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6,933 results on '"[SDV.CAN] Life Sciences [q-bio]/Cancer"'

1. Telomeres expand sphere of influence: emerging molecular impact of telomeres in non-telomeric functions

Author

Soujanya Vinayagamurthy, Sulochana Bagri, Jean-Louis Mergny, Shantanu Chowdhury, CSIR Institute of Genomics and Integrative Biology [New Delhi] (IGIB), Academy of Scientific and Innovative Research [Ghaziabad, India] (AcSIR), Partenaires INRAE, Laboratoire d'Optique et Biosciences (LOB), École polytechnique (X)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institute of Biophysics of the Czech Academy of Sciences (IBP / CAS), Czech Academy of Sciences [Prague] (CAS), and Mergny, Jean-Louis

Subjects
[SDV.GEN]Life Sciences [q-bio]/Genetics, G-quadruplex, aging, telomere signaling, [SDV.CAN]Life Sciences [q-bio]/Cancer, TRF2, [SDV.GEN] Life Sciences [q-bio]/Genetics, pluripotency, [SDV.CAN] Life Sciences [q-bio]/Cancer, gene-regulation, non-telomeric function, telomeric factors, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Genetics, cancer, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology
Abstract

International audience; Although the impact of telomeres on physiology stands well established, a question remains: how do telomeres impact cellular functions at a molecular level? This is because current understanding limits the influence of telomeres to adjacent subtelomeric regions despite the wide-ranging impact of telomeres. Emerging work in two distinct aspects offers opportunities to bridge this gap. First, telomere-binding factors were found with non-telomeric functions. Second, locally induced DNA secondary structures called G-quadruplexes are notably abundant in telomeres, and gene regulatory regions genome wide. Many telomeric factors bind to G-quadruplexes for non-telomeric functions. Here we discuss a more general model of how telomeres impact the non-telomeric genome – through factors that associate at telomeres and genome wide – and influence cell-intrinsic functions, particularly aging, cancer, and pluripotency.

Published
2023

2. FGFR3 Mutational Activation Can Induce Luminal-like Papillary Bladder Tumor Formation and Favors a Male Sex Bias

Author

Ming-Jun Shi, Jacqueline Fontugne, Aura Moreno-Vega, Xiang-Yu Meng, Clarice Groeneveld, Florent Dufour, Aurélie Kamoun, Sia Viborg Lindskrog, Luc Cabel, Clémentine Krucker, Audrey Rapinat, Claire Dunois-Larde, May-Linda Lepage, Elodie Chapeaublanc, Olivier Levrel, Victoria Dixon, Thierry Lebret, Anna Almeida, Aurélien De Reynies, Natacha Rochel, Lars Dyrskjøt, Yves Allory, François Radvanyi, Isabelle Bernard-Pierrot, Bernard-Pierrot, Isabelle, Biologie Cellulaire et Cancer, Institut Curie [Paris]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Ligue Nationale Contre le Cancer (LNCC), Institut Curie [Paris], Hôpital Foch [Suresnes], Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)

Subjects
Male, Urology, Urinary Bladder, Sexism, Fibroblast growth factor, Tyrosine kinase receptor, Mice, Transgenic, [SDV.CAN]Life Sciences [q-bio]/Cancer, Luminal tumors, [SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, Mouse model, Mice, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], receptor 3, Humans, Animals, Receptor, Fibroblast Growth Factor, Type 3, Estrogen receptor, Sex bias, Bladder cancer, [SDV.MHEP.UN] Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, Fibroblast growth factor receptor 3, Androgen receptor, Urinary Bladder Neoplasms, Tumor microenvironment, Mutation, Androgens, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Female
Abstract

Background: Bladder cancer (BCa) is more common in men and presents differences in molecular subtypes based on sex. Fibroblast growth factor receptor 3 (FGFR3) mutations are enriched in the luminal papillary muscle-invasive BCa (MIBC) and non-MIBC subtypes. Objective: To determine whether FGFR3 mutations initiate BCa and impact BCa male sex bias. Design, setting, and participants: We developed a transgenic mouse model expressing the most frequent FGFR3 mutation, FGFR3-S249C, in urothelial cells. Bladder tumorigenesis was monitored in transgenic mice, with and without carcinogen exposure. Mouse and human BCa transcriptomic data were compared. Intervention: Mutant FGFR3 overexpression in mouse urothelium and siRNA knockdown in cell lines, and N-butyl-N(4-hydroxybutyl)-nitrosamine (BBN) exposure. Outcome measurements and statistical analysis: Impact of transgene dosage on tumor frequency, synergy with BBN treatment, and FGFR3 pathway activation were analyzed. The sex-specific incidence of FGFR3-mutated tumors was evaluated in mice and humans. FGFR3 expression in FGFR3-S249C mouse urothelium and in various human epithelia was measured. Mutant FGFR3 regulation of androgen (AR) and estrogen (ESR1) receptor activity was evaluated, through target gene expression (regulon) and reporter assays. Results and limitations: FGFR3-S249C expression in mice induced low-grade papillary BCa resembling human luminal counterpart at histological, genomic, and transcriptomic levels, and promoted BBN-induced basal BCa formation. Mutant FGFR3 expression levels impacted tumor incidence in mice, and mutant FGFR3–driven human tumors were restricted to epithelia presenting high normal FGFR3 expression levels. BCa male sex bias, also found in our model, was even higher in human FGFR3-mutated tumors compared with wild-type tumors and was associated with higher AR and lower ESR1 regulon activity. Mutant FGFR3 expression inhibited both ESR1 and AR activity in mouse tumors and human cell lines, demonstrating causation only between FGFR3 activation and low ESR1 activity in tumors. Conclusions: Mutant FGFR3 initiates luminal papillary BCa formation and favors BCa male sex bias, potentially through FGFR3-dependent ESR1 downregulation. Patients with premalignant lesions or early-stage BCa could thus potentially benefit from FGFR3 targeting. FGFR3 expression level in epithelia could account for FGFR3-driven carcinoma tissue specificity. Patient summary: By developing a transgenic mouse model, we showed that gain-of-function mutations of FGFR3 receptor, among the most frequent genetic alterations in bladder cancer (BCa), initiate BCa formation. Our results could support noninvasive detection of FGFR3 mutations and FGFR3 targeting in early-stage bladder lesions.

Published
2023

3. CD44v3 is a marker of invasive cancer stem cells driving metastasis in gastric carcinoma

Author

Julie Giraud, Lornella Seeneevassen, Benoit Rousseau, Damien Bouriez, Elodie Sifré, Alban Giese, Tra Ly Nguyen, Camille Tiffon, Yannick Lippi, Lamia Azzi-Martin, Julie Pannequin, Armelle Ménard, Emilie Bessède, Cathy Staedel, Francis Mégraud, Geneviève Belleannée, Philippe Lehours, Caroline Gronnier, Pierre Dubus, Christine Varon, BoRdeaux Institute in onCology (Inserm U1312 - BRIC), Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Bordeaux (UB), Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], ToxAlim (ToxAlim), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut de Génomique Fonctionnelle (IGF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Régulations Naturelles et Artificielles (ARNA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bordeaux Ségalen [Bordeaux 2], Hôpital Pellegrin, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, French ‘Institut National du Cancer’ (PLBio INCa, grant number 2014-152), La Ligue contre le Cancer (C Tiffon PhD salary, regional research grants comité Dordogne grant number R17013GG and comité Gironde grant number GM/12.17/37), UFR des sciences médicales Univ. Bordeaux (J Giraud and D Bouriez financial support), French ministry of national education, research and technologies (L Seeneevassen PhD salary)., and LESUR, Hélène

Subjects
[SDV] Life Sciences [q-bio], Cancer Research, [SDV.CAN] Life Sciences [q-bio]/Cancer, Oncology, Cancer stem cells, Metastasis initiating cells, [SDV]Life Sciences [q-bio], Gastroenterology, [SDV.CAN]Life Sciences [q-bio]/Cancer, General Medicine, CD44 variant, Epithelial-mesenchymal transition, Gastric cancer
Abstract

Background Cancer stem cells (CSCs) are at the origin of tumour initiation and progression in gastric adenocarcinoma (GC). However, markers of metastasis-initiating cells remain unidentified in GC. In this study, we characterized CD44 variants expressed in GC and evaluated the tumorigenic and metastatic properties of CD44v3+ cells and their clinical significance in GC patients. Methods Using GC cell lines and patient-derived xenografts, we evaluated CD44+ and CD44v3+ GC cells molecular signature and their tumorigenic, chemoresistance, invasive and metastatic properties, and expression in patients-derived tissues. Results CD44v3+ cells, which represented a subpopulation of CD44+ cells, were detected in advanced preneoplastic lesions and presented CSCs chemoresistance and tumorigenic properties in vitro and in vivo. Molecular and functional analyses revealed two subpopulations of gastric CSCs: CD44v3+ CSCs with an epithelial-mesenchymal transition (EMT)-like signature, and CD44+/v3– CSCs with an epithelial-like signature; both were tumorigenic but CD44v3+ cells showed higher invasive and metastatic properties in vivo. CD44v3+ cells detected in the primary tumours of GC patients were associated with a worse prognosis. Conclusion CD44v3 is a marker of a subpopulation of CSCs with metastatic properties in GC. The identification of metastasis-initiating cells in GC represents a major advance for further development of anti-metastatic therapeutic strategies.

Published
2022

4. Virtual Memory CD8+ T Cells: Origin and Beyond

Author

Maria Estefania Viano, Natalia Soledad Baez, Constanza Savid-Frontera, Nicolás Leonel Lidon, Deborah L. Hodge, André Herbelin, Jean-Marc Gombert, Alice Barbarin, Maria Cecilia Rodriguez-Galan, Universidad Nacional de Córdoba [Argentina], National Institutes of Health [Bethesda] (NIH), Ischémie Reperfusion, Métabolisme et Inflammation Stérile en Transplantation (IRMETIST), Université de Poitiers-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'immunologie [CHU Poitiers], Centre hospitalier universitaire de Poitiers (CHU Poitiers), and Barbarin, Alice

Subjects
[SDV.IMM] Life Sciences [q-bio]/Immunology, Immunology, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Cell Biology, infection, human TVM cells, [SDV.CAN] Life Sciences [q-bio]/Cancer, Virology, Ag-specific T cells, cancer, [SDV.IMM]Life Sciences [q-bio]/Immunology, TVM cells, TIM cells, [SDV.BC] Life Sciences [q-bio]/Cellular Biology
Abstract

International audience; The presence of CD8+ T cells with a memory phenotype in nonimmunized mice has been noted for decades, but it was not until about 2 decades ago that they began to be studied in greater depth. Currently called virtual memory CD8+ T cells, they consist of a heterogeneous group of cells with memory characteristics, without any previous contact with their specific antigens. These cells were identified in mice, but a few years ago, a cell type with characteristics equivalent to the murine ones was described in healthy humans. In this review, we address the different aspects of its biology mainly developed in murine models and what is currently known about its cellular equivalent in humans.

Published
2022

5. Circulating tumor DNA: a help to guide therapeutic strategy in patients with borderline and locally advanced pancreatic adenocarcinoma?

Author

Olivier Caliez, Daniel Pietrasz, Feryel Ksontini, Solène Doat, Jean-Marc Simon, Jean-Christophe Vaillant, Valerie Taly, Pierre Laurent-Puig, Jean-Baptiste Bachet, TALY, Valerie, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), 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), Hôpital Paul Brousse, and Institut Salah Azaiz [Tunis] (ISA)

Subjects
Hepatology, Gastroenterology, [SDV.CAN]Life Sciences [q-bio]/Cancer, Adenocarcinoma, Prognosis, Circulating Tumor DNA, Pancreatic Neoplasms, Prognostic markers, [SDV.CAN] Life Sciences [q-bio]/Cancer, Borderline resectable and locally advanced pancreatic cancer, Biomarkers, Tumor, Humans, Neoplasm Recurrence, Local, Neutrophil-to-lymphocyte ratio, Biomarkers
Abstract

International audience; Background: prognostic biomarkers could be useful to better select patients with borderline resectable (BR) or locally advanced (LA) pancreatic adenocarcinoma (PA) for chemoradiotherapy (CRT) and/or secondary resection.Aims: The main objective of this work was to study characteristics, received treatments and prognostic of patients with BR or LA PA according to their baseline circulating tumor DNA status and, for secondary objective, neutrophil-to-lymphocyte Ratio (NLR).Methods: ctDNA status at baseline was determined using Next Generation Sequencing in a consecutive monocentric cohort of patients with a BR or LA PA.Results: 69 patients were included, 31 with BR PA and 38 with LA PA. 14 (20.3%) patients had baseline positive ctDNA. Five (7.8%) patients had NLR> 5. Patients with positive ctDNA had 3.7 months shorter progression free survival (p = 0.006). Patients with positive ctDNA had earlier progression after the beginning of CRT (4.4 vs 7.1 months; p = 0.068) and shorter relapse free survival after secondary resection (9.2 vs 22.9 months; p = 0.016).Conclusions: positive ctDNA at baseline was associated with a worse prognosis in patients with BR or LA PA. These data are exploratory and must be confirmed in further prospective trials.

Published
2022

6. Immune landscape after allo-HSCT: TIGIT- and CD161-expressing CD4 T cells are associated with subsequent leukemia relapse

Author

Viviane Gournay, Nicolas Vallet, Vivien Peux, Kristi Vera, Jennifer Bordenave, Marion Lambert, Aurélien Corneau, David Michonneau, Régis Peffault de Latour, Sophie Caillat-Zucman, Gérard Socié, Mathieu F. Chevalier, BRUNEL, Nadège, Immunologie humaine, physiopathologie & immunothérapie (HIPI (UMR_S_976 / U976)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut de Recherche Saint-Louis - Hématologie Immunologie Oncologie (Département de recherche de l’UFR de médecine, ex- Institut Universitaire Hématologie-IUH) (IRSL), Université Paris Cité (UPCité), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Cytométrie Pitié-Salpêtrière (PASS-CYPS), Unité Mixte de Service Production et Analyse de données en Sciences de la vie et en Santé (PASS), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)

Subjects
CD4-Positive T-Lymphocytes, [SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, Immunology, Hematopoietic Stem Cell Transplantation, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Cell Biology, Hematology, Ligands, Biochemistry, Leukemia, Myeloid, Acute, Cross-Sectional Studies, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, Recurrence, [SDV.IMM.IA] Life Sciences [q-bio]/Immunology/Adaptive immunology, Humans, Transplantation, Homologous, Blood Commentary, Receptors, Immunologic
Abstract

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the most effective treatment for selected patients with acute myeloid leukemia (AML) and relies on a “graft-versus-leukemia” effect (GVL) where donor T lymphocytes mediate control of malignant cell growth. However, relapse remains the major cause of death after allo-HSCT. In various malignancies, several immunoregulatory mechanisms have been shown to restrain antitumor immunity, including ligand-mediated engagement of inhibitory receptors (IRs) on effector cells, and induction of immunosuppressive cell subsets, such as regulatory T cells (Tregs) or myeloid-derived suppressor cells (MDSCs). Relapse after HSCT remains a major therapeutic challenge, but immunoregulatory mechanisms involved in restraining the GVL effect must be better deciphered in humans. We used mass cytometry to comprehensively characterize circulating leukocytes in 2 cohorts of patients after allo-HSCT. We first longitudinally assessed various immunoregulatory parameters highlighting specific trends, such as opposite dynamics between MDSCs and Tregs. More generally, the immune landscape was stable from months 3 to 6, whereas many variations occurred from months 6 to 12 after HSCT. Comparison with healthy individuals revealed that profound alterations in the immune equilibrium persisted 1 year after HSCT. Importantly, we found that high levels of TIGIT and CD161 expression on CD4 T cells at month 3 after HSCT were distinct features significantly associated with subsequent AML relapse in a second cross-sectional cohort. Altogether, these data provide global insights into the reconstitution of the immunoregulatory landscape after HSCT and highlight non-canonical IRs associated with relapse, which could open the path to new prognostic tools or therapeutic targets to restore subverted anti-AML immunity.

Published
2022

7. Mathematical modelling of cancer growth and drug treatments: taking into account cell population heterogeneity and plasticity

Author

Clairambault, Jean, Modelling and Analysis for Medical and Biological Applications (MAMBA), Inria de Paris, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire Jacques-Louis Lions (LJLL (UMR_7598)), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Silviu-Iulian Niculescu, Clairambault, Jean, Laboratoire Jacques-Louis Lions (LJLL (UMR_7598)), and Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)

Subjects
[SDV] Life Sciences [q-bio], MSC 35B40, 35G92, 49J20, 92C50, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV]Life Sciences [q-bio], [SDV.BA]Life Sciences [q-bio]/Animal biology, [MATH.MATH-AP]Mathematics [math]/Analysis of PDEs [math.AP], [MATH.MATH-OC] Mathematics [math]/Optimization and Control [math.OC], [SDV.CAN]Life Sciences [q-bio]/Cancer, [MATH] Mathematics [math], [MATH.MATH-OC]Mathematics [math]/Optimization and Control [math.OC], [MATH.MATH-AP] Mathematics [math]/Analysis of PDEs [math.AP], [MATH]Mathematics [math]
Abstract

Version v2 après acceptation du document par la conférence de la prépublication hal-03938311; International audience; Mathematical models of cancer growth and evolution of cancer cell characteristics, aka traits or phenotypes, together with optimisation and optimal control methods to contain them, in the framework of adaptive dynamics of cell populations, are presented. They take into account the heterogeneity of cancer cell populations, i.e., their biological variability, and their intrinsic plasticity, i.e., their nongenetic instability that allows them to quickly adapt to changing environments. The presented vision of the cancer disease, which is specific to multicellular organisms, relies on a relatively novel vision, consistent with a billion-year evolutionary perspective. Based on recent contributions from philosophy of cancer, these mathematical models aim at designing theoretical therapeutic strategies to simultaneously contain tumour progression and limit adverse events of drugs to healthy cell populations.

Published
2023

8. Curative high‐dose reirradiation for patients with recurrent head and neck squamous cell carcinoma using IMRT or proton therapy: Outcomes and analysis of patterns of failure

Author

Arnaud Beddok, Caroline Saint‐Martin, Samar Krhili, Catherine Ala Eddine, Laurence Champion, Anne Chilles, Farid Goudjil, Sofia Zefkili, Malika Amessis, Dominique Peurien, Olivier Choussy, Christophe le Tourneau, Remi Dendale, Irene Buvat, Gilles Créhange, Valentin Calugaru, Institut Curie [Paris], Laboratoire d'Imagerie Translationnelle en Oncologie (LITO ), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Curie Centre de Protonthérapie d'Orsay, Institut Curie - Saint Cloud (ICSC), Université Paris sciences et lettres (PSL), Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, 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), and Buvat, Irène

Subjects
Squamous Cell Carcinoma of Head and Neck, [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, toxicity, Radiotherapy Dosage, [SDV.CAN]Life Sciences [q-bio]/Cancer, head and neck carcinoma, Re-Irradiation, Reirradiation head and neck carcinoma IMRT proton therapy toxicity, [SDV.IB.IMA] Life Sciences [q-bio]/Bioengineering/Imaging, [SDV.CAN] Life Sciences [q-bio]/Cancer, Otorhinolaryngology, Head and Neck Neoplasms, Carcinoma, Squamous Cell, proton therapy, Humans, Radiotherapy, Intensity-Modulated, Neoplasm Recurrence, Local, IMRT, Reirradiation
Abstract

International audience; Purpose: To analyze outcomes of patients treated with curative reirradiation (reRT), with intensity-modulated radiation therapy (IMRT) or proton therapy (PT) for recurrent head and neck squamous cell carcinoma (HNSCC). Materials: Among the 55 patients reirradiated for head and neck cancer from 30/08/2012 to 08/04/2019, 23 had HNSCC and received IMRT (52.2%) or PT (47.8%) at a median maximum dose to the CTV of 66 Gy. Results: After a median follow-up of 41.3 months, 18 patients developed a locoregional recurrence (LR), of which eight (44.4%) occurred within the previously reirradiated volume. Two-year locoregional failure-free survival and overall survival were 18.3%[95%CI:7.1%-47.1%] and 42.5%[95%CI:26.2%-69.1%], respectively. Disease-free survival was significantly longer in the PT group (p = 0.031). Main late grade ≥2 toxicities were dysphagia and trismus. Conclusion: Curative reRT in HNSCC is possible for selected cases, but the LR rate in the irradiated field and the risk of toxicity grade ≥2 remain high.

Published
2022

9. Heparanase-1 is upregulated by hepatitis C virus and favors its replication

Author

Christophe Gallard, Nadjet Lebsir, Hira Khursheed, Emma Reungoat, Marie-Laure Plissonnier, Jennifer Bré, Maud Michelet, Yasmina Chouik, Fabien Zoulim, Eve-Isabelle Pécheur, Birke Bartosch, Boyan Grigorov, 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), UR CONFLUENCE : Sciences et Humanités (EA 1598), Université Catholique de Lyon (UCLy) (UCLy), Hospices Civils de Lyon (HCL), Service d'Hépatologie [Hôpital de la Croix-Rousse - HCL], Hôpital de la Croix-Rousse [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), and PECHEUR, Eve-Isabelle

Subjects
[SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Carcinoma, Hepatocellular, Hepatology, Liver Neoplasms, virus diseases, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Hepacivirus, Hepatitis C, Chronic, Virus Replication, Hepatitis C, digestive system diseases, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Humans, Glucuronidase
Abstract

International audience; Background & Aims: Over time, chronic HCV infection can lead to hepatocellular carcinoma (HCC), a process that involves changes to the liver extracellular matrix (ECM). However, the exact mechanisms by which HCV induces HCC remain unclear. Therefore, we sought to investigate the impact of HCV on the liver ECM, with a focus on heparanase-1 (HPSE).Methods: HPSE expression was assessed by quantitative reverse-transcription PCR, immunoblotting and immunofluorescence in liver biopsies infected or not with HCV, and in 10-day-infected hepatoma Huh7.5 cells. Cell lines deficient for or overexpressing HPSE were established to study its role during infection.Results: HCV propagation led to significant HPSE induction, in vivo and in vitro. HPSE enhanced infection when exogenously expressed or supplemented as a recombinant protein. Conversely, when HPSE expression was downregulated or its activity blocked, HCV infection dropped, suggesting a role of HPSE in the HCV life cycle. We further studied the underlying mechanisms of such observations and found that HPSE favored HCV release by enhancing CD63 synthesis and exosome secretion, but not by stimulating HCV entry or genome replication. We also showed that virus-induced oxidative stress was involved in HPSE induction, most likely through NF-κB activation.Conclusions: We report for the first time that HCV infection is favored by HPSE, and upregulates HPSE expression and secretion, which may result in pathogenic alterations of the ECM.Lay summary: Chronic hepatitis C virus (HCV) infection can lead to hepatocellular carcinoma development in a process that involves derangement of the extracellular matrix (ECM). Herein, we show that heparanase-1, a protein involved in ECM degradation and remodeling, favors HCV infection and is upregulated by HCV infection; this upregulation may result in pathogenic alterations of the ECM.

Published
2022

10. C1q+ macrophages: passengers or drivers of cancer progression

Author

Margot Revel, Catherine Sautès-Fridman, Wolf-Herman Fridman, Lubka T. Roumenina, 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), and Roumenina, Lubka

Subjects
Cancer Research, T cells exhaustion, tumor-associated macrophages, Complement C1q, Macrophages, [SDV]Life Sciences [q-bio], chemical and pharmacologic phenomena, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, [SDV] Life Sciences [q-bio], [SDV.CAN] Life Sciences [q-bio]/Cancer, Oncology, immune system diseases, Neoplasms, Humans, [SDV.IMM.II] Life Sciences [q-bio]/Immunology/Innate immunity, C1q, complement system
Abstract

The omics era made possible the quest for efficient markers for cancer progression and revealed that macrophage populations are much more complex than just the M1/M2 dichotomy. Complement C1q pops up as a marker of a tolerogenic and immunosuppressive macrophage populations in both healthy and tumor tissues, but the specific role of C1q+ tumor-associated macrophages (TAM) is poorly understood. C1q is co-expressed in healthy and tumor macrophages with human leukocyte antigen DR (HLA-DR), Apolipoprotein E (APOE), and mannose receptor C-type 1 (MRC1) (CD206), suggesting a resident origin of this population. TAM expressing C1q correlate with T cell exhaustion and poor prognosis in numerous cancers. Herein, we discuss the plural roles of C1q in these macrophages and how it could drive cancer progression.

Published
2022

11. A role for bioinorganic chemistry in the reactivation of mutant p53 in cancer

Author

Jessica J. Miller, Kalvin Kwan, Christian Gaiddon, Tim Storr, univOAK, Archive ouverte, Simon Fraser University (SFU.ca), Interface de Recherche Fondamentale et Appliquée en Cancérologie (IRFAC - Inserm U1113), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Paul Strauss : Centre Régional de Lutte contre le Cancer (CRLCC)-Fédération de Médecine Translationelle de Strasbourg (FMTS), and RGPIN-2019-06749

Subjects
[SDV.CAN]Life Sciences [q-bio]/Cancer, chemistry, Biochemistry, Metallochaperones, Inorganic Chemistry, Chemistry, Bioinorganic, Zinc, [SDV.CAN] Life Sciences [q-bio]/Cancer, Metals, Neoplasms, Mutation, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Humans, genetics, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Tumor Suppressor Protein p53, metabolism
Abstract

International audience; Metal ion dysregulation has been implicated in a number of diseases from neurodegeneration to cancer. While defective metal ion transport mechanisms are known to cause specific diseases of genetic origin, the role of metal dysregulation in many diseases has yet to be elucidated due to the complicated function (both good and bad!) of metal ions in the body. A breakdown in metal ion speciation can manifest in several ways from increased reactive oxygen species (ROS) generation to an increase in protein misfolding and aggregation. In this review, we will discuss the role of Zn in the proper function of the p53 protein in cancer. The p53 protein plays a critical role in the prevention of genome mutations via initiation of apoptosis, DNA repair, cell cycle arrest, anti-angiogenesis, and senescence pathways to avoid propagation of damaged cells. p53 is the most frequently mutated protein in cancer and almost all cancers exhibit malfunction along the p53 pathway. Thus, there has been considerable effort dedicated to restoring normal p53 expression and activity to mutant p53. This includes understanding the relative populations of the Zn-bound and Zn-free p53 in wild-type and mutant forms, and the development of metallochaperones to re-populate the Zn binding site to restore mutant p53 activity. Parallels will be made to the development of multifunctional metal binding agents for modulating the aggregation of the amyloid-beta peptide in Alzheimer's Disease (AD).

Published
2022

12. Occupational Exposure to Polycyclic Aromatic Hydrocarbons and Lung Cancer Risk: Results from a Pooled Analysis of Case–Control Studies (SYNERGY)

Author

Olsson, Ann, Guha, Neela, Bouaoun, Liacine, Kromhout, Hans, Peters, Susan, Siemiatycki, Jack, Ho, Vikki, Gustavsson, Per, Boffetta, Paolo, Vermeulen, Roel, Behrens, Thomas, Bruning, Thomas, Kendzia, Benjamin, Guénel, Pascal, Luce, Danièle, Karrasch, Stefan, Wichmann, Heinz-Erich, Consonni, Dario, Landi, Maria Teresa, Caporaso, Neil E, Merletti, Franco, Mirabelli, Dario, Richiardi, Lorenzo, Jöckel, Karl-Heinz, Ahrens, Wolfgang, Pohlabeln, Hermann, Tardon, Adonina, Zaridze, David, Field, John K, Lissowska, Jolanta, Świątkowska, Beata, McLaughlin, John R, Demers, Paul A, Bencko, Vladimir, Foretova, Lenka, Janout, Vladimir, Pandics, Tamas, Fabianova, Eleonora, Mates, Dana, Forastiere, Francesco, Bueno-de-Mesquita, Bas, Schüz, Joachim, Straif, Kurt, IRAS OH Epidemiology Chemical Agents, dIRAS RA-2, IRAS OH Epidemiology Chemical Agents, dIRAS RA-2, Centre International de Recherche contre le Cancer - International Agency for Research on Cancer (CIRC - IARC), Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), Utrecht University [Utrecht], Université de Montréal (UdeM), Karolinska Institutet [Stockholm], University of Bologna/Università di Bologna, Stony Brook University [SUNY] (SBU), State University of New York (SUNY), Institute for Prevention and Occupational Medicine of the German Social Accident Insurance (IPA), 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, Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-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 ), École des Hautes Études en Santé Publique [EHESP] (EHESP), Ludwig Maximilian University [Munich] (LMU), Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH), Department of Medical Sciences [Turin, Italy] (DMS), Università degli studi di Torino = University of Turin (UNITO), Universitätsklinikum Essen [Universität Duisburg-Essen] (Uniklinik Essen), Universität Bremen, Leibniz Institute for Prevention Research and Epidemiology - BIPS, Leibniz Association, University of Oviedo, N.N. Blokhin National Medical Research Center of Oncology, University of Liverpool, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology (MCMCC), Nofer Institute of Occupational Medicine (NIOM), University of Toronto, Occupational Cancer Research Centre, First Faculty of Medicine, Charles University [Prague] (CU), Masaryk Memorial Cancer Institute (MMCI), Faculty of Health Sciences [UEF, Kuopio, Finland], University of Eastern Finland, National Public Health Center, National Institute of Public Health [Romania] (INSP), Azienda Sanitaria Locale [ROMA] (ASL), National Institute for Public Health and the Environment [Bilthoven] (RIVM), Instituto de Salud Global - Institute For Global Health [Barcelona] (ISGlobal), Boston College (BC), and Chard-Hutchinson, Xavier

Subjects
Male, Lung Neoplasms, Epidemiology, Medizin, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, [SDV.CAN] Life Sciences [q-bio]/Cancer, Oncology, polycyclic aromatic hydrocarbons, benzo[a]pyrene, lung cancer, occupational exposures, case-control study, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Case-Control Studies, Occupational Exposure, Carcinogens, Humans, [SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Female, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Polycyclic Aromatic Hydrocarbons, Lung
Abstract

German Social Accident Insurance (DGUV) between 2007 and 2011, Olsson A, Guha N, Bouaoun L, Kromhout H, Peters S, Siemiatycki J, Ho V, Gustavsson P, Boffetta P, Vermeulen R, Behrens T, Brüning T, Kendzia B, Guénel P, Luce D, Karrasch S, Wichmann HE, Consonni D, Landi MT, Caporaso NE, Merletti F, Mirabelli D, Richiardi L, Jöckel KH, Ahrens W, Pohlabeln H, Tardón A, Zaridze D, Field JK, Lissowska J, Świątkowska B, McLaughlin JR, Demers PA, Bencko V, Foretova L, Janout V, Pándics T, Fabianova E, Mates D, Forastiere F, Bueno-de-Mesquita B, Schüz J, Straif K

Published
2022

13. Genomics of Clear-cell Renal Cell Carcinoma: A Systematic Review and Meta-analysis

Author

Thi Oanh Bui, Van Tu Dao, Van Tai Nguyen, Jean-Paul Feugeas, Frédéric Pamoukdjian, Guilhem Bousquet, Marqueurs cardiovasculaires en situation de stress (MASCOT (UMR_S_942 / U942)), Institut National de la Santé et de la Recherche Médicale (INSERM)-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 National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC), Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Sorbonne Paris Nord, and leboeuf, Christophe

Subjects
MESH: Humans, MESH: Genomics, Urology, [SDV.CAN]Life Sciences [q-bio]/Cancer, Genomics, MESH: Carcinoma, Renal Cell, Metastases, Renal cell carcinoma, MESH: Male, MESH: Prognosis, Primary tumor, [SDV.CAN] Life Sciences [q-bio]/Cancer, Mutation, MESH: DNA Copy Number Variations, MESH: Kidney Neoplasms, MESH: Female
Abstract

International audience; Context: Although antiangiogenic treatments and immunotherapies have significantly improved the prognosis of metastatic renal cell carcinoma (RCC), many patients will develop resistance, leading to treatment failure. Genetic tumor heterogeneity is a major cause of this resistance.Objective: To perform a meta-analysis of genomic data for clear-cell RCC obtained from primary tumors and metastases to assess the prevalence of gene mutations and copy number alterations (CNAs).Evidence acquisition: Articles were selected from Medline and Embase libraries using the search algorithm ("Kidney Neoplasms"[Mesh] OR "Renal Cell Carcinoma") AND ("Genomics"[Mesh] OR "Mutation") from January 1999 to February 2021. A critical review was conducted according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement. Ninety-three publications were selected for inclusion in this meta-analysis.Evidence synthesis: Our meta-analysis included a total 14 696 patients, 14 299 primary tumor samples, and 969 metastatic samples. We evaluated the overall and subgroup prevalence of gene mutations and CNAs, including comparisons between primary tumors and metastases. In particular, for metastases we observed that the mutation prevalence was significantly more marked for ten genes compared to primary tumors, with no or little heterogeneity across studies. The VHL mutation prevalence increased significantly from 64% in primary tumors to 75% in metastases (p < 0.001). There was a significant increase in CNA prevalence from primary tumors to metastases for chromosomes 1p36.11, 9p21.3, and 18 in terms of losses, and for chromosomes 1q21.3, 7q36.3, 8q, and 20q11.21 in terms of gains. CDKN2A, also called p16 and involved in cell-cycle progression, is located at the 9p21.3 locus and was lost in 76% of metastatic samples. ASXL1, located on 20p11.21 and amplified in 50% of metastatic RCCs compared to 21% of primary tumors (p < 0.001), is closely linked to BAP1 function.Conclusions: Our results underline the added value of preferential biopsies on RCC metastases to fully explore the biology of metastatic disease for therapeutic purposes.Patient summary: We reviewed the literature on genetic mutations in primary tumors and metastatic lesions in kidney cancer. Our pooled results for all the relevant studies show a higher level of mutations in metastases than in primary tumors. This highlights the importance of taking biopsies of metastases to analyze genetic mutations and potentially guide selection of the most suitable treatment strategy.

Published
2022

14. Niclosamide induces miR-148a to inhibit PXR and sensitize colon cancer stem cells to chemotherapy

Author

Lucile Bansard, Océane Bouvet, Elisa Moutin, Gaétan Le Gall, Alessandro Giammona, Elodie Pothin, Marion Bacou, Cédric Hassen-Khodja, Benoit Bordignon, Jean François Bourgaux, Michel Prudhomme, Frédéric Hollande, Julie Pannequin, Jean Marc Pascussi, Chris Planque, Guerineau, Nathalie C., Institut de Génomique Fonctionnelle (IGF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), BioCampus (BCM), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), and University of Melbourne

Subjects
cancer stem cell, PXR, [SDV]Life Sciences [q-bio], colorectal cancer, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, digestive system, Biochemistry, Mice, [SDV.CAN] Life Sciences [q-bio]/Cancer, Cell Line, Tumor, Genetics, Animals, Humans, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Pregnane X Receptor, Cell Biology, tumor recurrence, digestive system diseases, high-content screen, Gene Expression Regulation, Neoplastic, [SDV] Life Sciences [q-bio], MicroRNAs, miR-148a, Colonic Neoplasms, Neoplastic Stem Cells, Niclosamide, Neoplasm Recurrence, Local, Developmental Biology
Abstract

International audience; Tumor recurrence is often attributed to cancer stem cells (CSCs). We previously demonstrated that down-regulation of Pregnane X Receptor (PXR) decreases the chemoresistance of CSCs and prevents colorectal cancer recurrence. Currently, no PXR inhibitor is usable in clinic. Here, we identify miR-148a as a targetable element upstream of PXR signaling in CSCs, which when over-expressed decreases PXR expression and impairs tumor relapse after chemotherapy in mouse tumor xenografts. We then develop a fluorescent reporter screen for miR-148a activators and identify the anti-helminthic drug niclosamide as an inducer of miR-148a expression. Consequently, niclosamide decreased PXR expression and CSC numbers in colorectal cancer patient-derived cell lines and synergized with chemotherapeutic agents to prevent CSC chemoresistance and tumor recurrence in vivo. Our study suggests that endogenous miRNA inducers is a viable strategy to down-regulate PXR and illuminates niclosamide as a neoadjuvant repurposing strategy to prevent tumor relapse in colon cancer.

Published
2022

15. L1 chimeric transcripts are expressed in healthy brain and their deregulation in glioma follows that of their host locus

Author

Marie-Elisa Pinson, Franck Court, Aymeric Masson, Yoan Renaud, Allison Fantini, Ophélie Bacoeur-Ouzillou, Marie Barriere, Bruno Pereira, Pierre-Olivier Guichet, Emmanuel Chautard, Lucie Karayan-Tapon, Pierre Verrelle, Philippe Arnaud, Catherine Vaurs-Barrière, BARRIERE, Catherine, 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), Unité de Biostatistiques [CHU Clermont-Ferrand], Direction de la recherche clinique et de l’innovation [CHU Clermont-Ferrand] (DRCI), CHU Clermont-Ferrand-CHU Clermont-Ferrand, Service de Cancérologie Biologique [CHU Poitiers], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), Institut Curie [Paris], Laboratoire de neurosciences expérimentales et cliniques (LNEC), Université de Poitiers-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS)

Subjects
Retroelements, [SDV]Life Sciences [q-bio], [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Brain, [SDV.CAN]Life Sciences [q-bio]/Cancer, Glioma, General Medicine, Long Interspersed Nucleotide Elements, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Genetics, Humans, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Promoter Regions, Genetic, Molecular Biology, Genetics (clinical)
Abstract

Besides the consequences of retrotransposition, long interspersed element 1 (L1) retrotransposons can affect the host genome through their antisense promoter. In addition to the sense promoter, the evolutionarily recent L1 retrotransposons, which are present in several thousand copies, also possess an anti-sense promoter that can produce L1 chimeric transcripts (LCT) composed of the L1 5′ UTR followed by the adjacent genomic sequence. The full extent to which LCT expression occurs in a given tissue and whether disruption of the defense mechanisms that normally control L1 retrotransposons affects their expression and function in cancer cells, remain to be established. By using CLIFinder, a dedicated bioinformatics tool, we found that LCT expression was widespread in normal brain and aggressive glioma samples, and that approximately 17% of recent L1 retrotransposons, from the L1PA1 to L1PA7 subfamilies, were involved in their production. Importantly, the transcriptional activities of the L1 antisense promoters and of their host loci were coupled. Accordingly, we detected LCT-producing L1 retrotransposons mainly in transcriptionally active genes and genomic loci. Moreover, changes in the host genomic locus expression level in glioma were associated with a similar change in LCT expression level, regardless of the L1 promoter methylation status. Our findings support a model in which the host genomic locus transcriptional activity is the main driving force of LCT expression. We hypothesize that this model is more applicable when host gene and LCT are transcribed from the same strand.

Published
2022

16. The Association Between Antibiotic Use and Outcome Among Metastatic Melanoma Patients Receiving Immunotherapy

Author

Florence Poizeau, Sandrine Kerbrat, Frédéric Balusson, Pierre Tattevin, Matthieu Revest, Vincent Cattoir, David Luque-Paz, Thierry Lesimple, Marc Pracht, Monica Dinulescu, David Russo, Emmanuel Oger, Alain Dupuy, Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-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 ), École des Hautes Études en Santé Publique [EHESP] (EHESP), Recherche en Pharmaco-épidémiologie et Recours aux Soins (REPERES), Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP), 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 Eugène Marquis (CRLCC), This work was supported by the Ligue Contre le Cancer ([French] League Against Cancer) (PhD grant to FP)., and Chard-Hutchinson, Xavier

Subjects
Cancer Research, [SDV]Life Sciences [q-bio], Neoplasms, Second Primary, [SDV.CAN]Life Sciences [q-bio]/Cancer, Articles, Anti-Bacterial Agents, [SDV] Life Sciences [q-bio], [SDV.CAN] Life Sciences [q-bio]/Cancer, Oncology, Dysbiosis, Humans, Immunologic Factors, Immunotherapy, Immune Checkpoint Inhibitors, Melanoma, Retrospective Studies
Abstract

Background Several observational studies have reported a decreased response to immune checkpoint inhibitors (ICI) following antibiotic use. ICI activity has been hypothesized to be impaired by antibiotic-induced gut dysbiosis. Methods Patients with advanced melanoma receiving an anti-PD-1 antibody as a first-line therapy between 2015 and 2017 in France were selected using the French Health Insurance database. We compared overall survival and time-to-treatment discontinuation according to antibiotic exposure in the 3 months prior to the initiation of anti-PD-1 antibody. To disentangle a causal effect of antibiotics from a confounding bias, we balanced characteristics of patients exposed and nonexposed to antibiotics using an overlap weighting method based on a propensity score. We also evaluated a control cohort of patients with advanced melanoma receiving first-line targeted therapy, as there is no rationale for decreased efficacy of targeted therapy following antibiotic treatment. Results The anti-PD-1 antibody cohort comprised 2605 individuals. Antibiotic exposure in the 3 months prior to anti-PD-1 antibody initiation was not associated with shorter overall survival (weighted hazard ratio = 1.01, 95% confidence interval = 0.88 to 1.17) or time-to-treatment discontinuation (weighted hazard ratio = 1.00, 95% confidence interval = 0.89 to 1.11). Consistent results were observed when the time frame of antibiotics was narrowed to 1 month prior to anti-PD-1 initiation or when exposure was restricted to antibiotics leading to more profound gut dysbiosis. Similar results were observed in the targeted therapy cohort. Conclusions In a large cohort of advanced melanoma patients, we showed that antibiotic use preceding anti-PD-1 antibody was not associated with worse outcome. Physicians should not delay immunotherapy for patients who have recently received antibiotics.

Published
2022

17. Development and validation of a RNAseq signature for prognostic stratification in endometrial cancer

Author

Guillaume Beinse, Marie-Aude Le Frere Belda, Pierre-Alexandre Just, Nahina Bekmezian, Meriem Koual, Simon Garinet, Karen Leroy, Franck Letourneur, Adèle Lusson, Claire Mulot, Delphine Le Corre, Marie Metairie, Nicolas Delanoy, Helene Blons, Claire Gervais, Catherine Durdux, Charles Chapron, François Goldwasser, Benoit Terris, Cecile Badoual, Valerie Taly, Pierre Laurent-Puig, Bruno Borghese, Anne-Sophie Bats, Jérôme Alexandre, 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), Cancer Research and Personalized Medicine - CARPEM [Paris], 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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Cité (UPCité), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Epigenetec, Centre de Ressources Biologiques (CRB), and TALY, Valerie

Subjects
Obstetrics and Gynecology, [SDV.CAN]Life Sciences [q-bio]/Cancer, Endometrial carcinoma, Prognosis, Personalized medicine, Molecular characterization, Endometrial Neoplasms, [SDV.CAN] Life Sciences [q-bio]/Cancer, Oncology, Exome Sequencing, Biomarkers, Tumor, Humans, Female, Transcriptome analysis, Prognostic stratification, Proportional Hazards Models
Abstract

International audience; Background: Despite recent advances in endometrial carcinoma (EC) molecular characterization, its prognostication remains challenging. We aimed to assess whether RNAseq could stratify EC patient prognosis beyond current classification systems.Methods: A prognostic signature was identified using a LASSO-penalized Cox model trained on TCGA (N = 543 patients). A clinically applicable polyA-RNAseq-based work-flow was developed for validation of the signature in a cohort of stage I-IV patients treated in two Hospitals [2010-2017]. Model performances were evaluated using time-dependent ROC curves (prediction of disease-specific-survival (DSS)). The additional value of the RNAseq signature was evaluated by multivariable Cox model, adjusted on high-risk prognostic group (2021 ESGO-ESTRO-ESP guidelines: non-endometrioid histology or stage III-IVA orTP53-mutated molecular subgroup).Results: Among 209 patients included in the external validation cohort, 61 (30%), 10 (5%), 52 (25%), and 82 (40%), had mismatch repair-deficient, POLE-mutated, TP53-mutated tumors, and tumors with no specific molecular profile, respectively. The 38-genes signature accurately predicted DSS (AUC = 0.80). Most disease-related deaths occurred in high-risk patients (5-years DSS = 78% (95% CI = [68%-89%]) versus 99% [97%-100%] in patients without high-risk). A composite classifier accounting for the TP53-mutated subgroup and the RNAseq signature identified three classes independently associated with DSS: RNAseq-good prognosis (reference, 5-years DSS = 99%), non-TP53 tumors but with RNAseq-poor prognosis (adjusted-hazard ratio (aHR) = 5.75, 95% CI[1.14-29.0]), and TP53-mutated subgroup (aHR = 5.64 [1.12-28.3]). The model accounting for the high-risk group and the composite classifier predicted DSS with AUC = 0.84, versus AUC = 0.76 without (p = 0.01).Conclusion: RNA-seq profiling can provide an additional prognostic information to established classification systems, and warrants validation for potential RNAseq-based therapeutic strategies in EC.

Published
2022

18. Regulation of Mus81-Eme1 structure-specific endonuclease by Eme1 SUMO-binding and Rad3 ATR kinase is essential in the absence of Rqh1 BLM helicase

Author

gaillard, pierre-henri, Giaccherini, Cédric, Scaglione, S., Coulon, S., Dehé, P.M., Gaillard, P.H.L., Guervilly, Jean-Hugues, Blin, Marion, Laureti, Luisa, Baudelet, Emilie, Audebert, Stéphane, Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), 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), and gaillard, pierre-henri

Subjects
congenital, hereditary, and neonatal diseases and abnormalities, DNA Repair, DNA repair, Peptide, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, DNA Mismatch Repair, law.invention, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, law, [SDV.BC.BC] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Genetics, neoplasms, 030304 developmental biology, chemistry.chemical_classification, 0303 health sciences, nutritional and metabolic diseases, Genome integrity, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, [SDV.BBM.MN]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular Networks [q-bio.MN], Endonucleases, In vitro, digestive system diseases, Cell biology, DNA-Binding Proteins, MutS Homolog 2 Protein, chemistry, [SDV.BBM.MN] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular Networks [q-bio.MN], [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, MSH2, 030220 oncology & carcinogenesis, repair and replication, Suppressor, DNA mismatch repair, Function (biology), Binding domain
Abstract

The tumour suppressor SLX4 plays multiple roles in the maintenance of genome stability, acting as a scaffold for structure-specific endonucleases and other DNA repair proteins. It directly interacts with the mismatch repair (MMR) protein MSH2 but the significance of this interaction remained unknown until recent findings showing that MutSβ (MSH2-MSH3) stimulates in vitro the SLX4-dependent Holliday junction resolvase activity. Here, we characterize the mode of interaction between SLX4 and MSH2, which relies on an MSH2-interacting peptide (SHIP box) that drives interaction of SLX4 with both MutSβ and MutSα (MSH2-MSH6). While we show that this MSH2 binding domain is dispensable for the well-established role of SLX4 in interstrand crosslink repair, we find that it mediates inhibition of MutSα-dependent MMR by SLX4, unravelling an unanticipated function of SLX4.

Published
2022

19. RAD51 protects against nonconservative DNA double-strand break repair through a nonenzymatic function

Author

Ayeong So, Elodie Dardillac, Ali Muhammad, Catherine Chailleux, Laura Sesma-Sanz, Sandrine Ragu, Eric Le Cam, Yvan Canitrot, Jean Yves Masson, Pauline Dupaigne, Bernard S Lopez, Josée Guirouilh-Barbat, [Institut Cochin] Département Développement, Reproduction et Cancer (DRC), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Institut Gustave Roussy (IGR), 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), Centre de Biologie Intégrative (CBI), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Axe Oncologie [CRCHU de Québec], Centre de recherche du CHU de Québec-Université Laval (CRCHUQ), CHU de Québec–Université Laval, Université Laval [Québec] (ULaval)-Université Laval [Québec] (ULaval)-CHU de Québec–Université Laval, Université Laval [Québec] (ULaval)-Université Laval [Québec] (ULaval), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), and Guirouilh-Barbat, Josée

Subjects
DNA End-Joining Repair, DNA Repair, genetic processes, DNA, Single-Stranded, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Chromatin, enzymes and coenzymes (carbohydrates), [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV.CAN] Life Sciences [q-bio]/Cancer, health occupations, Genetics, Humans, DNA Breaks, Double-Stranded, Rad51 Recombinase, biological phenomena, cell phenomena, and immunity
Abstract

Selection of the appropriate DNA double-strand break (DSB) repair pathway is decisive for genetic stability. It is proposed to act according to two steps: 1-canonical nonhomologous end-joining (C-NHEJ) versus resection that generates single-stranded DNA (ssDNA) stretches; 2-on ssDNA, gene conversion (GC) versus nonconservative single-strand annealing (SSA) or alternative end-joining (A-EJ). Here, we addressed the mechanisms by which RAD51 regulates this second step, preventing nonconservative repair in human cells. Silencing RAD51 or BRCA2 stimulated both SSA and A-EJ, but not C-NHEJ, validating the two-step model. Three different RAD51 dominant-negative forms (DN-RAD51s) repressed GC and stimulated SSA/A-EJ. However, a fourth DN-RAD51 repressed SSA/A-EJ, although it efficiently represses GC. In living cells, the three DN-RAD51s that stimulate SSA/A-EJ failed to load efficiently onto damaged chromatin and inhibited the binding of endogenous RAD51, while the fourth DN-RAD51, which inhibits SSA/A-EJ, efficiently loads on damaged chromatin. Therefore, the binding of RAD51 to DNA, rather than its ability to promote GC, is required for SSA/A-EJ inhibition by RAD51. We showed that RAD51 did not limit resection of endonuclease-induced DSBs, but prevented spontaneous and RAD52-induced annealing of complementary ssDNA in vitro. Therefore, RAD51 controls the selection of the DSB repair pathway, protecting genome integrity from nonconservative DSB repair through ssDNA occupancy, independently of the promotion of CG.

Published
2022

20. BMI1 nuclear location is critical for RAD51-dependent response to replication stress and drives chemoresistance in breast cancer stem cells

Author

Violette Azzoni, Julien Wicinski, Manon Macario, Martin Castagné, Pascal Finetti, Katerina Ambrosova, Célia D. Rouault, Arnaud Sergé, Anne Farina, Emilie Agavnian, Sergiu Coslet, Emmanuelle Josselin, Arnaud Guille, José Adelaide, Emmanouil Zacharioudakis, Rémy Castellano, Francois Bertucci, Daniel Birnbaum, Raphael Rodriguez, Emmanuelle Charafe-Jauffret, Christophe Ginestier, Bertucci, François, 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), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Centre de recherche de l'Institut Curie [Paris], Institut Curie [Paris], Université Paris sciences et lettres (PSL), Chimie biologique des membranes et ciblage thérapeutique (CBMCT - UMR 3666 / U1143), and Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Cell Nucleus, DNA Replication, Polycomb Repressive Complex 1, Cancer Research, QH573-671, [SDV]Life Sciences [q-bio], Immunology, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Cell Biology, Cellular and Molecular Neuroscience, [SDV.CAN] Life Sciences [q-bio]/Cancer, Drug Resistance, Neoplasm, Neoplastic Stem Cells, Humans, Female, Rad51 Recombinase, Cisplatin, Homologous Recombination, Cytology, DNA Damage
Abstract

Replication stress (RS) has a pivotal role in tumor initiation, progression, or therapeutic resistance. In this study, we depicted the mechanism of breast cancer stem cells’ (bCSCs) response to RS and its clinical implication. We demonstrated that bCSCs present a limited level of RS compared with non-bCSCs in patient samples. We described for the first time that the spatial nuclear location of BMI1 protein triggers RS response in breast cancers. Hence, in bCSCs, BMI1 is rapidly located to stalled replication forks to recruit RAD51 and activate homologous-recombination machinery, whereas in non-bCSCs BMI1 is trapped on demethylated 1q12 megasatellites precluding effective RS response. We further demonstrated that BMI1/RAD51 axis activation is necessary to prevent cisplatin-induced DNA damage and that treatment of patient-derived xenografts with a RAD51 inhibitor sensitizes tumor-initiating cells to cisplatin. The comprehensive view of replicative-stress response in bCSC has profound implications for understanding and improving therapeutic resistance.

Published
2022

21. Measurable residual disease, FLT3‐ITD mutation, and disease status have independent prognostic influence on outcome of allogeneic stem cell transplantation in NPM1‐mutated acute myeloid leukemia

Author

Rama Al Hamed, Myriam Labopin, Etienne Daguindau, Riitta Niittyvuopio, Anne Huynh, Gerard Socié, Micha Srour, Jean Henri Bourhis, Nicolaus Kröger, Eleni Tholouli, Goda Choi, Xavier Poiré, Hans Martin, Marie‐Thérèse Rubio, Pavel Jindra, Didier Blaise, Dietrich Beelen, Hélène Labussière‐Wallet, Arnon Nagler, Ali Bazarbachi, Mohamad Mohty, Albert Einstein College of Medicine [New York], CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CEREST-TC [CHU Saint-Antoine], Université Pierre et Marie Curie - Paris 6 (UPMC)-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), Hôpital JeanMinjoz, Helsinki University Central Hospital [Finland] (HUCH), 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), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Lille, Université de Lille, Institut Gustave Roussy (IGR), Département d'hématologie [Gustave Roussy], University Hospital Hamburg-Eppendorf, Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), Manchester Royal Infirmary, University of Manchester [Manchester], University of Groningen [Groningen], Cliniques universitaires St Luc [Bruxelles], Goethe-Universität Frankfurt am Main, Service d’Hématologie Adulte [Hôpitaux de Brabois, CHU Nancy], Centre Hospitalier Universitaire de Nancy (CHU Nancy), Medicine Charles University and General Faculty Hospital in Prague, 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), University Hospital [Essen, Germany], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Chaim Sheba Medical Center, American University of Beirut [Beyrouth] (AUB), Centre International des greffes [CHU Saint-Antoine] (EBMT), 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)-CHU Saint-Antoine [AP-HP], Service d'hématologie, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Comprehensive Cancer Center [Helsinki, Finland], Helsinki University Hospital [Finland] (HUS), 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 Régional Universitaire [Lille] (CHRU Lille), University Medical Center Groningen [Groningen] (UMCG), Service d'Hématologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Charles University Hospital Pilsen, Dept. of Bone Marrow Transplantation, University Hospital, Essen, Universitätsklinikum Essen [Universität Duisburg-Essen] (Uniklinik Essen), Service d’Hématologie [Centre Hospitalier Lyon Sud - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Gestionnaire, Hal Sorbonne Université, NUNES, Jacques A, HUS Comprehensive Cancer Center, Clinicum, and Department of Oncology

Subjects
Adult, FLT3‐ITD, Cancer Research, FLT3-ITD, 3122 Cancers, Medizin, [SDV.CAN]Life Sciences [q-bio]/Cancer, acute myeloid leukemia, RELAPSE, [SDV.CAN] Life Sciences [q-bio]/Cancer, AML, Recurrence, hemic and lymphatic diseases, VERSUS-HOST-DISEASE, Humans, Radiology, Nuclear Medicine and imaging, NUCLEOPHOSMIN NPM1, RC254-282, Retrospective Studies, ACUTE MYELOGENOUS LEUKEMIA, Hematopoietic Stem Cell Transplantation, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, ADULTS, Prognosis, NPM-1 mutation, NPM‐1 mutation, SORAFENIB, Leukemia, Myeloid, Acute, DEFINITION, Oncology, fms-Like Tyrosine Kinase 3, Mutation, SURVIVAL, minimal residual disease, Nucleophosmin
Abstract

Nucleophosmin-1 (NPM1) mutations in acute myeloid leukemia (AML) confer a survival advantage in the absence of FLT3-internal tandem duplication (FLT3-ITD). Here, we investigated the main predictors of outcome after allogeneic hematopoietic stem cell transplantation (allo-HCT). We identified 1572 adult (age >= 18 year) patients with NPM1-mutated AML in first complete remission (CR1:78%) or second complete remission (CR2:22%) who were transplanted from matched sibling donors (30.8%) or unrelated donors (57.4%) between 2007 and 2019 at EBMT participating centers. Median follow-up for survivors was 23.7 months. FLT3-ITD was present in 69.3% of patients and 39.2% had detectable minimal/measurable residual disease (MRD) at transplant. In multivariate analysis, relapse incidence (RI) and leukemia-free survival (LFS) were negatively affected by concomitant FLT3-ITD mutation (HR 1.66 p = 0.0001, and HR 1.53, p < 0.0001, respectively), MRD positivity at transplant (HR 2.18, p < 10(-5) and HR 1.71, p < 10(-5), respectively), and transplant in CR2 (HR 1.36, p = 0.026, and HR 1.26, p = 0.033, respectively), but positively affected by Karnofsky score >= 90 (HR 0.74, p = 0.012, and HR 0.7, p = 0.0002, respectively). Overall survival (OS) was also negatively influenced by concomitant FLT3-ITD (HR 1.6, p = 0.0001), MRD positivity at transplant (HR 1.61, p < 10(-5)), and older age (HR 1.22 per 10 years, p < 0.0001), but positively affected by matched sibling donor (unrelated donor: HR 1.35, p = 0.012; haploidentical donor: HR 1.45, p = 0.037) and Karnofsky score >= 90 (HR 0.73, p = 0.004). These results highlight the independent and significant role of FLT3-ITD, MRD status, and disease status on posttransplant outcomes in patients with NPM1-mutated AML allowing physicians to identify patients at risk of relapse who may benefit from posttransplant prophylactic interventions.

Published
2022

22. Dairy product consumption and risk of cancer: A short report from the <scp>NutriNet‐Santé</scp> prospective cohort study

Author

Mélanie Deschasaux‐Tanguy, Laura Barrubés Piñol, Laury Sellem, Charlotte Debras, Bernard Srour, Eloi Chazelas, Gaëlle Wendeu‐Foyet, Serge Hercberg, Pilar Galan, Emmanuelle Kesse‐Guyot, Chantal Julia, Nancy Elvira Babio Sánchez, Jordi Salas Salvadó, Mathilde Touvier, Equipe 3: EREN- Equipe de Recherche en Epidémiologie Nutritionnelle (CRESS - U1153), Université Sorbonne Paris Nord-Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Réseau National Alimentation Cancer Recherche (réseau NACRe), Universitat Rovira i Virgili, Instituto de Salud Carlos III [Madrid] (ISC), Hospital Universitari de Sant Joan [Reus, Spain], and Bertram, Marie-Liesse

Subjects
Adult, Male, Cancer Research, [SDV.CAN]Life Sciences [q-bio]/Cancer, Breast Neoplasms, cohort, Middle Aged, Diet, Cohort Studies, [SDV.AEN] Life Sciences [q-bio]/Food and Nutrition, [SDV.CAN] Life Sciences [q-bio]/Cancer, Oncology, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Risk Factors, Neoplasms, cancer, Humans, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Female, Dairy Products, Prospective Studies, Colorectal Neoplasms, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, prospective study
Abstract

International audience; The impact of dairy product consumption for long-term health remains unclear, in particular regarding their involvement in cancer etiology for frequent locations like breast or prostate. Besides, little is known about potentially different effects of dairy product subtypes. Our objective was therefore to evaluate the associations between dairy product consumption (total and subtypes) and cancer risk. A total of 101 279 participants from the French NutriNet-Santé cohort study were included (78.7% women; mean [SD] age = 42.2 [14.5] years). Dairy product consumption was assessed using validated web-based 24-hour dietary records. Multiadjusted Cox models were computed. After a median [interquartile range] follow-up time of 5.9 [2.7-8.3] years, we documented 2503 incident cancer cases (783 breast, 323 prostate and 182 colorectal cancers). Total dairy product consumption was not significantly associated with cancer. However, the consumption of “fromage blanc” (a French type of quark/cottage cheese) was associated with an increased risk of cancer overall (HR for 1 serving increment [95% CI] = 1.11 [1.01-1.21]; P-trend = .03) and of colorectal cancer (HR = 1.39 [1.09-1.77]; P-trend < .01). Besides, sugary dairy dessert consumption was directly associated with colorectal cancer risk (HR for 1 serving increment = 1.58 [1.01-2.46]; P-trend = .046]. No association was observed between the consumption of dairy products or sugary dairy desserts and the risk of prostate and breast cancers. In our study, the consumption of dairy products was not associated with the risk of overall, colorectal, breast or prostate cancers. The consumption of “fromage blanc” and sugary dairy desserts were associated to an increased risk of colorectal cancer, but this warrants further investigations.

Published
2022

23. Frequency and Genomic Aspects of Intrinsic Resistance to Vismodegib in Locally Advanced Basal Cell Carcinoma

Author

Andrey A. Yurchenko, Oltin T. Pop, Meriem Ighilahriz, Ismael Padioleau, Fatemeh Rajabi, Hayley J. Sharpe, Nicolas Poulalhon, Brigitte Dreno, Amir Khammari, Marc Delord, Antonio Alberti, Nadem Soufir, Maxime Battistella, Samia Mourah, Fanny Bouquet, Ariel Savina, Andrej Besse, Max Mendez-Lopez, Florent Grange, Sandrine Monestier, Laurent Mortier, Nicolas Meyer, Caroline Dutriaux, Caroline Robert, Philippe Saiag, Florian Herms, Jerome Lambert, Frederic J. de Sauvage, Nicolas Dumaz, Lukas Flatz, Nicole Basset-Seguin, Sergey I. Nikolaev, Pecqueret, Valérie, 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), 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, Brustzentrum Kantonsspital St. Gallen, Immunologie humaine, physiopathologie & immunothérapie (HIPI (UMR_S_976 / U976)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), The Babraham Institute [Cambridge, UK], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), 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), Centre d’Investigation Clinique de Nantes (CIC Nantes), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes), Immunology and New Concepts in ImmunoTherapy (INCIT), Université d'Angers (UA)-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)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Centre hospitalier universitaire de Nantes (CHU Nantes), Université Paris Diderot, Sorbonne Paris Cité, Paris, France, Université Paris Diderot - Paris 7 (UPD7), Institut de Recherche Saint-Louis - Hématologie Immunologie Oncologie (Département de recherche de l’UFR de médecine, ex- Institut Universitaire Hématologie-IUH) (IRSL), Université Paris Cité (UPCité), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut ROCHE [Boulogne-Billancourt], Roche S.A.S, Centre Hospitalier Universitaire de Reims (CHU Reims), Hôpital de la Timone [CHU - APHM] (TIMONE), Equipe 3 - Facteurs de persistance des cellules leucémique - (INSERM U837), Institut pour la Recherche sur le Cancer de Lille (U837 INSERM - IRCL), Institut pour la recherche sur le cancer de Lille [Lille] (IRCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut pour la recherche sur le cancer de Lille [Lille] (IRCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), CHU Bordeaux [Bordeaux], Institut Gustave Roussy (IGR), Oncologie dermatologique, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Hôpital Ambroise Paré [AP-HP], Service de Dermatologie [AP-HP Hôpital Saint-Louis], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Genentech, Inc., and Genentech, Inc. [San Francisco]

Subjects
Cancer Research, Skin Neoplasms, animal structures, integumentary system, Pyridines, [SDV]Life Sciences [q-bio], fungi, Antineoplastic Agents, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV] Life Sciences [q-bio], [SDV.CAN] Life Sciences [q-bio]/Cancer, Oncology, Carcinoma, Basal Cell, Humans, Anilides, Hedgehog Proteins, Cerebellar Neoplasms
Abstract

Purpose: Vismodegib is approved for the treatment of locally advanced basal cell carcinoma (laBCC), but some cases demonstrate intrinsic resistance (IR) to the drug. We sought to assess the frequency of IR to vismodegib in laBCC and its underlying genomic mechanisms. Experimental Design: Response to vismodegib was evaluated in a cohort of 148 laBCC patients. Comprehensive genomic and transcriptomic profiling was performed in a subset of five intrinsically resistant BCC (IR-BCC). Results: We identified that IR-BCC represents 6.1% of laBCC in the studied cohort. Prior treatment with chemotherapy was associated with IR. Genetic events that were previously associated with acquired resistance (AR) in BCC or medulloblastoma were observed in three out of five IR-BCC. However, IR-BCCs were distinct by highly rearranged polyploid genomes. Functional analyses identified hyperactivation of the HIPPO-YAP and WNT pathways at RNA and protein levels in IR-BCC. In vitro assay on the BCC cell line further confirmed that YAP1 overexpression increases the cell proliferation rate. Conclusions: IR to vismodegib is a rare event in laBCC. IR-BCCs frequently harbor resistance mutations in the Hh pathway, but also are characterized by hyperactivation of the HIPPO-YAP and WNT pathways.

Published
2022

24. High-Relaxivity Molecular MRI Contrast Agent to Target Gb3-Expressing Cancer Cells

Author

Stéphanie Deville-Foillard, Anne Billet, Rose-Marie Dubuisson, Ludger Johannes, Philippe Durand, Frédéric Schmidt, Andreas Volk, Institut de Chimie des Substances Naturelles (ICSN), Institut de Chimie du CNRS (INC)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Chimie biologique des membranes et ciblage thérapeutique (CBMCT - UMR 3666 / U1143), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), LaBoratoire d'Imagerie biOmédicale MultimodAle Paris-Saclay (BIOMAPS), Service Hospitalier Frédéric Joliot (SHFJ), 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-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Chimie et modélisation pour la biologie du cancer (CMBC), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), ANR-11-INBS-0006,FLI,France Life Imaging(2011), ANR-11-LABX-0038,CelTisPhyBio,Des cellules aux tissus: au croisement de la Physique et de la Biologie(2011), ANR-10-IDEX-0001,PSL,Paris Sciences et Lettres(2010), Deville-Foillard, Stephanie, Infrastructures - France Life Imaging - - FLI2011 - ANR-11-INBS-0006 - INBS - VALID, Des cellules aux tissus: au croisement de la Physique et de la Biologie - - CelTisPhyBio2011 - ANR-11-LABX-0038 - LABX - VALID, and Initiative d'excellence - Paris Sciences et Lettres - - PSL2010 - ANR-10-IDEX-0001 - IDEX - VALID

Subjects
Pharmacology, [SDV.IB.IMA] Life Sciences [q-bio]/Bioengineering/Imaging, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, Organic Chemistry, Biomedical Engineering, Contrast Media, Pharmaceutical Science, [CHIM.COOR]Chemical Sciences/Coordination chemistry, [SDV.CAN]Life Sciences [q-bio]/Cancer, Bioengineering, [CHIM.COOR] Chemical Sciences/Coordination chemistry, Biotechnology
Abstract

International audience; Targeted contrast agents (CAs) can improve magnetic resonance imaging (MRI) for accurate cancer diagnosis. In this work, we used the Shiga toxin B-subunit (STxB) as a targeting agent, which binds to Gb3, a glycosphingolipid highly overexpressed on the surface of tumor cells. We developed STxB-targeted MRI probes from cyclic peptide scaffolds functionalized with six to nine monoamide DO3A[Gd(III)] chelates. The influence of structural constraints on the longitudinal relaxivity ($r_1$) of the CAs has been studied. The cyclic peptide carrying nine monoamide DO3A[Gd(III)] exhibited a r1 per compound of 32 and 93 mM$^{–1}$s$^{–1}$ at 9.4 and 1.5 T, respectively. Its conjugation to the pentameric STxB protein led to a 70 kDa compound with a higher $r_1$ of 150 and 475 mM$^{–1}$ s$^{–1}$ at 9.4 and 1.5 T, respectively. Specific accumulation and cellular distribution of this conjugate in Gb3-expressing cancer cells were demonstrated using immunofluorescence microscopy and quantified by an inductively coupled plasma–mass spectrometry dosage of Gd(III). Such an agent should enable the in vivo detection by MRI of tumors expressing Gb3 receptors.

Published
2022

25. Human MuStem cells repress T-cell proliferation and cytotoxicity through both paracrine and contact-dependent pathways

Author

Marine Charrier, Judith Lorant, Rafael Contreras-Lopez, Gautier Téjédor, Christophe Blanquart, Blandine Lieubeau, Cindy Schleder, Isabelle Leroux, Sophie Deshayes, Jean-François Fonteneau, Candice Babarit, Antoine Hamel, Armelle Magot, Yann Péréon, Sabrina Viau, Bruno Delorme, Patricia Luz-Crawford, Guillaume Lamirault, Farida Djouad, Karl Rouger, École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Physiopathologie Animale et bioThérapie du muscle et du système nerveux (PAnTher), École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), 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), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Hôpital Saint-Éloi [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Universidad de los Andes [Santiago] (UANDES), Immunogenic Cell Death and Mesothelioma Therapy (CRCINA-ÉQUIPE 4), 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), Immuno-Endocrinologie Cellulaire et Moléculaire (IECM), Université de Nantes (UN)-Ecole Nationale Vétérinaire de Nantes-École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre hospitalier universitaire de Nantes (CHU Nantes), Macopharma [Mouvaux], and Bernardo, Elizabeth

Subjects
Medicine (General), Research, Medicine (miscellaneous), Mesenchymal Stem Cells, [SDV.CAN]Life Sciences [q-bio]/Cancer, Cell Biology, QD415-436, Lymphocyte Activation, Muscular dystrophy, Biochemistry, Genetics and Molecular Biology (miscellaneous), Biochemistry, Coculture Techniques, Cell therapy, Immunomodulation, Adult Stem Cells, R5-920, [SDV.CAN] Life Sciences [q-bio]/Cancer, T-cell, Human adult stem cell, Molecular Medicine, Humans, MuStem cell, Cell Proliferation
Abstract

Background Muscular dystrophies (MDs) are inherited diseases in which a dysregulation of the immune response exacerbates disease severity and are characterized by infiltration of various immune cell types leading to muscle inflammation, fiber necrosis and fibrosis. Immunosuppressive properties have been attributed to mesenchymal stem cells (MSCs) that regulate the phenotype and function of different immune cells. However, such properties were poorly considered until now for adult stem cells with myogenic potential and advanced as possible therapeutic candidates for MDs. In the present study, we investigated the immunoregulatory potential of human MuStem (hMuStem) cells, for which we previously demonstrated that they can survive in injured muscle and robustly counteract adverse tissue remodeling. Methods The impact of hMuStem cells or their secretome on the proliferative and phenotypic properties of T-cells was explored by co-culture experiments with either peripheral blood mononucleated cells or CD3-sorted T-cells. A comparative study was produced with the bone marrow (BM)-MSCs. The expression profile of immune cell-related markers on hMuStem cells was determined by flow cytometry while their secretory profile was examined by ELISA assays. Finally, the paracrine and cell contact-dependent effects of hMuStem cells on the T-cell-mediated cytotoxic response were analyzed through IFN-γ expression and lysis activity. Results Here, we show that hMuStem cells have an immunosuppressive phenotype and can inhibit the proliferation and the cytotoxic response of T-cells as well as promote the generation of regulatory T-cells through direct contact and via soluble factors. These effects are associated, in part, with the production of mediators including heme-oxygenase-1, leukemia inhibitory factor and intracellular cell adhesion molecule-1, all of which are produced at significantly higher levels by hMuStem cells than BM-MSCs. While the production of prostaglandin E2 is involved in the suppression of T-cell proliferation by both hMuStem cells and BM-MSCs, the participation of inducible nitric oxide synthase activity appears to be specific to hMuStem cell-mediated one. Conclusions Together, our findings demonstrate that hMuStem cells are potent immunoregulatory cells. Combined with their myogenic potential, the attribution of these properties reinforces the positioning of hMuStem cells as candidate therapeutic agents for the treatment of MDs.

Published
2022

26. Effect of lockdown on digestive system cancer care amongst older patients during the first wave of COVID-19: The CADIGCOVAGE multicentre cohort study

Author

Nathalie Ganne, François Hemery, Laurent Quero, Frédéric Prat, Thomas Aparicio, Nicola de Angelis, Gilles Galula, Richard Layese, Marc-Antoine Benderra, Atanas Pachev, Christophe Tournigand, Elena Paillaud, Florence Canouï-Poitrine, Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de santé publique [Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), CHU Henri Mondor, Cooperator Multidisciplinary Oncology Group (GERCOR), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, Département de Santé Publique [Avicenne], Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Cochin [AP-HP], Service d'Oncologie médicale [CHU Tenon], CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), IMRB - CEPIA/'Clinical Epidemiology And Ageing : Geriatrics, Primary Care and Public Health' [Créteil] (U955 Inserm - UPEC), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), 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
Male, Paris, medicine.medical_specialty, Digestive cancer, [SDV.CAN]Life Sciences [q-bio]/Cancer, Disease, Digestive System Neoplasms, Health Services Accessibility, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, Lockdown, Older patients, medicine, Humans, 030212 general & internal medicine, Pandemics, Aged, Retrospective Studies, Aged, 80 and over, Public health, Hepatology, SARS-CoV-2, business.industry, Mortality rate, Gastroenterology, COVID-19, Cancer, Emergency department, medicine.disease, 3. Good health, Oncology, 030220 oncology & carcinogenesis, Communicable Disease Control, Cohort, Female, Observational study, business, Cohort study
Abstract

International audience; Background: The coronavirus disease 2019 (COVID-19) pandemic has had a dramatic impact on cancer diagnosis and treatment. Most patients newly diagnosed with digestive system cancer are aged 65 and over. Methods: We performed a retrospective, observational, multicentre cohort study based on prospectively collected electronic health records. All adults aged 65 or over and having been newly treated for a digestive system cancer between January 2018 until August 2020 were enroled. Results: Data on 7882 patients were analysed. The first COVID-19 lockdown period led to a 42.4% decrease in newly treated digestive system cancers, and the post-lockdown period was associated with a 17% decrease. The decrease in newly treated digestive system cancer did not differ as a function of age, sex, comorbidities, primary tumour site, and disease stage. The proportion of patients admitted to an emergency department increased during the lockdown period. We do not observe a higher 3-month mortality rate in 2020, relative to the corresponding calendar periods in 2018 and 2019. Conclusion: To avoid a decrease in newly treated cancers during future lockdown periods, access to healthcare will have to be modified. Although 3-month mortality did not increase in any of the patient subgroups, the 2020 cohort must be followed up for long-term mortality.

Published
2022

27. Cytokine release syndrome and tumor lysis syndrome in a multiple myeloma patient treated with palliative radiotherapy: A case report and review of the literature

Author

Bastien Jamet, Axel Cailleteau, Cyrille Touzeau, Stéphane Supiot, Valentine Guimas, Emmanuel Jouglar, Bernardo, Elizabeth, Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, Regulation of Bcl2 and p53 Networks in Multiple Myeloma and Mantle Cell Lymphoma (CRCINA-ÉQUIPE 10), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre hospitalier universitaire de Nantes (CHU Nantes), Site de Recherche Intégrée sur le Cancer - SIRIC « ILIAD » [Nantes], and Apoptosis and Tumor Progression (CRCINA-ÉQUIPE 9)

Subjects
medicine.medical_specialty, medicine.medical_treatment, R895-920, [SDV.CAN]Life Sciences [q-bio]/Cancer, Case Report, Radiation oncology, Gastroenterology, Medical physics. Medical radiology. Nuclear medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Cytokine release syndrome, Multiple myeloma, Total body irradiation, Internal medicine, medicine, Radiology, Nuclear Medicine and imaging, Respiratory system, Tumor lysis syndrome, RC254-282, Leukemia, Hematology, Radiotherapy, business.industry, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, medicine.disease, Radiation therapy, Oncology, business
Abstract

Highlights • Radiotherapy can trigger cytokine release syndrome and tumor lysis syndrome in association with chemotherapy drugs. • Extreme caution must be given when irradiating large tumor volumes at high risk of tumor lysis. • Evidence of cytokine release following radiotherapy unveils the systemic interactions of radiotherapy with the immune system., We present the case of a 53-year-old woman treated with analgesic radiotherapy for a multiple myeloma bone lesion of the forearm. After a first fraction of 5 Gray (Gy), she presented with an acute respiratory syndrome with fever a few hours after the treatment. The same symptoms occurred after the second fraction 3 days later. The patient recovered quickly thanks to intravenous hydration and suspension of the radiotherapy. Biological tests revealed a tumor lysis syndrome. We concluded that the clinical symptoms could be defined as cytokine release syndrome. This is the second time in the literature that cytokine release syndrome has been described following radiotherapy. First, we synthesize TLS and radiotherapy to determine how radiotherapy could be a trigger associated with other well-known factors. Furthermore, we discuss radiotherapy and cytokine release syndrome. Summary We present the case of a woman treated with analgesic radiotherapy for a multiple myeloma bone lesion. Following the first and the second treatment fraction, the patient presented with an acute respiratory syndrome with fever and biological tests revealed a tumor lysis syndrome. We concluded that the clinical symptoms could be defined as cytokine release syndrome. Furthermore, we discuss how radiotherapy could be a trigger of cytokine release syndrome and tumor lysis syndrome in association with chemotherapy drugs.

Published
2022

28. Prehabilitation sessions can be provided more frequently in a shortened regimen with similar or better efficacy in people with non-small cell lung cancer: a randomised trial

Author

Francis-Edouard Gravier, Pauline Smondack, Fairuz Boujibar, Guillaume Prieur, Clément Medrinal, Yann Combret, Jean-François Muir, Jean-Marc Baste, Antoine Cuvelier, David Debeaumont, Tristan Bonnevie, HAL UVSQ, Équipe, ADIR Association (ADIR), UNIROUEN - UFR Santé (UNIROUEN UFR Santé), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Groupe de Recherche sur le Handicap Ventilatoire et Neurologique (GRHVN), 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), CHU Rouen, Normandie Université (NU), Endothélium, valvulopathies et insuffisance cardiaque (EnVI), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Groupe Hospitalier du Havre Hôpital Jacques Monod (MONTIVILLIERS) (GHH), Equipe de Recherche Paramédicale sur le Handicap NeuroMoteur (ERPHAN), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay, Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil (UVSQ Santé), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Centre d'Investigation Clinique [CHU Rouen] (CIC Rouen), Hôpital Charles Nicolle [Rouen], Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), and This work was supported by ADIR Association .

Subjects
Lung Neoplasms, Preoperative care, Preoperative Exercise, [SDV.CAN]Life Sciences [q-bio]/Cancer, Physical Therapy, Sports Therapy and Rehabilitation, RM1-950, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Lung resection, Exercise training, [SDV.CAN] Life Sciences [q-bio]/Cancer, Non-small cell lung cancer, Carcinoma, Non-Small-Cell Lung, Exercise Test, Quality of Life, [SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Humans, Therapeutics. Pharmacology, Prehabilitation
Abstract

International audience; Question: In people with non-small cell lung cancer, what is the effect of condensing 15 prehabilitation sessions into a 3-week regimen compared with a 5-week regimen?Design: Randomised controlled trial with concealed allocation, intention-to-treat analysis and blinded assessment of the primary outcome.Participants: People with diagnosed or suspected non-small cell lung cancer and moderate-to-high risk of postoperative complications. Intervention: Fifteen supervised prehabilitation sessions delivered with either a dense regimen of five sessions/week for 3 weeks (experimental group) or a non-dense regimen of three sessions/week for 5 weeks (control group).Outcome measures: The primary outcome was the change in cardiorespiratory fitness measured by the V̇O2peak in ml/kg/min. The secondary outcomes were the change in other variables of interest measured during cardiopulmonary exercise testing, non-invasive nutritional markers, quadriceps maximal voluntary isometric contractions, maximal inspiratory pressure, quality of life, adherence and postoperative complications.Results: Changes with the experimental regimen were similar to or better than changes with the control regimen for: V̇O2peak (MD 1.2 ml/kg/min, 95% CI −0.1 to 2.6); V̇E/V̇CO2 slope (MD −3.6 points, 95% CI −8.7 to 1.5); and work rate at ventilatory threshold (MD 3.7 W, 95% CI −5.6 to 13.0). The two regimens had similar effects on: peak work rate (MD 1.3 W, 95% CI −6.4 to 9.0), V̇O2 at ventilatory threshold (MD 0.0 ml/kg/min, 95% CI −1.4 to 1.4); body mass index (MD −0.2 kg/m2, 95% CI −0.5 to 0.1); and maximal inspiratory pressure (MD −0.7 cmH2O, 95% CI −9.8 to 8.4). The relative effect was uncertain for quadriceps maximal voluntary isometric contractions, quality of life and complications.Conclusion: Condensing prehabilitation sessions led to similar or better improvement in cardiorespiratory fitness and did not decrease adherence or increase adverse events. This could increase the number of patients who can be referred for prehabilitation, despite short presurgical periods. Trial registration: NCT03936764.

Published
2022

29. RIP140 regulates POLK gene expression and the response to alkylating drugs in colon cancer cells

Author

Pascale Palassin, Marion Lapierre, Sandrine Bonnet, Marie-Jeanne Pillaire, Balázs Győrffy, Catherine Teyssier, Stéphan Jalaguier, Jean-Sébastien Hoffmann, Vincent Cavaillès, Audrey Castet-Nicolas, Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Institut de pharmacologie et de biologie structurale (IPBS), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Semmelweis University [Budapest], Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), 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 Régional Universitaire [Montpellier] (CHRU Montpellier), and Herrada, Anthony

Subjects
Cancer Research, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Pol Kappa, Colorectal cancer, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, RIP140, [SDV.CAN] Life Sciences [q-bio]/Cancer, translesion DNA synthesis polymerase, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Pharmacology (medical), genome stability
Abstract

International audience; Aim: The transcription factor RIP140 (receptor interacting protein of 140 kDa) is involved in intestinal tumorigenesis. It plays a role in the control of microsatellite instability (MSI), through the regulation of MSH2 and MSH6 gene expression. The aim of this study was to explore its effect on the expression of POLK, the gene encoding the specialized translesion synthesis (TLS) DNA polymerase κ known to perform accurate DNA synthesis at microsatellites.Methods: Different mouse models and engineered human colorectal cancer (CRC) cell lines were used to analyze by RT-qPCR, while Western blotting and luciferase assays were used to elucidate the role of RIP140 on POLK gene expression. Published DNA microarray datasets were reanalyzed. The in vitro sensitivity of CRC cells to methyl methane sulfonate and cisplatin was determined.Results: RIP140 positively regulates, at the transcriptional level, the expression of the POLK gene, and this effect involves, at least partly, the p53 tumor suppressor. In different cohorts of CRC biopsies (with or without MSI), a strong positive correlation was observed between RIP140 and POLK gene expression. In connection with its effect on POLK levels and the TLS function of this polymerase, the cellular response to methyl methane sulfonate was increased in cells lacking the Rip140 gene. Finally, the association of RIP140 expression with better overall survival of CRC patients was observed only when the corresponding tumors exhibited low levels of POLK, thus strengthening the functional link between the two genes in human CRC.Conclusion: The regulation of POLK gene expression by RIP140 could thus contribute to the maintenance of microsatellite stability, and more generally to the control of genome integrity.

Published
2022

30. Eco-friendly processes for the synthesis of amorphous calcium carbonate nanoparticles in ethanol and their stabilisation in aqueous media

Author

Lauriane Chuzeville, Frank Boury, David Duday, Resmi Anand, Enzo Moretto, Jean-Sébastien Thomann, Luxembourg Institute of Science and Technology (LIST), University of Luxembourg [Luxembourg], Design and Application of Innovative Local Treatments in Glioblastoma (CRCINA-ÉQUIPE 17), 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), and Bernardo, Elizabeth

Subjects
[SDV.CAN] Life Sciences [q-bio]/Cancer, Environmental Chemistry, [SDV.CAN]Life Sciences [q-bio]/Cancer, Pollution
Abstract

International audience; Amorphous calcium carbonate nanoparticles (ACC NPs) are promising multifunctional materials for healthcare applications. Due to their instability in aqueous media, pure ACC NPs for the biomedical field are increasingly synthesised in absolute ethanol, using the ammonia diffusion method (ADM). Although this method presents the advantage of providing stable ACC NPs without additives, it requires the use of pure ethanol as solvent. New insights into the formation mechanisms of ACC NPs in ethanol using gas diffusion are presented in this article. The optimisation of the process according to these findings can increase the mass concentration of ACC NPs by a factor of 3.5. As a result, the amount of ethanol required to produce a target mass of particles is significantly decreased, reducing the ecological impact of the process. The stabilisation of the resulting ACC NPs in aqueous media is achieved by a short-time process using phospholipids based on the ethanol injection method. By using the natural electrostatic affinity of negatively charged materials for the positive surface of ACC NPs in ethanol, we reduced the process time from 24 h to 2 minutes, compared with the closest state of the art, decreasing the operating time and corresponding energy consumption. The process does not require the use of synthetic PEGylated lipids for steric stabilisation. In addition, a natural egg-sourced phospholipid was identified as an efficient stabiliser for the first time. The upscaling of our process was successfully demonstrated using a 50 L reactor for bulk synthesis, as well as a continuous flow reactor for industrial continuous flow production.

Published
2022

31. Galectin functions in cancer-associated inflammation and thrombosis

Author

Kruk, Linus, Braun, Attila, Cosset, Erika, Gudermann, Thomas, Mammadova-Bach, Elmina, Ludwig-Maximilians University [Munich] (LMU), Ludwig-Maximilians University Hospital (LMU Munich), 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), Centre Léon Bérard [Lyon], German Center for Lung Research, and Manship, Brigitte

Subjects
galectins, [SDV.CAN] Life Sciences [q-bio]/Cancer, inflammation, anti-cancer therapies, cancer, [SDV.CAN]Life Sciences [q-bio]/Cancer, Cardiology and Cardiovascular Medicine, thrombosis
Abstract

International audience; Galectins are carbohydrate-binding proteins that regulate many cellular functions including proliferation, adhesion, migration, and phagocytosis. Increasing experimental and clinical evidence indicates that galectins influence many steps of cancer development by inducing the recruitment of immune cells to the inflammatory sites and modulating the effector function of neutrophils, monocytes, and lymphocytes. Recent studies described that different isoforms of galectins can induce platelet adhesion, aggregation, and granule release through the interaction with platelet-specific glycoproteins and integrins. Patients with cancer and/or deep-venous thrombosis have increased levels of galectins in the vasculature, suggesting that these proteins could be important contributors to cancer-associated inflammation and thrombosis. In this review, we summarize the pathological role of galectins in inflammatory and thrombotic events, influencing tumor progression and metastasis. We also discuss the potential of anti-cancer therapies targeting galectins in the pathological context of cancer-associated inflammation and thrombosis.

Published
2023

32. Flow cytometric analysis of myelodysplasia: Pre-analytical and technical issues—Recommendations from the European LeukemiaNet

Author

Vincent H. J. van der Velden, Frank Preijers, Ulrika Johansson, Theresia M. Westers, Alan Dunlop, Anna Porwit, Marie C. Béné, Peter Valent, Jeroen te Marvelde, Orianne Wagner‐Ballon, Uta Oelschlaegel, Leonie Saft, Sharham Kordasti, Robin Ireland, Eline Cremers, Canan Alhan, Carolien Duetz, Willemijn Hobo, Nicolas Chapuis, Michaela Fontenay, Peter Bettelheim, Lisa Eidenshink‐Brodersen, Patricia Font, Michael R. Loken, Sergio Matarraz, Kiyoyuki Ogata, Alberto Orfao, Katherina Psarra, Dolores Subirá, Denise A. Wells, Matteo G. Della Porta, Kate Burbury, Frauke Bellos, Elisabeth Weiß, Wolfgang Kern, Arjan van de Loosdrecht, Hematology laboratory, Internal medicine, Hematology, VU University medical center, AII - Cancer immunology, CCA - Cancer biology and immunology, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Radboudumc Nijmegen [The Netherlands], University Hospitals Bristol, Amsterdam UMC - Amsterdam University Medical Center, Royal Marsden Hospital [Surrey, UK], Lund University [Lund], Immunobiology of Human αβ and γδ T Cells and Immunotherapeutic Applications (CRCINA-ÉQUIPE 1), 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), Centre hospitalier universitaire de Nantes (CHU Nantes), Medizinische Universität Wien = Medical University of Vienna, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), CHU Henri Mondor, University Hospital Carl Gustav Carus [Dresden, Germany], Technische Universität Dresden = Dresden University of Technology (TU Dresden), Karolinska Institutet [Stockholm], King‘s College London, Maastricht University [Maastricht], Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Ordensklinikum Linz Elisabethinen, HematoLogics, Inc. [Seattle, WA, USA], Hospital General Universitario 'Gregorio Marañón' [Madrid], Universidad de Salamanca, Instituto de Salud Carlos III [Madrid] (ISC), Metropolitan Research and Treatment Centre for Blood Disorders [Tokyo, Japan] (MRTC Japan), Evangelismos Athens General Hospital, Universidad de Guadalajara, Humanitas University [Milan] (Hunimed), University of Melbourne, Munich Leukemia Laboratory [Munich, Germany], MUMC+: MA Med Staf Artsass Interne Geneeskunde (9), RS: FHML non-thematic output, Immunology, and Bernardo, Elizabeth

Subjects
Histology, MASTOCYTOSIS, Cancer development and immune defence Radboud Institute for Molecular Life Sciences [Radboudumc 2], BONE-MARROW, DIAGNOSTIC-CRITERIA, [SDV.CAN]Life Sciences [q-bio]/Cancer, REFRACTORY CYTOPENIA, CLASSIFICATION, Pathology and Forensic Medicine, pre-analytic issues, 03 medical and health sciences, 0302 clinical medicine, All institutes and research themes of the Radboud University Medical Center, [SDV.CAN] Life Sciences [q-bio]/Cancer, SDG 3 - Good Health and Well-being, hemic and lymphatic diseases, MDS, 030304 developmental biology, 0303 health sciences, flow cytometry, Cell Biology, QUANTIFICATION, LOW-GRADE, 3. Good health, CONSENSUS STATEMENTS, ELN, 030215 immunology, STANDARDS
Abstract

Contains fulltext : 290818.pdf (Publisher’s version ) (Open Access) BACKGROUND: Flow cytometry (FCM) aids the diagnosis and prognostic stratification of patients with suspected or confirmed myelodysplastic syndrome (MDS). Over the past few years, significant progress has been made in the FCM field concerning technical issues (including software and hardware) and pre-analytical procedures. METHODS: Recommendations are made based on the data and expert discussions generated from 13 yearly meetings of the European LeukemiaNet international MDS Flow working group. RESULTS: We report here on the experiences and recommendations concerning (1) the optimal methods of sample processing and handling, (2) antibody panels and fluorochromes, and (3) current hardware technologies. CONCLUSIONS: These recommendations will support and facilitate the appropriate application of FCM assays in the diagnostic workup of MDS patients. Further standardization and harmonization will be required to integrate FCM in MDS diagnostic evaluations in daily practice. 01 januari 2023

Published
2023

33. Molecular characterization of Richter syndrome identifies de novo diffuse large B-cell lymphomas with poor prognosis

Author

Broséus, Julien, Hergalant, Sébastien, Vogt, Julia, Tausch, Eugen, Kreuz, Markus, Dartigeas, Caroline, Schneider, Christof, Mottok, Anja, Roos-Weil, Damien, Quinquenel, Anne, Moulin, Charline, Ott, German, Blanchet, Odile, Tomowiak, Cécile, Lazarian, Grégory, Rouyer, Pierre, Tournilhac, Olivier, Bernhart, Stephan H., Chteinberg, Emil, Gauchotte, Guillaume, Lomazzi, Sandra, Chapiro, Elise, Nguyen-Khac, Florence, Chery, Céline, Davi, Frédéric, Hunault, Mathilde, Houlgatte, Rémi, Rosenwald, Andreas, Delmer, Alain, Meyre, David, Béné, Marie-Christine, Thieblemont, Catherine, Lichter, Peter, Guéant, Jean-Louis, Guièze, Romain, Martin-Subero, José Ignacio, Ammerpohl, Ole, Cymbalista, Florence, Feugier, Pierre, Siebert, Reiner, Stilgenbauer, Stephan, Publica, Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Universität Ulm - Ulm University [Ulm, Allemagne], Universitätsklinikum Ulm - University Hospital of Ulm, Fraunhofer Institute for Cell Therapy and Immunology (Fraunhofer IZI), Fraunhofer (Fraunhofer-Gesellschaft), Service d'hématologie [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Service d'Hématologie Biologique [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), Immuno-Régulation dans les Maladies Auto-Immunes Inflammatoires et le Cancer - EA 7509 (IRMAIC), Université de Reims Champagne-Ardenne (URCA), Service d'Hématologie [CHRU Nancy], Centre d'investigation clinique - Epidémiologie clinique [Nancy] (CIC-EC), Centre d'investigation clinique [Nancy] (CIC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Robert-Bosch-Krankenhaus, Dr. Margarete Fischer-Bosch Institute for Clinical Pharmacology [Stuttgart], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Centre hospitalier universitaire de Poitiers (CHU Poitiers), Service d'hématologie biologique [Avicenne], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Sorbonne Paris Nord, Interdisciplinary Centre for Bioinformatics [Leipzig] (IZBI), Universität Leipzig [Leipzig], 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, Centre de Ressources Biologiques - [Nancy] (CRB Nancy), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), 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), Biochimie – Biologie moléculaire et Nutrition [CHRU Nancy], Service d'hématologie [Angers], PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Institute of pathology [Würzburg], Centre hospitalier universitaire de Nantes (CHU Nantes), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), 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), Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany, Cancer Epigenetics Group, Cancer Epigenetics and Biology Program, Bellvitge Biomedical Research Institute, Barcelona, Spain, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona (UB), and Hergalant, Sébastien

Subjects
[SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, Epigenomics, Chronic lymphocytic leukaemia, Lymphoma, B-Cell, B-Zell-Lymphom, biostatistics, General Physics and Astronomy, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.GEN] Life Sciences [q-bio]/Genetics, General Biochemistry, Genetics and Molecular Biology, integrative genomics, DDC 570 / Life sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], ddc:570, ddc:610, Transcriptomics, Epigenetik, [SDV.GEN]Life Sciences [q-bio]/Genetics, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Multidisciplinary, B-cell lymphoma, Gene Expression Profiling, Computational Biology, classifiers, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, bioinformatics, General Chemistry, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Computational biology and bioinformatics, DLBCL, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Chronic lymphocytic leukemia, Epigenetics, Richter syndrome, DDC 610 / Medicine & health, CLL
Abstract

Richter syndrome (RS) is the transformation of chronic lymphocytic leukemia (CLL) into aggressive lymphoma, most commonly diffuse large B-cell lymphoma (DLBCL). We characterize 58 primary human RS samples by genome-wide DNA methylation and whole-transcriptome profiling. Our comprehensive approach determines RS DNA methylation profile and unravels a CLL epigenetic imprint, allowing CLL-RS clonal relationship assessment without the need of the initial CLL tumor DNA. DNA methylation- and transcriptomic-based classifiers were developed, and testing on landmark DLBCL datasets identifies a poor-prognosis, activated B-cell-like DLBCL subset in 111/1772 samples. The classification robustly identifies phenotypes very similar to RS with a specific genomic profile, accounting for 4.3-8.3% of de novo DLBCLs. In this work, RS multi-omics characterization determines oncogenic mechanisms, establishes a surrogate marker for CLL-RS clonal relationship, and provides a clinically relevant classifier for a subset of primary “RS-type DLBCL” with unfavorable prognosis., publishedVersion

Published
2023

34. One‐year COVID‐19 outcomes on the oncology care patient pathway: Results of a French descriptive, cross‐sectional comprehensive study (ONCOCARE‐COV)

Author

Léonard Laurent, Mathias Brugel, Claire Carlier, Florentin Clere, Aurélie Bertrand, Damien Botsen, Camille Boulagnon‐Rombi, Véronique Dalstein, Adeline Debreuve‐Theresette, Sophie Deguelte, Christian Garbar, Rachid Mahmoudi, Antonin Marechal, David Morland, Jean‐Baptiste Rey, Claire Schvartz, Catherine Vallet, Yacine Merrouche, Florian Slimano, Olivier Bouché, Institut Jean Godinot [Reims], UNICANCER, Centre Hospitalier Universitaire de Reims (CHU Reims), 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), Université de Reims Champagne-Ardenne (URCA), Centre de Recherche en Sciences et Technologies de l'Information et de la Communication - EA 3804 (CRESTIC), and Passat, Nicolas

Subjects
Cancer Research, Oncology, [SDV.CAN] Life Sciences [q-bio]/Cancer, backlog, lockdowns, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, COVID-19 pandemic, Radiology, Nuclear Medicine and imaging, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, cancer care pathway
Abstract

International audience; Background: The COVID-19 pandemic led to a widely documented disruption in cancer care pathway. Since a resurgence of the pandemic was expected after the first lockdown in France, the global impact on the cancer care pathway over the year 2020 was investigated.Aims: This study aimed to describe the changes in the oncology care pathway for cancer screening, diagnosis, assessment, diagnosis annoucement procedure and treatment over a one-year period.Materials & Methods: The ONCOCARE-COV study was a comprehensive, retrospective, descriptive, and cross-sectional study comparing the years 2019 and 2020. All key indicators along the cancer care pathway assessing the oncological activity over four periods were described. This study was set in a high-volume, public, single tertiary care center divided in two complementary sites (Reims University Hospital and Godinot Cancer Institute, Reims, France) which was located in a high COVID-19 incidence area during both peaks of the outbreak.Results: A total of 26,566 patient's files were active during the year 2020. Breast screening (−19.5%), announcement dedicated consultations (−9.2%), Intravenous and Hyperthermic Intraoperative Intraperitoneal Chemotherapy (HIPECs) (−25%), and oncogeriatric evaluations (−14.8%) were heavily disrupted in regard to 2020 activity. We identified a clear second outbreak wave impact on medical announcement procedures (October, −14.4%), radiotherapy sessions (October, −16%), number of new health record discussed in multidisciplinary tumor board meeting (November, −14.6%) and HIPECs (November, −100%). Moreover, 2020 cancer care activity stagnated compared to 2019.Discussion: The oncological care pathway was heavily disrupted during the first and second peaks of the COVID-19 outbreak. Between lockdowns, we observed a remarkable but non-compensatory recovery as well as a lesser impact from the pandemic resurgence. However, in absence of an increase in activity, a backlog persisted.Conclusion: Public health efforts are needed to deal with the consequences of the COVID-19 pandemic on the oncology care pathway.

Published
2023

35. Occupational disruption in older adults with cancer: a pilot study

Author

Atallah, Anne-Myriam, Dufrier, Laureline, Magny, Emmanuelle, Canouï-Poitrine, Florence, Médecin, Adolfo Gonzalez-Serrano, Ergothérapeute, Cynthia, and Tapia, Claudia

Subjects
Occupational engagement, [SDV.MHEP.GEG] Life Sciences [q-bio]/Human health and pathology/Geriatry and gerontology, [SDV.CAN] Life Sciences [q-bio]/Cancer, Older adults, Occupational therapy, Occupational disruption, Cancer
Abstract

Background. Cancer is growing around the world, especially among older adults. However, there is little evidence about the consequences of cancer and its treatments on occupational engagement in older adults. Before conceiving a cohort study to assess the outcomes of an occupational-therapy follow-up with older adults with cancer, we wanted to test our hypothesis that cancer and its treatments might affect all three occupational domains, and not only self-care. Objectives. i. Identify occupational problems in older adults with cancer in a pilot sample; and ii. Analyze how much the individuals valued those restricted occupations. Secondary objectives were to i. Assess the feasibility of recruiting, and ii. Precise the inclusion and exclusion criteria for participants. Methods. We conducted a retrospective pilot study, in one single geriatric rehabilitation ward. We studied the Canadian Occupational Performance Measure (COPM) results of older adults with cancer, and analyzed occupational problems and self-perceived occupational importance, performance and satisfaction. Results. Among 30 patients referred to occupational therapy, seven were included, identifying 21 occupational problems. Four respondents were women; the median age was 84 [71;89]. Nine of the 21 occupational problems were among self-care, six among productivity and six were leisure occupations. All occupational domains were valued. Main limits were the small sample size and only in-hospital follow-up. Conclusion. The three domains of occupations may be altered and not-only self-care in older patients with cancer. Productivity and leisure restrictions have to be assessed more in-depth to understand determinants and ways to improve.

Published
2023

36. Clinical application of flow cytometry in patients with unexplained cytopenia and suspected myelodysplastic syndrome: A report of the European LeukemiaNet International MDS-Flow Cytometry Working Group

Author

Loosdrecht, Arjan, Kern, Wolfgang, Porwit, Anna, Valent, Peter, Kordasti, Sharham, Cremers, Eline, Alhan, Canan, Duetz, Carolien, Dunlop, Alan, Hobo, Willemijn, Preijers, Frank, Wagner‐ballon, Orianne, Chapuis, Nicolas, Fontenay, Michaela, Bettelheim, Peter, Eidenschink‐brodersen, Lisa, Font, Patricia, Johansson, Ulrika, Loken, Michael, Marvelde, Jeroen, Matarraz, Sergio, Ogata, Kiyoyuki, Oelschlaegel, Uta, Orfao, Alberto, Psarra, Katherina, Subirá, Dolores, Wells, Denise, Béné, Marie, Della Porta, Matteo, Burbury, Kate, Bellos, Frauke, Velden, Vincent, Westers, Theresia, Saft, Leonie, Ireland, Robin, MUMC+: MA Med Staf Artsass Interne Geneeskunde (9), RS: FHML non-thematic output, Amsterdam UMC - Amsterdam University Medical Center, Munich Leukemia Laboratory [Munich, Germany] (M2L), Lund University [Lund], Medizinische Universität Wien = Medical University of Vienna, King‘s College London, Maastricht University Medical Centre (MUMC), Maastricht University [Maastricht], The Royal Marsden, Radboud University Medical Center [Nijmegen], Hôpital Henri Mondor, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Ordensklinikum Linz Elisabethinen, HematoLogics, Inc. [Seattle, WA, USA], Hospital General Universitario 'Gregorio Marañón' [Madrid], University Hospitals Bristol, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Universidad de Salamanca, Metropolitan Research and Treatment Centre for Blood Disorders [Tokyo, Japan] (MRTC Japan), University Hospital Carl Gustav Carus [Dresden, Germany], Technische Universität Dresden = Dresden University of Technology (TU Dresden), Evangelismos Athens General Hospital, Universidad de Guadalajara, Immunobiology of Human αβ and γδ T Cells and Immunotherapeutic Applications (CRCINA-ÉQUIPE 1), 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), Centre hospitalier universitaire de Nantes (CHU Nantes), Humanitas University [Milan] (Hunimed), Istituto Clinico Humanitas [Milan] (IRCCS Milan), University of Melbourne, Karolinska Institutet [Stockholm], King's College Hospital (KCH), Hematology, CCA - Cancer biology and immunology, Internal medicine, Hematology laboratory, Immunology, and Bernardo, Elizabeth

Subjects
standardization, Cancer development and immune defence Radboud Institute for Molecular Life Sciences [Radboudumc 2], flow cytometry, CONSORTIUM, [SDV.CAN]Life Sciences [q-bio]/Cancer, PROGNOSTIC SCORING SYSTEM, DIAGNOSIS, CYTOGENETICS, myelodysplastic syndromes, CLASSIFICATION, VALIDATION, All institutes and research themes of the Radboud University Medical Center, [SDV.CAN] Life Sciences [q-bio]/Cancer, consensus, hemic and lymphatic diseases, CELLS, SUBGROUPS, ELN, CYTOMORPHOLOGY
Abstract

Contains fulltext : 290800.pdf (Publisher’s version ) (Open Access) This article discusses the rationale for inclusion of flow cytometry (FCM) in the diagnostic investigation and evaluation of cytopenias of uncertain origin and suspected myelodysplastic syndromes (MDS) by the European LeukemiaNet international MDS Flow Working Group (ELN iMDS Flow WG). The WHO 2016 classification recognizes that FCM contributes to the diagnosis of MDS and may be useful for prognostication, prediction, and evaluation of response to therapy and follow-up of MDS patients. 01 januari 2023

Published
2023

37. EGFR-dependent mechanisms of resistance to osimertinib determined by ctDNA NGS analysis identify patients with better outcome

Author

Xavier Quantin, Jérôme Solassol, Isabelle Serre, Julie A. Vendrell, Audrey Aussel, Isabelle Solassol, Département Pathologie et Onco-biologie [CHU Montpellier], Pôle Biologie-Pathologie [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Institut du Cancer de Montpellier (ICM), and Herrada, Anthony

Subjects
circulating tumor DNA, Oncology, medicine.medical_specialty, EGFR-TKI resistance, business.industry, clinical outcome, [SDV.CAN]Life Sciences [q-bio]/Cancer, medicine.disease, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Outcome (game theory), lung cancer, [SDV.CAN] Life Sciences [q-bio]/Cancer, osimertinib, Internal medicine, medicine, [SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Original Article, Osimertinib, Lung cancer, business
Abstract

International audience; Background: Osimertinib is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that is highly selective for EGFR T790M subclones in patients with EGFR sensitizing non-small cell lung cancer (NSCLC). Unfortunately, all patients develop resistance through EGFR-dependent or EGFR-independent pathways. Recently, circulating tumoral DNA (ctDNA) analysis has highlighted the usefulness of plasma genotyping for exploring patient survival outcomes after disease progression under osimertinib.Methods: Plasma samples from patients treated with osimertinib as a second-line therapy were collected and the presence of molecular alterations of acquired resistance was evaluated after relapse under osimertinib using ctDNA molecular profiling by next-generation sequencing (NGS) assays. The clinical implications of these genomic alterations for the efficiency of the third-generation TKI were further assessed.Results: Our ctDNA molecular profiling of plasma samples highlighted large number of actionable genomic alterations. According to ctDNA NGS results, patients were classified as having developed an EGFR-dependent or EGFR-independent mechanism of resistance. Thus, patients who developed an EGFR-dependent mechanism of resistance responded longer to osimertinib (13.8 vs. 4.6 months; P

Published
2021

38. Lifestyle correlates of eight breast cancer-related metabolites: a cross-sectional study within the EPIC cohort

Author

Mathilde His, Vivian Viallon, Laure Dossus, Julie A. Schmidt, Ruth C. Travis, Marc J. Gunter, Kim Overvad, Cecilie Kyrø, Anne Tjønneland, Lucie Lécuyer, Joseph A. Rothwell, Gianluca Severi, Theron Johnson, Verena Katzke, Matthias B. Schulze, Giovanna Masala, Sabina Sieri, Salvatore Panico, Rosario Tumino, Alessandra Macciotta, Jolanda M. A. Boer, Evelyn M. Monninkhof, Karina Standahl Olsen, Therese H. Nøst, Torkjel M. Sandanger, Antonio Agudo, Maria-Jose Sánchez, Pilar Amiano, Sandra M. Colorado-Yohar, Eva Ardanaz, Linda Vidman, Anna Winkvist, Alicia K. Heath, Elisabete Weiderpass, Inge Huybrechts, Sabina Rinaldi, International Agency for Cancer Research (IACR), University of Oxford, Aarhus University [Aarhus], Danish Cancer Society Research Center [Copenhagen, Denmark] (DCSRC), University of Copenhagen = Københavns Universitet (UCPH), 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, Università degli Studi di Firenze = University of Florence (UniFI), Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), German Institute of Human Nutrition Potsdam-Rehbruecke [Nuthetal, Germany] (GIHNP-R), University of Potsdam = Universität Potsdam, Istituto per lo Studio, la Prevenzione e la rete Oncologica [Florence, Italy] (ISPRO), IRCCS Istituto Nazionale dei Tumori [Milano], University of Naples Federico II = Università degli studi di Napoli Federico II, Provincial Health Authority (ASP 7) [Ragusa, Italy], Università degli studi di Torino = University of Turin (UNITO), National Institute for Public Health and the Environment [Bilthoven] (RIVM), University Medical Center [Utrecht], The Arctic University of Norway [Tromsø, Norway] (UiT), Catalan Institute of Oncology [Barcelone, Espagne], L’Hospitalet de Llobregat [Barcelona, Spain], Escuela Andaluza de Salud Pública [Granada, Spain] (EASP), Universidad de Granada = University of Granada (UGR), CIBER de Epidemiología y Salud Pública (CIBERESP), Public Health Division of Gipuzkoa, Basque Government, CIBER en Salud Pública, CIBERSP, Biodonostia Health Research Institute [Donostia-San Sebastian, Spain] (IIS Biodonostia), Murcia Regional Health Council [Murcia], Universidad de Antioquia = University of Antioquia [Medellín, Colombia], Navarra Public Health Institute, Umeå University, Imperial College London, Kræftens Bekæmpelse, DCS, Deutsches Krebsforschungszentrum, DKFZ, Centre International de Recherche sur le Cancer, CIRC, National Research Council, NRC, University of Maryland School of Public Health, SPH, Cancer Research UK, CRUK, World Cancer Research Fund, WCRF, University of Cambridge, Institut National de la Santé et de la Recherche Médicale, Inserm, Bundesministerium für Bildung und Forschung, BMBF, Cancerfonden, Ministerie van Volksgezondheid, Welzijn en Sport, VWS, Fondation ARC pour la Recherche sur le Cancer, ARC, Ligue Contre le Cancer, Vetenskapsrådet, VR, Instituto de Salud Carlos III, ISCIII, Associazione Italiana per la Ricerca sul Cancro, AIRC, Deutsche Krebshilfe, Institut National Du Cancer, INCa: 2015-166, Institut Gustave-Roussy, Mutuelle Générale de l'Education Nationale, MGEN, NIHR Imperial Biomedical Research Centre, BRC, The national cohorts are supported by Danish Cancer Society (Denmark), Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Générale de l’Education Nationale, Institut National de la Santé et de la Recherche Médicale (INSERM) (France), German Cancer Aid, German Cancer Research Center (DKFZ), German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), Federal Ministry of Education and Research (BMBF) (Germany), Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy, Compagnia di SanPaolo and National Research Council (Italy), Dutch Ministry of Public Health, Welfare and Sports (VWS), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF) (The Netherlands), Health Research Fund (FIS) - Instituto de Salud Carlos III (ISCIII), Regional Governments of Andalucía, Asturias, Basque Country, Murcia and Navarra, and the Catalan Institute of Oncology - ICO (Spain), Swedish Cancer Society, Swedish Research Council and County Councils of Skåne and Västerbotten (Sweden), and Cancer Research UK (14136 to EPIC-Norfolk (DOI 10.22025/2019.10.105.00004), C8221/A29017 to EPIC-Oxford), Medical Research Council (1000143, MR/N003284/1, MC-UU_12015/1 and MC_UU_00006/1 to EPIC-Norfolk, MR/M012190/1 to EPIC-Oxford) (UK). The funders were not involved in designing the study, collecting, analyzing, or interpreting the data, or writing or submitting the manuscript for publication., The coordination of EPIC is financially supported by International Agency for Research on Cancer (IARC) and also by the Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, which has additional infrastructure support provided by the NIHR Imperial Biomedical Research Centre (BRC)., This work was funded by the French National Cancer Institute (grant number 2015-166). Mathilde His’ work reported here was undertaken during the tenure of a postdoctoral fellowship awarded by the International Agency for Research on Cancer, financed by the Fondation ARC., The authors would like to thank Mr Bertrand Hemon for his support in preparing the databases, Ms Audrey Gicquiau and Dr David Achaintre for the analyses of samples in several of the original studies, and all EPIC participants. The EPIC-Norfolk team thank all the participants who have been part of the project and the many members of the study teams at the University of Cambridge who have enabled this research. Where authors are identified as personnel of the International Agency for Research on Cancer/World Health Organization, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy, or views of the International Agency for Research on Cancer/World Health Organization., and HAL UVSQ, Équipe

Subjects
cross-sectional, lifestyle, Estils de vida, BIOMARKERS, Lifestyles, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, DIET, SERUM, Càncer de mama, Cohort Studies, Medicine, General & Internal, Breast cancer, [SDV.CAN] Life Sciences [q-bio]/Cancer, Risk Factors, Cross-sectional, General & Internal Medicine, Metabolites, Humans, Metabolomics, Prospective Studies, VALIDITY, Life Style, 11 Medical and Health Sciences, metabolites, RISK, Cancer och onkologi, Science & Technology, anthropometry, Anthropometry, Public Health, Global Health, Social Medicine and Epidemiology, General Medicine, PROFILES, Lifestyle, AMINO-ACID, BODY-MASS INDEX, Folkhälsovetenskap, global hälsa, socialmedicin och epidemiologi, PHYSICAL-ACTIVITY, Cross-Sectional Studies, Metabolòmica, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Cancer and Oncology, TARGETED METABOLOMICS, Medicine, Female, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Life Sciences & Biomedicine, Research Article
Abstract

This work was funded by the French National Cancer Institute (grant number 2015-166). Mathilde His' work reported here was undertaken during the tenure of a postdoctoral fellowship awarded by the International Agency for Research on Cancer, financed by the Fondation ARC. The coordination of EPIC is financially supported by International Agency for Research on Cancer (IARC) and also by the Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, which has additional infrastructure support provided by the NIHR Imperial Biomedical Research Centre (BRC). The national cohorts are supported by Danish Cancer Society (Denmark); Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Generale de l'Education Nationale, Institut National de la Sante et de la Recherche Medicale (INSERM) (France); German Cancer Aid, German Cancer Research Center (DKFZ), German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), Federal Ministry of Education and Research (BMBF) (Germany); Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy, Compagnia di SanPaolo and National Research Council (Italy); Dutch Ministry of Public Health, Welfare and Sports (VWS), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF) (The Netherlands); Health Research Fund (FIS) - Instituto de Salud Carlos III (ISCIII), Regional Governments of Andalucia, Asturias, Basque Country, Murcia and Navarra, and the Catalan Institute of Oncology-ICO (Spain); Swedish Cancer Society, Swedish Research Council and County Councils of Skane and Vasterbotten (Sweden); and Cancer Research UK (14136 to EPIC-Norfolk (DOI 10.22025/2019.10.105.00004); C8221/A29017 to EPIC-Oxford), Medical Research Council (1000143, MR/N003284/1, MC-UU_12015/1 and MC_UU_00006/1 to EPIC-Norfolk; MR/M012190/1 to EPIC-Oxford) (UK). The funders were not involved in designing the study; collecting, analyzing, or interpreting the data; or writing or submitting the manuscript for publication., Background: Metabolomics is a promising molecular tool for identifying novel etiological pathways leading to cancer. In an earlier prospective study among pre- and postmenopausal women not using exogenous hormones, we observed a higher risk of breast cancer associated with higher blood concentrations of one metabolite (acetylcarnitine) and a lower risk associated with higher blood concentrations of seven others (arginine, asparagine, phosphatidylcholines (PCs) aa C36:3, ae C34:2, ae C36:2, ae C36:3, and ae C38:2). Methods: To identify determinants of these breast cancer-related metabolites, we conducted a cross-sectional analysis to identify their lifestyle and anthropometric correlates in 2358 women, who were previously included as controls in case-control studies nested within the European Prospective Investigation into Cancer and Nutrition cohort and not using exogenous hormones at blood collection. Associations of each metabolite concentration with 42 variables were assessed using linear regression models in a discovery set of 1572 participants. Significant associations were evaluated in a validation set (n = 786). Results: For the metabolites previously associated with a lower risk of breast cancer, concentrations of PCs ae C34: 2, C36:2, C36:3, and C38:2 were negatively associated with adiposity and positively associated with total and saturated fat intakes. PC ae C36:2 was also negatively associated with alcohol consumption and positively associated with two scores reflecting adherence to a healthy lifestyle. Asparagine concentration was negatively associated with adiposity. Arginine and PC aa C36:3 concentrations were not associated to any of the factors examined. For the metabolite previously associated with a higher risk of breast cancer, acetylcarnitine, a positive association with age was observed. Conclusions: These associations may indicate possible mechanisms underlying associations between lifestyle and anthropometric factors, and risk of breast cancer. Further research is needed to identify potential non-lifestyle correlates of the metabolites investigated., Institut National du Cancer (INCA) France 2015-166, International Agency for Research on Cancer - Fondation ARC, World Health Organization, Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, Danish Cancer Society, Ligue Contre le Cancer (France), Institut Gustave Roussy (France), Mutuelle Generale de l'Education Nationale (France), Institut National de la Sante et de la Recherche Medicale (Inserm), Deutsche Krebshilfe, German Cancer Research Center (DKFZ) (Germany), German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE) (Germany), Federal Ministry of Education & Research (BMBF), Fondazione AIRC per la ricerca sul cancro, Compagnia di San Paolo, Consiglio Nazionale delle Ricerche (CNR), Netherlands Government, World Cancer Research Fund International (WCRF), Health Research Fund (FIS) - Instituto de Salud Carlos III (ISCIII) (Spain), Junta de Andalucia, Regional Government of Asturias (Spain), Regional Government of Basque Country (Spain), Regional Government of Murcia (Spain), Regional Government of Navarra (Spain), Catalan Institute of Oncology-ICO (Spain), Swedish Cancer Society, Swedish Research Council, County Council of Skane (Sweden), County Council of Vasterbotten (Sweden), Cancer Research UK 14136 C8221/A29017, UK Research & Innovation (UKRI), Medical Research Council UK (MRC) 1000143 MR/N003284/1 MC-UU_12015/1 MC_UU_00006/1 MR/M012190/1

Published
2021

39. IRE1α overexpression in malignant cells limits tumor progression by inducing an anti-cancer immune response

Author

Adriana Martinez-Turtos, Rachel Paul, Manuel Grima-Reyes, Hussein Issaoui, Adrien Krug, Rana Mhaidly, Jozef P. Bossowski, Johanna Chiche, Sandrine Marchetti, Els Verhoeyen, Eric Chevet, Jean-Ehrland Ricci, Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (1965 - 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), Equipe Labellisée LIGUE Contre le Cancer [Nice] (EL/LCC), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CRLCC Eugène Marquis (CRLCC), Oncogenesis, Stress, Signaling (OSS), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), la Ligue Nationale Contre le Cancer 'Equipe Labellisée, Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS 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), and Ricci, Jean-Ehrland

Subjects
X-Box Binding Protein 1, [SDV]Life Sciences [q-bio], Immunology, Immunity, apoptosis, [SDV.CAN]Life Sciences [q-bio]/Cancer, IRE1α, UPR, Protein Serine-Threonine Kinases, [SDV] Life Sciences [q-bio], Mice, [SDV.CAN] Life Sciences [q-bio]/Cancer, Oncology, Neoplasms, Endoribonucleases, Animals, Immunology and Allergy, RIDD, anti-cancer immunosurveillance, XBP1s, Neoplastic Processes, Signal Transduction, Cancer
Abstract

International audience; IRE1α is one of the three ER transmembrane transducers of the Unfolded Protein Response (UPR) activated under endoplasmic reticulum (ER) stress. IRE1α activation has a dual role in cancer as it may be either pro- or anti-tumoral depending on the studied models. Here, we describe the discovery that exogenous expression of IRE1α, resulting in IRE1α auto-activation, did not affect cancer cell proliferation in but resulted in a tumor-suppressive phenotype in syngeneic immunocompetent mice. We found that exogenous expression of IRE1α in murine colorectal and Lewis lung carcinoma cells impaired tumor growth when syngeneic tumor cells were subcutaneously implanted in immunocompetent mice but not in immunodeficient mice. Mechanistically, the in vivo tumor-suppressive effect of overexpressing IRE1α in tumor cells was associated with IRE1α RNAse activity driving both XBP1 mRNA splicing and regulated IRE1-dependent decay of RNA (RIDD). We showed that the tumor-suppressive phenotype upon IRE1α overexpression was characterized by the induction of apoptosis in tumor cells along with an enhanced adaptive anti-cancer immunosurveillance. Hence, our work indicates that IRE1α overexpression and/or activation in tumor cells can limit tumor growth in immunocompetent mice. This finding might point toward the need of adjusting the use of IRE1α inhibitors in cancer treatments based on the predominant outcome of the RNAse activity of IRE1α.

Published
2022

40. Targeting PCSK9 in Liver Cancer Cells Triggers Metabolic Exhaustion and Cell Death by Ferroptosis

Author

Malak Alannan, Hala Fatrouni, Véronique Trézéguet, Franziska Dittrich-Domergue, Patrick Moreau, Géraldine Siegfried, Benjamin Liet, Abdel-Majid Khatib, Christophe F. Grosset, Bassam Badran, Hussein Fayyad-Kazan, Aksam J. Merched, BoRdeaux Institute in onCology (Inserm U1312 - BRIC), Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de biogenèse membranaire (LBM), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Lebanese University [Beirut] (LU), Association Cassandra contre les Leucémies et Cancers Pédiatriques (OPE-2018-0144), Association Les Récoltes de l’Espoir (RE-2021-1AD-F), and Merched, Aksam

Subjects
[SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, [SDV]Life Sciences [q-bio], [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, [SDV.CAN]Life Sciences [q-bio]/Cancer, hepatocellular carcinoma, General Medicine, hepatoblastoma, ferroptosis, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, PCSK9, lipid metabolism, [SDV] Life Sciences [q-bio], [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], [SDV.BBM.BC] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; Deregulated lipid metabolism is a common feature of liver cancers needed to sustain tumor cell growth and survival. We aim at taking advantage of this vulnerability and rewiring the oncogenic metabolic hub by targeting the key metabolic player pro-protein convertase subtilisin/kexin type 9 (PCSK9). We assessed the effect of PCSK9 inhibition using the three hepatoma cell lines Huh6, Huh7 and HepG2 and validated the results using the zebrafish in vivo model. PCSK9 deficiency led to strong inhibition of cell proliferation in all cell lines. At the lipid metabolic level, PCSK9 inhibition was translated by an increase in intracellular neutral lipids, phospholipids and polyunsaturated fatty acids as well as a higher accumulation of lipid hydroperoxide. Molecular signaling analysis involved the disruption of the sequestome 1/Kelch-like ECH-associated protein 1/nuclear factor erythroid 2-related factor 2 (p62/Keap1/Nrf2) antioxidative axis, leading to ferroptosis, for which morphological features were confirmed by electron and confocal microscopies. The anti-tumoral effects of PCSK9 deficiency were validated using xenograft experiments in zebrafish. The inhibition of PCSK9 was effective in disrupting the oncometabolic process, inducing metabolic exhaustion and enhancing the vulnerability of cancer cells to iron-triggered lipid peroxidation. We provide strong evidence supporting the drug repositioning of anti-PCSK9 approaches to treat liver cancers.

Published
2022
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41. Rewiring Lipid Metabolism by Targeting PCSK9 and HMGCR to Treat Liver Cancer

Author

Malak Alannan, Véronique Trézéguet, Nivea Dias Amoêdo, Rodrigue Rossignol, Walid Mahfouf, Hamid Reza Rezvani, Franziska Dittrich-Domergue, Patrick Moreau, Sabrina Lacomme, Etienne Gontier, Christophe F. Grosset, Bassam Badran, Hussein Fayyad-Kazan, Aksam J. Merched, Merched, Aksam, BoRdeaux Institute in onCology (Inserm U1312 - BRIC), Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM), Cellomet [CHU Pellegrin, Bordeaux], CHU de Bordeaux Pellegrin [Bordeaux], Laboratoire de biogenèse membranaire (LBM), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Bordeaux Imaging Center (BIC), Université de Bordeaux (UB)-Institut François Magendie-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Lebanese University [Beirut] (LU), Association Cassandra contre les Leucémies et Cancers Pédiatriques (OPE-2018-0144), and Association les Récoltes de l’Espoir (RE-2021-1AD-F

Subjects
Cancer Research, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, [SDV]Life Sciences [q-bio], [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, [SDV.CAN]Life Sciences [q-bio]/Cancer, hepatocellular carcinoma, hepatoblastoma, lipotoxicity, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, [SDV] Life Sciences [q-bio], Oncology, peridroplet mitochondria, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; Alterations in lipid handling are an important hallmark in cancer. Our aim here is to target key metabolic enzymes to reshape the oncogenic lipid metabolism triggering irreversible cell breakdown. We targeted the key metabolic player proprotein convertase subtilisin/kexin type 9 (PCSK9) using a pharmacological inhibitor (R-IMPP) alone or in combination with 3-hydroxy 3-methylglutaryl-Coenzyme A reductase (HMGCR) inhibitor, simvastatin. We assessed the effect of these treatments using 3 hepatoma cell lines, Huh6, Huh7 and HepG2 and a tumor xenograft in chicken choriorallantoic membrane (CAM) model. PCSK9 deficiency led to dose-dependent inhibition of cell proliferation in all cell lines and a decrease in cell migration. Co-treatment with simvastatin presented synergetic anti-proliferative effects. At the metabolic level, mitochondrial respiration assays as well as the assessment of glucose and glutamine consumption showed higher metabolic adaptability and surge in the absence of PCSK9. Enhanced lipid uptake and biogenesis led to excessive accumulation of intracellular lipid droplets as revealed by electron microscopy and metabolic tracing. Using xenograft experiments in CAM model, we further demonstrated the effect of anti-PCSK9 treatment in reducing tumor aggressiveness. Targeting PCSK9 alone or in combination with statins deserves to be considered as a new therapeutic option in liver cancer clinical applications.

Published
2022
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42. A tumor volume and performance status model to predict outcome before treatment in diffuse large B-cell lymphoma

Author

Catherine Thieblemont, Loic Chartier, Ulrich Dührsen, Umberto Vitolo, Sally F. Barrington, Jan M. Zaucha, Laetitia Vercellino, Maria Gomes Silva, Ines Patrocinio-Carvalho, Pierre Decazes, Pierre-Julien Viailly, Herve Tilly, Alina Berriolo-Riedinger, Oliver Casasnovas, Andreas Hüttmann, Hajira Ilyas, N. George Mikhaeel, Joel Dunn, Anne-Ségolène Cottereau, Christine Schmitz, Lale Kostakoglu, Joseph N. Paulson, Tina Nielsen, Michael Meignan, Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), The Lymphoma Academic Research Organisation [Lyon] (LYSARC), Universitätsklinikum Essen [Universität Duisburg-Essen] (Uniklinik Essen), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), King‘s College London, Guy's and St Thomas' Hospital [London], Medical University of Gdańsk, Service de Médecine Nucléaire [Saint-Louis], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Instituto Português de Oncologia do Porto / Portuguese Oncology Institute of Porto (IPO Porto), Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital du Bocage, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Laboratoire d'Imagerie Translationnelle en Oncologie (LITO ), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Cochin [AP-HP], University of Virginia, Genentech, Inc. [San Francisco], F. Hoffmann-La Roche [Basel], CHU Henri Mondor, and leboeuf, Christophe

Subjects
Clinical Trials as Topic, [SDV.CAN] Life Sciences [q-bio]/Cancer, Medizin, Humans, [SDV.CAN]Life Sciences [q-bio]/Cancer, Hematology, Lymphoma, Large B-Cell, Diffuse, Neoplasm Recurrence, Local, Tumor Burden
Abstract

Aggressive large B-cell lymphoma (LBCL) has variable outcomes. Current prognostic tools use factors for risk stratification that inadequately identify patients at high risk of refractory disease or relapse before initial treatment. A model associating 2 risk factors, total metabolic tumor volume (TMTV) >220 cm3 (determined by fluorine-18 fluorodeoxyglucose positron emission tomography coupled with computed tomography) and performance status (PS) ≥2, identified as prognostic in 301 older patients in the REMARC trial (#NCT01122472), was validated in 2174 patients of all ages treated in 2 clinical trials, PETAL (Positron Emission Tomography-Guided Therapy of Aggressive Non-Hodgkin Lymphomas; N = 510) and GOYA (N = 1315), and in real-world clinics (N = 349) across Europe and the United States. Three risk categories, low (no factors), intermediate (1 risk factor), and high (2 risk factors), significantly discriminated outcome in most of the series. Patients with 2 risk factors had worse outcomes than patients with no risk factors in the PETAL, GOYA, and real-world series. Patients with intermediate risk also had significantly worse outcomes than patients with no risk factors. The TMTV/Eastern Cooperative Oncology Group-PS combination outperformed the International Prognostic Index with a positive C-index for progression-free survival and overall survival in most series. The combination of high TMTV > 220 cm3 and ECOG-PS ≥ 2 is a simple clinical model to identify aggressive LBCL risk categories before treatment. This combination addresses the unmet need to better predict before treatment initiation for aggressive LBCL the patients likely to benefit the most or not at all from therapy.

Published
2022

43. Biological differences between two commercial anti-CD19 CAR T cells products and impact on outcomes in lymphoma patients

Author

Tessoulin, Benoit, Grain, Audrey, Ollier, Jocelyn, Gastinne, Thomas, Dubruille, Viviane, Mahé, Béatrice, Blin, Nicolas, Lok, Anne, Vantyghem, Sophie, Sortais, Clara, Touzeau, Cyrille, Moreau, Philippe, Le Gouill, Steven, Chevallier, Patrice, Clémenceau, Béatrice, 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), Manipulation of Lymphocytes for Immunotherapy (CRCI2NA / Eq 12), 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)-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 (Nantes Univ)-Nantes Université (Nantes Univ), Centre hospitalier universitaire de Nantes (CHU Nantes), Service d'Hématologie Clinique [CHU Nantes] (Unité d'Investigation Clinique), Service d'Hématologie Clinique [Nantes] (Unité d'Investigation Clinique), Département d'Hématologie Clinique [CHU Nantes], Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), university hospital, University Hospital, Immunobiology of Human αβ and γδ T Cells and Immunotherapeutic Applications (CRCINA-ÉQUIPE 1), 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), LabEX IGO Immunothérapie Grand Ouest, Nantes Université (Nantes Univ), and Ollier, Jocelyn

Subjects
[SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.IMM] Life Sciences [q-bio]/Immunology, [SDV.IMM]Life Sciences [q-bio]/Immunology, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology
Abstract

International audience

Published
2022

44. Viral Mimicry Response Is Associated With Clinical Outcome in Pleural Mesothelioma

Author

Suna Sun, Weihong Qi, Hubert Rehrauer, Manuel Ronner, Ananya Hariharan, Martin Wipplinger, Clément Meiller, Rolf Stahel, Martin Früh, Ferdinando Cerciello, Jean-François Fonteneau, Didier Jean, Emanuela Felley-Bosco, University hospital of Zurich [Zurich], Universität Zürich [Zürich] = University of Zurich (UZH), 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), Stiftung European Thoracic Oncology Platform [Bern, Switzerland] (ETOP), Swiss Group for Clinical Cancer Research [Bern, Switzerland], Brustzentrum Kantonsspital St. Gallen, Bern University Hospital [Berne] (Inselspital), University of Bern, 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), Jean, Didier, University of Zurich, and Felley-Bosco, Emanuela

Subjects
Pulmonary and Respiratory Medicine, 10255 Clinic for Thoracic Surgery, 610 Medicine & health, 10071 Functional Genomics Center Zurich, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, BRCA-associated protein 1, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Oncology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV.CAN] Life Sciences [q-bio]/Cancer, 2740 Pulmonary and Respiratory Medicine, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], 570 Life sciences, biology, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], 2730 Oncology, Endogenous retroviruses, Type I interferon, Pleural mesothelioma, 610 Medizin und Gesundheit, [SDV.BC] Life Sciences [q-bio]/Cellular Biology
Abstract

Introduction: The aim of this study was to investigate endogenous retrovirus (ERV) expression and type I interferon (IFN) activation in human pleural mesothelioma (PM) and their association with clinical outcome. Methods: The expression of ERV was determined from PM cohorts and mesothelial precursor RNA sequencing data. The expression of ERV was confirmed by quantitative polymerase chain reaction (qPCR). Methylation of genomic DNA was assessed by quantitative methylation-specific PCR. DNA demethylation was induced in cells by demethylating agent 5-Aza-2’-deoxycytidine (5-Aza-CdR) treatment. To block type I IFN signaling, the cells were treated with ruxolitinib or MAVS silencing. The expression of IFN-stimulated genes (ISGs) was determined by qPCR and Western blot. Circulating ERVs were detected by qPCR. Results: Long terminal repeats (LTRs) represent the most abundant transposable elements up-regulated in PM. Within the LTR, ERVmap_1248 and LTR7Y, which are specifically enriched in PM, were further analyzed. The 5-Aza-CdR treatment increased the levels of ERVmap_1248 expression and induced ERVmap_1248 promoter demethylation in mesothelial cells. In addition, ERVmap_1248 promoter was more demethylated in the mesothelioma tissue compared with nontumor tissue. The 5-Aza-CdR treatment of the mesothelial cells also increased the levels of ISGs. Basal ISG expression was higher in the mesothelioma cells compared with the mesothelial cells, and it was significantly decreased by ruxolitinib treatment or MAVS silencing. Furthermore, ISG expression was higher in the tumor tissue with high expression levels of ERVmap_1248. High expression of ERVmap_1248 was associated with longer overall survival and BAP1 mutations. ERVmap_1248 and LTR7Y can be detected in the PM plasma. Conclusions: We provide clues for patient stratification especially for immunotherapy where best clinical responses are associated with an activated basal immune response., JTO Clinical and Research Reports, 3 (12), ISSN:2666-3643

Published
2022

45. Increased Production of B-Cell Activating Cytokines and Altered Peripheral B-Cell Subset Distribution during HIV-Related Classical Hodgkin Lymphoma

Author

Raphael, Lievin, Houria, Hendel-Chavez, Aliou, Baldé, Rémi, Lancar, Michèle, Algarte-Génin, Roman, Krzysiek, Dominique, Costagliola, Lambert, Assoumou, Yassine, Taoufik, Caroline, Besson, Centre Hospitalier de Versailles André Mignot (CHV), Hôpital Bicêtre, Immunologie intégrative des tumeurs et immunothérapie des cancers (INTIM), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-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, Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil (UVSQ Santé), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Agence Nationale de Recherches sur le Sida et les Hépatites Virales, ANRS: Lymphovir-CO16, Funding: This research was funded by ANRS, grant number: Lymphovir-CO16., and HAL UVSQ, Équipe

Subjects
[SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, HIV, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, macromolecular substances, Article, cytokines, immunology, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, [SDV.IMM.IA] Life Sciences [q-bio]/Immunology/Adaptive immunology, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Hodgkin lymphoma, RC254-282
Abstract

Simple Summary Patients with HIV are at high risk of developing Hodgkin’s lymphoma. This is potentially due to alterations in blood circulating B-lymphocytes and their activating cytokines. We analyzed the distribution of circulating B-lymphocytes and the level of the activating cytokines IL6, IL10 and BAFF in 38 patients with HIV-related Hodgkin’s lymphoma during a 2-year follow-up. We also compared their characteristics at diagnosis with (1) pre-diagnosis serum samples and (2) samples from control HIV-infected subjects without lymphoma. We found an increase in activating cytokines in cases compared to controls. The level of activating cytokines increased in advanced lymphoma. It decreased over time during follow-up. B-lymphocytic count was similar between patients and controls, but their subset distribution differed. There was an overrepresentation of naive B-lymphocytes over memory B-lymphocytes in HIV-associated Hodgkin lymphoma patients, more pronounced in those with advanced lymphoma. Follow-up showed an increase in B-lymphocytic count with an even greater proportion of naive B-cells. Together this suggests that in HIV-infected patients, Hodgkin lymphoma is associated with an altered blood distribution of B-lymphocytic subsets and an increased production of activating cytokines. This environment may contribute to the process of tumorigenesis. Abstract Classical Hodgkin Lymphoma incidence increases in HIV-1-infected patients (HIV-cHL). HIV infection is associated with higher B-cell activation. Here, in 38 HIV-cHL patients from the French cohort ANRS-CO16 Lymphovir, we examined longitudinally over 24 months the serum levels of the B-cell activating cytokines IL10, IL6, and BAFF, and blood distribution of B-cell subsets. Fourteen HIV-cHL patients were also compared to matched HIV-infected controls without cHL. IL10, IL6, and BAFF levels were higher in HIV-cHL patients than in controls (p < 0.0001, p = 0.002, and p < 0.0001, respectively). Cytokine levels increased in patients with advanced-stage lymphoma compared to those with limited-stage (p = 0.002, p = 0.03, and p = 0.01, respectively). Cytokine levels significantly decreased following HIV-cHL diagnosis and treatment. Blood counts of whole B-cells were similar in HIV-cHL patients and controls, but the distribution of B-cell subsets was different with higher ratios of naive B-cells over memory B-cells in HIV-cHL patients. Blood accumulation of naive B-cells was more marked in patients with advanced cHL stages (p = 0.06). During the follow-up, total B-cell counts increased (p < 0.0001), and the proportion of naive B-cells increased further (p = 0.04). Together the results suggest that in HIV-infected patients, cHL is associated with a particular B-cell-related environment that includes increased production of B-cell-activating cytokines and altered peripheral distribution of B-cell subsets. This B-cell-related environment may fuel the process of tumorigenesis.

Published
2022

46. PCSK9 in Liver Cancers at the Crossroads between Lipid Metabolism and Immunity

Author

Malak Alannan, Nabil Seidah, Aksam Merched, BoRdeaux Institute in onCology (Inserm U1312 - BRIC), Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université du Québec à Montréal = University of Québec in Montréal (UQAM), Institut de Recherches Cliniques de Montréal (IRCM), Université de Montréal (UdeM), and Merched, Aksam

Subjects
PCSK9, liver cancer, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, [SDV.CAN]Life Sciences [q-bio]/Cancer, General Medicine, immuno-oncology, metabolism, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology
Abstract

International audience; Metabolic rewiring and defective immune responses are considered to be the main driving forces sustaining cell growth and oncogenesis in many cancers. The atypical enzyme, proprotein convertase subtilisin/kexin type 9 (PCSK9), is produced by the liver in large amounts and plays a major role in lipid metabolism via the control of the low density lipoprotein receptor (LDLR) and other cell surface receptors. In this context, many clinical studies have clearly demonstrated the high efficacy of PCSK9 inhibitors in treating hyperlipidemia and cardiovascular diseases. Recent data implicated PCSK9 in the degradation of major histocompatibility complex I (MHC-I) receptors and the immune system as well as in other physiological activities. This review highlights the complex crosstalk between PCSK9, lipid metabolism and immunosuppression and underlines the latest advances in understanding the involvement of this convertase in other critical functions. We present a comprehensive assessment of the different strategies targeting PCSK9 and show how these approaches could be extended to future therapeutic options to treat cancers with a main focus on the liver.

Published
2022

47. A polygenic risk score for multiple myeloma risk prediction

Author

Angelica Macauda, Matteo Pelosini, Krzysztof Jamroziak, Mario Petrini, Annette Juul Vangsted, Chiara Piredda, Stephane Minvielle, Marek Dudziński, Hervé Avet-Loiseau, Aleksandra Butrym, Ulla Vogel, Niels Abildgaard, Fabienne Lesueur, Waldemar Tomczak, Vibeke Andersen, Herlander Marques, Daniele Campa, Judit Várkonyi, Rui Manuel Reis, Katalin Kadar, Gabriele Buda, Małgorzata Raźny, Charles Dumontet, Juan Sainz, Anna Suska, Enrico Orciuolo, Agnieszka Druzd-Sitek, Marcin Kruszewski, Daria Zawirska, Niels Frost Andersen, Artur Jurczyszyn, Grzegorz Mazur, Marcin Rymko, Federica Gemignani, Edyta Subocz, Federico Canzian, Katia Beider, Jan Maciej Zaucha, Marzena Wątek, Arnon Nagler, Genomic Epidemiology Group [Heidelberg, Germany] (GEP / DKFZ), German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), University of Pisa - Università di Pisa, University Hospital of Cracow/Szpital Uniwersytecki w Krakowie [Poland] (SUK), Aarhus University Hospital, Chaim Sheba Medical Center, Sea Hospital [Gdynia, Poland] (SH), Wroclaw Medical University [Wrocław, Pologne] (WMU), Hospices Civils de Lyon (HCL), Holycross Cancer Center of Kelce, Hematology Clinic, Kielce, Institute of Hematology and Transfusion Medicine [Warsaw, Poland] (IHTM), Centre for Genomics and Oncological Research Pfizer [Granada, Spain] (GENYO), University of Granada [Granada]-Andalusian Regional Government [Granada, Spain], Hospital Universitario Virgen de las Nieves [Granada, Spain] (HUVN), Semmelweis University [Budapest], Odense University Hospital (OUH), 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), Teaching Hospital No 1 [Rzeszów, Poland] (TH1), University of Copenhagen = Københavns Universitet (KU), Military Institute of Medicine [Warsaw, Poland] (MIM), Rydygier Specialistic Hospital [Cracow, Poland] (RSH), University of Minho [Braga], Jagiellonian University Medical College [Cracow, Poland] (JUMC), Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology (MCMCC), The National Research Center for Work Environment [Copenhagen, Denmark] (NRCWE), University of Southern Denmark (SDU), ICVS/3B's - PT Government Associate Laboratory [Braga/Guimarães, Portugal] (AL), Barretos Cancer Hospital [São Paulo, Brazil] (BCH), 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), University Hospital Bydgoszcz [Bydgoszcz, Poland] (UHB), Medical University of Lublin, N. Copernicus Town Hospital [Torun, Poland] (NCTH), Integrative Oncogenomics of Multiple Myeloma Pathogenesis and Progression (CRCINA-ÉQUIPE 11), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Bernardo, Elizabeth, Wrocław Medical University, 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), Universidad de Granada = University of Granada (UGR)-Andalusian Regional Government [Granada, Spain], 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), University of Copenhagen = Københavns Universitet (UCPH), Uniwersytet Jagielloński w Krakowie = Jagiellonian University (UJ), 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), and 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)

Subjects
Oncology, medicine.medical_specialty, Population, [SDV.CAN]Life Sciences [q-bio]/Cancer, Single-nucleotide polymorphism, Genome-wide association study, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Risk Factors, Internal medicine, Genetics, medicine, Genetic predisposition, Humans, Genetic Predisposition to Disease, education, Genetics (clinical), Multiple myeloma, 030304 developmental biology, Genetic association, 0303 health sciences, education.field_of_study, business.industry, medicine.disease, Penetrance, 3. Good health, 030220 oncology & carcinogenesis, Polygenic risk score, Multiple Myeloma, business, Genome-Wide Association Study
Abstract

This work was partially supported by intramural funds of the University of Pisa, DKFZ, and University Hospital of Southern Jutland, Denmark, and by a grant of the French National Cancer Institute (INCA). The authors wish to thank Dr. Dominic Edelmann (Division of Biostatistics, DKFZ) for helpful advice about data analysis., There is overwhelming epidemiologic evidence that the risk of multiple myeloma (MM) has a solid genetic background. Genome-wide association studies (GWAS) have identified 23 risk loci that contribute to the genetic susceptibility of MM, but have low individual penetrance. Combining the SNPs in a polygenic risk score (PRS) is a possible approach to improve their usefulness. Using 2361 MM cases and 1415 controls from the International Multiple Myeloma rESEarch (IMMEnSE) consortium, we computed a weighted and an unweighted PRS. We observed associations with MM risk with OR = 3.44, 95% CI 2.53-4.69, p = 3.55 x 10(-15) for the highest vs. lowest quintile of the weighted score, and OR = 3.18, 95% CI 2.1 = 34-4.33, p = 1.62 x 10(-13) for the highest vs. lowest quintile of the unweighted score. We found a convincing association of a PRS generated with 23 SNPs and risk of MM. Our work provides additional validation of previously discovered MM risk variants and of their combination into a PRS, which is a first step towards the use of genetics for risk stratification in the general population., University of Pisa, DKFZ, University Hospital of Southern Jutland, Denmark, Institut National du Cancer (INCA) France

Published
2021

48. Joint modelling with competing risks of dropout for longitudinal analysis of health-related quality of life in cancer clinical trials

Author

Thierry Conroy, Benjamin Cuer, Sophie Gourgou, Caroline Mollevi, C. Touraine, Beata Juzyna, Institut du Cancer de Montpellier (ICM), 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), Plateforme Nationale Qualité de vie et Cancer, Institut de Cancérologie de Lorraine - Alexis Vautrin [Nancy] (UNICANCER/ICL), UNICANCER, Adaptation, mesure et évaluation en santé. Approches interdisciplinaires (APEMAC), Université de Lorraine (UL), Institut Desbrest de santé publique (IDESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), and Cuer, Benjamin

Subjects
MESH: Computer simulation, Cancer clinical trial, Health-related quality of life, MESH: Quality of life, 01 natural sciences, law.invention, 010104 statistics & probability, Clinical trials, 0302 clinical medicine, [STAT.AP] Statistics [stat]/Applications [stat.AP], Quality of life, Randomized controlled trial, law, Neoplasms, Medicine, MESH: Neoplasms, Longitudinal Studies, MESH: Longitudinal Studies, Joint modelling, health care economics and organizations, Dropout (neural networks), [STAT.AP]Statistics [stat]/Applications [stat.AP], Competing risks, 3. Good health, Oncology, 030220 oncology & carcinogenesis, medicine.medical_specialty, Patient Dropouts, Missing data, education, [SDV.CAN]Life Sciences [q-bio]/Cancer, behavioral disciplines and activities, MESH: Patient Dropouts, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, mental disorders, Humans, Computer Simulation, 0101 mathematics, Health related quality of life, MESH: Humans, Models, Statistical, business.industry, Public Health, Environmental and Occupational Health, Clinical trial, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Quality of Life, Physical therapy, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, MESH: Models, Statistical
Abstract

International audience; Purpose: Health-related quality of life (HRQoL) is an important endpoint in cancer clinical trials. Analysis of HRQoL longitudinal data is plagued by missing data, notably due to dropout. Joint models are increasingly receiving attention for modelling longitudinal outcomes and the time-to-dropout. However, dropout can be informative or non-informative depending on the cause.Methods We propose using a joint model that includes a competing risks sub-model for the cause-specific time-to-dropout. We compared a competing risks joint model (CR JM) that distinguishes between two causes of dropout with a standard joint model (SJM) that treats all the dropouts equally. First, we applied the CR JM and SJM to data from 267 patients with advanced oesophageal cancer from the randomized clinical trial PRODIGE 5/ACCORD 17 to analyse HRQoL data in the presence of dropouts unrelated and related to a clinical event. Then, we compared the models using a simulation study.Results We showed that the CR JM performed as well as the SJM in situations where the risk of dropout was the same whatever the cause. In the presence of both informative and non-informative dropouts, only the SJM estimations were biased, impacting the HRQoL estimated parameters Conclusion The systematic collection of the reasons for dropout in clinical trials would facilitate the use of CR JMs, which could be a satisfactory approach to analysing HRQoL data in presence of both informative and non-informative dropout.Trial registration: This study is registered with ClinicalTrials.gov, number NCT00861094.

Published
2021

49. Peripheral Blood Mononuclear Cells (PBMCs) to Dissect the Underlying Mechanisms of Bone Disease in Chronic Kidney Disease and Rare Renal Diseases

Author

Candide Alioli, Marie-Noelle Meaux, Julie Bernardor, Irma Machuca-Gayet, Justine Bacchetta, Olivier Peyruchaud, Physiopathologie, diagnostic et traitements des maladies osseuses / Pathophysiology, Diagnosis & Treatments of Bone Diseases (LYOS), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Référence des Maladies Rares du Métabolisme du Phosphore et du Calcium and Filière de Santé Maladies Rares (OSCAR), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL), Université Côte d'Azur (UCA), Hôpital Archet 2 [Nice] (CHU), Filières Maladies Rares ORKID et ERK-Net, and Peyruchaud, Olivier

Subjects
Stromal cell, Bone disease, Endocrinology, Diabetes and Metabolism, Cystinosis, Cell Culture Techniques, Osteoclasts, [SDV.CAN]Life Sciences [q-bio]/Cancer, Bone tissue, Peripheral blood mononuclear cell, Bone resorption, Bone remodeling, [SDV.CAN] Life Sciences [q-bio]/Cancer, CKD, medicine, Animals, Humans, Renal Insufficiency, Chronic, Kidney, Osteoblasts, business.industry, medicine.disease, medicine.anatomical_structure, PBMCs, Immunology, Leukocytes, Mononuclear, Bone Diseases, business, Kidney disease
Abstract

International audience; Purpose of review: To describe the methods that can be used to obtain functional and mature osteoclasts from peripheral blood mononuclear cells (PBMCs) and report the data obtained with this model in two peculiar diseases, namely pediatric chronic kidney disease-associated mineral and bone disorders (CKD-MBD) and nephropathic cystinosis. To discuss future research possibilities in the field.Recent findings: Bone tissue undergoes continuous remodeling throughout life to maintain bone architecture; it involves two processes: bone formation and bone resorption with the coordinated activity of osteoblasts, osteoclasts, and osteocytes. Animal models fail to fully explain human bone pathophysiology during chronic kidney disease, mainly due to interspecies differences. The development of in vitro models has permitted to mimic human bone-related diseases as an alternative to in vivo models. Since 1997, osteoclasts have been generated in cell cultures, notably when culturing PBMCs with specific growth factors and cytokines (i.e., M-CSF and RANK-L), without the need for osteoblasts or stromal cells. These models may improve the global understanding of bone pathophysiology. They can be been used not only to evaluate the direct effects of cytokines, hormones, cells, or drugs on bone remodeling during CKD-MBD, but also in peculiar genetic renal diseases inducing specific bone impairment.

Published
2021

50. IAEA Activities on 67Cu, 186Re, 47Sc Theranostic Radionuclides and Radiopharmaceuticals

Author

G. Pupillo, Mohamed A. Gizawy, Amir Reza Jalilian, Aruna Korde, Cyrille Alliot, Sandor Takacs, Katherine Gagnon, Joao A. Osso, Jeong H. Park, Kotaro Nagatsu, Mayeen Uddin Khandaker, Aleksander Bilewicz, Suzanne E. Lapi, Sudipta Chakarborty, Subhani Okarvi, Mohammad R.A. Rovais, Valeriia N. Starovoitova, Renata Mikolajczak, Abdul Hamid Al Rayyes, International Atomic Energy Agency [Vienna] (IAEA), Egyptian Atomic Energy Authority (EAEA), Nuclear Oncology (CRCINA-ÉQUIPE 13), 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), GIPARRONAX [Saint-Herblain, France], Institute For Nuclear Research and Nuclear Energy (INRNE), Bulgarian Academy of Sciences (BAS), Bhabha Atomic Research Centre (BARC), Government of India, Department of Atomic Energy, Nuclear Science and Technology Research Institute [Tehran, Iran] (NSTRI), Istituto Nazionale di Fisica Nucleare (INFN), National Institutes for Quantum and Radiological Science and Technology (QST), Korea Atomic Energy Research Institute [Daejeon, south Korea] (KAERI), Sunway University [Malaysia], Radioisotope Centre POLATOM [Otwock, Pologne] (POLATOM), Institute of Nuclear Chemistry and Technology [Warsaw, Poland] (INCT), King Faisal Specialist Hospital and Resarch Centre [Riyadh, Saudi Arabia] (KFSHRC), Biacore/GE Healthcare [Uppsala], Atomic Energy Commission of Syria (AECS), Gouvernement de la Syrie, University of Alabama at Birmingham [ Birmingham] (UAB), and Bernardo, Elizabeth

Subjects
Pharmacology, Engineering, medicine.medical_specialty, 186Re, business.industry, theranostic, Member states, IAEA, [SDV.CAN]Life Sciences [q-bio]/Cancer, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, 0302 clinical medicine, research reactor, [SDV.CAN] Life Sciences [q-bio]/Cancer, 030220 oncology & carcinogenesis, 47Sc, 67Cu, medicine, cyclotron, Radiology, Nuclear Medicine and imaging, Medical physics, CRP, business
Abstract

Despite interesting properties, the use of 67Cu, 186Re and 47Sc theranostic radionuclides in preclinical studies and clinical trials is curtailed by their limited availability due to a lack of widely established production methods. An IAEA Coordinated Research Project (CRP) was initiated to identify important technical issues related to the production and quality control of these emerging radionuclides and related radiopharmaceuticals, based on the request from IAEA Member States. The international team worked on targetry, separation, quality control and radiopharmaceutical aspects of the radionuclides obtained from research reactors and cyclotrons leading to preparation of a standard recommendations for all Member States. The CRP was initiated in 2016 with fourteen participants from thirteen Member States from four continents. Extraordinary results on the production, quality control and preclinical evaluation of selected radionuclides were reported in this project that was finalized in 2020. The outcomes, outputs and results of this project achieved by participating Member States are described in this minireview.

Published
2021

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