistance of tumor cell intermediates. We report that these tumors maintain a robust apico-basolateral polarity as they spread in the peritumoral stroma or organotypic collagen-I gels. We identified two distinct topologies – MUC CRCs either display a conventional ‘apical-in’ polarity or, more frequently, harbor an inverted ‘apical-out’ topology. Transcriptomic analyses combined with interference experiments on organoids showed that TGFβ and focal adhesion signaling pathways are the main drivers of polarity orientation. Finally, we show that the apical-out topology is associated with increased resistance to chemotherapeutic treatments in organoids and decreased patient survival in the clinic. Thus, studies on patient-derived organoids have the potential to bridge histological, cellular and molecular analyses to decrypt onco-morphogenic programs and stratify cancer patients. This article has an associated First Person interview with the first author of the paper.
Published: 2022

20. Utilisation clinique et évolution des biomarqueurs circulants à l’ère de l’oncologie personnalisée : des marqueurs protéiques aux scores clinicobiologiques

Author: Alexandre, Perrier, Pierre, Hainaut, Alexandre, Guenoun, Dinh-Phong, Nguyen, Pierre-Jean, Lamy, Fabrice, Guerber, Frédéric, Troalen, Jérôme Alexandre, Denis, Mathieu, Boissan, HAL-SU, Gestionnaire, Service de Génétique médicale [CHU Pitié-Salpêtrière], 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), Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), KIRO, Institut médical d'anayse génomique (IMAGENOME), Labosud, Clinique Médicale Beausoleil, Laboratoire Oriade-Noviale-Biogroup, Institut Gustave Roussy (IGR), Département de biologie et pathologie médicales [Gustave Roussy], Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Service de Biochimie Endocrinienne et Oncologie [CHU Pitié-Salpêtrière], Service de biochimie et hormonologie [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Tenon [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)
Subjects: Artificial intelligence, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Liquid biopsy, High-Throughput Nucleotide Sequencing, Intelligence artificielle, Medical Oncology, Neoplastic Cells, Circulating, Circulating Tumor DNA, Valeur théranostique, MicroRNAs, Neoplasms, Tumor markers, Clinicobiological scores, Marqueurs tumoraux, Biomarkers, Tumor, Theranostic value, Humans, Biopsie liquide, Immunotherapy, Neoplasm Recurrence, Local, Precision Medicine, Scores clinico-biologiques, Early Detection of Cancer, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Data Management
Abstract: Technological advances, in particular the development of high-throughput sequencing, have led to the emergence of a new generation of molecular biomarkers for tumors. These new tools have profoundly changed therapeutic management in oncology, with increasingly precise molecular characterization of tumors leading to increasingly personalized therapeutic targeting. Detection of circulating tumor cells and/or circulating tumor DNA in blood samples -so-called 'liquid biopsies'- can now provide a genetic snapshot of the patient's tumor through an alternative and less invasive procedure than biopsy of the tumor tissue itself. This procedure for characterizing and monitoring the disease in real time facilitates the search for possible relapses, the emergence of resistance, or emergence of a new therapeutic target. In the long term, it might also provide a means of early detection of cancer. These new approaches require the treatment of ever-increasing amounts of clinical data, notably, with the goal of calculating composite clinical-biological predictive scores. The use of artificial intelligence will be unavoidable in this domain, but it raises ethical questions and implications for the health-care system that will have to be addressed., Les progrès technologiques, en particulier le développement du séquençage à haut débit, ont conduit à l’émergence d’une nouvelle génération de biomarqueurs tumoraux moléculaires. Ces nouveaux outils ont profondément modifié la prise en charge thérapeutique en oncologie avec une caractérisation moléculaire de plus en plus précise des tumeurs amenant à un ciblage thérapeutique personnalisé. La détection des cellules tumorales circulantes et/ou de l’ADN tumoral circulant dans des prélèvements sanguins, encore appelés « biopsies liquides », peut désormais fournir un instantané du profil génétique de la tumeur du patient grâce à une procédure alternative et moins invasive qu’une biopsie du tissu tumoral lui-même. Cette méthode de caractérisation moléculaire et de suivi de la maladie en temps réel facilite la recherche d’éventuelles rechutes, de l’émergence de résistances ou d’une nouvelle cible thérapeutique. À long terme, les biopsies liquides pourraient également fournir un moyen de détection précoce du cancer. Ces nouvelles approches nécessitent le traitement d’une quantité, toujours croissante, de données, en particulier cliniques, notamment dans l’optique d’élaborer des scores clinico-biologiques composites. L’utilisation de l’intelligence artificielle est un outil d’avenir dans ce domaine, mais elle soulève des questions éthiques et des implications pour l’organisation du système de santé qui devront être abordées.
Published: 2022

21. Comprehensive Genome Profiling in Patients With Metastatic Non-Small Cell Lung Cancer: The Precision Medicine Phase II Randomized SAFIR02-Lung Trial

Author: Boyault, Sandrine, Attignon, Valery, Soubeyran, Isabelle, Morel, Alain, Tran-Dien, Alicia, Jacquet, Alexandra, Dall'Olio, Filippo Gustavo, Jimenez, Marta, Soria, Jean-Charles, Besse, Benjamin, Barlesi, Fabrice, Tomasini, Pascale, Karimi, Maryam, Michiels, Stefan, Raimbourg, Judith, Daniel, Catherine, Janicot, Henri, Madroszyk, Anne, Audigier-Valette, Clarisse, Quoix, Elisabeth, Mazieres, Julien, Moro-Sibilot, Denis, Dansin, Eric, Molinier, Olivier, Morel, Hugues, Pichon, Eric, Cortot, Alexis, Otto, Josiane, Chomy, Francois, Souquet, Pierre-Jean, Cloarec, Nicolas, Giroux-Leprieur, Etienne, Bieche, Ivan, Lacroix, Ludovic, Fondation Synergie Lyon Cancer [Lyon], Centre Léon Bérard [Lyon], Institut Bergonié [Bordeaux], UNICANCER, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Centre de Recherche en Cancérologie et Immunologie Intégrée Nantes-Angers (CRCI2NA ), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), Prédicteurs moléculaires et nouvelles cibles en oncologie (PMNCO), 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), Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Multidisciplinary Oncology and Therapeutic Innovations Unit, Hôpital Nord [CHU - APHM], Tarbiat Modares University [Tehran], Service de biostatistique et d'épidémiologie (SBE), Direction de la recherche clinique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Oncostat (U1018 (Équipe 2)), Institut Gustave Roussy (IGR)-Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Institut Curie [Paris], Service de Pneumologie [CHU Clermont-Ferrand], Pôle RHEUNNIRS [CHU Clermont-Ferrand], CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand-CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Centre Hospitalier Intercommunal Toulon-La Seyne sur Mer - Hôpital Sainte-Musse, CHU Strasbourg, Service de pneumologie [Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), CHU de Grenoble-Alpes, Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université de Lille-UNICANCER, Centre Hospitalier Le Mans (CH Le Mans), Intergroupe Francophone de Cancérologie Thoracique [Paris] (IFCT), Intergroupe Francophone de Cancérologie thoracique, Centre Hospitalier Régional d'Orléans (CHRO), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Site de Recherche Intégrée en Cancérologie (SIRIC-ONCOLille), Université de Lille, Sciences et Technologies-Université de Lille, Sciences Humaines et Sociales-Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université de Lille-UNICANCER-Université de Lille-UNICANCER-Cancéropole Nord-Ouest-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Université Côte d'Azur (UCA), Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Centre Hospitalier Henri Duffaut (Avignon), Biomarqueurs et essais cliniques en Cancérologie et Onco-Hématologie (BECCOH), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay, and Département de biologie et pathologie médicales [Gustave Roussy]
Subjects: ErbB Receptors, Lung Neoplasms, Carcinoma, Non-Small-Cell Lung, [SDV]Life Sciences [q-bio], Antineoplastic Combined Chemotherapy Protocols, Mutation, Humans, Receptor Protein-Tyrosine Kinases, Precision Medicine, B7-H1 Antigen
Abstract: International audience; Purpose: Targeted therapies (TT) and immune checkpoint blockers (ICB) have revolutionized the approach to non-small cell lung cancer (NSCLC) treatment in the era of precision medicine. Their impact as switch maintenance therapy based on molecular characterization is unknown.Patients and Methods: SAFIR02-Lung was an open-label, randomized, phase II trial, involving 33 centers in France. We investigated eight TT (substudy-1) and one ICB (substudy-2), compared with standard-of-care as a maintenance strategy in patients with advanced EGFR, ALK wild-type (wt) NSCLC without progression after first-line chemotherapy, based on high-throughput genome analysis. The primary outcome was progression-free survival (PFS).Results: Among the 175 patients randomized in substudy-1, 116 received TT (selumetinib, vistusertib, capivasertib, AZD4547, AZD8931, vandetanib, olaparib, savolitinib) and 59 standard-of-care. Median PFS was 2.7 months [95% confidence interval (CI), 1.6-2.9] with TT versus 2.7 months (1.6-4.1) with standard-of-care (HR, 0.97; 95% CI, 0.7-1.36; P = 0.87). There were no significant differences in PFS within any molecular subgroup. In substudy-2, 183 patients were randomized, 121 received durvalumab and 62 standard-of-care. Median PFS was 3.0 months (2.3-4.4) with durvalumab versus 3.0 months (2.0-5.1) with standard-of-care (HR, 0.86; 95% CI, 0.62-1.20; P = 0.38). Preplanned subgroup analysis showed an enhanced benefit with durvalumab in patients with PD-L1 tumor proportion score (TPS) >= 1%, (n = 29; HR, 0.29; 95% CI, 0.11-0.75) as compared with PD-L1 < 1% (n = 31; HR, 0.71; 95% CI, 0.31-1.60; P-interaction = 0.036). Conclusions: Molecular profiling can feasibly be implemented to guide treatment choice for the maintenance strategy in EGFR/ALK wt NSCLC; in this study it did not lead to substantial treatment benefits beyond durvalumab for PD-L1 >= 1 patients.
Published: 2022

22. An epitranscriptomic mechanism underlies selective mRNA translation remodelling in melanoma persister cells

Author: Jean-Yves Scoazec, Sara Faouzi, Amandine Bastide, Fabrice Andre, Shensi Shen, Séverine Roy, Emilie Routier, Hélène Malka-Mahieu, Caroline Robert, Yu Fu, Laurent Désaubry, Alexandre David, Alexander M.M. Eggermont, Stéphan Vagner, Xiaoxiao Sun, Christine Mateus, Sylvain Martineau, Université de Picardie Jules Verne (UPJV), Institut de Génomique Fonctionnelle (IGF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Stress génotoxiques et cancer, Université Paris-Sud - Paris 11 (UP11)-Institut Curie [Paris]-Centre National de la Recherche Scientifique (CNRS), Nanjing University (NJU), Département Interdisciplinaire de Soins de Support aux Patients en Onco-hématologie [Gustave Roussy] (DISSPO), Institut Gustave Roussy (IGR), Oncologie dermatologique, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Laboratoire des biomolécules (LBM UMR 7203), Université Pierre et Marie Curie - Paris 6 (UPMC)-Département de Chimie - ENS Paris, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Pathologie mammaire, 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-Sud - Paris 11 - Faculté de médecine (UP11 UFR Médecine), Université Paris-Sud - Paris 11 (UP11), Pathologie morphologique, Département de biologie et pathologie médicales [Gustave Roussy], Hematopoïèse et Cellules Souches (U362), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Chimie - ENS Paris, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Laboratoire de Cardio-Oncologie et Chimie Médicinale, and Centre National de la Recherche Scientifique (CNRS)
Subjects: Untranslated region, Adenosine, Skin Neoplasms, Transcription, Genetic, [SDV]Life Sciences [q-bio], Aucun, General Physics and Astronomy, Epigenesis, Genetic, Eukaryotic initiation factor 4F, 0302 clinical medicine, Antineoplastic Combined Chemotherapy Protocols, Protein biosynthesis, genetics, lcsh:Science, Melanoma, ComputingMilieux_MISCELLANEOUS, Regulation of gene expression, 0303 health sciences, Multidisciplinary, Chemistry, food and beverages, Translation (biology), MAP Kinase Kinase Kinases, RNA Helicase A, 3. Good health, Cell biology, Gene Expression Regulation, Neoplastic, Cancer therapeutic resistance, 030220 oncology & carcinogenesis, RNA Helicases, Proto-Oncogene Proteins B-raf, Science, drug effects, [SDV.CAN]Life Sciences [q-bio]/Cancer, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, drug therapy, pathology, antagonists & inhibitors, Cell Line, Tumor, Humans, analogs & derivatives, metabolism, RNA, Messenger, Protein Kinase Inhibitors, 030304 developmental biology, fungi, General Chemistry, DNA Methylation, pharmacology, therapeutic use, Cell culture, Drug Resistance, Neoplasm, eIF4A, Eukaryotic Initiation Factor-4A, Mutation, lcsh:Q, 5' Untranslated Regions
Abstract: Cancer persister cells tolerate anticancer drugs and serve as the founders of acquired resistance and cancer relapse. Here we show that a subpopulation of BRAFV600 mutant melanoma cells that tolerates exposure to BRAF and MEK inhibitors undergoes a reversible remodelling of mRNA translation that evolves in parallel with drug sensitivity. Although this process is associated with a global reduction in protein synthesis, a subset of mRNAs undergoes an increased efficiency in translation. Inhibiting the eIF4A RNA helicase, a component of the eIF4F translation initiation complex, abrogates this selectively increased translation and is lethal to persister cells. Translation remodelling in persister cells coincides with an increased N6-methyladenosine modification in the 5′-untranslated region of some highly translated mRNAs. Combination of eIF4A inhibitor with BRAF and MEK inhibitors effectively inhibits the emergence of persister cells and may represent a new therapeutic strategy to prevent acquired drug resistance., Melanoma persister cells are tolerant to anti-BRAF and anti-MEK inhibition and can trigger cancer relapse. Here the authors show that a subset of N6-methyladenosine modified mRNAs is translationally activated in persister cells. This preferential translation can be abrogated via eIF4A inhibition.
Published: 2019

23. The clinical and molecular spectrum of QRICH1 associated neurodevelopmental disorder

Author: Kumble, Smitha, Levy, Amanda, Punetha, Jaya, Gao, Hua, Ah Mew, Nicholas, Anyane-Yeboa, Kwame, Benke, Paul, Berger, Sara, Bjerglund, Lise, Campos-Xavier, Belinda, Ciliberto, Michael, Cohen, Julie, Comi, Anne, Curry, Cynthia, Damaj, Lena, Denommé-Pichon, Anne-Sophie, Emrick, Lisa, Faivre, Laurence, Fasano, Mary Beth, Fiévet, Alice, Finkel, Richard, García-Miñaúr, Sixto, Gerard, Amanda, Gomez-Puertas, Paulino, Guillen Sacoto, Maria, Hoffman, Trevor, Howard, Lillian, Iglesias, Alejandro, Izumi, Kosuke, Larson, Austin, Leiber, Anja, Lozano, Reymundo, Marcos-Alcalde, Iñigo, Mintz, Cassie, Mullegama, Sureni, Møller, Rikke, Odent, Sylvie, Oppermann, Henry, Ostergaard, Elsebet, Pacio-Míguez, Marta, Palomares-Bralo, Maria, Parikh, Sumit, Paulson, Anna, Platzer, Konrad, Posey, Jennifer, Potocki, Lorraine, Revah-Politi, Anya, Rio, Marlene, Ritter, Alyssa, Robinson, Scott, Rosenfeld, Jill, Santos-Simarro, Fernando, Anyane‐Yeboa, Kwame, Campos‐Xavier, Belinda, Denommé‐Pichon, Anne‐Sophie, García‐Miñaúr, Sixto, Gomez‐Puertas, Paulino, Marcos‐Alcalde, Iñigo, Pacio‐Míguez, Marta, Palomares‐Bralo, Maria, Revah‐Politi, Anya, Santos‐Simarro, Fernando, Sombra, Sérgio Sousa, Wéber, Mathys, Xie, Yili, Chung, Wendy K., Brown, Natasha, Tümer, Zeynep, Murdoch Children's Research Institute (MCRI), Copenhagen University Hospital, Baylor College of Medicine (BCM), Baylor University, Icahn School of Medicine at Mount Sinai [New York] (MSSM), CHU Pontchaillou [Rennes], Université Bourgogne Franche-Comté [COMUE] (UBFC), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Institut Gustave Roussy (IGR), Institut de Génétique et Développement de Rennes (IGDR), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Centre de référence Maladies Rares CLAD-Ouest [Rennes], CIBER de Enfermedades Raras (CIBERER), GeneDx [Gaithersburg, MD, USA], Columbia University Irving Medical Center (CUIMC), University of Melbourne, University of Copenhagen = Københavns Universitet (KU), Spanish Ministry of Science / State Research Agency projects. Grant Numbers: DTS20-00024, RTC-2017-6494-1, RTI2018-094434-B-I00 SFARI and JPB Foundation, Raregenomics network, financed by the Consejería de Educación de la C. de Madrid. Grant Number: S2017 / BMD-3721, European Comission JPIAMR projects CONNECT and AEPIC, National Center for Advancing Translational Sciences, National Institutes of Health. Grant Number: UL1TR001873, National Human Genome Research Institute (NHGRI) and National Heart, Lung, and Blood Institute (NHLBI). Grant Number: UM1 HG006542 Undiagnosed Diseases Network, European Social Fund, Rashid Family Fund, NIH Common Fund, through the Office of Strategic Coordination/Office of the NIH Director. Grant Number: U01HG007709, ISCIII, Ministerio de Ciencia e Innovación. Grant Number: PI19/01681, Baylor Hopkins Center for Mendelian Genomics. Grant Numbers: NHGRI K08 HG008986, NHGRI/NLHBI UM1 HG006542, Centro Portugal Regional Operational Programme (CENTRO 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (ERDF). Grant Number: CENTRO-01-0247-FEDER-017800, Département de biologie et pathologie médicales [Gustave Roussy], Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and University of Copenhagen = Københavns Universitet (UCPH)
Subjects: Autism Spectrum Disorder, [SDV]Life Sciences [q-bio], Dwarfism, Biology, Bioinformatics, Weight Gain, Short stature, 03 medical and health sciences, 0302 clinical medicine, Neurodevelopmental disorder, Neuroimaging, Seizures, variable expressivity, Intellectual disability, Genetics, medicine, Missense mutation, Humans, QRICH1, hypotonia, Genetics (clinical), 030304 developmental biology, 0303 health sciences, medicine.disease, Hypotonia, short stature, Scoliosis, variant, Autism spectrum disorder, Neurodevelopmental Disorders, intellectual disability, Muscle Hypotonia, medicine.symptom, 030217 neurology & neurosurgery
Abstract: De novo variants in QRICH1 (Glutamine-rich protein 1) has recently been reported in 11 individuals with intellectual disability. The function of QRICH1 is largely unknown but it is likely to play a key role in the unfolded response of endoplasmic reticulum (ER) stress through transcriptional control of proteostasis. In this study, we present 27 additional individuals and delineate the clinical and molecular spectrum of the individuals (n=38) with QRICH1 variants. The main clinical features were mild to moderate developmental delay/intellectual disability (71%), non-specific facial dysmorphism (92%) and hypotonia (39%). Additional findings included poor weight gain (29%), short stature (29%), autism spectrum disorder (29%), seizures (24%) and scoliosis (18%). Minor structural brain abnormalities were reported in 52% of the individuals with brain imaging. Truncating or splice variants were found in 28 individuals and 10 had missense variants. Four variants were inherited from mildly affected parents. This study confirms that heterozygous QRICH1 variants cause a neurodevelopmental disorder including short stature and expands the phenotypic spectrum to include poor weight gain, scoliosis, hypotonia, minor structural brain anomalies, and seizures. Inherited variants from mildly affected parents are reported for the first time, suggesting variable expressivity. This article is protected by copyright. All rights reserved.
Published: 2021

24. Molecular genotyping in refractory thyroid cancers in 2021: When, how and why? A review from the TUTHYREF network

Author: Slimane Zerdoud, Camille Buffet, Stéphane Bardet, Abir Al Ghuzlan, Myriam Decaussin-Petrucci, Johanna Wassermann, Sophie Leboulleux, Isabelle Borget, Yann Godbert, Fabien Calcagno, Christelle De La Fouchardiere, Christine Do Cao, Françoise Borson Chazot, Centre Léon Bérard [Lyon], Service d'Oncologie médicale [CHU Pitié-Salpêtrière], 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), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Institut Gustave Roussy (IGR), Pathologie morphologique, Département de biologie et pathologie médicales [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Service de biostatistique et d'épidémiologie (SBE), Direction de la recherche clinique [Gustave Roussy], Hospices Civils de Lyon (HCL), CHU Lille, Institut E3M [CHU Pitié-Salpêtrière], Institut Universitaire de Cancérologie [Paris] (IUC), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), 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 Bergonié [Bordeaux], UNICANCER, Médecine nucléaire, Département d'imagerie médicale [Gustave Roussy], and HAL-SU, Gestionnaire
Subjects: Oncology, Cancer Research, medicine.medical_specialty, TUTHYREF, medicine.medical_treatment, Locally advanced, BRAF, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Radiology, Nuclear Medicine and imaging, 030304 developmental biology, International level, 0303 health sciences, Refractory thyroid cancer, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, business.industry, Thyroid, Cancers thyroïdiens réfractaires, Inhibiteurs de kinase, Treatment options, Hematology, General Medicine, Molecular genotyping, 3. Good health, Radiation therapy, medicine.anatomical_structure, ALK, Kinase inhibitors, 030220 oncology & carcinogenesis, business, RET, NTRK, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Refractory thyroid cancers include radio-iodine-refractory cancers, metastatic or locally advanced unresectable medullary and anaplastic thyroid cancers. Their management has been based for several years on the use of multi-target kinase inhibitors, with anti-angiogenic action, with the exception of anaplastic cancers usually treated with chemo- and radiotherapy. The situation has recently evolved due to the availability of molecular genotyping techniques allowing the discovery of rare but targetable molecular abnormalities. New treatment options have become available, more effective and less toxic than the previously available multi-target kinase inhibitors. The management of refractory thyroid cancers is therefore becoming more complex both at a diagnosis level with the need to know when, how and why to look for these molecular abnormalities but also at a therapeutic level, innovative treatments being hardly accessible. The cost of molecular analyzes and the access to treatments need also to be homogenized because disparities could lead to inequality of care at a national or international level. Finally, the strategy of identifying molecular alterations and treating these rare tumors reinforces the importance of a discussion in a multidisciplinary consultation meeting., Les cancers thyroïdiens réfractaires regroupent les cancers de souche folliculaire réfractaires à l’iode, les cancers médullaires métastatiques ou localement avancés non résécables et les cancers anaplasiques. Leur prise en charge est basée depuis quelques années sur l’utilisation d’inhibiteurs de kinase multicibles, à action principalement anti-angiogénique, exception faite des cancers anaplasiques habituellement traités par chimio- et radiothérapie. La situation a récemment évolué en raison de la mise à disposition de techniques de génotypage moléculaire permettant la découverte d’anomalies moléculaires rares mais ciblables, et de nouveaux traitements, possiblement plus efficaces et moins toxiques que les inhibiteurs de kinase multicibles préalablement disponibles. La prise en charge de ces cancers se complexifie donc à la fois au niveau diagnostique avec la nécessité de savoir quand, comment et pourquoi rechercher ces anomalies moléculaires mais également au niveau thérapeutique, avec la question de la disponibilité des traitements innovants et de l’accès aux essais cliniques. Le coût des analyses moléculaires et l’accès aux médicaments sont à harmoniser car des disparités pourraient conduire à une inégalité des soins au niveau national ou international. Enfin, la stratégie d’identification des altérations moléculaires et de traitement pour ces tumeurs rares renforce l’importance d’une discussion en réunion de concertation pluridisciplinaire.
Published: 2021

25. Génotypage moléculaire dans les cancers réfractaires de la thyroïde en 2021 : quand, comment, et pourquoi ? Un travail du réseau TUTHYREF

Author: De La Fouchardière, Christelle, Wassermann, Johanna, Calcagno, Fabien, Bardet, Stéphane, Al Ghuzlan, Abir, Borget, Isabelle, Borson Chazot, Françoise, Do Cao, Christine, Buffet, Camille, Zerdoud, Slimane, Decaussin-Petrucci, Myriam, Godbert, Yann, Leboulleux, Sophie, Centre Léon Bérard [Lyon], Service d'Oncologie médicale [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), Institut Gustave Roussy (IGR), Pathologie morphologique, Département de biologie et pathologie médicales [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Service de biostatistique et d'épidémiologie (SBE), Direction de la recherche clinique [Gustave Roussy], Hospices Civils de Lyon (HCL), CHU Lille, Institut E3M [CHU Pitié-Salpêtrière], Institut Universitaire de Cancérologie [Paris] (IUC), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Bergonié [Bordeaux], UNICANCER, Médecine nucléaire, Département d'imagerie médicale [Gustave Roussy], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Refractory thyroid cancer, ALK, Kinase inhibitors, TUTHYREF, Cancers thyroïdiens réfractaires, Inhibiteurs de kinase, RET, NTRK, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, BRAF
Abstract: International audience; Refractory thyroid cancers include radio-iodine-refractory cancers, metastatic or locally advanced unresectable medullary and anaplastic thyroid cancers. Their management has been based for several years on the use of multi-target kinase inhibitors, with anti-angiogenic action, with the exception of anaplastic cancers usually treated with chemo- and radiotherapy. The situation has recently evolved due to the availability of molecular genotyping techniques allowing the discovery of rare but targetable molecular abnormalities. New treatment options have become available, more effective and less toxic than the previously available multi-target kinase inhibitors. The management of refractory thyroid cancers is therefore becoming more complex both at a diagnosis level with the need to know when, how and why to look for these molecular abnormalities but also at a therapeutic level, innovative treatments being hardly accessible. The cost of molecular analyzes and the access to treatments need also to be homogenized because disparities could lead to inequality of care at a national or international level. Finally, the strategy of identifying molecular alterations and treating these rare tumors reinforces the importance of a discussion in a multidisciplinary consultation meeting.; Les cancers thyroïdiens réfractaires regroupent les cancers de souche folliculaire réfractaires à l’iode, les cancers médullaires métastatiques ou localement avancés non résécables et les cancers anaplasiques. Leur prise en charge est basée depuis quelques années sur l’utilisation d’inhibiteurs de kinase multicibles, à action principalement anti-angiogénique, exception faite des cancers anaplasiques habituellement traités par chimio- et radiothérapie. La situation a récemment évolué en raison de la mise à disposition de techniques de génotypage moléculaire permettant la découverte d’anomalies moléculaires rares mais ciblables, et de nouveaux traitements, possiblement plus efficaces et moins toxiques que les inhibiteurs de kinase multicibles préalablement disponibles. La prise en charge de ces cancers se complexifie donc à la fois au niveau diagnostique avec la nécessité de savoir quand, comment et pourquoi rechercher ces anomalies moléculaires mais également au niveau thérapeutique, avec la question de la disponibilité des traitements innovants et de l’accès aux essais cliniques. Le coût des analyses moléculaires et l’accès aux médicaments sont à harmoniser car des disparités pourraient conduire à une inégalité des soins au niveau national ou international. Enfin, la stratégie d’identification des altérations moléculaires et de traitement pour ces tumeurs rares renforce l’importance d’une discussion en réunion de concertation pluridisciplinaire.
Published: 2021

26. In Vitro Antimicrobial Susceptibility Profiles of Gram-Positive Anaerobic Cocci Responsible for Human Invasive Infections

Author: Guérin, François, Dejoies, Loren, Degand, Nicolas, Guet-Revillet, Hélène, Janvier, Frédéric, Corvec, Stéphane, Barraud, Olivier, Guillard, Thomas, Walewski, Violaine, Gallois, Emmanuelle, Cattoir, Vincent, Group, on behalf of the GMC Study, CHU Pontchaillou [Rennes], Centre Hospitalier Universitaire de Nice (CHU Nice), Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Hopital d'instruction des armées Sainte-Anne [Toulon] (HIA), Centre hospitalier universitaire de Nantes (CHU Nantes), Hôpital Dupuytren [CHU Limoges], Centre Hospitalier Universitaire de Reims (CHU Reims), Groupe Hospitalier Hôpitaux Universitaires Paris Seine-Saint-Denis [Bobigny] (GH HUPSSD), Institut Gustave Roussy (IGR), Microbiologie, Département de biologie et pathologie médicales [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), ARN régulateurs bactériens et médecine (BRM), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), This research received no external funding., dormoy, valerian, Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), and Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )
Subjects: Microbiology (medical), Peptoniphilus, Imipenem, food.ingredient, Cefotaxime, QH301-705.5, [SDV]Life Sciences [q-bio], ved/biology.organism_classification_rank.species, Biology, Microbiology, Article, 03 medical and health sciences, food, Parvimonas micra, Virology, medicine, polycyclic compounds, antimicrobial resistance, Biology (General), 030304 developmental biology, 0303 health sciences, 030306 microbiology, ved/biology, Peptostreptococcus anaerobius, GPAC, Clindamycin, Anaerococcus, Amoxicillin, biochemical phenomena, metabolism, and nutrition, bacterial infections and mycoses, Finegoldia magna, 3. Good health, [SDV] Life Sciences [q-bio], medicine.drug, Piperacillin
Abstract: The aim of this multicentre study was to determine the in vitro susceptibility to anti-anaerobic antibiotics of Gram-positive anaerobic cocci (GPAC) isolates responsible for invasive infections in humans. A total of 133 GPAC isolates were collected in nine French hospitals from 2016 to 2020. All strains were identified to the species level (MALDI-TOF mass spectrometry, 16S rRNA sequencing). Minimum inhibitory concentrations (MICs) of amoxicillin, piperacillin, cefotaxime, imipenem, clindamycin, vancomycin, linezolid, moxifloxacin, rifampicin, and metronidazole were determined by the reference agar dilution method. Main erm-like genes were detected by PCR. The 133 GPAC isolates were identified as follows: 10 Anaerococcus spp., 49 Finegoldia magna, 33 Parvimonas micra, 30 Peptoniphilus spp., and 11 Peptostreptococcus anaerobius. All isolates were susceptible to imipenem, vancomycin (except 3 P. micra), linezolid and metronidazole. All isolates were susceptible to amoxicillin and piperacillin, except for P. anaerobius (54% and 45% susceptibility only, respectively). MICs of cefotaxime widely varied while activity of rifampicin, and moxifloxacin was also variable. Concerning clindamycin, 31 were categorized as resistant (22 erm(A) subclass erm(TR), 7 erm(B), 1 both genes and 1 negative for tested erm genes) with MICs from 8 to &gt, 32 mg/L. Although GPACs are usually susceptible to drugs commonly used for the treatment of anaerobic infections, antimicrobial susceptibility should be evaluated in vitro.
Published: 2021
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27. Therapy-related myeloid neoplasms following treatment with PARP inhibitors: new molecular insights

Author: Sylvain Garciaz, Olivier Caron, Amine Belhabri, Norbert Vey, Jacques Vargaftig, Veronique Verge, Sophie Cotteret, S. de Botton, Flore Salviat, Suzette Delaloge, Iléana Antony-Debré, Patricia Pautier, Christophe Marzac, Sarah Bertoli, Florence Pasquier, Jean-Baptiste Micol, Sabine Khalife-Hachem, Alexandra Leary, Etienne Rouleau, A Renneville, M Kfoury, Filippo Rosselli, Thomas Grinda, Christian Recher, Madalina Uzunov, Jean-Edouard Martin, Gabriel Etienne, Institut Gustave Roussy (IGR), Université Paris-Saclay, Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Cellules souches hématopoïétiques et développement des hémopathies myéloïdes (CSHMyelo), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Institut Curie [Paris], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Léon Bérard [Lyon], Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Intégrité du génome et cancers (IGC), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Gustave Roussy (IGR)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Service de biostatistique et d'épidémiologie (SBE), Direction de la recherche clinique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Département de médecine oncologique [Gustave Roussy], Oncologie gynécologique, Institut Bergonié [Bordeaux], UNICANCER, Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], Biomarqueurs prédictifs et nouvelles stratégies moléculaires en thérapeutique anticancéreuse (U981), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département d'hématologie [Gustave Roussy], Institut Gustave Roussy (IGR)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Génétique (Biologie pathologie), Département de biologie et pathologie médicales [Gustave Roussy], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), École pratique des hautes études (EPHE), and NUNES, Jacques A
Subjects: Myeloid, DNA Repair, Poly ADP ribose polymerase, [SDV]Life Sciences [q-bio], MEDLINE, [SDV.CAN]Life Sciences [q-bio]/Cancer, Poly(ADP-ribose) Polymerase Inhibitors, Bioinformatics, 03 medical and health sciences, 0302 clinical medicine, Text mining, [SDV.CAN] Life Sciences [q-bio]/Cancer, Neoplasms, Humans, Medicine, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Ovarian Neoplasms, 0303 health sciences, Therapy related, business.industry, Hematology, 3. Good health, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, Female, Poly(ADP-ribose) Polymerases, business
Abstract: International audience; No abstract available
Published: 2021

28. TUMOSPEC: A Nation-Wide Study of Hereditary Breast and Ovarian Cancer Families with a Predicted Pathogenic Variant Identified through Multigene Panel Testing

Author: Celine Garrec, Monique Mozelle-Nivoix, Jérôme Lemonnier, Etienne Rouleau, Tan Dat Nguyen, Dominique Vaur, Elodie Lacaze, Sarah Bonnet-Boissinot, Sophie Nambot, Jean Chiesa, Sophie Giraud, Dominique Stoppa-Lyonnet, Michel Longy, Alain Lortholary, Jean-Marc Rey, Olivier Caron, Christine Lasset, Claude Houdayer, Christine Maugard, Virginie Bubien, Véronique Mari, Marie-Emmanuelle Morin-Meschin, Nadine Andrieu, Nancy Uhrhammer, Louise Crivelli, Hélène Dreyfus, Vincent Goussot, Stephanie Chieze-Valéro, Nicolas Sevenet, Lisa Golmard, Séverine Eon-Marchais, Mathilde Martinez, Isabelle Coupier, Marie-Gabrielle Dondon, Odile Béra, Paul Vilquin, Capucine Delnatte, Odile Cohen-Haguenauer, Cornel Popovici, Christine Toulas, Laurence Gladieff, Marie-Agnès Collonge-Rame, Chrystelle Colas, Paul Gesta, Catherine Noguès, Fanny Brayotel, Audrey Mailliez, Fabienne Lesueur, Julie Tinat, Marie Bidart, Yves-Jean Bignon, Florence Coulet, Nadia Boutry-Kryza, Fabienne Prieur, Juana Beauvallet, Philippe Denizeau, Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Curie [Paris], Institut Gustave Roussy (IGR), Génétique (Biologie pathologie), Département de biologie et pathologie médicales [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Hôtel-Dieu de Nantes, CHU Rouen, Normandie Université (NU), Institut Claudius Regaud, Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Jean Godinot [Reims], UNICANCER, Centre Eugène Marquis (CRLCC), Institut de Cancérologie de Strasbourg Europe (ICANS), Centre Paul Strauss, CRLCC Paul Strauss, Institut Bergonié [Bordeaux], Actions for OnCogenesis understanding and Target Identification in ONcology (ACTION), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Bordeaux Segalen - Bordeaux 2-Institut Bergonié [Bordeaux], UNICANCER-UNICANCER, Centre Hospitalier Georges Renon [Niort] (CH Georges Renon Niort), Genetic and Immunology Medical Institute (GIMI), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-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-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté]), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), CHU de Saint-Étienne Hôpital Nord [Saint Etienne], Hôpital Nord (Saint Etienne), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), CHU Bordeaux [Bordeaux], Centre Catherine-de-Sienne [Nantes] (CCS), Hôpital privé du Confluent [Nantes], Institut Sainte Catherine [Avignon], hôpital couple-enfant [CHU Grenoble Alpes], Centre Hospitalier Universitaire [Grenoble] (CHU), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Centre Hospitalier de Troyes, Hospices Civils de Lyon (HCL), Groupement Hospitalier Lyon-Est (GHE), Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Hôpital Sud [CHU Rennes], CHU Pontchaillou [Rennes], Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), Immunologie humaine, physiopathologie & immunothérapie (HIPI (UMR_S_976 / U976)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université Lille Nord de France (COMUE)-UNICANCER, Hôpital Arnaud de Villeneuve [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut de recherche en cancérologie de Montpellier (IRCM - U896 Inserm - UM1), Université Montpellier 1 (UM1)-CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Groupe Hospitalier du Havre, CHU de la Martinique [Fort de France], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CRLCC René Gauducheau, Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Centre Léon Bérard [Lyon], Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale (SESSTIM - U1252 INSERM - Aix Marseille Univ - UMR 259 IRD), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de génétique et biologie des cancers (U830), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), Centre médical de Bligny, Onco-génétique, Département de médecine oncologique [Gustave Roussy], COLO, Mouniati, Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), UNICANCER-UNICANCER-Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de médecine génomique et d’immunothérapie (Genomic and Immunotherapy Medical Institute) (institut GIMI), UNICANCER-UNICANCER-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-FHU TRANSLAD (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Université de Lille-UNICANCER, Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), UNICANCER-UNICANCER-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS BFC)-FHU TRANSLAD (CHU de Dijon), and Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E)
Subjects: 0301 basic medicine, Cancer Research, medicine.medical_specialty, Sequencing data, [SDV.CAN]Life Sciences [q-bio]/Cancer, Context (language use), [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, [SDV.MHEP.GEO]Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, 030105 genetics & heredity, Article, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Care plan, Internal medicine, Epidemiology, medicine, RC254-282, Genetic testing, medicine.diagnostic_test, business.industry, Cancer, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, medicine.disease, 3. Good health, genetic predisposition to breast and ovarian cancer, [SDV.MHEP.GEO] Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Oncology, 030220 oncology & carcinogenesis, multigene panels, Cancer risk, Ovarian cancer, business, cancer risk estimate, penetrance of pathogenic variants
Abstract: Simple Summary TUMOSPEC was designed for estimating the risk of cancer for carriers of a predicted pathogenic variant (PPV) in a gene usually tested in a hereditary breast and ovarian cancer context. Index cases are enrolled consecutively among patients who undergo genetic testing as part of their care plan in France. First- and second-degree relatives and cousins of PPV carriers are invited to participate whether they are affected by cancer or not, and are tested for the familial PPV. Genetic, clinical, family and epidemiological data are centralized at the coordinating centre. The three-year feasibility study included 4431 prospective index cases, with 19.1% of them carrying a PPV. This showed that the study logistics are well adapted to clinical and laboratory constraints, and collaboration between partners (clinicians, biologists, coordinating centre and participants) is smooth. Hence, TUMOSPEC is being pursued, with the aim of optimizing clinical management guidelines specific to each gene. Abstract Assessment of age-dependent cancer risk for carriers of a predicted pathogenic variant (PPV) is often hampered by biases in data collection, with a frequent under-representation of cancer-free PPV carriers. TUMOSPEC was designed to estimate the cumulative risk of cancer for carriers of a PPV in a gene that is usually tested in a hereditary breast and ovarian cancer context. Index cases are enrolled consecutively among patients who undergo genetic testing as part of their care plan in France. First- and second-degree relatives and cousins of PPV carriers are invited to participate whether they are affected by cancer or not, and genotyped for the familial PPV. Clinical, family and epidemiological data are collected, and all data including sequencing data are centralized at the coordinating centre. The three-year feasibility study included 4431 prospective index cases, with 19.1% of them carrying a PPV. When invited by the coordinating centre, 65.3% of the relatives of index cases (5.7 relatives per family, on average) accepted the invitation to participate. The study logistics were well adapted to clinical and laboratory constraints, and collaboration between partners (clinicians, biologists, coordinating centre and participants) was smooth. Hence, TUMOSPEC is being pursued, with the aim of optimizing clinical management guidelines specific to each gene.
Published: 2021

29. Temocillin susceptibility among Enterobacterales strains recovered from blood culture in France

Author: Philippe Lesprit, Emmanuelle Bille, Paul-Louis Woerther, Typhaine Billard-Pomares, Cécile Le Brun, Christophe Isnard, Nicolas Yin, Audrey Mérens, Nicolas Degand, Eric Farfour, J. Lourtet, Antoine Grillon, S. Corvec, Emilie Flevin, Damien Fournier, Thomas Guillard, Vincent Cattoir, Anne-Gaëlle Si Larbi, Alban Le Monnier, Chloé Plouzeau, Hôpital Foch [Suresnes], CHU Pontchaillou [Rennes], ARN régulateurs bactériens et médecine (BRM), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre hospitalier universitaire de Nantes (CHU Nantes), Pathologies Pulmonaires et Plasticité Cellulaire - UMR-S 1250 (P3CELL), Université de Reims Champagne-Ardenne (URCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Reims (CHU Reims), Les Hôpitaux Universitaires de Strasbourg (HUS), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Centre Hospitalier Universitaire de Nice (CHU Nice), Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Hôpital Bretonneau, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Centre hospitalier universitaire de Poitiers (CHU Poitiers), Centre hospitalier de Dieppe, Institut Gustave Roussy (IGR), Génétique (Biologie pathologie), Département de biologie et pathologie médicales [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), CHU Henri Mondor, Centre hospitalier Saint-Joseph [Paris], None, Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), and CHU Henri Mondor [Créteil]
Subjects: 0301 basic medicine, Microbiology (medical), Extended-spectrum beta-lactamases (ESBL), medicine.drug_class, Antibiotic resistance, [SDV]Life Sciences [q-bio], 030106 microbiology, Cephalosporin, Microbial Sensitivity Tests, Penicillins, Third-generation cephalosporin (3GC), Microbiology, 03 medical and health sciences, 0302 clinical medicine, Enterobacteriaceae, Enterobacterales, Drug Resistance, Bacterial, medicine, Humans, Blood culture, Temocillin, 030212 general & internal medicine, Cephalosporinase-overproducing strain (COPE), medicine.diagnostic_test, Dose-Response Relationship, Drug, business.industry, Enterobacteriaceae Infections, General Medicine, 3. Good health, Anti-Bacterial Agents, Infectious Diseases, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, France, business, medicine.drug
Abstract: International audience; Temocillin is used for several years in some European countries but, only since 2015 in France. We assessed the susceptibility of Enterobacterales strains isolated from blood culture 1 year before (2014) and 2 years after (2017) its use in France. 1,387 strains were included by 17 clinical laboratories located throughout France: 363 in 2014 and 1,024 in 2017. The rate of resistance to temocillin was 4.6% and 26.7% in 3rd generation cephalosporin (3GC) susceptible and resistant strains respectively. Cephalosporinase-overproducer (COPE) strains were significantly more resistant to temocillin (37.7%) than ESBL-producer (ESBL-PE) (23.5%) (P < 0.01). The rate of temocillin resistance was correlated to the number of inactive beta-lactams. The rate of resistance to temocillin trend to increase from 13.9% in 2014 to 23.9% in 2017 (P < 0.01). Temocillin remains highly active against Enterobacterales but the trend in resistance should be assessed over time.
Published: 2021

30. Classification of 101 BRCA1 and BRCA2 variants of uncertain significance by cosegregation study: A powerful approach

Author: Marie-Noëlle Bonnet-Dupeyron, Helene Dreyfus, Nadia Boutry-Kryza, Cornel Popovici, Laurent Castera, Nancy Uhrhammer, Anthony Laugé, Yves-Jean Bignon, Hélène Delhomelle, Alice Fiévet, Christophe Guy, Noémie Bronnec, Bruno Buecher, Fabienne Prieur, Sophie Demontety, Vincent Goussot, Emmanuelle Mouret-Fourme, Claire Saule, Helene Zattara, Sarah Malsa, Paul Gesta, Cindy Meira, Erell Guillerm, Isabelle Turbiez, Agathe Ricou, Mélanie Léoné, Pierre Vande Perre, Sarab Lizard, Pascaline Berthet, Norbert Lignon, Adrien Buisson, Anne-Marie Birot, Philippe Denizeau, Etienne Rouleau, Odile Cohen-Haguenauer, Veronica Goldbarg, Virginie Moncoutier, Charlotte Benigni, Emmanuelle Barouk-Simonet, Flavie Boulouard, Caroline Jacquot-Sawka, Alice Yvard, Hakima Lallaoui, Veronica Cusin, Angélina Legros, Muriel Belotti, Christine Maugard, Marine Guillaud-Bataille, Jean-Marc Limacher, Marion Gauthier-Villars, Louise Crivelli, Afane Brahimi, Odile Cabaret, Ophelie Bertrand, Michel Longy, Gabrielle Le Guyadec, Doriane Livon, Amelie Bloucard, Dominique Stoppa-Lyonnet, Capucine Delnatte, Caroline Lecerf, Jennifer Carriere, Virginie Guibert, Véronique Mari, Anne-Sophie Allary, Florence Coulet, Françoise Bonnet, Paul Vilquin, Noémie Basset, Khadija Abidallah, Pierre Macquere, Nicolas Derive, Manon Boulaire, Stephanie Chieze-Valéro, Marine Le Mentec, Mathilde Gay-Bellile, Anne-Laure Conoy, Henri Margot, Pierre Devulder, Mathias Schwartz, Isabelle Tennevet, Stéphane Bézieau, Francesca Damiola, Violaine Bourdon, Audrey Mailliez, Zoe Nevière, Nicolas Viellard, Laurence Venat, Antoine De Pauw, Brigitte Bressac-de Paillerets, Agnès Hardouin, Sofiane Lacoste, Sandra Fert-Ferrer, Maud Privat, Helene Larbre, Dominique Vaur, Etienne Muller, Françoise Revillion, Clémentine Legrand, Rosette Lidereau, Laurence Gladieff, Sabine Raad, Jean Chiesa, Diane Molière, Ahmed Bouras, Nicolas Sevenet, Patrick R. Benusiglio, Sophie Giraud, Christine Toulas, Voreak Suybeng, Florine Oca, Tetsuro Noguchi, Catherine Dehainault, Sophie Lejeune, Céline Heude, Catherine Dubois d’Enghein, Thien-vu Nguyen Minh Tuan, Olivier Caron, Mathilde Warcoin, Christine Lasset, Claude Houdayer, Jessica Moretta-Serra, Julie Tinat, Hagay Sobol, Natalie Jones, Fanny Brayotel, Anne Fajac, Virginie Bubien, Maud Blanluet, Jean-Marc Rey, Anne Durlach, Sandrine M. Caputo, Isabelle Coupier, Fatoumata Simaga, Sophie Krieger, Catherine Noguès, Fabrice Airaud, Robin Fouillet, Celine Garrec, Valérie Bonadona, Julie Menjard, Bérengère Legendre, Chrystelle Colas, Christelle Berthemin, Camille Cohen, Caroline Abadie, Olivier Ingster, Audrey Remenieras, Anaïs Dupré, Jessica Le Gall, Lisa Golmard, Marie Bidart, Henrique Tenreiro, J Bombled, Marie-Charlotte Villy, Marie-Agnès Collonge-Rame, Sophie Dussart, Alain Lortholary, Lucie Salle, Samira Fekairi, Service de Génétique Oncologique, Institut Curie [Paris], Université Paris sciences et lettres (PSL), Département de Biologie des Tumeurs, Unité de génétique et biologie des cancers (U830), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Hospices Civils de Lyon (HCL), Centre Léon Bérard [Lyon], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut Gustave Roussy (IGR), Génétique (Biologie pathologie), Département de biologie et pathologie médicales [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Institut de biochimie et génétique cellulaires (IBGC), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Centre de Références Cancers Rares (PREDIR), INCA, Institut national du cancer [Boulogne] (INCA), 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 de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), Centre Hospitalier Universitaire de Reims (CHU Reims), dormoy, valerian, Unité fonctionnelle de neurogénétique moléculaire et cellulaire, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière]
Subjects: Cosegregation, Genotype, [SDV]Life Sciences [q-bio], Breast Neoplasms, Biology, Article, 03 medical and health sciences, Likely benign, Genetics, medicine, Humans, Clinical significance, Genetic Predisposition to Disease, Genetic Testing, Uncertain significance, Gene, ComputingMilieux_MISCELLANEOUS, Genetics (clinical), 030304 developmental biology, BRCA2 Protein, Ovarian Neoplasms, 0303 health sciences, Cancer predisposition, BRCA1 Protein, 030305 genetics & heredity, Cancer, Genetic Variation, medicine.disease, 3. Good health, [SDV] Life Sciences [q-bio], Classification methods, Female
Abstract: Up to 80% of BRCA1 and BRCA2 genetic variants remain of uncertain clinical significance (VUSs). Only variants classified as pathogenic or likely pathogenic can guide breast and ovarian cancer prevention measures and treatment by PARP inhibitors. We report the first results of the ongoing French national COVAR (cosegregation variant) study, the aim of which is to classify BRCA1/2 VUSs. The classification method was a multifactorial model combining different associations between VUSs and cancer, including cosegregation data. At this time, among the 653 variants selected, 101 (15%) distinct variants shared by 1,624 families were classified as pathogenic/likely pathogenic or benign/likely benign by the COVAR study. Sixty-six of the 101 (65%) variants classified by COVAR would have remained VUSs without cosegregation data. Of note, among the 34 variants classified as pathogenic by COVAR, 16 remained VUSs or likely pathogenic when following the ACMG/AMP variant classification guidelines. Although the initiation and organization of cosegregation analyses require a considerable effort, the growing number of available genetic tests results in an increasing number of families sharing a particular variant, and thereby increases the power of such analyses. Here we demonstrate that variant cosegregation analyses are a powerful tool for the classification of variants in the BRCA1/2 breast-ovarian cancer predisposition genes.
Published: 2021

31. Starting Imatinib at 400 mg Daily in Patients with Gastrointestinal Stromal Tumors Harboring KIT Exon 9 Mutations: A Retrospective, Multicenter Study

Author: Jean-Yves Blay, Philippe Terrier, Sara Faouzi, Florence Duffaud, Olivier Mir, François Bertucci, Olivier Collard, Axel Le Cesne, Olivier Bouché, Nicolas Penel, Nicolas Isambert, Almudena Callejo, Thomas Chevalier, Université de Picardie Jules Verne (UPJV), Centre Hospitalier Universitaire de Reims (CHU Reims), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Hôpital de la Timone [CHU - APHM] (TIMONE), Institut de Cancérologie de la Loire Lucien Neuwirth, Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), University of Lille, Département de biologie et pathologie médicales [Gustave Roussy], Institut Gustave Roussy (IGR), Département de médecine oncologique [Gustave Roussy], and Centre Léon Bérard [Lyon]
Subjects: 0301 basic medicine, Adult, Male, Cancer Research, medicine.medical_specialty, Stromal cell, Adolescent, Gastrointestinal Stromal Tumors, medicine.medical_treatment, [SDV.CAN]Life Sciences [q-bio]/Cancer, Gastroenterology, 03 medical and health sciences, Exon, Young Adult, 0302 clinical medicine, hemic and lymphatic diseases, Internal medicine, medicine, Advanced disease, Humans, Pharmacology (medical), In patient, neoplasms, Protein Kinase Inhibitors, ComputingMilieux_MISCELLANEOUS, Aged, Retrospective Studies, Aged, 80 and over, GiST, business.industry, Imatinib, Exons, Middle Aged, 030104 developmental biology, Oncology, Multicenter study, 030220 oncology & carcinogenesis, Mutation, Imatinib Mesylate, Female, business, Adjuvant, medicine.drug
Abstract: Retrospective analyses suggest that patients with advanced KIT exon 9-mutated gastrointestinal stromal tumors (GISTs) receiving imatinib 800 mg (rather than 400 mg) daily have better outcomes. In the adjuvant setting, the question of the optimal dose of imatinib remains unsettled. We aimed to retrospectively assess the activity of imatinib 400 mg in both the adjuvant and the advanced settings. We performed a multicenter study of patients with KIT exon 9-mutated GIST starting imatinib at 400 mg daily. We examined the relapse-free survival (RFS) among high-risk patients either receiving or not receiving adjuvant imatinib. In patients with advanced disease, progression-free survival (PFS, progression under imatinib 400 mg), time to imatinib failure (TIF, progression under imatinib 400, then 800 mg upon first progression), and overall survival (OS) were analyzed. In the post-operative setting (n = 37), 20 patients received adjuvant imatinib. Median RFS in high-risk patients receiving adjuvant imatinib (n = 14) was not reached (95% CI 17.5–46.6) versus 13.6 months (95% CI 4.7–13.6) for those who did not (p = 0.37), after a median follow-up of 58 months. RFS at 36 months was 63% (30.3–96.6) versus 40% (95% CI 0–82.9), p = 0.2. In advanced disease (n = 28), median PFS, TIF and OS were 12.7 months (95% CI 6.1–18.2), 21.0 months (95% CI 17.4–28.1) and 47.0 months (95% CI 33.5–69.2), respectively. Despite the limitations of a retrospective analysis and the small number of patients, the benefit of adjuvant imatinib 400 mg daily in high-risk patients appeared relevant. Patients with advanced disease receiving imatinib 400 mg with subsequent dose escalation had a TIF similar to that observed with an initial dose of 800 mg. Intra-patient dose escalation in this setting might be an option.
Published: 2021

32. Peritoneal or mesenteric tumours revealing histiocytosis

Author: Janick Selves, Sébastien Humbert, Peggy Dartigues, Manuela Delage-Corre, Chrystalla Prokopiou, Liana Veresezan, Jean Donadieu, Séverine Valmary-Degano, Patrick Tas, Olivier Lucidarme, Frédéric Charlotte, Andreas Seeber, Alexandre Malakhia, Julien Haroche, Zofia Hélias-Rodzewicz, Jerome Razanamahery, Fleur Cohen-Aubart, Merja Kunnamo, Abdellatif Tazi, Irena Ungureanu, Dominique Cazals-Hatem, Jean-François Emile, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital Ambroise Paré [AP-HP], Emergency Hospital Floreasca Bucharest, Emergency Hospital Floreasca Bucharest, 8 Calea Floresca, Sector 1, 014461 Bucharest, Romania, CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Service de pathologie [CHU Pitié-Salpêtrière], 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), Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Biomarqueurs et essais cliniques en Cancérologie et Onco-Hématologie (BECCOH), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay, Hôpital Beaujon, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Gustave Roussy (IGR), Pathologie morphologique, Département de biologie et pathologie médicales [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), CHU Limoges, Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pontchaillou [Rennes], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), Limassol General Hospital, Innsbruck Medical University [Austria] (IMU), Hopital Saint-Louis [AP-HP] (AP-HP), Service d'hématologie-immunologie-oncologie pédiatrique [CHU Trousseau], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Laboratoire d'Imagerie Biomédicale (LIB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service de Radiologie [CHU Pitié-Salpétrière], Centre National de Référence Maladies auto-immunes Systémiques Rares [CHU Pitié-Salpêtrière], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: Proto-Oncogene Proteins B-raf, Abdominal pain, Pathology, medicine.medical_specialty, Delayed Diagnosis, [SDV]Life Sciences [q-bio], RC799-869, Liposarcoma, Sclerosing mesenteritis, 03 medical and health sciences, 0302 clinical medicine, Neoplasms, Medicine, molecular biology, Humans, Mesentery, Histiocyte, Cancer, Retrospective Studies, business.industry, CD68, Gastroenterology, abdominal pain, Diseases of the digestive system. Gastroenterology, medicine.disease, 3. Good health, Histiocytosis, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Histiocytoses, 030211 gastroenterology & hepatology, medicine.symptom, business
Abstract: ObjectivePeritoneal or mesenteric tumours may correspond to several tumour types or tumour-like conditions, some of them being represented by histiocytosis. This rare condition often poses diagnostic difficulties that can lead to important time delay in targeted therapies. Our aim was to describe main features of histiocytoses with mesenteric localisation that can improve the diagnostic process.DesignWe performed a retrospective study on 22 patients, whose peritoneal/mesenteric biopsies were infiltrated by histiocytes.ResultsAbdominal pain was the revealing symptom in 10 cases, and 19 patients underwent surgical biopsies. The diagnosis of histiocytosis was proposed by initial pathologists in 41% of patients. The other initial diagnoses were inflammation (n=7), sclerosing mesenteritis (n=4) and liposarcoma (n=1). The CD163/CD68+CD1a- histiocytes infiltrated subserosa and/or deeper adipose tissues in 16 and 14 cases, respectively. A BRAFV600E mutation was detected within the biopsies in 11 cases, and two others were MAP2K1 mutated. The final diagnosis was histiocytosis in 18 patients, 15 of whom had Erdheim-Chester disease. The median diagnostic delay of histiocytosis was 9 months. Patients treated with BRAF or MEK inhibitors showed a partial response or a stable disease. One patient died soon after surgery, and five died by the progression of the disease.ConclusionDiagnosis of masses arising in the mesentery should be carefully explored as one of the possibilities in histiocytosis. This diagnosis is frequently missed on mesenteric biopsies. Molecular biology for detecting the mutations in BRAF or in genes of the MAP kinase pathway is a critical diagnostic tool.
Published: 2021

33. Activity of EGFR Tyrosine Kinase Inhibitors in NSCLC With Refractory Leptomeningeal Metastases

Author: Ludovic Lacroix, Benjamin Besse, Michèle Beau-Faller, Pamela Biondani, Lizza E.L. Hendriks, Pernelle Lavaud, Julien Adam, Anas Gazzah, Charlotte Leduc, Jordi Remon, Emilie Le Rhun, Ronan Flippot, Caroline Caramella, C. Naltet, David Planchard, Radj Gervais, Cécile Le Péchoux, Laura Mezquita, Dingyu Xiao, Edouard Auclin, Département d'hématologie [Gustave Roussy], Institut Gustave Roussy (IGR), Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), School for Oncology and Developmental Biology [Maastricht] (GROW), Maastricht University [Maastricht]-Maastricht University Medical Centre (MUMC), Maastricht University [Maastricht], University of Lille, Department of Radiology, CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Department of Radiotherapy, Pulmonologie, Promovendi ODB, MUMC+: MA Med Staf Spec Longziekten (9), RS: GROW - R3 - Innovative Cancer Diagnostics & Therapy, Département de médecine oncologique [Gustave Roussy], Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Département de biologie et pathologie médicales [Gustave Roussy], and Département d’Innovation Thérapeutique et essais précoces [Gustave Roussy] (DITEP)
Subjects: 0301 basic medicine, Pulmonary and Respiratory Medicine, Oncology, Male, medicine.medical_specialty, Lung Neoplasms, medicine.drug_class, Afatinib, [SDV]Life Sciences [q-bio], EGFR, CELL LUNG-CANCER, BRAIN METASTASES, Tyrosine kinase inhibitor, NSCLC, Tyrosine-kinase inhibitor, 03 medical and health sciences, 0302 clinical medicine, Gefitinib, Refractory, Internal medicine, Carcinoma, Non-Small-Cell Lung, medicine, Humans, Osimertinib, Dosing, Protein Kinase Inhibitors, Retrospective Studies, Leptomeningeal metastases, business.industry, Retrospective cohort study, Middle Aged, Survival Analysis, respiratory tract diseases, 3. Good health, ErbB Receptors, 030104 developmental biology, Treatment Outcome, DOSE WEEKLY ERLOTINIB, 030220 oncology & carcinogenesis, Mutation, Female, Erlotinib, business, Meningeal Carcinomatosis, medicine.drug
Abstract: Introduction: Leptomeningeal metastases (LMs) are associated with dismal prognosis in NSCLC. Optimal management remains unknown in patients with EGFR-mutated NSCLC after initial tyrosine kinase inhibitor (TKI) failure.Methods: We conducted a multicenter retrospective study including patients with EGFR-mutated NSCLC and LM. TKI failure was defined as diagnosis of LM on TKI, or progression of known LM on TKI.Results: Ninety-two patients were included, median age of 60 years, predominantly female (68%), never-smokers (74%). EGFR mutations included L858R (45%), exon 19 deletions (28%), or other mutations (14%). Median time to LM diagnosis was 18.5 months after initial diagnosis of advanced NSCLC. LM was diagnosed after a median of 2 (range: 0-9) systemic therapies. Median overall survival from LM diagnosis was 6.1 months (95% confidence interval [ CI]: 4.2-7.6 months). Among 87 patients with TKI failure, patients rechallenged with TKI (n = 50) had a median LM overall survival of 7.6 months (95% CI: 5.7-10.9) compared to 4.2 months (95% CI: 1.6-6.7) in patients without further therapy. Overall, 60% of patients rechallenged with TKI experienced clinical benefit (clinical response or stable disease >2 months), and 23% were treatment failure-free at 6 months. Clinical benefit was reported in 11 of 20 (55%) patients treated with erlotinib after afatinib or gefitinib. Strategies based on increasing dose intensity (n = 17) yielded clinical benefit in 59% of patients. All four patients who received osimertinib after first-and second-generation TKI experienced clinical benefit.Conclusions: TKI rechallenge strategies, including dosing intensification, may improve clinical outcomes of patients with LM from EGFR-mutated NSCLC after initial TKI failure. (C) 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
Published: 2019

34. Well-Differentiated Papillary Mesothelioma of the Peritoneum: A Retrospective Study from the RENAPE Observational Registry

Author: Guillaume, Vogin, Liza, Hettal, Jean-Michel, Vignaud, Peggy, Dartigues, Diane, Goere, Gwenaël, Ferron, Bruno, Heyd, Jean-Marc, Bereder, Jean-Jacques, Tuech, Olivier, Glehen, Cécile, de Chaisemartin, Yoann, Lherm, Laurent, Villeneuve, Vahan, Kepenekian, Frédéric, Marchal, Franck, Zinzindohoue, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Pathologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Pathologie morphologique, Département de biologie et pathologie médicales [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Immunologie des tumeurs et immunothérapie (UMR 1015), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Département de chirurgie viscérale [Gustave Roussy], Institut Gustave Roussy (IGR), Institut Claudius Regaud, Service d'oncologie chirurgicale, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), Département de chirurgie [CHU Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Ciblage thérapeutique en Oncologie (EA3738), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Centre de Recherche en Automatique de Nancy (CRAN), and Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL)
Subjects: Adult, Male, Mesothelioma, medicine.medical_specialty, Malignancy, Young Adult, 03 medical and health sciences, 0302 clinical medicine, medicine, Carcinoma, Humans, Registries, Survival rate, Peritoneal Neoplasms, Aged, Retrospective Studies, business.industry, Cancer, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Retrospective cohort study, Cytoreduction Surgical Procedures, Hyperthermia, Induced, Middle Aged, Prognosis, medicine.disease, Combined Modality Therapy, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Carcinoma, Papillary, 3. Good health, Surgery, Survival Rate, Oncology, Chemotherapy, Cancer, Regional Perfusion, 030220 oncology & carcinogenesis, Peritoneal Cancer Index, Female, 030211 gastroenterology & hepatology, Hyperthermic intraperitoneal chemotherapy, business, Follow-Up Studies
Abstract: Well-differentiated papillary mesothelioma of the peritoneum (WDPMP) is a rare entity. Questions regarding management are still being debated as no more than 50 cases have been reported in the literature. We aimed to analyze the clinical, therapeutic, and prognostic data of patients with WDPMP from the RENAPE observational registry. All patients diagnosed with WDPMP and prospectively included in the RENAPE national registry between 2010 and 2018 were also included in our study. Expert pathologists from the RENA-PATH group confirmed all cases. All clinical, therapeutic, postoperative, and prognostic data were extracted and analyzed. We report on 56 patients with a mean age of 52 years (range 21–74). WDPMP was incidentally diagnosed during imaging or surgery in 16% and 36% of patients, respectively, and an association with synchronous malignancy was found in 18% of patients. Nine lesions showed discrete signs of fatty invasion. The median Peritoneal Cancer Index was 11 (range 0–33). Eleven patients were treated with definitive excision, 4 were treated with cytoreductive surgery (CRS) only, 37 were treated with CRS and hyperthermic intraperitoneal chemotherapy (HIPEC), and 2 were treated with CRS plus HIPEC plus early postoperative intraperitoneal chemotherapy. CRS was considered to be complete in 90% of cases. One patient died postoperatively and 16 patients (31%) faced postoperative complications. The median disease-free survival was 144 months; Four patients relapsed, with a median period of 27 months. No prognostic factors could be identified. Our analysis confirms the favorable prognosis of WDPMP. CRS and HIPEC could be a therapeutic option for diffuse, symptomatic, and/or recurrent disease.
Published: 2019

35. FOLFIRINEC: a randomized phase II trial of mFOLFIRINOX vs platinum-etoposide for metastatic neuroendocrine carcinoma of gastroenteropancreatic or unknown origin

Author: Véronique Lorgis, Eric Baudin, Romain Desgrippes, Frédéric Thuillier, Jean-Yves Scoazec, Côme Lepage, Pauline Afchain, Thomas Walter, David Tougeron, Carole Monterymard, Vincent Hautefeuille, Julien Hadoux, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR), Service d'Oncologie Médicale [CHU Saint -Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Hospices Civils de Lyon (HCL), Centre hospitalier universitaire de Poitiers (CHU Poitiers), Service d'Hépato Gastroenterologie [CHU Amiens-Picardie], CHU Amiens-Picardie, Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Service d'Oncologie médicale [CHU Limoges], CHU Limoges, Département de biologie et pathologie médicales [Gustave Roussy], CH de Saint-Malo [Broussais], Service d'Oncologie Médicale [CHU Saint-Antoine], CHU Saint-Antoine [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), and Gestionnaire, HAL Sorbonne Université 5
Subjects: Oncology, Male, FOLFIRINOX, medicine.medical_treatment, Leucovorin, Phases of clinical research, Platinum Compounds, 0302 clinical medicine, Antineoplastic Combined Chemotherapy Protocols, Prospective Studies, Neoplasm Metastasis, Etoposide, Gastroenterology, Evaluable Disease, Progression-Free Survival, 3. Good health, Oxaliplatin, Survival Rate, Neuroendocrine Tumors, Treatment Outcome, 030220 oncology & carcinogenesis, Neuroendocrine carcinoma, 030211 gastroenterology & hepatology, Female, Fluorouracil, medicine.drug, Adult, medicine.medical_specialty, Irinotecan, Gastroenteropancreatic, 03 medical and health sciences, Stomach Neoplasms, Internal medicine, Intestinal Neoplasms, medicine, Chemotherapy, Humans, Contraindication, Hepatology, Performance status, business.industry, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Carcinoma, Neuroendocrine, Pancreatic Neoplasms, Regimen, Quality of Life, Neoplasms, Unknown Primary, business, Biomarkers
Abstract: Background Poorly differentiated neuroendocrine carcinomas (NEC) are rare diseases with a poor prognosis. Platinum-etoposide (PE) has been the recommended first-line treatment for decades. FOLFIRINEC (NCT04325425) is a national multicenter randomized phase II study which aims to challenge this standard regimen. Methods The primary objective is to compare the median progression-free survival (PFS) under mFOLFIRINOX versus PE. The secondary objectives are to evaluate the objective response rates (ORR), median overall survival (OS), safety and quality of life. The associated real-time translational study will establish a molecular profile for each patient enrolled. Main inclusion criteria are NEC of gastroenteropancreatic (GEP) or unknown origin, metastatic and RECIST 1.1 evaluable disease, tumor sample available and no contraindication to chemotherapy. Patients will be randomized 1:1 between PE every 21 days for 6–8 cycles and mFOLFIRINOX every 14 days for up to 12 cycles and stratified according to center, performance status, Ki67 and pathological subtype. This trial will randomize 218 patients (24 months of follow-up) to have 80% power to detect an improvement of the median PFS from 5 months under PE to 7.5 months under mFOLFIRINOX (HR of 0.67, α =5%, two-sided). An intermediate analysis is planned at 50% of events. Recruitment started on October 20, 2020.
Published: 2021

36. Metabolomic analyses of COVID-19 patients unravel stage-dependent and prognostic biomarkers

Author: Giulia Baciarello, Guido Kroemer, Fanny Pommeret, Allan Sauvat, Eric Solary, Delphine Bredel, Nitharsshini Nirmalathasan, Agathe Dubuisson, Lisa Derosa, Annabelle Stoclin, Frank Griscelli, Mathilde Roumier, Fabrice Andre, Jean-Marie Michot, Frédéric Pène, Claudia Grajeda-Iglesias, Jean-Charles Soria, François-Xavier Danlos, Fabrice Barlesi, Jérôme Duchemin, Flore Rozenberg, Caroline Pradon, Françoise Levavasseur, Anne-Gaëlle Goubet, Julien Rohmer, Luc Mouthon, Laurence Zitvogel, Laurence Albiges, Severine Mouraud, Jean-Eudes Fahrner, Christophe Willekens, Sylvère Durand, Emeline Colomba, Aurélien Marabelle, Félix Ackerman, Syrine Ellouze, Michaela Fontenay, Georges Jourdi, Marc Vasse, Delphine Cantin, Immunologie anti-tumorale et immunothérapie des cancers (ITIC), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Institut Gustave Roussy (IGR), 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 de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Institut Universitaire de France (IUF), Ministère de l'Education nationale, de l’Enseignement supérieur et de la Recherche (M.E.N.E.S.R.), Métabolisme, Cancer et Immunité (CRC - UMR_S 1138), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité)-Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Service de Médecine Interne [Hôpital Foch, Suresnes] (SMI), Hôpital Foch [Suresnes], Oncologie gynécologique, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Centre de Référence National des Syndromes Hyperéosinophiliques (CEREO), Département de cancérologie de l'enfant et de l'adolescent [Gustave Roussy], 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, Université Paris-Saclay, Département de biologie et pathologie médicales [Gustave Roussy], Département de soins aigus [Gustave Roussy] (DSA), Direction de la recherche [Gustave Roussy], ANR-16-RHUS-0008,LUMIERE,LUMIERE(2016), ANR-18-IDEX-0001,Université de Paris,Université de Paris(2018), and European Project: 825410,ONCOBIOME
Subjects: Male, Cancer Research, Kynurenine pathway, Metabolite, [SDV]Life Sciences [q-bio], Immunology, [SDV.CAN]Life Sciences [q-bio]/Cancer, Disease, Pharmacology, Antibodies, Monoclonal, Humanized, Article, Cellular and Molecular Neuroscience, chemistry.chemical_compound, Metabolomics, Tocilizumab, Intensive care, medicine, Metabolome, Humans, lcsh:QH573-671, Pneumonitis, SARS-CoV-2, business.industry, lcsh:Cytology, COVID-19, Cell Biology, Prognosis, medicine.disease, COVID-19 Drug Treatment, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, chemistry, Viral infection, Female, business, Biomarkers
Abstract: The circulating metabolome provides a snapshot of the physiological state of the organism responding to pathogenic challenges. Here we report alterations in the plasma metabolome reflecting the clinical presentation of COVID-19 patients with mild (ambulatory) diseases, moderate disease (radiologically confirmed pneumonitis, hospitalization and oxygen therapy), and critical disease (in intensive care). This analysis revealed major disease- and stage-associated shifts in the metabolome, meaning that at least 77 metabolites including amino acids, lipids, polyamines and sugars, as well as their derivatives, were altered in critical COVID-19 patient’s plasma as compared to mild COVID-19 patients. Among a uniformly moderate cohort of patients who received tocilizumab, only 10 metabolites were different among individuals with a favorable evolution as compared to those who required transfer into the intensive care unit. The elevation of one single metabolite, anthranilic acid, had a poor prognostic value, correlating with the maintenance of high interleukin-10 and -18 levels. Given that products of the kynurenine pathway including anthranilic acid have immunosuppressive properties, we speculate on the therapeutic utility to inhibit the rate-limiting enzymes of this pathway including indoleamine 2,3-dioxygenase and tryptophan 2,3-dioxygenase.
Published: 2021

37. False negative rate at 18F-FDG PET/CT in para-aortic lymphnode involvement in patients with locally advanced cervical cancer: impact of PET technology

Author: Amandine Maulard, Catherine Genestie, Marie Terroir, Sebastien Gouy, Alexandra Leary, Patricia Pautier, Serena Grimaldi, Cyrus Chargari, Veronika Seebacher, Désirée Deandreis, Philippe Morice, Anna Ilenko, Malbec, Odile, Département de chirurgie gynécologique [Gustave Roussy], Institut Gustave Roussy (IGR), Université Paris-Sud - Paris 11 (UP11), Radiothérapie Moléculaire et Innovation Thérapeutique (RaMo-IT), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Département de radiothérapie [Gustave Roussy], Institut de Recherche Biomédicale des Armées (IRBA), Médecine nucléaire, Département d'imagerie médicale [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Pathologie morphologique, Département de biologie et pathologie médicales [Gustave Roussy], Biomarqueurs prédictifs et nouvelles stratégies moléculaires en thérapeutique anticancéreuse (U981), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de médecine oncologique [Gustave Roussy], Università degli studi di Torino = University of Turin (UNITO), Imagerie thérapeutique (radiologie interventionnelle), and University of Turin
Subjects: Cancer Research, [SDV]Life Sciences [q-bio], Cervical cancer, FDG, LACC, Para-aortic lymph node, PET/CT, TOF, Adenocarcinoma, Adult, Aged, Aorta, Carcinoma, Squamous Cell, Chemoradiotherapy, False Negative Reactions, Female, Humans, Laparoscopy, Lymph Node Excision, Lymph Nodes, Middle Aged, Neoplasm Staging, Pelvis, Positron Emission Tomography Computed Tomography, Retrospective Studies, Uterine Cervical Neoplasms, Young Adult, Fluorodeoxyglucose F18, Radiopharmaceuticals, medicine.medical_treatment, 030218 nuclear medicine & medical imaging, 0302 clinical medicine, Medicine, Stage (cooking), medicine.diagnostic_test, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, 3. Good health, [SDV] Life Sciences [q-bio], Oncology, Positron emission tomography, 030220 oncology & carcinogenesis, medicine.drug, lcsh:RC254-282, 03 medical and health sciences, Genetics, Fluorodeoxyglucose, PET-CT, business.industry, Carcinoma, Magnetic resonance imaging, medicine.disease, Squamous Cell, Lymphadenectomy, business, Nuclear medicine
Abstract: Background The identification of factors responsible for false negative (FN) rate at 18F- Fluorodeoxyglucose (FDG) Positron Emission Tomography /Computed Tomography (PET/CT) in para-aortic (PA) lymph nodes in the presurgical staging of patients with locally advanced cervical cancer (LACC) is challenging. The aim of this study was to evaluate the impact of PET/CT technology. Methods A total of 240 consecutive patients with LACC (International Federation of Gynecology and Obstetrics, FIGO, stage IB2-IVA) and negative Magnetic Resonance Imaging (MRI) and/or Computed Tomography (CT) and negative 18F-FDG PET/CT in the PA region, undergoing laparoscopic PA lymphadenectomy before chemoradiotherapy were included. The FN rate in patients studied with Time of flight (TOF) PET/CT (TOF PET) or non-Time of flight PET/CT (no-TOF PET) technology was retrospectively compared. Results Patients presented with FIGO stage IB (n = 78), stage IIA-B (n = 134), stage III (n = 18) and stage IVa (n = 10), squamous cell carcinoma (n = 191) and adenocarcinoma (n = 49). 141/240 patients were evaluated with no-TOF PET/CT and 99/240 with TOF PET/CT. Twenty-two patients (9%) had PA nodal involvement at histological analysis and considered PET/CT FN findings. The FN rate was 8.5% for no-TOF PET and 10% for TOF PET subgroup respectively (p = 0.98). Ninety patients (38%) presented with pelvic node uptakes at PET/CT. The FN rate in the PA region was 18% (16/90) and 4% (6/150) in patients with and without pelvic node involvement at PET/CT respectively (19 vs 3% for no-TOF PET and 17 vs 5% for TOF PET subgroup). Conclusions In LACC, FN rate in PA lymph nodes detection is a clinical issue even for modern PET/CT, especially in patients with pelvic uptake. Surgical lymphadenectomy should be performed in case of negative PET/CT at PA level in these patients, while it could be discussed in the absence of pelvic uptake.
Published: 2021

38. La carence en PBRM1 dans le cancer est létale de synthèse avec les inhibiteurs de réparation de l'ADN

Author: Chabanon, Roman M, Morel, Daphné, Eychenne, Thomas, Colmet-Daage, Léo, Bajrami, Ilirjana, Dorvault, Nicolas, Garrido, Marlène, Meisenberg, Cornelia, Lamb, Andrew, Ngo, Carine, Hopkins, Suzanna R, Roumeliotis, Theodoros I, Jouny, Samuel, Hénon, Clémence, Kawai-Kawachi, Asuka, Astier, Clémence, Konde, Asha, Nery, Elaine Del, Massard, Christophe, Pettitt, Stephen J, Margueron, Raphaël, Choudhary, Jyoti S, Almouzni, Geneviève, Soria, Jean-Charles, Deutsch, Eric, Downs, Jessica A, Lord, Christopher J, Postel-Vinay, Sophie, Institut Gustave Roussy (IGR), Pathologie morphologique, Département de biologie et pathologie médicales [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Dynamique du noyau, Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Direction de la recherche [Gustave Roussy], The institute of cancer research [London], Biomarqueurs prédictifs et nouvelles stratégies moléculaires en thérapeutique anticancéreuse (U981), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), and ATIP-Avenir INSERM
Subjects: ATR inhibitors, [SDV]Life Sciences [q-bio], R-loop, PBRM1 deficiency, cGAS/STING, PARP inhibitors, synthetic lethality
Abstract: Polybromo 1 (PBRM1), a subunit of the PBAF chromatin-remodeling complex, is recurrently inactivated in cancer. To uncover novel synthetic lethal (SL) approaches for targeting PBRM1-defective cancers, we used a series of orthogonal functionalgenomic screens which identified SL between PBRM1 deficiency and inhibition of PARP1. This effect was elicited with clinical PARP inhibitors in vitro and in vivo and also operated when PARP inhibitors were combined with ATR inhibitors. These SL effects were characterized by pre-existing replication stress in PBRM1-defective cells and an increase in R-loops, micronuclei and tumor cell-autonomous cGAS/STING signaling in response to PARP inhibitors. Quantitative mass spectrometry indicated that PBRM1-defective cells exhibited downregulation of multiple R-loop processing factors, and exogenous expression of the R-loop resolution enzyme RNase H1 partially reversed PARP inhibitor sensitivity, providing a mechanistic rationale for the SL effects. Our data provide the preclinical basis for using PARP inhibitors in PBRM1-defective cancers.; Le polybromo 1 (PBRM1), une sous-unité du complexe PBAF remodelant la chromatine, est inactivé de manière récurrente dans le cancer. Pour découvrir de nouvelles approches létales synthétiques (SL) pour cibler les cancers défectueux PBRM1, nous avons utilisé une série de tests fonctionnels orthogonaux qui a permis d'identifier la SL entre la déficience en PBRM1 et l'inhibition de la PARP1.Cet effet a été obtenu avec des inhibiteurs cliniques de PARP in vitro et in vivo et a également fonctionné lorsque les inhibiteurs PARP ont été combinés avec les inhibiteurs ATR. Ces effets SL étaient caractérisés par un stress de réplication préexistant dans les cellules déficientes en PBRM1 et une augmentation des boucles R, des micronoyaux et des cellules tumorales - cGAS/STING autonomes en réponse aux inhibiteurs PARP. La spectrométrie de masse quantitative a indiqué que les cellules défectueuses PBRM1 présentaient une régulation à la baisse du traitement en boucle R multiple et l'expression exogène de l'enzyme de résolution de la boucle R, la RNase H1 a partiellement inversé la sensibilité aux inhibiteurs PARP, ce qui fournit une justification mécaniste des effets SL. Nos données fournissent la base préclinique de l'utilisation des inhibiteurs PARP dans les PBRM1- les cancers défectueux.
Published: 2020

39. PBRM1 deficiency in cancer is synthetic lethal with DNA repair inhibitors

Author: Chabanon, Roman M, Morel, Daphné, Eychenne, Thomas, Colmet-Daage, Léo, Bajrami, Ilirjana, Dorvault, Nicolas, Garrido, Marlène, Meisenberg, Cornelia, Lamb, Andrew, Ngo, Carine, Hopkins, Suzanna R, Roumeliotis, Theodoros I, Jouny, Samuel, Hénon, Clémence, Kawai-Kawachi, Asuka, Astier, Clémence, Konde, Asha, Nery, Elaine Del, Massard, Christophe, Pettitt, Stephen J, Margueron, Raphaël, Choudhary, Jyoti S, Almouzni, Geneviève, Soria, Jean-Charles, Deutsch, Eric, Downs, Jessica A, Lord, Christopher J, Postel-Vinay, Sophie, Institut Gustave Roussy (IGR), Pathologie morphologique, Département de biologie et pathologie médicales [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Dynamique du noyau, Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Direction de la recherche [Gustave Roussy], The institute of cancer research [London], Biomarqueurs prédictifs et nouvelles stratégies moléculaires en thérapeutique anticancéreuse (U981), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), and ATIP-Avenir INSERM
Subjects: ATR inhibitors, [SDV]Life Sciences [q-bio], R-loop, PBRM1 deficiency, cGAS/STING, PARP inhibitors, synthetic lethality
Abstract: Polybromo 1 (PBRM1), a subunit of the PBAF chromatin-remodeling complex, is recurrently inactivated in cancer. To uncover novel synthetic lethal (SL) approaches for targeting PBRM1-defective cancers, we used a series of orthogonal functionalgenomic screens which identified SL between PBRM1 deficiency and inhibition of PARP1. This effect was elicited with clinical PARP inhibitors in vitro and in vivo and also operated when PARP inhibitors were combined with ATR inhibitors. These SL effects were characterized by pre-existing replication stress in PBRM1-defective cells and an increase in R-loops, micronuclei and tumor cell-autonomous cGAS/STING signaling in response to PARP inhibitors. Quantitative mass spectrometry indicated that PBRM1-defective cells exhibited downregulation of multiple R-loop processing factors, and exogenous expression of the R-loop resolution enzyme RNase H1 partially reversed PARP inhibitor sensitivity, providing a mechanistic rationale for the SL effects. Our data provide the preclinical basis for using PARP inhibitors in PBRM1-defective cancers.; Le polybromo 1 (PBRM1), une sous-unité du complexe PBAF remodelant la chromatine, est inactivé de manière récurrente dans le cancer. Pour découvrir de nouvelles approches létales synthétiques (SL) pour cibler les cancers défectueux PBRM1, nous avons utilisé une série de tests fonctionnels orthogonaux qui a permis d'identifier la SL entre la déficience en PBRM1 et l'inhibition de la PARP1.Cet effet a été obtenu avec des inhibiteurs cliniques de PARP in vitro et in vivo et a également fonctionné lorsque les inhibiteurs PARP ont été combinés avec les inhibiteurs ATR. Ces effets SL étaient caractérisés par un stress de réplication préexistant dans les cellules déficientes en PBRM1 et une augmentation des boucles R, des micronoyaux et des cellules tumorales - cGAS/STING autonomes en réponse aux inhibiteurs PARP. La spectrométrie de masse quantitative a indiqué que les cellules défectueuses PBRM1 présentaient une régulation à la baisse du traitement en boucle R multiple et l'expression exogène de l'enzyme de résolution de la boucle R, la RNase H1 a partiellement inversé la sensibilité aux inhibiteurs PARP, ce qui fournit une justification mécaniste des effets SL. Nos données fournissent la base préclinique de l'utilisation des inhibiteurs PARP dans les PBRM1- les cancers défectueux.
Published: 2020

40. Comparison of pathogenicity prediction tools on somatic variants

Author: Alexandre Harlé, Florence Koeppel, Voreak Suybeng, Etienne Rouleau, Département de biologie et pathologie médicales [Gustave Roussy], Institut Gustave Roussy (IGR), Direction de la recherche [Gustave Roussy], Centre de Recherche en Automatique de Nancy (CRAN), and Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Somatic cell, Clinical Decision-Making, Population, Mutation, Missense, [SDV.CAN]Life Sciences [q-bio]/Cancer, Computational biology, Biology, Polymorphism, Single Nucleotide, Sensitivity and Specificity, Germline, Pathology and Forensic Medicine, 03 medical and health sciences, 0302 clinical medicine, Gene Frequency, Neoplasms, Databases, Genetic, Humans, Exome, Genes, Tumor Suppressor, education, Allele frequency, education.field_of_study, Receiver operating characteristic, Computational Biology, High-Throughput Nucleotide Sequencing, Oncogenes, Matthews correlation coefficient, Data Accuracy, 030104 developmental biology, 030220 oncology & carcinogenesis, Principal component analysis, Molecular Medicine
Abstract: Genomic sequencing is increasingly used in managing patients with cancer. Interpretation of somatic variants and their pathogenicity is often complex. Pathogenicity prediction tools are commonly used as part of the expert interpretation of somatic variants, but most of these tools were initially developed for germline variants. Our aim was to benchmark their performance for somatic variants. A gold standard list was assembled of 4319 somatic single-nucleotide variants, classified as oncogenic (n = 2996) or neutral (n = 1323), based on their presence in curated databases or on their allele frequency in the general population. These variants were annotated with the most commonly used prediction tools [Database for Nonsynonymous SNPs' Functional Predictions (dbNSFP) and Universal Mutation Database Predictor (UMD-Predictor)] and computed performance calculations. Stratification of the prediction tools based on Matthews correlation coefficient and area under the receiver operating characteristic curve allowed the identification of the top-performing ones, namely, Combined Annotation-Dependent Depletion (CADD), Eigen or Eigen Principal Components (Eigen-PC), Polymorphism Phenotyping version 2 (PolyPhen-2), Protein Variation Effect Analyzer (PROVEAN), UMD-Predictor, and Rare Exome Variant Ensemble Learner (REVEL). Interestingly, Sorting Intolerant From Tolerant (SIFT), which is a commonly used prediction tool for somatic variants, was ranked in the second performance category. Combining tools two by two only marginally improved performances, mainly because of the occurrence of discordant predictions.
Published: 2020

41. FBXO32 links ubiquitination to epigenetic reprograming of melanoma cells

Author: Habel, Nadia, El-Hachem, Najla, Soysouvanh, Frédéric, Hadhiri-Bzioueche, Hanene, Giuliano, Serena, Nguyen, Sophie, Horák, Pavel, Gay, Anne-Sophie, Debayle, Delphine, Nottet, Nicolas, Béranger, Guillaume, Paillerets, Brigitte Bressac-de, Bertolotto, Corine, Ballotti, Robert, Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), Institut de pharmacologie moléculaire et cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de biologie et pathologie médicales [Gustave Roussy], Institut Gustave Roussy (IGR), BERTOLOTTO-BALLOTTI, BERTOLOTTO-BALLOTTI, Université Nice Sophia Antipolis (1965 - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)
Subjects: Proteomics, SKP Cullin F-Box Protein Ligases, Ubiquitination, Mice, Nude, Muscle Proteins, [SDV.CAN]Life Sciences [q-bio]/Cancer, Oncogenes, Cellular Reprogramming, Transfection, Xenograft Model Antitumor Assays, Article, Epigenesis, Genetic, Mice, [SDV.CAN] Life Sciences [q-bio]/Cancer, Cell Line, Tumor, Animals, Humans, Epigenetics, Melanoma, Cell Proliferation
Abstract: International audience; Ubiquitination by serving as a major degradation signal of proteins, but also by controlling protein functioning and localization, plays critical roles in most key cellular processes. Here, we show that MITF, the master transcription factor in melanocytes, controls ubiquitination in melanoma cells. We identified FBXO32, a component of the SCF E3 ligase complex as a new MITF target gene. FBXO32 favors melanoma cell migration, proliferation, and tumor development in vivo. Transcriptomic analysis shows that FBXO32 knockdown induces a global change in melanoma gene expression profile. These include the inhibition of CDK6 in agreement with an inhibition of cell proliferation and invasion upon FBXO32 silencing. Furthermore, proteomic analysis identifies SMARC4, a component of the chromatin remodeling complexes BAF/PBAF, as a FBXO32 partner. FBXO32 and SMARCA4 co-localize at loci regulated by FBXO32, such as CDK6 suggesting that FBXO32 controls transcription through the regulation of chromatin remodeling complex activity. FBXO32 and SMARCA4 are the components of a molecular cascade, linking MITF to epigenetics, in melanoma cells.
Published: 2020

42. Immunodynamics of explanted human tumors for immuno‐oncology

Author: Dubuisson, Agathe, Fahrner, Jean Eudes, Goubet, Anne Gaëlle, Terrisse, Safae A., Voisin, Nicolas, Bayard, Charles, Lofek, Sébastien, Drubay, Damien, Bredel, Delphine, Mouraud, Séverine, Susini, Sandrine, Cogdill, Alexandria P., Rebuffet, Lucas, Ballot, Elise, Jacquelot, Nicolas, Thomas de Montpreville, Vincent, Casiraghi, Odile, Radulescu, Camélia, Ferlicot, Sophie, Figueroa, David J., Yadavilli, Sapna, Waight, Jeremy D., Ballas, Marc S., Hoos, Axel X., Condamine, Thomas, Parier, Bastien, Gaudillat, Christophe, Routy, Bertrand, Ghiringhelli, François, Derosa, Lisa, Breuskin, Ingrid, Rouanne, Mathieu, André, Fabrice, Lebacle, Cédric, Baumert, Hervé, Wislez, Marie, Fadel, Élie, Cremer, Isabelle, Albiges, Laurence, Geoerger, Birgit, Scoazec, Jean Yves, Loriot, Yohann, Kroemer, Guido, Marabelle, Aurélien, Bonvalet, Mélodie, Zitvogel, Laurence, Immunologie des tumeurs et immunothérapie (UMR 1015), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Centre de recherche en épidémiologie et santé des populations (CESP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Service de biostatistique et d'épidémiologie (SBE), Direction de la recherche clinique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), The University of Texas M.D. Anderson Cancer Center [Houston], Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, The Walter and Eliza Hall Institute of Medical Research (WEHI), Département de biologie et pathologie médicales [Gustave Roussy], Institut Gustave Roussy (IGR), Centre hospitalier Saint-Joseph [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CR CHUM), Centre Hospitalier de l'Université de Montréal (CHUM), Université de Montréal (UdeM)-Université de Montréal (UdeM), Département de médecine oncologique [Gustave Roussy], Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Hôpital Foch [Suresnes], Direction de la recherche [Gustave Roussy], AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris], CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), Vectorologie et thérapeutiques anti-cancéreuses [Villejuif] (UMR 8203), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse (AMMICa), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), 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), Karolinska University Hospital [Stockholm], Chancellerie des Universités de Paris Agence Nationale de la Recherche, ANR Seerave Foundation Association pour la Recherche sur le Cancer, ARC ANR‐16‐RHUS‐0008 Ligue Contre le Cancer European Commission, EC Fondation pour la Recherche Médicale, FRM Institut National Du Cancer, INCa Institut Universitaire de France, IUF European Research Council, ERC Fondation Leducq RP170067 Association pour la Recherche sur le Cancer, ARC, LZ and GK were supported by the Ligue contre le Cancer (équipe labelisée), Agence Nationale de la Recherche (ANR) francogermanique ANR‐19‐CE15‐0029, ANR Projects blancs, ANR under the frame of E‐Rare‐2, the ERA‐Net for Research on Rare Diseases, Association pour la recherche sur le cancer (ARC), Bristol‐Myers Squibb Company (International Immuno‐Oncology Network), Cancéropôle Ile‐de‐France, Chancellerie des universités de Paris (Legs Poix), Fondation pour la Recherche Médicale (FRM), a donation by Elior, the European Commission (ArtForce), the European Research Council (ERC), Fondation Carrefour, Institut National du Cancer (INCa), Inserm (HTE), Institut Universitaire de France, LeDucq Foundation, the LabEx Immuno‐Oncology, the RHU Torino Lumière (ANR‐16‐RHUS‐0008), H2020 ONCOBIOME, the Seerave Foundation, the SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE), FHU CARE, Dassault, and Badinter Philantropia, and the Paris Alliance of Cancer Research Institutes (PACRI). AC is supported by the CPRIT Research Training Program (RP170067). JEF was supported by Transgene and AGG was supported by FRM. AM has been or is currently an investigator in clinical trials sponsored by BMS, MSD, GSK/Tesaro, Janssen, Roche/Genentech, Pfizer, Astra Zeneca (AZ), Amgen. AM has been or is currently a member of Clinical Trial Scientific Steering Committee for AZ and GSK. AM has been or is currently a member of the scientific advisory board of the following companies: Merck Serono, Novartis, BMS, Symphogen, Amgen, Tesaro/GSK, Pfizer, Astra Zeneca/Medimmune, Servier, Sanofi. AM has provided Scientific & Medical Consulting to the following companies: Roche, Sanofi. AM is a member of the Data Safety and Monitoring Board for the following trial NCT02423863 (TLR3 agonist, Oncovir). AM has received research funding and or drug supply for pre‐Clinical and clinical research projects from: BMS, Boehringer Ingelheim, Idera, MSD, Fondation MSD Avenir, SIRIC (INCa‐DGOS‐Inserm_12551)., ANR-16-RHUS-0008,LUMIERE,LUMIERE(2016), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPC)
Subjects: Medicine (General), [SDV]Life Sciences [q-bio], Immunology, QH426-470, Medical Oncology, immune checkpoint inhibitors, R5-920, immunomonitoring, Report, precision oncology, Neoplasms, Genetics, “in sitro” assay, Tumor Microenvironment, cancer, Humans, Immunotherapy, Prospective Studies, Reports
Abstract: Decision making in immuno‐oncology is pivotal to adapt therapy to the tumor microenvironment (TME) of the patient among the numerous options of monoclonal antibodies or small molecules. Predicting the best combinatorial regimen remains an unmet medical need. Here, we report a multiplex functional and dynamic immuno‐assay based on the capacity of the TME to respond to ex vivo stimulation with twelve immunomodulators including immune checkpoint inhibitors (ICI) in 43 human primary tumors. This "in sitro" (in situ/in vitro) assay has the potential to predict unresponsiveness to anti‐PD‐1 mAbs, and to detect the most appropriate and personalized combinatorial regimen. Prospective clinical trials are awaited to validate this in sitro assay., To predict cancer resistance to PD‐1 blockade and design suitable combinations of immunomodulators, a 60‐h functional in sitro assay was set up in 43 tumors that allowed calculation of the “Immune Reactivity Score (IRS)” based on 17 TCR‐dependent‐ cytokines/chemokines.
Published: 2020

43. BCG therapy downregulates HLA-I on malignant cells to subvert antitumor immune responses in bladder cancer

Author: Mathieu Rouanne, Julien Adam, Camélia Radulescu, Diane Letourneur, Delphine Bredel, Séverine Mouraud, Anne-Gaëlle Goubet, Marion Leduc, Noah Chen, Tuan Zea Tan, Nicolas Signolle, Amélie Bigorgne, Michael Dussiot, Lambros Tselikas, Sandrine Susini, François-Xavier Danlos, Anna K. Schneider, Roman Chabanon, Sophie Vacher, Ivan Bièche, Thierry Lebret, Yves Allory, Jean-Charles Soria, Nicholas Arpaia, Guido Kroemer, Oliver Kepp, Jean Paul Thiery, Laurence Zitvogel, Aurélien Marabelle, Immunologie anti-tumorale et immunothérapie des cancers (ITIC), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Columbia University [New York], Hôpital Foch [Suresnes], Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil (UVSQ Santé), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Département de biologie et pathologie médicales [Gustave Roussy], Institut Gustave Roussy (IGR), Immunologie intégrative des tumeurs et immunothérapie des cancers (INTIM), École normale supérieure de Lyon (ENS de Lyon), Département de médecine oncologique [Gustave Roussy], National University of Singapore (NUS), Biomarqueurs prédictifs et nouvelles stratégies moléculaires en thérapeutique anticancéreuse (U981), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Département d’Innovation Thérapeutique et essais précoces [Gustave Roussy] (DITEP), The institute of cancer research [London], Institut Curie [Paris], Biologie Cellulaire et Cancer, Institut Curie [Paris]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Pôle de biologie, 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), Bristol-Myers Squibb, BMS, Ipsen, Boston Scientific Corporation, BSC, Daiichi-Sankyo, Institut National de la Santé et de la Recherche Médicale, Inserm, Fondation Gustave Roussy, Seerave Foundation, Association pour la Recherche sur le Cancer, ARC, Institut National de la Santé et de la Recherche Médicale, Inserm: CIC1428, Agence Nationale de la Recherche, ANR: UMS3655, Institut National Du Cancer, INCa, Institut Universitaire de France, IUF: ANR-18-IDEX-0001, Fondation Leducq, Cancéropôle Ile de France, National Cancer Institute, NCI, National Institutes of Health, NIH: U01CA247573, Fondation pour la Recherche Médicale, FRM, Association Française d'Urologie, AFU, Conflict of interest: Over the past 2 years, JCS has received consultancy fees and shares from Relay Therapeutics and Gritstone bio, was on the board of directors of Hookipa Pharmaceuticals (2018–2021), was full-time employee (2017–2019) at AstraZeneca, and has been a full-time employee at Amgen since August 2021. Over the past 7 years, AM has received institutional funding grants from AstraZeneca, Merus, Bristol Myers Squibb (BMS), Boehringer Ingelheim, Transgene, Fondation MSD Avenir, and Sanofi, is member of the Clinical Trial Steering Committee for NCT02528357 (GlaxoSmithKline [GSK]), NCT03334617 (AstraZeneca), is a member of the Data Safety and Monitoring Board for NCT02423863 (sponsor: Oncovir) and NCT03818685 (sponsor: Centre Léon Bérard), has participated on the scientific advisory boards of the following companies: Merck Serono, eTheRNA, Lytix Biopharma, Kyowa Kirin Pharma, Novartis, BMS, Symphogen, Genmab, Amgen, Biothera, Nektar, Tesaro/GSK, Oncosec, Pfizer, Seattle Genetics, AstraZeneca/Medimmune, Servier, Gritstone, Molecular Partners, Bayer, Partner Therapeutics, Sanofi, Pierre Fabre, RedX Pharma, OSE Immunotherapeutics, Medicxi, HiFiBio, IMCheck, MSD, Innate Pharma, and HotSpot Therapeutics, has received teaching/speaker honoraria from Roche/Genentech, BMS, Merck (MSD), Merck Serono, AstraZeneca/Medimmune, Amgen, Sanofi, and Servier, has received fees for scientific and medical consulting from Roche, Pierre Fabre, Onxeo, EISAI, Bayer, Genticel, Rigontec, Daichii Sankyo, Imaxio, Sanofi/BioNTech, Molecular Partners, Pillar Partners, Benta Pharma Industries (BPI), and Faron, has received nonfinancial support (travel expenses) from AstraZeneca, BMS, Merck (MSD), and Roche, and is co-founder and shareholder of Centessa, holds a patent titled 'Humanized and chimeric monoclonal antibodies to CD81' (US patent application serial no. 62/351,054). LZ is founder of EverImmune, a cancer/microbiome biotechnology company, is a member of the board of directors of Transgene, is a member of the scientific advisory board of Transgene, EpiVax, Lytix Biopharma, has received past research contracts with Merus, Roche, and Tusk and honoraria from Transgene, has current research contracts with Innovate Pharma, Kaleido, Pileje, Incyte, BMS, GSK, and Transgene, and is an employee of Gustave Roussy and the Faculté de Médecine Paris XI. GK is on the board of directors of the BMS Foundation (France), receives grants and research support form Daiichi Sankyo, Eleor, Kaleido, Lytix Pharma, PharmaMar, Samsara, Sotio, and Vasculox/Tioma, is founder and shareholder of EverImmune, Osasuna Therapeutics, Samsara Therapeutics, and Therafast Bio, and is an employee of the University of Paris, AP-HP, Gustave Roussy. OK receives grant and research support from Daiichi Sankyo, Eleor, Kaleido, Lytix Pharma, PharmaMar, Samsara, Sotio, and Vasculox/Tioma, is founder and shareholder of Samsara Therapeutics, and is an employee of INSERM, Gustave Roussy. JPT is the scientific founder and chairman of BioCheetah Pte Ltd (Singapore), a company involved in urine-based bladder cancer diagnostics. LT has received research grants from the BMS Foundation and Terumo and honoraria or consulting fees from Boston Scientific, General Electric, and Ipsen., The authors thank Alice Perchenet and Laetitia Grynszpan for technical support and William Y. Kim (University of North Carolina) for providing the UPPL1541 murine bladder cancer cell line. MR is supported by the Fondation Foch and the Association Française d’Urologie (AFU). AM is supported by the Fondation MSD Avenir, Fondation Gustave Roussy, SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE) and INSERM CIC1428. AGG is supported by the Fondation pour la Recherche Médicale (FRM). NA is supported by the National Cancer Institute (NCI), NIH grant U01CA247573. GK is supported by the Ligue con-tre le Cancer (équipe labellisée), the Agence National de la Recherche (ANR) – Projets blancs, the AMMICa US23/CNRS UMS3655, the Association pour la recherche sur le cancer (ARC), Cancéropôle Ile-de-France, the FRM, a donation by Elior, Equipex Onco-Pheno-Screen, the European Joint Programme on Rare Diseases (EJPRD), Gustave Roussy Odyssea, the European Union Horizon 2020 Projects Oncobiome and Crimson, the Fondation Carrefour, the Institut National du Cancer (INCa), the Institut Universitaire de France, LabEx Immuno – Oncology (ANR-18-IDEX-0001), the Leducq Foundation, a Cancer Research ASPIRE Award from the Mark Foundation, the RHU Torino Lumière, the Seerave Foundation, SIRIC (SOCRATE), and SIRIC Cancer Research and Personalized Medicine (CARPEM). This study contributes to the IDEX Université de Paris ANR-18-IDEX-0001. AB and MD are supported by ANR-10-IAHU-01., ANR-18-IDEX-0001,Université de Paris,Université de Paris(2018), HAL UVSQ, Équipe, École normale supérieure - Lyon (ENS Lyon), and École pratique des hautes études (EPHE)
Subjects: nonmuscle-invasive bladder cancer, Immunity, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, General Medicine, [SDV.MHEP.UN] Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, [SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, Mycobacterium bovis, immunology, Administration, Intravesical, [SDV.CAN] Life Sciences [q-bio]/Cancer, Urinary Bladder Neoplasms, oncology, BCG Vaccine, Tumor Microenvironment, Humans, Immunotherapy, [SDV.IMM.IMM] Life Sciences [q-bio]/Immunology/Immunotherapy, bacillus Calmette-Guérin (BCG), Neoplasm Recurrence, Local
Abstract: International audience; Patients with high-risk, nonmuscle-invasive bladder cancer (NMIBC) frequently relapse after standard intravesical bacillus Calmette-Guérin (BCG) therapy and may have a dismal outcome. The mechanisms of resistance to such immunotherapy remain poorly understood. Here, using cancer cell lines, freshly resected human bladder tumors, and samples from cohorts of patients with bladder cancer before and after BCG therapy, we demonstrate 2 distinct patterns of immune subversion upon BCG relapse. In the first pattern, intracellular BCG infection of cancer cells induced a posttranscriptional downregulation of HLA-I membrane expression via inhibition of autophagy flux. Patients with HLA-I–deficient cancer cells following BCG therapy had a myeloid immunosuppressive tumor microenvironment (TME) with epithelial-mesenchymal transition (EMT) characteristics and dismal outcomes. Conversely, patients with HLA-I–proficient cancer cells after BCG therapy presented with CD8+ T cell tumor infiltrates, upregulation of inflammatory cytokines, and immune checkpoint–inhibitory molecules. The latter patients had a very favorable outcome. We surmise that HLA-I expression in bladder cancers at relapse following BCG does not result from immunoediting but rather from an immune subversion process directly induced by BCG on cancer cells, which predicts a dismal prognosis. HLA-I scoring of cancer cells by IHC staining can be easily implemented by pathologists in routine practice to stratify future treatment strategies for patients with urothelial cancer. Copyright
Published: 2020

44. High throughput profiling of undifferentiated pleomorphic sarcomas identifies two main subgroups with distinct immune profile, clinical outcome and sensitivity to targeted therapies

Author: Audrey Laroche-Clary, Carlo Lucchesi, François Le Loarer, Damien Geneste, Bérengère Dadone-Montaudié, Amandine Crombé, Todd Hembrough, Laurence Bianchini, Antoine Italiano, Steve M. M. Sweet, Julien Adam, Vanessa Chaire, Fabiola Cecchi, Frederic Bertolo, Stéphanie Verbeke, Yeoun Jin Kim, François Bertucci, Maud Toulmonde, Raul Perret, Institut Bergonié [Bordeaux], UNICANCER, Institut Gustave Roussy (IGR), Département de biologie et pathologie médicales [Gustave Roussy], Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Institut de Recherche sur le Cancer et le Vieillissement (IRCAN), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), and Nantomics
Subjects: 0301 basic medicine, Proteomics, FGFR Inhibition, T-Lymphocytes, Immunology, lcsh:Medicine, [SDV.CAN]Life Sciences [q-bio]/Cancer, Disease, Biology, General Biochemistry, Genetics and Molecular Biology, Undifferentiated Pleomorphic Sarcoma, Transcriptome, 03 medical and health sciences, Mice, 0302 clinical medicine, Lymphocytes, Tumor-Infiltrating, Exome Sequencing, medicine, Biomarkers, Tumor, Therapeutic targets, Animals, Humans, lcsh:R5-920, Gene Expression Profiling, lcsh:R, Sarcomas, Cell Cycle, Computational Biology, Sarcoma, General Medicine, Genomics, medicine.disease, Prognosis, Phenotype, Immunohistochemistry, Preclinical, 3. Good health, 030104 developmental biology, 030220 oncology & carcinogenesis, Cancer research, lcsh:Medicine (General), Research Paper
Abstract: International audience; Background: Undifferentiated pleomorphic sarcoma (UPS) is the most frequent, aggressive and less-characterized sarcoma subtype. This study aims to assess UPS molecular characteristics and identify specific therapeutic targets. Methods: High-throughput technologies encompassing immunohistochemistry, RNA-sequencing, whole exomesequencing, mass spectrometry, as well as radiomics were used to characterize three independent cohorts of 110, 25 and 41 UPS selected after histological review performed by an expert pathologist. Correlations were made with clinical outcome. Cell lines and xenografts were derived from human samples for functional experiments. Findings: CD8 positive cell density was independently associated with metastatic behavior and prognosis. RNA-sequencing identified two main groups: the group A, enriched in genes involved in development and stemness, including FGFR2, and the group B, strongly enriched in genes involved in immunity. Immune infiltrate patterns on tumor samples were highly predictive of gene expression classification, leading to call the group B 'immune-high' and the group A 'immune-low'. This molecular classification and its prognostic impact were confirmed on an independent cohort of UPS from TCGA. Copy numbers alterations were significantly more frequent in immune-low UPS. Proteomic analysis identified two main proteomic groups that highly correlated with the two main transcriptomic groups. A set of nine radiomic features from conventional MRI sequences provided the basis for a radiomics signature that could select immune-high UPS on their pre-therapeutic imaging. Finally, in vitro and in vivo anti-tumor activity of FGFR inhibitor JNJ-42756493 was selectively shown in cell lines and patient-derived xenograft models derived from immune-low UPS. Interpretation: Two main disease entities of UPS, with distinct immune phenotypes, prognosis, molecular features and MRI textures, as well as differential sensitivity to specific anticancer agents were identified. Immune-high UPS may be the best candidates for immune checkpoint inhibitors, whereas this study provides rational for assessing FGFR inhibition in immune-low UPS. Funding: This work was partly founded by a grant from La Ligue.
Published: 2020

45. CD103+CD8+ TRM Cells Accumulate in Tumors of Anti-PD-1-Responder Lung Cancer Patients and Are Tumor-Reactive Lymphocytes Enriched with Tc17

Author: Julien Adam, Heloise Halse, Pierre Validire, David Planchard, Jamila Kacher, Marine Leclerc, Stéphanie Corgnac, Olaf Mercier, Christophe Massard, Laura Mezquita, Fathia Mami-Chouaib, Nathalie Droin, Ines Malenica, Salem Chouaib, Edouard Auclin, Benjamin Besse, Vincent Thomas de Montpréville, Jean-Yves Scoazec, Nicolas Signolle, Laetitia Grynszpan, Elodie Voilin, Thibault Dayris, Immunologie intégrative des tumeurs (UMR 1186), 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), 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), Biomarqueurs prédictifs et nouvelles stratégies moléculaires en thérapeutique anticancéreuse (U981), Hôpital Marie-Lannelongue, Institut Mutualiste de Montsouris (IMM), Département de biologie et pathologie médicales [Gustave Roussy], Département d’Innovation Thérapeutique et essais précoces [Gustave Roussy] (DITEP), Département de médecine oncologique [Gustave Roussy], CCSD, Accord Elsevier, Prédicteurs moléculaires et nouvelles cibles en oncologie (PMNCO), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse (AMMICa), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Dynamique moléculaire de la transformation hématopoïétique (Dynamo)
Subjects: Cytotoxicity, Immunologic, Lung Neoplasms, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Programmed Cell Death 1 Receptor, CD8-Positive T-Lymphocytes, CD103 integrin, Lymphocyte Activation, B7-H1 Antigen, CD49a, anti-PD-1 immunotherapy, 0302 clinical medicine, Antineoplastic Agents, Immunological, Carcinoma, Non-Small-Cell Lung, Tumor Microenvironment, Phosphorylation, Cytotoxicity, ComputingMilieux_MISCELLANEOUS, lcsh:R5-920, 0303 health sciences, Chemistry, Interleukin-17, hemic and immune systems, Prognosis, Aiolos, 3. Good health, [SDV] Life Sciences [q-bio], 030220 oncology & carcinogenesis, tumor-infiltrating lymphocytes, Immunotherapy, lcsh:Medicine (General), Integrin alpha Chains, Signal Transduction, STAT3 Transcription Factor, CD8 Antigens, and T-bet transcription factors, Tc17, chemical and pharmacologic phenomena, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Ikaros Transcription Factor, Lymphocytes, Tumor-Infiltrating, Antigens, CD, medicine, Humans, Lymphocyte Count, Lung cancer, 030304 developmental biology, Retrospective Studies, ICB response biomarkers, Tumor-infiltrating lymphocytes, AhR, medicine.disease, Survival Analysis, Immune checkpoint, CD8 TRM cells, Aiolos, AhR, and T-bet transcription factors, TCR repertoire, lung cancer, Gene Expression Regulation, Cancer cell, CTL, Cancer research, Immunologic Memory, CD8
Abstract: Summary Accumulation of CD103+CD8+ resident memory T (TRM) cells in human lung tumors has been associated with a favorable prognosis. However, the contribution of TRM to anti-tumor immunity and to the response to immune checkpoint blockade has not been clearly established. Using quantitative multiplex immunofluorescence on cohorts of non-small cell lung cancer patients treated with anti-PD-(L)1, we show that an increased density of CD103+CD8+ lymphocytes in immunotherapy-naive tumors is associated with greatly improved outcomes. The density of CD103+CD8+ cells increases during immunotherapy in most responder, but not in non-responder, patients. CD103+CD8+ cells co-express CD49a and CD69 and display a molecular profile characterized by the expression of PD-1 and CD39. CD103+CD8+ tumor TRM, but not CD103−CD8+ tumor-infiltrating counterparts, express Aiolos, phosphorylated STAT-3, and IL-17; demonstrate enhanced proliferation and cytotoxicity toward autologous cancer cells; and frequently display oligoclonal expansion of TCR-β clonotypes. These results explain why CD103+CD8+ TRM are associated with better outcomes in anti-PD-(L)1-treated patients., Graphical Abstract, Highlights A high density of CD103+CD8+ cells in tumors correlates with response to anti-PD-(L)1 The density of CD103+CD8+ cells increases after anti-PD-1 in most responder patients CD103+CD8+ TRM cells are enriched with tumor-specific T cells A subset of CD103+CD8+ TRM cells display a Tc17 differentiation program, Using retrospective cohorts of anti-PD-(L)1-treated NSCLC, Corgnac et al. show that the density of CD103+CD8+ cells in tumors is associated with better progression-free survival. CD103+CD8+ tumor-infiltrating lymphocytes are tumor-specific resident memory T cells (TRM) enriched with a subset displaying a unique Tc1/Tc17 differentiation program that differs from CD103−CD8+ T cells (non-TRM).
Published: 2020

46. Weakly Supervised Multiple Instance Learning Histopathological Tumor Segmentation

Author: Théophraste Henry, Enzo Battistella, Théo Estienne, Alexandre Carré, Eric Deutsch, Marion Classe, Julien Adam, Maria Vakalopoulou, Nikos Paragios, Marvin Lerousseau, OPtimisation Imagerie et Santé (OPIS), Inria Saclay - Ile de France, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre de vision numérique (CVN), Institut National de Recherche en Informatique et en Automatique (Inria)-CentraleSupélec-Université Paris-Saclay-CentraleSupélec-Université Paris-Saclay, Mathématiques et Informatique pour la Complexité et les Systèmes (MICS), CentraleSupélec-Université Paris-Saclay, Département de biologie et pathologie médicales [Gustave Roussy], Institut Gustave Roussy (IGR), Biomarqueurs prédictifs et nouvelles stratégies moléculaires en thérapeutique anticancéreuse (U981), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris-Saclay, Radiothérapie Moléculaire et Innovation Thérapeutique (RaMo-IT), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Direction de la recherche [Gustave Roussy], and TheraPanacea [Paris]
Subjects: FOS: Computer and information sciences, 0301 basic medicine, Scheme (programming language), Computer Science - Machine Learning, Computer science, Computer Vision and Pattern Recognition (cs.CV), Tumor segmentation, Computer Science - Computer Vision and Pattern Recognition, [SDV.CAN]Life Sciences [q-bio]/Cancer, Machine learning, computer.software_genre, Machine Learning (cs.LG), [INFO.INFO-AI]Computer Science [cs]/Artificial Intelligence [cs.AI], 03 medical and health sciences, 0302 clinical medicine, Histopathological segmentation, FOS: Electrical engineering, electronic engineering, information engineering, Medical imaging, [INFO.INFO-IM]Computer Science [cs]/Medical Imaging, Segmentation, computer.programming_language, business.industry, Weakly supervised learning, Multiple instance learning, Image and Video Processing (eess.IV), Image segmentation, Electrical Engineering and Systems Science - Image and Video Processing, 3. Good health, 030104 developmental biology, 030220 oncology & carcinogenesis, Artificial intelligence, business, computer
Abstract: Histopathological image segmentation is a challenging and important topic in medical imaging with tremendous potential impact in clinical practice. State of the art methods rely on hand-crafted annotations which hinder clinical translation since histology suffers from significant variations between cancer phenotypes. In this paper, we propose a weakly supervised framework for whole slide imaging segmentation that relies on standard clinical annotations, available in most medical systems. In particular, we exploit a multiple instance learning scheme for training models. The proposed framework has been evaluated on multi-locations and multi-centric public data from The Cancer Genome Atlas and the PatchCamelyon dataset. Promising results when compared with experts' annotations demonstrate the potentials of the presented approach. The complete framework, including $6481$ generated tumor maps and data processing, is available at https://github.com/marvinler/tcga_segmentation., Accepted MICCAI 2020; added code + results url; 10 pages, 3 figures
Published: 2020

47. Long term follow-up of a large series of stage-II/III atypical proliferative serous ovarian tumors

Author: Amandine Maulard, Catherine Genestie, Matthieu Faron, Sophie Maria, Alexandra Leary, Sebastien Gouy, Philippe Morice, Patricia Pautier, Cyrus Chargari, Institut Gustave Roussy (IGR), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Département de chirurgie viscérale [Gustave Roussy], Département de chirurgie gynécologique [Gustave Roussy], Oncologie gynécologique, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Département de radiothérapie [Gustave Roussy], Pathologie morphologique, Département de biologie et pathologie médicales [Gustave Roussy], Radiothérapie Moléculaire et Innovation Thérapeutique (RaMo-IT), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, and CCSD, Accord Elsevier
Subjects: 0301 basic medicine, Adult, Prognostic factor, medicine.medical_specialty, Adolescent, Long term follow up, [SDV]Life Sciences [q-bio], Ovary, Stage ii, Gastroenterology, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Internal medicine, Overall survival, Medicine, Humans, Atypical proliferative serous tumor, Neoplasm Invasiveness, Aged, Cell Proliferation, Neoplasm Staging, Retrospective Studies, Ovarian Neoplasms, business.industry, Obstetrics and Gynecology, Large series, Middle Aged, Invasive implants, Prognosis, Survival Analysis, 3. Good health, Cystadenocarcinoma, Serous, Conservative treatment, [SDV] Life Sciences [q-bio], Serous fluid, 030104 developmental biology, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, Extraovarian low-grade serous carcinoma, Female, Neoplasm Recurrence, Local, business, Follow-Up Studies, Noninvasive implants
Abstract: International audience; Background: The aim of this study was to assess prognostic factors and implications on further management in a large series of stage-II or III Atypical Proliferative Serous Tumors (APST) with a long-term follow-up.Patients and methods: Patients with APSTs and peritoneal implants treated in, or referred to, our institution were retrospectively reviewed. Prognostic factors on invasive recurrence, disease-free (DFS) and overall survival (OS) were analyzed.Results: Between 1971 and 2017, 212 patients were identified and followed (33 having invasive implants). After a median follow-up of 115 months, 70 recurrences were observed, 28 of them under the form of invasive disease. DFS at 5 years and 10 years was 73% and 62% respectively. The use of a conservative treatment (HR = 5.5[3.33-9.08], p < .0001), the presence of ≥3 peritoneal sites with implants (HR = 1.65[1.01-2.72], p = .045) were unfavorable prognostic factors for DFS. The presence of ≥3 peritoneal sites with implants (HR = 3.02[0.96-9.53], p = .049) and the presence of stromal microinvasion (HR = 3.19[1.12-9.1], p = .022) were unfavorable prognostic factors for OS. Non-conservative surgery (HR = 7[2.35-20.87], p = .0002), invasive implants (HR = 5.37[1.29-22.26], p = .013), and ≥ 3 peritoneal sites with implants (HR = 3.56 [1.11-11.39], p = .024) were identified as predictors of recurrence in the form of an invasive disease. Invasive implants were not associated with DFS (HR = 1.39[0.77-2.51], p = .27), nor OS (HR = 1.76[0.57-5.47], p = .32).Conclusion: After a long-term follow-up, type of peritoneal implants is no longer a prognostic factor for OS. Implants ≥3 peritoneal sites seem to impact significantly OS and then require a specific follow-up in this subgroup of patients.
Published: 2020

48. Association of metastatic pattern and molecular status in stage IV non-small cell lung cancer adenocarcinoma

Author: Anas Gazzah, David Planchard, Lambros Tselikas, Nathalie Lassau, Etienne Rouleau, Melodie Tazdait, Alison Dormieux, Caroline Caramella, Cécile Le Péchoux, Jordi Remon, Laura Mezquita, Paul Henry Cournede, Francesco Facchinetti, Frank Aboubakar, Ludovic Lacroix, Charles Naltet, Corinne Balleyguier, Julien Adam, Maria-Virginia Bluthgen, Pernelle Lavaud, Benjamin Besse, Département d'imagerie médicale [Gustave Roussy], Institut Gustave Roussy (IGR), Mathématiques et Informatique pour la Complexité et les Systèmes (MICS), CentraleSupélec-Université Paris-Saclay, Centro Integral Oncologico Clara Campal, Génétique (Biologie pathologie), Département de biologie et pathologie médicales [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Pathologie morphologique, Biomarqueurs prédictifs et nouvelles stratégies moléculaires en thérapeutique anticancéreuse (U981), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Oncologie thoracique, Département de médecine oncologique [Gustave Roussy], Département de radiothérapie [Gustave Roussy], Imagerie par Résonance Magnétique Médicale et Multi-Modalités (IR4M), Centre National de la Recherche Scientifique (CNRS)-Hôpital Bicêtre-Université Paris-Sud - Paris 11 (UP11), UCL - SSS/IREC/PNEU - Pôle de Pneumologie, ORL et Dermatologie, and UCL - (SLuc) Service de pneumologie
Subjects: Adult, Male, medicine.medical_specialty, Lung Neoplasms, Neoplasm metastasis, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Bone Neoplasms, Gastroenterology, 030218 nuclear medicine & medical imaging, Targeted therapy, 03 medical and health sciences, 0302 clinical medicine, Multimodal imaging, Carcinoma, Non-Small-Cell Lung, Internal medicine, Biomarkers, Tumor, medicine, Humans, Radiology, Nuclear Medicine and imaging, [MATH]Mathematics [math], Tropism, ComputingMilieux_MISCELLANEOUS, Aged, Neoplasm Staging, Retrospective Studies, Lung, Oncogene, business.industry, DNA, Neoplasm, General Medicine, Middle Aged, medicine.disease, 3. Good health, ErbB Receptors, Serous fluid, medicine.anatomical_structure, Lymphangitis, 030220 oncology & carcinogenesis, Mutation, Adenocarcinoma of lung, Adenocarcinoma, Female, Radiology, business, Brain metastasis
Abstract: OBJECTIVES: The aim of our study was to investigate the association between driver oncogene alterations and metastatic patterns on imaging assessment, in a large cohort of metastatic lung adenocarcinoma patients. METHODS: From January 2010 to May 2017, 550 patients with stage IV lung adenocarcinoma with molecular analysis were studied retrospectively including 135 EGFR-mutated, 81 ALK-rearrangement, 47 BRAF-mutated, 141 KRAS-mutated, and 146 negative tumors for these 4 mutations (4N). After review of the complete imaging report by two radiologists (junior and senior) to identify metastatic sites, univariate correlation analyzes were performed. RESULTS: We found differences in metastatic tropism depending on the molecular alteration type when compared with the non-mutated 4N group: in the EGFR group, pleural metastases were more frequent (32% versus 20%; p = 0.021), and adrenal and node metastases less common (6% versus 23%; p < 0.001 and 11% versus 23%; p = 0.011). In the ALK group, there were more brain and lung metastases (respectively 42% versus 29%; p = 0.043 and 37% versus 24%; p = 0.037). In the BRAF group, pleural and pericardial metastases were more common (respectively 47% versus 20%; p < 0.001 and 11% versus 3%; p = 0.04) and bone metastases were rarer (21% versus 42%; p = 0.011). Lymphangitis was more frequent in EGFR, ALK, and BRAF groups (respectively 6%, 7%, and 15% versus 1%); p = 0.016; p = 0.009; and p < 0.001. CONCLUSION: The application of these correlations between molecular status and metastatic tropism in clinical practice may lead to earlier and more accurate identification of patients for targeted therapy. KEY POINTS: • Bone and brain metastasis are the most common organs involved in lung adenocarcinoma but the relative incidence of each metastatic site depends on the molecular alteration. • EGFR-mutated tumors preferentially spread to the pleura and less commonly to adrenals, ALK-rearrangement tumors usually spread to the brain and the lungs, whereas BRAF-mutated tumors are unlikely to spread to bones and have a serous (pericardial ad pleural) tropism. • These correlations could help in the clinical management of patients with metastatic lung adenocarcinoma.
Published: 2020

49. Serum Detection of Nonadherence to Adjuvant Tamoxifen and Breast Cancer Recurrence Risk

Author: Léonor Fasse, Charles Coutant, Laurence Vanlemmens, A. Bardet, Arlindo R. Ferreira, Alexandra L. Dima, Angelo Paci, Agnès Dumas, Olivier Tredan, Florence Lerebours, Christelle Jouannaud, Fabrice Andre, Nan Lin, Patrick Soulié, Ann H. Partridge, Suzette Delaloge, Stefan Michiels, Ines Vaz-Luis, Gwenn Menvielle, Sandrine Pinto, Antonio Di Meglio, Barbara Pistilli, Sarah Dauchy, Anne Laure Martin, Paul Cottu, A. Lesur, Vianney Poinsignon, Sibille Everhard, Patrick Arveux, Christelle Levy, Institut Gustave Roussy (IGR), Pharmacologie, Département de biologie et pathologie médicales [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Champalimaud Centre for the Unknown [Lisbon], Prédicteurs moléculaires et nouvelles cibles en oncologie (PMNCO), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Roche France, Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Epidémiologie Clinique et Evaluation Economique Appliquées aux Populations Vulnérables (ECEVE (U1123 / UMR_S_1123)), Institut National de la Santé et de la Recherche Médicale (INSERM)-AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université de Paris (UP), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département Interdisciplinaire de Soins de Support aux Patients en Onco-hématologie [Gustave Roussy] (DISSPO), Département de médecine oncologique [Gustave Roussy], Service de biostatistique et d'épidémiologie (SBE), Direction de la recherche clinique [Gustave Roussy], and Direction de la recherche [Gustave Roussy]
Subjects: Adult, Oncology, Cancer Research, medicine.medical_specialty, Antineoplastic Agents, Hormonal, medicine.medical_treatment, Breast Neoplasms, Medication Adherence, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, Internal medicine, Breast Cancer, medicine, Humans, Prospective Studies, 030212 general & internal medicine, Medical prescription, Prospective cohort study, ComputingMilieux_MISCELLANEOUS, Chemotherapy, [SHS.SOCIO]Humanities and Social Sciences/Sociology, medicine.diagnostic_test, business.industry, Hazard ratio, ORIGINAL REPORTS, Middle Aged, medicine.disease, 3. Good health, Tamoxifen, Treatment Outcome, Chemotherapy, Adjuvant, Therapeutic drug monitoring, 030220 oncology & carcinogenesis, Cohort, Female, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, medicine.drug
Abstract: PURPOSE Nonadherence to long-term treatments is often under-recognized by physicians and there is no gold standard for its assessment. In breast cancer, nonadherence to tamoxifen therapy after surgery constitutes a major obstacle to optimal outcomes. We sought to evaluate the rate of biochemical nonadherence to adjuvant tamoxifen using serum assessment and to examine its effects on short-term, distant disease-free survival (DDFS). PATIENTS AND METHODS We studied 1,177 premenopausal women enrolled in a large prospective study (CANTO/NCT01993498). Definition of biochemical nonadherence was based on a tamoxifen serum level < 60 ng/mL, assessed 1 year after prescription. Self-reported nonadherence to tamoxifen therapy was collected at the same time through semistructured interviews. Survival analyses were conducted using an inverse probability weighted Cox proportional hazards model, using a propensity score based on age, staging, surgery, chemotherapy, and center size. RESULTS Serum assessment of tamoxifen identified 16.0% of patients (n = 188) below the set adherence threshold. Patient-reported rate of nonadherence was lower (12.3%). Of 188 patients who did not adhere to the tamoxifen prescription, 55% self-reported adherence to tamoxifen. After a median follow-up of 24.2 months since tamoxifen serum assessment, patients who were biochemically nonadherent had significantly shorter DDFS (for distant recurrence or death, adjusted hazard ratio, 2.31; 95% CI, 1.05 to 5.06; P = .036), with 89.5% of patients alive without distant recurrence at 3 years in the nonadherent cohort versus 95.4% in the adherent cohort. CONCLUSION Therapeutic drug monitoring may be a useful method to promptly identify patients who do not take adjuvant tamoxifen as prescribed and are at risk for poorer outcomes. Targeted interventions facilitating patient adherence are needed and have the potential to improve short-term breast cancer outcomes.
Published: 2020

50. Long-term follow-up of JAK2 exon 12 polycythemia vera: a French Intergroup of Myeloproliferative Neoplasms (FIM) study

Author: Laurane Cottin, Sylvie Tondeur, Jean-Christophe Ianotto, Olivier Mansier, Lenaïg Le Clech, Jean-Marie Chrétien, Franciane Paul, Mélanie Mercier, Laurent Voillat, Dana Ranta, Benoit de Renzis, Olivier Allangba, François Girodon, Christophe Marzac, Mathilde Hunault-Berger, Valérie Ugo, Corentin Orvain, Driss Chaoui, Jérémie Riou, Eric Lippert, Bruno Cassinat, Jean-Jacques Kiladjian, Suzanne Tavitian, Françoise Boyer, Damien Luque Paz, Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Institut de Biologie et Pathologie [CHU Grenoble] (IBP), CHU Grenoble-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Département d’Hématologie Clinique [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Micro et Nanomédecines Translationnelles (MINT), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Biologie des maladies cardiovasculaires = Biology of Cardiovascular Diseases, Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'Hématologie Clinique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Hématologie Clinique [CHI Cornouaille, Quimper], Centre Hospitalier Intercommunal de Cornouaille [Quimper] (CHI Cornouaille [Quimper]), CHRU Brest - Service d'Hématologie (CHU-Brest-Hemato), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Fédération Hospitalo-Universitaire 'Grand Ouest Against Leukemia' [Brest] (FHU GOAL), Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Service Hématologie - IUCT-Oncopole [CHU Toulouse], Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle IUCT [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Service d'Hématologie [CH Argenteuil], CH Argenteuil, Hématologie Clinique [CH Vannes], Centre hospitalier Bretagne Atlantique (Morbihan) (CHBA), Service d’Hématologie Biologique [CHU Clermont-Ferrand], CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand-CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand, Innate Immunity and Immunotherapy (CRCINA-ÉQUIPE 7), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Laboratoire d'Hématologie [CHU Angers], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), UFR Santé [UNIV Angers], Université d'Angers (UA), Laboratoire de Biologie Cellulaire [AP-HP Hôpital Saint-Louis], Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Cellule de Gestion des Données et Evaluation [CHU Angers] (DRCI - CGDE), Service d'hématologie clinique [CHRU de Brest], Hôpital Morvan [Brest]-Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Service d'Hématologie Clinique [CH Saint-Brieuc], Centre hospitalier Saint-Brieuc, Département de biologie et pathologie médicales [Gustave Roussy], Institut Gustave Roussy (IGR), Centre Hospitalier Chalon-sur-Saône William Morey, Service des maladies du sang [Angers], Service d'hématologie [Angers], Service d'hématologie biologique (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Hématopoïèse normale et pathologique : émergence, environnement et recherche translationnelle [Paris] ((UMR_S1131 / U1131)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Bernardo, Elizabeth, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Hématologie [IUCT Toulouse], Université Fédérale Toulouse Midi-Pyrénées-Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)
Subjects: Adult, Male, Cancer Research, Pediatrics, medicine.medical_specialty, Long term follow up, MEDLINE, [SDV.CAN]Life Sciences [q-bio]/Cancer, Cohort Studies, 03 medical and health sciences, Exon, 0302 clinical medicine, Polycythemia vera, [SDV.CAN] Life Sciences [q-bio]/Cancer, Biomarkers, Tumor, medicine, Humans, article clinique, Polycythemia Vera, ComputingMilieux_MISCELLANEOUS, Aged, 030304 developmental biology, 0303 health sciences, Myeloproliferative Disorders, business.industry, Exons, Hematology, Janus Kinase 2, Middle Aged, Prognosis, medicine.disease, Survival Rate, Oncology, Mutation, Female, France, business, Follow-Up Studies, 030215 immunology
Abstract: International audience; No abstract available
Published: 2020

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