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1. Cumulative incidence and risk factors for radiation induced leukoencephalopathy in high grade glioma long term survivors

Author

Robert Terziev, Dimitri Psimaras, Yannick Marie, Loic Feuvret, Giulia Berzero, Julian Jacob, Caroline Dehais, Flavie Bompaire, Wolf Mueller, Ben Kinnersley, Jean-Yves Delattre, Ahmed Idbaih, Khe Hoang-Xuan, Marc Sanson, and Damien Ricard

Subjects
Medicine, Science
Abstract

Abstract The incidence and risk factors associated with radiation-induced leukoencephalopathy (RIL) in long-term survivors of high-grade glioma (HGG) are still poorly investigated. We performed a retrospective research in our institutional database for patients with supratentorial HGG treated with focal radiotherapy, having a progression-free overall survival > 30 months and available germline DNA. We reviewed MRI scans for signs of leukoencephalopathy on T2/FLAIR sequences, and medical records for information on cerebrovascular risk factors and neurological symptoms. We investigated a panel of candidate single nucleotide polymorphisms (SNPs) to assess genetic risk. Eighty-one HGG patients (18 grade IV and 63 grade III, 50M/31F) were included in the study. The median age at the time of radiotherapy was 48 years old (range 18–69). The median follow-up after the completion of radiotherapy was 79 months. A total of 44 patients (44/81, 54.3%) developed RIL during follow-up. Twenty-nine of the 44 patients developed consistent symptoms such as subcortical dementia (n = 28), gait disturbances (n = 12), and urinary incontinence (n = 9). The cumulative incidence of RIL was 21% at 12 months, 42% at 36 months, and 48% at 60 months. Age > 60 years, smoking, and the germline SNP rs2120825 (PPARg locus) were associated with an increased risk of RIL. Our study identified potential risk factors for the development of RIL (age, smoking, and the germline SNP rs2120825) and established the rationale for testing PPARg agonists in the prevention and management of late-delayed radiation-induced neurotoxicity.

Published
2021
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2. The level of activity of the alternative lengthening of telomeres correlates with patient age in IDH-mutant ATRX-loss-of-expression anaplastic astrocytomas

Author

Nathalie Grandin, Bruno Pereira, Camille Cohen, Pauline Billard, Caroline Dehais, Catherine Carpentier, Ahmed Idbaih, Franck Bielle, François Ducray, Dominique Figarella-Branger, Jean-Yves Delattre, Marc Sanson, Patrick Lomonte, Delphine Poncet, Pierre Verrelle, Michel Charbonneau, and POLA network

Subjects
Anaplastic astrocytoma, Secondary glioblastoma, Alternative lengthening of telomeres, IDH1/2 mutations, ATRX loss of expression, Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract All cancer cells need to maintain functional telomeres to sustain continuous cell division and proliferation. In human diffuse gliomas, functional telomeres are maintained due either to reactivation of telomerase expression, the main pathway in most cancer types, or to activation of a mechanism called the alternative lengthening of telomeres (ALT). The presence of IDH1/2 mutations (IDH-mutant) together with loss of ATRX expression (ATRX-lost) are frequently associated with ALT in diffuse gliomas. However, detection of ALT, and a fortiori its quantification, are rarely, if ever, measured in neuropathology laboratories. We measured the level of ALT activity using the previously described quantitative “C-circle” assay and analyzed it in a well characterized cohort of 104 IDH-mutant and ATRX-lost adult diffuse gliomas. We report that in IDH-mutant ATRX-lost anaplastic astrocytomas, the intensity of ALT was inversely correlated with age (p

Published
2019
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3. Rare Primary Central Nervous System Tumors in Adults: An Overview

Author

Enrico Franceschi, Didier Frappaz, Roberta Rudà, Peter Hau, Matthias Preusser, Caroline Houillier, Giuseppe Lombardi, Sofia Asioli, Caroline Dehais, Franck Bielle, Vincenzo Di Nunno, Martin van den Bent, Alba A. Brandes, Ahmed Idbaih, EURACAN Domain, Paul Clement Radek, Lakomý Nicolai El-Hindy, Jean-Yves Delattre, Ville Vuorinen, Silvia Scoccianti, Riccardo SoffiettiLucia Monti, Andrea Pace, Gaetano Finocchiaro, Arimantas TamasauskasMark ter Laan, Anja Gijtenbeek, Michiel Wagemakers, David NoskeUroš Smrdel, Puneet Plaha, and Naomi Fersht

Subjects
pineal tumors, mesenchymal non meningothelial intracranial tumors, CNS lymphoma, germ cell tumors, pituitary tumor, glioneural tumor, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Overall, tumors of primary central nervous system (CNS) are quite common in adults with an incidence rate close to 30 new cases/100,000 inhabitants per year. Significant clinical and biological advances have been accomplished in the most common adult primary CNS tumors (i.e., diffuse gliomas). However, most CNS tumor subtypes are rare with an incidence rate below the threshold defining rare disease of 6.0 new cases/100,000 inhabitants per year. Close to 150 entities of primary CNS tumors have now been identified by the novel integrated histomolecular classification published by the World Health Organization (WHO) and its updates by the c-IMPACT NOW consortium (the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy). While these entities can be better classified into smaller groups either by their histomolecular features and/or by their location, assessing their treatment by clinical trials and improving the survival of patients remain challenging. Despite these tumors are rare, research, and advances remain slower compared to diffuse gliomas for instance. In some cases (i.e., ependymoma, medulloblastoma) the understanding is high because single or few driver mutations have been defined. The European Union has launched European Reference Networks (ERNs) dedicated to support advances on the clinical side of rare diseases including rare cancers. The ERN for rare solid adult tumors is termed EURACAN. Within EURACAN, Domain 10 brings together the European patient advocacy groups (ePAGs) and physicians dedicated to improving outcomes in rare primary CNS tumors and also aims at supporting research, care and teaching in the field. In this review, we discuss the relevant biological and clinical characteristics, clinical management of patients, and research directions for the following types of rare primary CNS tumors: medulloblastoma, pineal region tumors, glioneuronal and rare glial tumors, ependymal tumors, grade III meningioma and mesenchymal tumors, primary central nervous system lymphoma, germ cell tumors, spinal cord tumors and rare pituitary tumors.

Published
2020
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4. Somatostatin receptor 2A protein expression characterizes anaplastic oligodendrogliomas with favorable outcome

Author

Romain Appay, Emeline Tabouret, Mehdi Touat, Catherine Carpentier, Carole Colin, François Ducray, Ahmed Idbaih, Karima Mokhtari, Emmanuelle Uro-Coste, Caroline Dehais, Dominique Figarella-Branger, and the POLA network

Subjects
Somatostatin receptor subtype 2A (SSTR2A), Glioma, Biomarker, Therapeutic target, Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract Diffuse gliomas are classified according to the 2016 WHO Classification of Tumors of the Central Nervous System, which now defines entities by both histology and molecular features. Somatostatin receptor subtype 2A (SSTR2A) expression has been reported in various solid tumors as associated with favorable outcomes. Its expression has been reported in gliomas with uncertain results regarding its prognostic value. The objective of this study was to assess the prognostic impact of SSTR2A protein expression in a large cohort of grade III and IV gliomas classified according to the updated 2016 WHO classification. We further validated our result with an independent cohort of low grade glioma using dataset generated by The Cancer Genome Atlas (TCGA) Research Network. We analyzed clinical and molecular data from 575 patients. SSTR2A protein expression was evaluated using immunohistochemistry on tissue microarrays. High expression of SSTR2A protein associated with the anaplastic oligodendroglioma IDH-mutant and 1p/19q-codeleted subgroup (p

Published
2018
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5. Integrated multi-omics analysis of oligodendroglial tumours identifies three subgroups of 1p/19q co-deleted gliomas

Author

Aurélie Kamoun, Ahmed Idbaih, Caroline Dehais, Nabila Elarouci, Catherine Carpentier, Eric Letouzé, Carole Colin, Karima Mokhtari, Anne Jouvet, Emmanuelle Uro-Coste, Nadine Martin-Duverneuil, Marc Sanson, Jean-Yves Delattre, Dominique Figarella-Branger, Aurélien de Reyniès, François Ducray, and POLA network

Subjects
Science
Abstract

Oligodendroglial tumours are characterized into three different molecular subtypes. Here, the authors use genomic data to identify a further three subgroups of 1p/19q co-deleted tumours and demonstrate an association with an aggressive phenotype.

Published
2016
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6. Correction: SNP Array Analysis Reveals Novel Genomic Abnormalities Including Copy Neutral Loss of Heterozygosity in Anaplastic Oligodendrogliomas.

Author

Ahmed Idbaih, François Ducray, Caroline Dehais, Célia Courdy, Catherine Carpentier, Simon de Bernard, Emmanuelle Uro-Coste, Karima Mokhtari, Anne Jouvet, Jérôme Honnorat, Olivier Chinot, Carole Ramirez, Patrick Beauchesne, Alexandra Benouaich-Amiel, Joël Godard, Sandrine Eimer, Fabrice Parker, Emmanuelle Lechapt-Zalcman, Philippe Colin, Delphine Loussouarn, Thierry Faillot, Phong Dam-Hieu, Selma Elouadhani-Hamdi, Luc Bauchet, Olivier Langlois, Caroline Le Guerinel, Denys Fontaine, Elodie Vauleon, Philippe Menei, Marie Janette Motsuo Fotso, Christine Desenclos, Pierre Verrelle, François Ghiringhelli, Georges Noel, François Labrousse, Antoine Carpentier, Frédéric Dhermain, Jean-Yves Delattre, and Dominique Figarella-Branger

Subjects
Medicine, Science
Published
2013
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7. SNP array analysis reveals novel genomic abnormalities including copy neutral loss of heterozygosity in anaplastic oligodendrogliomas.

Author

Ahmed Idbaih, François Ducray, Caroline Dehais, Célia Courdy, Catherine Carpentier, Simon de Bernard, Emmanuelle Uro-Coste, Karima Mokhtari, Anne Jouvet, Jérôme Honnorat, Olivier Chinot, Carole Ramirez, Patrick Beauchesne, Alexandra Benouaich-Amiel, Joël Godard, Sandrine Eimer, Fabrice Parker, Emmanuelle Lechapt-Zalcman, Philippe Colin, Delphine Loussouarn, Thierry Faillot, Phong Dam-Hieu, Selma Elouadhani-Hamdi, Luc Bauchet, Olivier Langlois, Caroline Le Guerinel, Denys Fontaine, Elodie Vauleon, Philippe Menei, Marie Janette Motsuo Fotso, Christine Desenclos, Pierre Verrelle, François Ghiringhelli, Georges Noel, François Labrousse, Antoine Carpentier, Frédéric Dhermain, Jean-Yves Delattre, Dominique Figarella-Branger, and POLA Network

Subjects
Medicine, Science
Abstract

Anaplastic oligodendrogliomas (AOD) are rare glial tumors in adults with relative homogeneous clinical, radiological and histological features at the time of diagnosis but dramatically various clinical courses. Studies have identified several molecular abnormalities with clinical or biological relevance to AOD (e.g. t(1;19)(q10;p10), IDH1, IDH2, CIC and FUBP1 mutations).To better characterize the clinical and biological behavior of this tumor type, the creation of a national multicentric network, named "Prise en charge des OLigodendrogliomes Anaplasiques (POLA)," has been supported by the Institut National du Cancer (InCA). Newly diagnosed and centrally validated AOD patients and their related biological material (tumor and blood samples) were prospectively included in the POLA clinical database and tissue bank, respectively.At the molecular level, we have conducted a high-resolution single nucleotide polymorphism array analysis, which included 83 patients. Despite a careful central pathological review, AOD have been found to exhibit heterogeneous genomic features. A total of 82% of the tumors exhibited a 1p/19q-co-deletion, while 18% harbor a distinct chromosome pattern. Novel focal abnormalities, including homozygously deleted, amplified and disrupted regions, have been identified. Recurring copy neutral losses of heterozygosity (CNLOH) inducing the modulation of gene expression have also been discovered. CNLOH in the CDKN2A locus was associated with protein silencing in 1/3 of the cases. In addition, FUBP1 homozygous deletion was detected in one case suggesting a putative tumor suppressor role of FUBP1 in AOD.Our study showed that the genomic and pathological analyses of AOD are synergistic in detecting relevant clinical and biological subgroups of AOD.

Published
2012
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8. A Multigene Signature Associated with Progression-Free Survival after Treatment for IDH Mutant and 1p/19q Codeleted Oligodendrogliomas

Author

Network, Julia Gilhodes, Adèle Meola, Bastien Cabarrou, Guillaume Peyraga, Caroline Dehais, Dominique Figarella-Branger, François Ducray, Claude-Alain Maurage, Delphine Loussouarn, Emmanuelle Uro-Coste, Elizabeth Cohen-Jonathan Moyal, and POLA Network POLA

Subjects
glioma, 1p/19q codeletion, gene signature, treatment response
Abstract

Background. IDH mutant and 1p/19q codeleted oligodendrogliomas are the gliomas associated with the best prognosis. However, despite their sensitivity to treatment, patient survival remains heterogeneous. We aimed to identify gene expressions associated with response to treatment from a national cohort of patients with oligodendrogliomas, all treated with radiotherapy +/− chemotherapy. Methods. We extracted total RNA from frozen tumor samples and investigated enriched pathways using KEGG and Reactome databases. We applied a stability selection approach based on subsampling combined with the lasso-pcvl algorithm to identify genes associated with progression-free survival and calculate a risk score. Results. We included 68 patients with oligodendrogliomas treated with radiotherapy +/− chemotherapy. After filtering, 1697 genes were obtained, including 134 associated with progression-free survival: 35 with a better prognosis and 99 with a poorer one. Eight genes (ST3GAL6, QPCT, NQO1, EPHX1, CST3, S100A8, CHI3L1, and OSBPL3) whose risk score remained statistically significant after adjustment for prognostic factors in multivariate analysis were selected in more than 60% of cases were associated with shorter progression-free survival. Conclusions. We found an eight-gene signature associated with a higher risk of rapid relapse after treatment in patients with oligodendrogliomas. This finding could help clinicians identify patients who need more intensive treatment.

Published
2023
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9. Incidence and Characteristics of Pseudoprogression in IDH-mutant High-Grade Gliomas: A POLA Network Study

Author

Antoine Seyve, Caroline Dehais, Olivier Chinot, Apolline Djelad, Elisabeth Cohen-Moyal, Charlotte Bronnimann, Carole Gourmelon, Evelyne Emery, Philippe Colin, Mathieu Boone, Elodie Vauléon, Olivier Langlois, Anna-Luisa di Stefano, Romuald Seizeur, François Ghiringhelli, Anne D’Hombres, Loic Feuvret, Jacques Guyotat, Laurent Capelle, Catherine Carpentier, Louis Garnier, Jérôme Honnorat, David Meyronet, Karima Mokhtari, Dominique Figarella-Branger, François Ducray, Hospices Civils de Lyon, Departement de Neurologie (HCL), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut de neurophysiopathologie (INP), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Hôpital de la Timone [CHU - APHM] (TIMONE), CHU Bordeaux [Bordeaux], Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, Service de Neurochirurgie [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Institut Toulousain des Maladies Infectieuses et Inflammatoires (Infinity), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Amiens-Picardie, CHirurgie, IMagerie et REgénération tissulaire de l’extrémité céphalique - Caractérisation morphologique et fonctionnelle - UR UPJV 7516 (CHIMERE), Université de Picardie Jules Verne (UPJV), Chemistry, Oncogenesis, Stress and Signaling (COSS), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CRLCC Eugène Marquis (CRLCC), Culture et Environnements, Préhistoire, Antiquité, Moyen-Age (CEPAM), 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)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Service de neurochirurgie [Brest], Hôpital de la Cavale Blanche - CHRU Brest (CHU - BREST ), Laboratoire de Traitement de l'Information Medicale (LaTIM), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire de Brest (CHRU Brest)-IMT Atlantique (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), Hospices Civils de Lyon (HCL), Institut NeuroMyoGène (INMG), 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 de Référence Maladie Rare 'Syndromes neurologiques Paranéoplasiques', Hospices Civils de Lyon (HCL)-Hopital Neurologique, and Hôpital neurologique et neurochirurgical Pierre Wertheimer [CHU - HCL]

Subjects
Cancer Research, High-grade glioma, Oncology, pseudoprogression, Neurology (clinical), IDH-mutant, chemotherapy, radiotherapy, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Background Incidence and characteristics of pseudoprogression in isocitrate dehydrogenase-mutant high-grade gliomas (IDHmt HGG) remain to be specifically described. Methods We analyzed pseudoprogression characteristics and explored the possibility of pseudoprogression misdiagnosis in IDHmt HGG patients, treated with radiotherapy (RT) (with or without chemotherapy [CT]), included in the French POLA network. Pseudoprogression was analyzed in patients with MRI available for review (reference cohort, n = 200). Pseudoprogression misdiagnosis was estimated in this cohort and in an independent cohort (control cohort, n = 543) based on progression-free survival before and after first progression. Results In the reference cohort, 38 patients (19%) presented a pseudoprogression after a median time of 10.5 months after RT. Pseudoprogression characteristics were similar across IDHmt HGG subtypes. In most patients, it consisted of the appearance of one or several infracentimetric, asymptomatic, contrast-enhanced lesions occurring within 2 years after RT. The only factor associated with pseudoprogression occurrence was adjuvant PCV CT. Among patients considered as having a first true progression, 7 out of 41 (17%) in the reference cohort and 35 out of 203 (17%) in the control cohort were retrospectively suspected to have a misdiagnosed pseudoprogression. Patients with a misdiagnosed pseudoprogression were characterized by a time to event and an outcome similar to that of patients with a pseudoprogression but presented with larger and more symptomatic lesions. Conclusion In patients with an IDHmt HGG, pseudoprogression occurs later than in IDH-wildtype glioblastomas and seems not only frequent but also frequently misdiagnosed. Within the first 2 years after RT, the possibility of a pseudoprogression should be carefully considered.

Published
2023

10. Characteristics, Patterns of Care and Predictive Geriatric Factors in Elderly Patients Treated for High-Grade IDH-Mutant Gliomas: A French POLA Network Study

Author

Coline Montégut, Jean-Sébastien Guillamo, François Ducray, Caroline Dehais, Elisabeth Cohen-Jonathan Moyal, Christine Desenclos, Antoine Petit, Romuald Seizeur, Lien Bekaert, Claude Gaultier, Marie Jeannette Motuo Fotso, Marie Blonski, Jean-Sébastien Frenel, Elodie Vauléon, Olivier Langlois, Georges Noel, Antoine F. Carpentier, Anna Luisa Di Stefano, Charlotte Bronnimann, Dominique Figarella-Branger, Olivier Chinot, Emeline Tabouret, Aix-Marseille Université - École de médecine (AMU SMPM MED), Aix-Marseille Université - Faculté des sciences médicales et paramédicales (AMU SMPM), Aix Marseille Université (AMU)-Aix Marseille Université (AMU), Hôpital de la Timone [CHU - APHM] (TIMONE), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut Claudius Regaud, CHU Amiens-Picardie, CHirurgie, IMagerie et REgénération tissulaire de l’extrémité céphalique - Caractérisation morphologique et fonctionnelle - UR UPJV 7516 (CHIMERE), Université de Picardie Jules Verne (UPJV), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Service de neurochirurgie [Brest], Hôpital de la Cavale Blanche - CHRU Brest (CHU - BREST ), Laboratoire de Traitement de l'Information Medicale (LaTIM), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire de Brest (CHRU Brest)-IMT Atlantique (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Service de Neurochirurgie [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Service de neurologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, Chemistry, Oncogenesis, Stress and Signaling (COSS), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CRLCC Eugène Marquis (CRLCC), Hôpital Charles Nicolle [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU), Institut de Cancérologie de Strasbourg Europe (ICANS), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Foch [Suresnes], CHU Bordeaux [Bordeaux], Service d'Anatomie Pathologique et de Neuropathologie [Hôpital de la Timone - CHU - APHM], Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Institut de neurophysiopathologie (INP), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Rôle et mécanismes d'action de l'adrenomedulline dans la croissance tumorale : Application au modèle des gliomes, Université de la Méditerranée - Aix-Marseille 2-IFR11-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Service d'Onco-neurologie = Département de neurologie 2 [CHU Pitié Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Commissariat à l'énergie atomique et aux énergies alternatives - Laboratoire d'Electronique et de Technologie de l'Information (CEA-LETI), Direction de Recherche Technologique (CEA) (DRT (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'Études Préhistoire, Antiquité, Moyen-Age (CEPAM), Université Nice Sophia Antipolis (1965 - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Cancer Research, high grade glioma, Oncology, geriatric assessment, IDH mutation, elderly, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; Background: Describe the characteristics, patterns of care, and predictive geriatric factors of elderly patients with IDHm high-grade glioma (HGG) included in the French POLA network. Material and Methods: The characteristics of elderly (≥70 years) patients IDHm HGG were compared to those of younger patients IDHm HGG (

Published
2022

11. The TeloDIAG: how telomeric parameters can help in glioma rapid diagnosis and liquid biopsy approaches

Author

C Guerriau, Delphine Maucort-Boulch, Pauline Billard, Pierre Verrelle, Michel Charbonneau, Ruth Rimokh, Catherine Carpentier, Delphine Poncet, Dominique Figarella-Branger, François Ducray, David Meyronet, Patrick Lomonte, Nathalie Grandin, N Dufay, Marc Barritault, P Kantapareddy, Caroline Dehais, F Juillard, Service de Biostatistiques [Lyon], Hospices Civils de Lyon (HCL), 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), Institut de neurophysiopathologie (INP), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Service d’Anatomie Pathologique et de Neuropathologie, APHM, Hôpital de la Timone, and Hôpital de la Timone [CHU - APHM] (TIMONE)

Subjects
Oncology, Telomerase, medicine.medical_specialty, X-linked Nuclear Protein, [SDV]Life Sciences [q-bio], [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Internal medicine, Glioma, medicine, Humans, Liquid biopsy, neoplasms, Grading (tumors), ComputingMilieux_MISCELLANEOUS, ATRX, business.industry, Brain Neoplasms, Liquid Biopsy, Astrocytoma, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Hematology, Telomere, medicine.disease, Isocitrate Dehydrogenase, nervous system diseases, Isocitrate dehydrogenase, Oligodendroglioma, business
Abstract

Background In glioma, TERT promoter mutation and loss of ATRX (ATRX loss) are associated with reactivation of telomerase or alternative lengthening of telomeres (ALT), respectively, i.e. the two telomere maintenance mechanisms (TMM). Strangely, 25% of gliomas have been reported to display neither or both of these alterations. Materials and methods The C-circle (CC) assay was adapted to tumor (formalin-fixed paraffin-embedded and frozen) and blood samples to investigate the TMM. Results We constructed a CC-based algorithm able to identify the TMM and reported a sensitivity of 100% and a specificity of 97.3% (n = 284 gliomas). By combining the TMM, the mutational status of the isocitrate dehydrogenase 1/2 (IDH) gene (IDHmt), and the histological grading, we propose a new classification tool: TeloDIAG. This classification defined five subtypes: tOD, tLGA, tGBM_IDHmt, tGBM, and tAIV, corresponding to oligodendroglioma, IDHmt low-grade astrocytoma, IDHmt glioblastoma, and IDHwt glioblastoma (GBM), respectively; the last class gathers ALT+ IDHwt gliomas that tend to be related to longer survival (21.2 months) than tGBM (16.5 months). The TeloDIAG was 99% concordant with the World Health Organization classification (n = 312), and further modified the classification of 55 of 144 (38%) gliomas with atypical molecular characteristics. As an example, 14 of 69 (20%) of TERTwt, ATRXwt, and IDHwt GBM were actually tAIV. Outstandingly, CC in blood sampled from IDHmt astrocytoma patients was detected with a sensitivity of 56% and a specificity of 97% (n = 206 gliomas and 30 healthy donors). Conclusion The TeloDIAG is a new, simple, and effective tool helping in glioma diagnosis and a promising option for liquid biopsy.

Published
2021

12. Olaparib in recurrent IDH-mutant high-grade glioma (OLAGLI)

Author

Delphine Maucort-Boulch, Amelie Darlix, Roxana Ameli, Olivier Chinot, Caroline Dehais, David Meyronet, Laure Thomas-Maisonneuve, Alice Bonneville-Levard, Jérôme Honnorat, François Gueyffier, Marc Sanson, François Ducray, Emeline Tabouret, Laurent Remontet, Maxime Fontanilles, Stéphanie Cartalat, Romain Rivoirard, Institut de neurophysiopathologie (INP), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Neuro-Oncologie [Hôpital de la Timone - APHM], and Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)

Subjects
Cancer Research, Chemotherapy, business.industry, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Mutant, Olaparib, Radiation therapy, chemistry.chemical_compound, Oncology, chemistry, Cancer research, medicine, business, High-Grade Glioma
Abstract

2007 Background: There is a need to develop new treatments in IDH-mutant high-grade gliomas recurring after radiotherapy and chemotherapy. Based on preclinical studies showing that IDH-mutant tumors could be vulnerable to PARP inhibition we launched a phase II study to test the efficacy of olaparib (Lynparza) monotherapy in this population. Methods: Adults with recurrent high-grade IDH-mutant gliomas after radiotherapy and at least one line of alkylating chemotherapy (PCV or TMZ), KPS > 60, normal organ function were enrolled. The primary endpoint was 6 months PFS according to RANO criteria. Patients were treated with olaparib 300 mg twice daily. We used a single-stage Fleming design with p0 = 30%, p1 = 50%, a type I unilateral error rate of 5% and a power of 80%. Results: 35 patients with recurrent IDH-mutant gliomas (IDH1R132H-mutant n = 32, other IDH mutation n = 3, 1p/19 codeleted n = 16, 1p/19q non-codeleted n = 14) were enrolled (malignantly transformed low-grade gliomas n = 21, anaplastic gliomas n = 8, glioblastomas n = 6). Median time since diagnosis was 7.4 years (1-22 years), median time since radiotherapy was 2.8 years (0.6-18 years), median number of previous chemotherapy lines was 2 (1-5). With a median follow-up of 11 months, 30 patients had stopped treatment due to tumor progression and 2 patients were still on treatment 16 to 18 months after treatment start. At 6 months, 11/35 patients were progression-free (31 %). According to RANO criteria, based on local investigator analysis, 2 patients (5%) had a partial response and 14 patients a stable disease (37%) with a median duration of response of 9 months (4-18 months+). Median PFS and OS were 2.3 and 15.9 months and were similar in 1p/19q codeleted and non-codeleted patients. A grade 3 olaparib-related adverse event was observed in 5 patients (14%, lymphopenia n = 3, fatigue n = 2, diarrhea n = 1) and a grade 2 in 15 patients (43%), most frequently consisting in fatigue (23%), gastrointestinal disorders (20%) and lymphopenia (20%). No patient definitively stopped olaparib due to side effects. Conclusions: In this heavily pre-treated population of recurrent IDH-mutant gliomas, olaparib monotherapy was well tolerated and resulted in some activity supporting its evaluation in association with alkylating chemotherapy in recurrent IDH-mutant gliomas in future studies. Clinical trial information: NCT03561870.

Published
2021

13. Cumulative incidence and risk factors for radiation induced leukoencephalopathy in high grade glioma long term survivors

Author

Ben Kinnersley, Julian Jacob, Wolf Mueller, Flavie Bompaire, Giulia Berzero, Yannick Marie, Robert Terziev, Damien Ricard, Caroline Dehais, Marc Sanson, Loïc Feuvret, Ahmed Idbaih, Khê Hoang-Xuan, Jean-Yves Delattre, Dimitri Psimaras, Terziev, R., Psimaras, D., Marie, Y., Feuvret, L., Berzero, G., Jacob, J., Dehais, C., Bompaire, F., Mueller, W., Kinnersley, B., Delattre, J. -Y., Idbaih, A., Hoang-Xuan, K., Sanson, M., Ricard, D., Sorbonne Université - Département de neurologie 2 - Mazarin, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Leipzig University, University hospital of Zurich [Zurich], Hôpital d'instruction des Armées Percy, Service de Santé des Armées, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service de Radiothérapie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), CB - Centre Borelli - UMR 9010 (CB), Service de Santé des Armées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Ecole Normale Supérieure Paris-Saclay (ENS Paris Saclay)-Université de Paris (UP), The institute of cancer research [London], École du Val de Grâce (EVDG), CHU Pitié-Salpêtrière [AP-HP], Gestionnaire, Hal Sorbonne Université, Service d'Onco-neurologie = Département de neurologie 2 [CHU Pitié Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service d'Oncologie Radiothérapie [CHU Pitié Salpétrière], and Service de Santé des Armées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Ecole Normale Supérieure Paris-Saclay (ENS Paris Saclay)-Université Paris Cité (UPCité)

Subjects
Oncology, Male, Cancer therapy, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Urinary incontinence, Leukoencephalopathy, 0302 clinical medicine, Cancer Survivors, Leukoencephalopathies, Risk Factors, White matter disease, Cumulative incidence, Survivors, Multidisciplinary, Molecular medicine, Brain Neoplasms, Incidence (epidemiology), Medical record, Incidence, Smoking, Age Factors, Glioma, Middle Aged, Magnetic Resonance Imaging, Progression-Free Survival, 3. Good health, [SDV] Life Sciences [q-bio], 030220 oncology & carcinogenesis, Medicine, Female, medicine.symptom, Adult, medicine.medical_specialty, Adolescent, Science, Single-nucleotide polymorphism, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Young Adult, Neurotoxicity syndromes, Internal medicine, medicine, Humans, Radiation Injuries, Aged, Retrospective Studies, Radiotherapy, business.industry, medicine.disease, Radiation therapy, CNS cancer, business, 030217 neurology & neurosurgery
Abstract

The incidence and risk factors associated with radiation-induced leukoencephalopathy (RIL) in long-term survivors of high-grade glioma (HGG) are still poorly investigated. We performed a retrospective research in our institutional database for patients with supratentorial HGG treated with focal radiotherapy, having a progression-free overall survival > 30 months and available germline DNA. We reviewed MRI scans for signs of leukoencephalopathy on T2/FLAIR sequences, and medical records for information on cerebrovascular risk factors and neurological symptoms. We investigated a panel of candidate single nucleotide polymorphisms (SNPs) to assess genetic risk. Eighty-one HGG patients (18 grade IV and 63 grade III, 50M/31F) were included in the study. The median age at the time of radiotherapy was 48 years old (range 18–69). The median follow-up after the completion of radiotherapy was 79 months. A total of 44 patients (44/81, 54.3%) developed RIL during follow-up. Twenty-nine of the 44 patients developed consistent symptoms such as subcortical dementia (n = 28), gait disturbances (n = 12), and urinary incontinence (n = 9). The cumulative incidence of RIL was 21% at 12 months, 42% at 36 months, and 48% at 60 months. Age > 60 years, smoking, and the germline SNP rs2120825 (PPARg locus) were associated with an increased risk of RIL. Our study identified potential risk factors for the development of RIL (age, smoking, and the germline SNP rs2120825) and established the rationale for testing PPARg agonists in the prevention and management of late-delayed radiation-induced neurotoxicity.

Published
2021

14. An AI-Powered Blood Test to Detect Cancer Using NanoDSF

Author

Hamed Benazha, Caroline Dehais, Svetlana Gorokhova, Olivier Chinot, Rémi Eyraud, Philipp O. Tsvetkov, Stéphane Ayache, Anton A. Bougaev, Emeline Tabouret, Christophe Buffat, Dominique Figarella-Branger, Soazig Malesinski, François Devred, Marc Sanson, Franck Bielle, Devred, François, Institut de neurophysiopathologie (INP), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Hubert Curien [Saint Etienne] (LHC), Institut d'Optique Graduate School (IOGS)-Université Jean Monnet - Saint-Étienne (UJM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Informatique et Systèmes (LIS), Aix Marseille Université (AMU)-Université de Toulon (UTLN)-Centre National de la Recherche Scientifique (CNRS), éQuipe d'AppRentissage de MArseille (QARMA), Aix Marseille Université (AMU)-Université de Toulon (UTLN)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)-Université de Toulon (UTLN)-Centre National de la Recherche Scientifique (CNRS), Oracle Labs, Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Hôpital de la Timone [CHU - APHM] (TIMONE), Canceropôle PACA: Emergence, Institut National de laSantéet de la Recherche Médicale: Inserm Cancer MIC, ARTC Sud: Patient association and SIRICCURAMUS: INCa-DGOS-Inserm_12560, Université Jean Monnet [Saint-Étienne] (UJM)-Centre National de la Recherche Scientifique (CNRS)-Institut d'Optique Graduate School (IOGS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and Laboratoire Hubert Curien (LHC)

Subjects
FOS: Computer and information sciences, Computer Science - Machine Learning, Diagnostic methods, Computer science, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV.BBM.BP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics, diagnostic, [SDV.CAN]Life Sciences [q-bio]/Cancer, Quantitative Biology - Quantitative Methods, lcsh:RC254-282, Article, Machine Learning (cs.LG), 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Glioma, glioma, medicine, cancer, Blood test, Tissues and Organs (q-bio.TO), Throughput (business), Quantitative Methods (q-bio.QM), 030304 developmental biology, 0303 health sciences, medicine.diagnostic_test, liquid biopsy, business.industry, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Cancer, Quantitative Biology - Tissues and Organs, Pattern recognition, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, medicine.disease, 3. Good health, [SDV.BBM.BP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics, FOS: Biological sciences, 030220 oncology & carcinogenesis, biomarker, Artificial intelligence, business, nanoDSF
Abstract

Simple Summary Brain cancers, such as gliomas, are very difficult to detect because of their localization and late onset of symptoms. Here, we have developed a novel cancer detection method based on plasma denaturation profiles obtained by a non-conventional use of Differential Scanning Fluorimetry. Using blood samples from glioma patients and healthy controls, we show that their denaturation profiles can be automatically distinguished with the help of machine learning algorithms with 92% accuracy. This promising approach can now be extended to other types of cancers and could become a powerful pan-cancer diagnostic and monitoring tool requiring only a simple blood test. Abstract Glioblastoma is the most frequent and aggressive primary brain tumor. Its diagnosis is based on resection or biopsy that could be especially difficult and dangerous in the case of deep location or patient comorbidities. Monitoring disease evolution and progression also requires repeated biopsies that are often not feasible. Therefore, there is an urgent need to develop biomarkers to diagnose and follow glioblastoma evolution in a minimally invasive way. In the present study, we described a novel cancer detection method based on plasma denaturation profiles obtained by a non-conventional use of differential scanning fluorimetry. Using blood samples from 84 glioma patients and 63 healthy controls, we showed that their denaturation profiles can be automatically distinguished with the help of machine learning algorithms with 92% accuracy. Proposed high throughput workflow can be applied to any type of cancer and could become a powerful pan-cancer diagnostic and monitoring tool requiring only a simple blood test.

Published
2021
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15. Radiotherapy Plus Procarbazine, Lomustine, and Vincristine Versus Radiotherapy Plus Temozolomide for IDH‐Mutant Anaplastic Astrocytoma: A Retrospective Multicenter Analysis of the French POLA Cohort

Author

Vincent Esteyrie, Caroline Dehais, Elodie Martin, Catherine Carpentier, Emmanuelle Uro-Coste, Dominique Figarella-Branger, Charlotte Bronniman, Damien Pouessel, Delphine Larrieu Ciron, François Ducray, Elizabeth Cohen-Jonathan Moyal, and Pola Network

Subjects
Oncology, Cancer Research, medicine.medical_specialty, Vincristine, Astrocytoma, Procarbazine, 03 medical and health sciences, 0302 clinical medicine, Lomustine, Internal medicine, PCV Regimen, Antineoplastic Combined Chemotherapy Protocols, medicine, Temozolomide, Humans, Neuro‐Oncology, Retrospective Studies, business.industry, Brain Neoplasms, medicine.disease, Chemotherapy regimen, 3. Good health, Regimen, 030220 oncology & carcinogenesis, business, 030217 neurology & neurosurgery, Anaplastic astrocytoma, medicine.drug
Abstract

Background IDH-mutant anaplastic astrocytomas (AAs) are chemosensitive tumors for which the best choice of adjuvant chemotherapy between procarbazine, lomustine, and vincristine (PCV) or temozolomide (TMZ) after radiotherapy (RT) remains unclear. Methods In a large cohort of patients with histologically proven 2016 World Health Organization classification AA with IDH1/2 mutations included in the French national POLA cohort (n = 355), the primary objective was to compare progression-free survival (PFS) between the two treatment regimens (n = 311). Secondary endpoints were overall survival (OS), progression type, pseudoprogression rate, and toxicity. Results The 4-year PFS in the RT + PCV arm was 70.8% versus 53.5% in the RT + TMZ arm, with a hazard ratio (HR) of 0.58 (95% confidence interval [CI], 0.38–0.87; p = .0074) in univariable analysis and 0.63 (95% CI, 0.41–0.97; p = .0348) in multivariable analysis. The 4-year OS in the RT + PCV arm was 84.3% versus 76.6% in the RT + TMZ arm, with an HR of 0.57 (95% CI, 0.30–1.05; p = .0675) in univariable analysis. Toxicity was significantly higher in the RT + PCV arm with more grade ≥3 toxicity (46.7% vs. 8.6%, p < .0001). Conclusion RT + PCV significantly improved PFS compared with RT + TMZ for IDH-mutant AA. However, RT + TMZ was better tolerated. Implications for Practice In the absence of fully conducted randomized trials comparing procarbazine, lomustine, and vincristine (PCV) with temozolomide (TMZ) in adjuvant treatment after radiotherapy (RT) for the management of IDH-mutant anaplastic astrocytoma (AA) and a similar level of evidence, these two chemotherapies are both equally recommended in international guidelines. This study in a national cohort of IDH-mutant AA defined according the 2016 World Health Organization (WHO) classification shows for the first time that the RT + PCV regimen significantly improves progression-free survival in comparison with the RT + TMZ regimen. Even if at the time of analysis the difference in overall survival was not significant, this result provides new evidence for the debate about the chemotherapy regimen to prescribe in adjuvant treatment to RT for WHO 2016 IDH-mutant AA.

Published
2021

16. Germline mutations in the new E1' cryptic exon of the VHL gene in patients with tumours of von Hippel- Lindau disease spectrum or with paraganglioma

Author

Caroline Dehais, Bruna Calsina, Anne Paule Gimenez-Roqueplo, Judith Favier, Brigitte Bressac-de Paillerets, Shahida K. Flores, Javier Aller, Stéphane Richard, Philippe Herman, Pauline Romanet, Peter Kamenický, Marion Lenglet, S. Giraud, Anne Barlier, Atanaska Elenkova, Sophie Lejeune, Betty Gardie, Alexandre Buffet, Mercedes Robledo, Elisa Deflorenne, María Calatayud, J.-L. Sadoul, Erwan De Mones Del Pujol, Isabelle Bourdeau, Nelly Burnichon, Patricia L. M. Dahia, Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), 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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Spanish National Cancer Research Center (CNIO), The University of Texas at San Antonio (UTSA), Hospices Civils de Lyon (HCL), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Hospital Universitario Puerta de Hierro, Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM), Centre Hospitalier de l'Université de Montréal (CHUM), Université de Montréal (UdeM)-Université de Montréal (UdeM), Institut Gustave Roussy (IGR), Génétique (Biologie pathologie), Département de biologie et pathologie médicales [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Hospital Universitario 12 de Octubre [Madrid], Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-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), Hôpital Pellegrin, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Medical University of Sofia [Bulgarie], Hôpital Lariboisière-Fernand-Widal [APHP], Hôpital Bicêtre, CHU Lille, Service d'endocrinologie [CHU Nice], Centre Hospitalier Universitaire de Nice (CHU Nice), 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, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), 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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Unité de recherche de l'institut du thorax (ITX-lab), romanet, pauline, École Pratique des Hautes Études (EPHE), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut Marseille Maladies Rares (MarMaRa), Aix Marseille Université (AMU), Laboratoire de Biochimie et de Biologie Moléculaire [Hôpital de la Conception - APHM], and Hôpital de la Conception [CHU - APHM] (LA CONCEPTION)

Subjects
0301 basic medicine, Oncology, Male, von Hippel-Lindau Disease, endocrine system diseases, urologic and male genital diseases, Germline, 0302 clinical medicine, Paraganglioma, Genetics (clinical), Exome sequencing, ComputingMilieux_MISCELLANEOUS, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, medicine.diagnostic_test, High-Throughput Nucleotide Sequencing, Exons, Middle Aged, female genital diseases and pregnancy complications, cryptic exon, 3. Good health, Pedigree, Von Hippel-Lindau Tumor Suppressor Protein, 030220 oncology & carcinogenesis, Cohort, Female, Adult, medicine.medical_specialty, Pheochromocytoma, 03 medical and health sciences, Young Adult, Germline mutation, Internal medicine, Genetics, medicine, Cancer Genetics, Humans, Genetic Predisposition to Disease, Genetic Testing, Von Hippel–Lindau disease, neoplasms, Germ-Line Mutation, Genetic testing, Aged, business.industry, medicine.disease, 030104 developmental biology, business, von Hippel-Lindau, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

BackgroundsThe incidence of germline mutations in the newly discovered cryptic exon (E1’) of VHL gene in patients with von Hippel-Lindau (VHL) disease and in patients with paraganglioma or pheochromocytoma (PPGL) is not currently known.MethodsWe studied a large international multicentre cohort of 1167 patients with a previous negative genetic testing. Germline DNA from 75 patients with a single tumour of the VHL spectrum (‘Single VHL tumour’ cohort), 70 patients with multiple tumours of the VHL spectrum (‘Multiple VHL tumours’ cohort), 76 patients with a VHL disease as described in the literature (‘VHL-like’ cohort) and 946 patients with a PPGL were screened for E1’ genetic variants.ResultsSix different genetic variants in E1' were detected in 12 patients. Two were classified as pathogenic, 3 as variants of unknown significance and 1 as benign. The rs139622356 was found in seven unrelated patients but described in only 16 patients out of the 31 390 of the Genome Aggregation Database (pConclusionsVHL E1’ cryptic exon mutations contribute to 1.32% (1/76) of ‘VHL-like’ cohort and to 0.11% (1/946) of PPGL cohort and should be screened in patients with clinical suspicion of VHL, and added to panels for Next Generation Sequencing (NGS) diagnostic testing of hereditary PPGL. Our data highlight the importance of studying variants identified in deep intronic sequences, which would have been missed by examining only coding sequences of genes/exomes. These variants will likely be more frequently detected and studied with the upcoming implementation of whole-genome sequencing into clinical practice.

Published
2020

17. Same-day genomic and epigenomic diagnosis of brain tumors using real-time nanopore sequencing

Author

Franck Bielle, Karim Labreche, Caroline Dehais, Charlotte Schmitt, Mailys Daniau, Shai Rosenberg, Julien Masliah-Planchon, Wigard P. Kloosterman, Franck Bourdeaut, Ahmed Idbaih, Yannick Marie, Jean-Yves Delattre, and Philipp Euskirchen

Subjects
0301 basic medicine, Cancer genome sequencing, Epigenomics, Nanopore sequencing, DNA Copy Number Variations, Methods Paper, Molecular neuropathology, Genomics, Biology, Pathology and Forensic Medicine, 03 medical and health sciences, Cellular and Molecular Neuroscience, Nanopores, Humans, Promoter Regions, Genetic, Exome sequencing, Genetics, Whole genome sequencing, Brain Neoplasms, Glioma, DNA Methylation, Molecular diagnostics, Brain tumor, 030104 developmental biology, Single cell sequencing, Neurology (clinical)
Abstract

Molecular classification of cancer has entered clinical routine to inform diagnosis, prognosis, and treatment decisions. At the same time, new tumor entities have been identified that cannot be defined histologically. For central nervous system tumors, the current World Health Organization classification explicitly demands molecular testing, e.g., for 1p/19q-codeletion or IDH mutations, to make an integrated histomolecular diagnosis. However, a plethora of sophisticated technologies is currently needed to assess different genomic and epigenomic alterations and turnaround times are in the range of weeks, which makes standardized and widespread implementation difficult and hinders timely decision making. Here, we explored the potential of a pocket-size nanopore sequencing device for multimodal and rapid molecular diagnostics of cancer. Low-pass whole genome sequencing was used to simultaneously generate copy number (CN) and methylation profiles from native tumor DNA in the same sequencing run. Single nucleotide variants in IDH1, IDH2, TP53, H3F3A, and the TERT promoter region were identified using deep amplicon sequencing. Nanopore sequencing yielded ~0.1X genome coverage within 6 h and resulting CN and epigenetic profiles correlated well with matched microarray data. Diagnostically relevant alterations, such as 1p/19q codeletion, and focal amplifications could be recapitulated. Using ad hoc random forests, we could perform supervised pan-cancer classification to distinguish gliomas, medulloblastomas, and brain metastases of different primary sites. Single nucleotide variants in IDH1, IDH2, and H3F3A were identified using deep amplicon sequencing within minutes of sequencing. Detection of TP53 and TERT promoter mutations shows that sequencing of entire genes and GC-rich regions is feasible. Nanopore sequencing allows same-day detection of structural variants, point mutations, and methylation profiling using a single device with negligible capital cost. It outperforms hybridization-based and current sequencing technologies with respect to time to diagnosis and required laboratory equipment and expertise, aiming to make precision medicine possible for every cancer patient, even in resource-restricted settings. Electronic supplementary material The online version of this article (doi:10.1007/s00401-017-1743-5) contains supplementary material, which is available to authorized users.

Published
2017

18. The level of activity of the alternative lengthening of telomeres correlates with patient age in IDH-mutant ATRX-loss-of-expression anaplastic astrocytomas

Author

Pierre Verrelle, Nathalie Grandin, Bruno Pereira, Ahmed Idbaih, Delphine Poncet, François Ducray, Franck Bielle, Pauline Billard, Patrick Lomonte, Jean-Yves Delattre, Dominique Figarella-Branger, Marc Sanson, Caroline Dehais, Catherine Carpentier, Camille Cohen, Michel Charbonneau, Génétique, Reproduction et Développement (GReD), Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Clermont-Ferrand, Université Paris Descartes - Faculté de Médecine (UPD5 Médecine), Université Paris Descartes - Paris 5 (UPD5), Université de Caen Normandie (UNICAEN), Normandie Université (NU), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 (UPMC), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de neurophysiopathologie (INP), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de génétique et de physiologie moléculaire et cellulaire (CGPhiMC), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Cancer Resistance Exploring and Targeting (CREaT), Université d'Auvergne - Clermont-Ferrand I (UdA), Institut Armand Frappier (INRS-IAF), Institut National de la Recherche Scientifique [Québec] (INRS)-Réseau International des Instituts Pasteur (RIIP), Pola Network, 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, Institut NeuroMyoGène (INMG), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Charles Foix [AP-HP], Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Hôpital de la Timone [CHU - APHM] (TIMONE), Chimie, Modélisation et Imagerie pour la Biologie [Orsay], Université Paris-Sud - Paris 11 (UP11)-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), Sorbonne Université - Département de neurologie 2 - Mazarin, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, 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), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP]-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [APHP], Centre de Recherche en Cancérologie de Lyon (CRCL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Réseau International des Instituts Pasteur (RIIP)-Institut National de la Recherche Scientifique [Québec] (INRS), and LOMONTE, PATRICK

Subjects
Male, Telomerase, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV]Life Sciences [q-bio], [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], lcsh:RC346-429, MESH: Isocitrate Dehydrogenase, Cohort Studies, 0302 clinical medicine, ATRX loss of expression, Medicine, MESH: Cohort Studies, ComputingMilieux_MISCELLANEOUS, MESH: Aged, 0303 health sciences, MESH: Middle Aged, MESH: X-linked Nuclear Protein, Brain Neoplasms, MESH: Gene Expression Regulation, Neoplastic, Middle Aged, Isocitrate Dehydrogenase, 3. Good health, Gene Expression Regulation, Neoplastic, Secondary glioblastoma, 030220 oncology & carcinogenesis, MESH: Brain Neoplasms, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Female, Anaplastic astrocytoma, Adult, X-linked Nuclear Protein, IDH1, MESH: Mutation, [SDV.CAN]Life Sciences [q-bio]/Cancer, Neuropathology, Astrocytoma, Pathology and Forensic Medicine, MESH: Telomere Homeostasis, 03 medical and health sciences, Cellular and Molecular Neuroscience, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Alternative lengthening of telomeres, Humans, lcsh:Neurology. Diseases of the nervous system, ATRX, Aged, 030304 developmental biology, IDH1/2 mutations, MESH: Humans, business.industry, Research, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Telomere Homeostasis, Cancer, MESH: Adult, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease, MESH: Male, Telomere, MESH: Astrocytoma, Mutation, Cancer cell, Cancer research, Neurology (clinical), business, MESH: Female
Abstract

All cancer cells need to maintain functional telomeres to sustain continuous cell division and proliferation. In human diffuse gliomas, functional telomeres are maintained due either to reactivation of telomerase expression, the main pathway in most cancer types, or to activation of a mechanism called the alternative lengthening of telomeres (ALT). The presence of IDH1/2 mutations (IDH-mutant) together with loss of ATRX expression (ATRX-lost) are frequently associated with ALT in diffuse gliomas. However, detection of ALT, anda fortioriits quantification, are rarely, if ever, measured in neuropathology laboratories. We measured the level of ALT activity using the previously described quantitative “C-circle” assay and analyzed it in a well characterized cohort of 104 IDH-mutant and ATRX-lost adult diffuse gliomas. We report that in IDH-mutant ATRX-lost anaplastic astrocytomas, the intensity of ALT was inversely correlated with age (p

Published
2019

19. DRES-08. CLINICAL SIGNIFICANCE OF HYPERMUTATION IN GLIOMAS

Author

Bryan Iorgulescu, Mehdi Touat, Andrew D. Cherniack, Agusti Alentorn, David A. Reardon, Caroline Dehais, Rameen Beroukhim, Capucine Baldini, Khê Hoang-Xuan, Karima Mokhtari, Aurélien Marabelle, Alexandre Carpentier, Raymond Y. Huang, Alex Duval, Marc Sanson, Sangita Pal, Adam Boynton, Maite Verreault, Franck Bielle, Azra H. Ligon, Brian M. Alexander, Pratiti Bandopadhayay, Ennio Antonio Chiocca, David Meredith, Frédéric Beuvon, Erell Guillerm, Patrick Y. Wen, Lakshmi Nayak, Nadia Younan, Sandro Santagata, Florence Laigle-Donadey, Daphne A. Haas-Kogan, Ruben Ferrer-Luna, Florence Coulet, Jack Geduldig, Eudocia Q. Lee, Susan N. Chi, Sanda Alexandrescu, Jean-Yves Delattre, Wenya Bi, Christina Birzu, Samy Ammari, Ahmed Idbaih, Keith L. Ligon, Bertrand Mathon, Philippe Cornu, Liam F. Spurr, Yvonne Y. Li, Caroline Houiller, and Charlotte Bellamy

Subjects
Cancer Research, Standard of care, business.industry, Cancer therapy, Drug Resistance, Somatic hypermutation, medicine.disease, Oncology, Glioma, Cancer research, medicine, Clinical significance, Neurology (clinical), business
Abstract

BACKGROUND Hypermutation is an emerging biomarker for predicting response to immunotherapy in cancer patients, however its clinical value in gliomas is not established. We sought to assess the determinants of hypermutation in gliomas, and its value for predicting response to standard of care and immune checkpoint blockade (ICB). METHODS We performed comprehensive genomic characterization of 2,420 clinically annotated gliomas. We assessed the clinical and molecular characteristics associated with hypermutation and relationships between hypermutation and response to cancer treatments. RESULTS Hypermutation occurred predominantly as an adaptive resistance mechanism to temozolomide in gliomas and was most prevalent in recurrent gliomas with MGMTpromoter methylation (33.8%), IDH1/2mutation (41.0%) or 1p/19q co-deletion (59.5%). Hypermutation was almost always associated with molecular defects in DNA mismatch repair (MMR), and was associated with shorter survival after its appearance based on multivariate analysis (hazard ratio 1.91; 95% CI 1.24–2.94; P=0.004). The molecular mechanisms whereby gliomas undergo hypermutation during therapy with alkylating agents were dissected using patient-derived glioma models in vitro and in vivo. Outcomes of hypermutated gliomas treated with immune checkpoint blockade or with standard of care agents will be presented at the conference. CONCLUSIONS Using the largest set of hypermutated gliomas described to date, this study establishes that mutational burden and mutation signatures are clinically and biologically significant biomarkers that can be used to predict therapy response and guide treatment decisions in gliomas

Published
2019

20. Ki‐67 and MCM6 labeling indices are correlated with overall survival in anaplastic oligodendroglioma, IDH1‐mutant and 1p/19q‐codeleted: a multicenter study from the French POLA network

Author

Celso Pouget, Sébastien Hergalant, Emilie Lardenois, Stéphanie Lacomme, Rémi Houlgatte, Catherine Carpentier, Caroline Dehais, Fabien Rech, Luc Taillandier, Marc Sanson, Romain Appay, Carole Colin, Dominique Figarella‐Branger, Shyue‐Fang Battaglia‐Hsu, Guillaume Gauchotte, Christine Desenclos, H. Sevestre, Philippe Menei, A. Rousseau, T. Cruel, S. Lopez, M.I. Mihai, A. Petit, R. Seizeur, I. Quintin‐Roué, C. Adam, F. Parker, S. Eimer, H. Loiseau, L. Bekaert, F. Chapon, D. Ricard, C. Godfraind, T. Khallil, D. Cazals‐Hatem, T. Faillot, C. Gaultier, M. C Tortel, I. Carpiuc, P. Richard, W. Lahiani, H. Aubriot‐Lorton, F. Ghiringhelli, C‐A Maurage, E. Le Rhun, E. M. Gueye, F. Labrousse, F. Ducray, D. Meyronet, O. Chinot, L. Bauchet, V. Rigau, P. Beauchesne, M. Campone, D. Loussouarn, D. Fontaine, F. Vandenbos‐Burel, A. Le. Floch, P. Roger, C. Blechet, M. Fesneau, A. Carpentier, A. Idbaih, J. Y. Delattre, K. Mokhtari, F. Bielle, S. Hamdi, M. Polivka, S. Milin, P. Colin, M. D. Diebold, D. Chiforeanu, E. Vauleon, O. Langlois, A. Laquerriere, F. Forest, M. J. Motso‐Fotso, M. Andraud, G. Runavot, B. Lhermitte, G. Noel, S. Gaillard, C. Villa, N. Desse, C. Rousselot‐Denis, I. Zemmoura, E. Cohen‐Moyal, E. Uro‐Coste, F. Dhermain, Service de Pathologie [CHRU Nancy], 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), Centre de Ressources Biologiques - [Nancy] (CRB Nancy), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Neurochirurgie [CHRU Nancy], Institut des Neurosciences de Montpellier (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Service de neurologie [CHRU Nancy], OncoNeuroTek [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Institut de neurophysiopathologie (INP), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Aix Marseille Université (AMU), Laboratoire d'Anatomie Pathologique-Neuropathologique [AP-HM Hôpital La Timone], Hôpital de la Timone [CHU - APHM] (TIMONE), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université - Département de neurologie 2 - Mazarin, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP]

Subjects
0301 basic medicine, Male, Proliferation index, [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], 0302 clinical medicine, Research Articles, Aged, 80 and over, Brain Neoplasms, General Neuroscience, [SDV.BBM.MN]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular Networks [q-bio.MN], Middle Aged, Prognosis, Isocitrate Dehydrogenase, 3. Good health, Survival Rate, Microglial cell activation, Ki-67, Immunohistochemistry, Female, France, [STAT.ME]Statistics [stat]/Methodology [stat.ME], Adult, IDH1, Mitotic index, Oligodendroglioma, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Postsynaptic specialization, Pathology and Forensic Medicine, 03 medical and health sciences, Young Adult, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Glioma, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], [SDV.MHEP.AHA]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], medicine, Mitotic Index, Humans, Aged, [INFO.INFO-DB]Computer Science [cs]/Databases [cs.DB], Gene Expression Profiling, medicine.disease, Minichromosome Maintenance Complex Component 6, 030104 developmental biology, Ki-67 Antigen, Mutation, biology.protein, Cancer research, Neurology (clinical), [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], 030217 neurology & neurosurgery, Gene Deletion
Abstract

International audience; Anaplastic oligodendroglioma (AO), IDH‐mutant and 1p/19q codeleted (IDHmut+/1p19qcodel), is a high‐grade glioma with only limited prognostic markers. The primary objective of this study was to evaluate, by immunohistochemistry, the prognostic value of two proliferation markers, MCM6 and Ki‐67, in a large series of IDHmut+/1p19qcodel AO included in the POLA (“Prise en charge des Oligodendrogliomes Anaplasiques”) French national multicenter network. We additionally examined the transcriptome obtained from this series to understand the functional pathways dysregulated with the mRNA overexpression of these two markers. The labelling indices (LI) of MCM6 and Ki‐67 were obtained via computer‐assisted color image analyses on immunostained AO tissues of the cohort (n=220). Furthermore, a subgroup of AO (n=68/220) was used to perform transcriptomic analyses. A high LI of either MCM6 (≥50%) or Ki‐67 (≥ 15%) correlated with shorter overall survival, both in univariate (P=0.013 and P=0.004, respectively) and multivariate analyses (P=0.027; multivariate Cox model including age, mitotic index, MCM6 and Ki‐67). MCM6 and Ki‐67 LI also correlated with overall survival in an additional retrospective cohort of 30 grade II IDHmut+/1p19qcodel oligodendrogliomas. The prognostic value of MCM6 mRNA level was confirmed in The Cancer Genome Atlas (TCGA) IDHmut+/1p19qcodel gliomas. The transcriptomic approach revealed that high transcriptional expressions of MCM6 and MKI67 were both linked positively with cell cycle progression, DNA replication, mitosis, pro‐neural phenotype as well as neurogenesis, and negatively with microglial cell activation, immune response, positive regulation of myelination, oligodendrocyte development, beta‐amyloid binding, and postsynaptic specialization.In conclusion, the overexpression of MCM6 and/or Ki‐67 is independently associated to shorter overall survival in IDHmut+/1p19qcodel AO. These two easy‐to‐use and cost‐effective markers could thus be used concurrently in routine pathology practice. Additionally, the transcriptomic analyses showed that AO with high proliferation index have down‐regulated immune response and lower microglial cells activation, and bears pro‐neural phenotype.

Published
2019

21. P04.12 Characteristics of IDH-mutant gliomas with non-canonical IDH mutations

Author

C Ferec, Charlotte Bronnimann, Catherine Carpentier, Caroline Dehais, M. Sanson, A Siegfried, D Cappellen, Dominique Figarella-Branger, J.-Y. Delattre, François Ducray, Jean-Sebastien Frenel, S Lacomme, L Poetsch, Delphine Larrieu-Ciron, Sandrine Eimer, Delphine Loussouarn, and Romuald Seizeur

Subjects
Cancer Research, Mutant, Astrocytoma, Cancer, Biology, medicine.disease, nervous system diseases, Poster Presentations, Oncology, Frontal lobe, Non canonical, Glioma, Mutation (genetic algorithm), Cancer research, medicine, Neurology (clinical), Oligodendroglioma, neoplasms
Abstract

BACKGROUND About 10% of IDH-mutant gliomas harbor non-canonical IDH mutations (non-R132H IDH1 and IDH2 mutations). The aim of the present study was to analyze the characteristics of these gliomas in comparison to those of IDH1 R132H mutant gliomas. MATERIAL AND METHODS We retrospectively analyzed the characteristics of a multicentric series of 161 gliomas with non-canonical IDH mutations and compared them to those of consecutive series of 109 IDH1 R132H mutant gliomas. Medical, radiological and pathological were reviewed. RESULTS Median age at diagnosis was 35 years in gliomas with a non-canonical IDH1 mutation, 42 years in those with an IDH2 mutation and 44 years in those with an IDH1R132H mutation. A familial history of cancer was more frequent in gliomas with a non-canonical IDH mutation than in those with an IDH1 R132H mutation (22,3% vs 5,5%, p CONCLUSION Gliomas with non-canonical IDH mutations are associated with distinct clinical, radiological and histological characteristics. Their prognosis, however, is similar to that of gliomas with canonical IDH mutations.

Published
2019

22. CDKN2A homozygous deletion is a strong adverse prognosis factor in diffuse malignant IDH-mutant gliomas

Author

Jean-Yves Delattre, Ahmed Idbaih, Dominique Figarella-Branger, Caroline Dehais, Fabienne Escande, Emeline Tabouret, Agusti Alentorn, Nesrine Trabelsi, Romain Appay, Claude-Alain Maurage, François Ducray, Karima Mokhtari, Catherine Carpentier, Yannick Marie, Emmanuelle Uro-Coste, Carole Colin, Aurélie Kamoun, Institut de neurophysiopathologie (INP), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Service d’Anatomie Pathologique et de Neuropathologie, APHM, Hôpital de la Timone, Hôpital de la Timone [CHU - APHM] (TIMONE), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 (UPMC), 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), biology and pathological laboratory, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), (le programme) Cartes d'identité des tumeurs (CIT), Ligue Nationales Contre le Cancer (LNCC), Biologie des Interactions Neurones / Glie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Département de neurooncologie, Service d'anatomie pathologique et histologie-cytologie [Rangueil], Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Service de neurologie 1 [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital de Rangueil, CHU Toulouse [Toulouse], Service de Neurologie [CHU Pitié-Salpêtrière], and IFR70-CHU Pitié-Salpêtrière [AP-HP]

Subjects
Male, Cancer Research, Necrosis, [SDV]Life Sciences [q-bio], Cohort Studies, 0302 clinical medicine, CDKN2A, Medicine, ComputingMilieux_MISCELLANEOUS, Sequence Deletion, Aged, 80 and over, Kinase, Retinoblastoma, Brain Neoplasms, Homozygote, Glioma, Middle Aged, Prognosis, Combined Modality Therapy, Isocitrate Dehydrogenase, 3. Good health, Survival Rate, Isocitrate dehydrogenase, Oncology, Chromosomes, Human, Pair 1, 030220 oncology & carcinogenesis, Female, medicine.symptom, Adult, Adolescent, 03 medical and health sciences, Young Adult, Biomarkers, Tumor, Humans, Progression-free survival, neoplasms, Cyclin-Dependent Kinase Inhibitor p16, Aged, business.industry, Editorials, medicine.disease, Mutation, Cancer research, Neurology (clinical), business, Chromosomes, Human, Pair 19, 030217 neurology & neurosurgery, Anaplastic astrocytoma, Follow-Up Studies
Abstract

Background The 2016 WHO classification of the central nervous system tumors stratifies IDH-mutant gliomas into two major groups depending on the presence or absence of 1p/19q-codeletion. However, the grading system remains unchanged and it is now controversial whether it can be still applied to this updated molecular classification. Methods In a large cohort of 911 high grade IDH-mutant gliomas from the French national POLA network (including 428 IDH-mutant gliomas without 1p/19q-codeletion and 483 anaplastic oligodendrogliomas, IDH-mutant and 1p/19q-codeleted), we investigated the prognostic value of CDKN2A gene homozygous deletion as well as WHO grading criteria (mitoses, microvascular proliferation and necrosis). In addition, we also searched for other retinoblastoma pathway gene alterations (CDK4 amplification and RB1 homozygous deletion) in a subset of patients. CDKN2A homozygous deletion was also searched in an independent series of 40 grade II IDH-mutant gliomas. Results CDKN2A homozygous deletion was associated with dismal outcome among IDH-mutant gliomas lacking 1p/19q-codeletion (p Conclusions Our study pointed out the utmost relevance of CDKN2A homozygous deletion as an adverse prognostic factor in the two broad categories of IDH-mutant gliomas stratified on 1p/19q-codeletion and suggest to refine the grading of these tumors.

Published
2019

23. Integrated multi-omics analysis of oligodendroglial tumours identifies three subgroups of 1p/19q co-deleted gliomas

Author

Anne Jouvet, Karima Mokhtari, Marc Sanson, Eric Letouzé, François Ducray, Ahmed Idbaih, Aurélien de Reyniès, Nadine Martin-Duverneuil, Emmanuelle Uro-Coste, Caroline Dehais, Aurélie Kamoun, Dominique Figarella-Branger, Catherine Carpentier, Carole Colin, Jean-Yves Delattre, Nabila Elarouci, (le programme) Cartes d'identité des tumeurs (CIT), Ligue Nationales Contre le Cancer (LNCC), Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de Recherches en Oncologie biologique et Oncopharmacologie (CRO2), Aix Marseille Université (AMU)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Neuropathologie Raymond Escourolle [CHU Pitié-Salpétriêre], Université Pierre et Marie Curie - Paris 6 (UPMC)-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), Hôpital neurologique et neurochirurgical Pierre Wertheimer [CHU - HCL], Hospices Civils de Lyon (HCL), Faculté de Médecine [Rangueil], Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), OncoNeuroTek [Paris], Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Neuro-Oncologie [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), 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), UPMC - Département de neurologie 2 - Mazarin, Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Laboratoire de Neuropathologie Raymond Escourolle, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Université Pierre et Marie Curie - Paris 6 (UPMC), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse], Service de Neuroradiologie [CHU Pitié-Salpêtrière], Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), and HAL UPMC, Gestionnaire

Subjects
Male, 0301 basic medicine, General Physics and Astronomy, Transcriptome, Cluster Analysis, Aged, 80 and over, Neurons, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Multidisciplinary, Stem Cells, Genomics, Glioma, Middle Aged, 3. Good health, Oligodendroglia, medicine.anatomical_structure, Chromosomes, Human, Pair 1, DNA methylation, Female, Chromosome Deletion, Signal Transduction, Adult, Cell type, Science, Oligodendroglioma, Biology, Article, General Biochemistry, Genetics and Molecular Biology, Proto-Oncogene Proteins c-myc, Young Adult, 03 medical and health sciences, medicine, Humans, Survival analysis, Aged, Gene Expression Profiling, General Chemistry, DNA Methylation, medicine.disease, Survival Analysis, Oligodendrocyte, Gene expression profiling, 030104 developmental biology, Cancer research, Chromosomes, Human, Pair 19, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Oligodendroglial tumours (OT) are a heterogeneous group of gliomas. Three molecular subgroups are currently distinguished on the basis of the IDH mutation and 1p/19q co-deletion. Here we present an integrated analysis of the transcriptome, genome and methylome of 156 OT. Not only does our multi-omics classification match the current classification but also reveals three subgroups within 1p/19q co-deleted tumours, associated with specific expression patterns of nervous system cell types: oligodendrocyte, oligodendrocyte precursor cell (OPC) and neuronal lineage. We confirm the validity of these three subgroups using public datasets. Importantly, the OPC-like group is associated with more aggressive clinical and molecular patterns, including MYC activation. We show that the MYC activation occurs through various alterations, including MYC genomic gain, MAX genomic loss, MYC hypomethylation and microRNA-34b/c down-regulation. In the lower grade glioma TCGA dataset, the OPC-like group is associated with a poorer outcome independently of histological grade. Our study reveals previously unrecognized heterogeneity among 1p/19q co-deleted tumours., Oligodendroglial tumours are characterized into three different molecular subtypes. Here, the authors use genomic data to identify a further three subgroups of 1p/19q co-deleted tumours and demonstrate an association with an aggressive phenotype.

Published
2016

24. Early intravenous immunoglobulin treatment in paraneoplastic neurological syndromes with onconeural antibodies

Author

Véronique Rogemond, Evgenia Karantoni, Jean-Yves Delattre, Jean-Christophe Antoine, Dimitri Psimaras, Géraldine Picard, Caroline Dehais, Laure Thomas, Jérôme Honnorat, François Ducray, Jean-Philippe Camdessanché, Amélie Liou-Schischmanoff, Gaëlle Candelier, Giulia Berzero, Jérôme De Seze, Biopathologie de la Myéline, Neuroprotection et Stratégies Thérapeutiques (BMNST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Strasbourg (UNISTRA), Berzero, G., Karantoni, E., Dehais, C., Ducray, F., Thomas, L., Picard, G., Rogemond, V., Candelier, G., Camdessanche, J. -P., Antoine, J. -C., De Seze, J., Liou-Schischmanoff, A., Honnorat, J., Delattre, J. -Y., and Psimaras, D.

Subjects
medicine.medical_specialty, Pediatrics, medicine.medical_treatment, Selective IgA deficiency, Thrombophilia, cancer treatment, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, intravenous immunoglobulin, medicine, Clinical endpoint, Stage (cooking), Prospective cohort study, Creatinine, business.industry, Immunotherapy, PostScript, paraneoplastic neurological syndromes, medicine.disease, onconeural antibodies, 3. Good health, Surgery, Psychiatry and Mental health, chemistry, 030220 oncology & carcinogenesis, Concomitant, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neurology (clinical), immunotherapy, business, 030217 neurology & neurosurgery
Abstract

Paraneoplastic neurological syndromes (PNS) are immune-mediated complications of cancer, characterised by relentless progression. The mainstay of PNS treatment is the achievement of tumour remission,1 while immunotherapy provides only little additional benefit.2 3 However, in historical series, immunotherapy was initiated over 6 months after neurological onset and, at that stage, neuronal loss is already extensive and irreversible. Among available immunotherapies, intravenous immunoglobulin (IVIg) has been used in single cases4 and in one retrospective series,3 showing some efficacy when administered timely.4 Based on these findings, we designed a prospective study to assess the efficacy and safety of early IVIg treatment in patients with PNS. ### Study design This prospective, multicentre, non-comparative, phase II clinical study was performed by the ‘Centre de Reference Francais des Syndromes Neurologiques Paraneoplasiques’. Written informed consent was obtained from all participants. This trial is registered at ClinicalTrials.gov (NCT02343211). ### Participants Inclusion criteria were: (1) diagnosis of ‘definite’ PNS5; (2) anti-Hu, anti-Yo, or anti-CV2/CRMP5 antibodies in the serum and/or in the cerebrospinal fluid; (3) neurological symptom onset within 6 months; (4) modified Rankin Score (mRS) 2 or 3; (5) neurological deterioration over the last 3 weeks. Exclusion criteria were: (1) other concomitant immunotherapy; (2) absolute contraindications to IVIg (hypersensitivity to IVIg, selective IgA deficiency); (3) thrombophilia; (4) renal insufficiency (creatinine clearance

Published
2017

25. OS11.3 Machine learning for better prognostic stratification and driver genes identification in 1p/19q-codeleted grade III gliomas

Author

Shai Rosenberg, A. Idbaih, Dominique Figarella-Branger, J.-Y. Delattre, François Ducray, Marie-Laure Tanguy, A. Alentron, A. De Reyneis, Caroline Dehais, and Nabila Elarouci

Subjects
0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, business.industry, medicine.disease, Prognostic stratification, 03 medical and health sciences, Identification (information), ORAL PRESENTATIONS, 030104 developmental biology, 0302 clinical medicine, Internal medicine, Glioma, medicine, Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract

BACKGROUND: Although major advances have been accomplished over the last years in their characterization, 1p/19q-codeleted anaplastic gliomas have variable clinical behavior and mysterious 1p/19q-codeletion “driven” molecular oncogenesis. We have recently shown that the most common alteration (i.e. 9p21.3 allelic loss detected in 42% of cases) is an independent prognostic factor in this tumor type. However, less frequent Genomic Copy Number Variations (CNV) may also have clinical value and may shed light on molecular oncogenesis of this tumor type. METHODS: A cohort of 197, 1p/19q-codeleted grade III gliomas was collected as part of the French POLA network. Clinical, pathological and molecular information were recorded and the patients were clinically followed up. CNV analysis was performed using SNP arrays. Computational biology and machine learning analysis were applied to identify less common additional CNV events associated with overall survival and other clinical-pathological variables Results: Recurrent chromosomal events were identified in chromosomes 4, 9, and 11. 46 focal amplification events and 22 focal deletion events were identified. 12 of the focal events overlapped with known cancer related genomic regions. 24 focal CNV areas were associated with survival and five of them were significantly associated with survival after multivariate analysis. 9/24 signals, detected in 3 to 26 percent of patients, were validated using an external cohort of gliomas of the Cancer Genome Atlas. Five of the validated signals contain a cancer related gene or MIR: CDKN2A deletion, SS18L1 amplification, RHOA/MIR191 copy-neutral loss of heterozigosity, FGFR3 amplification, and ARNT amplification. The CNV profile enables better survival prediction compared to clinical risk assessment. Conclusions: Several recurrent CNV events are characteristics for 1p/19q-codeleted grade III gliomas. These genomic regions are associated with survival and enable better survival prediction. More important, they may help identifying potential genes for understanding oncogenesis and for personalized therapy.

Published
2017

26. Paraneoplastic cerebellar degeneration associated with Anti-ITPR1 antibodies

Author

Bruno Buecher, Lars Komorowski, Dimitri Psimaras, Delphine Leclercq, Jérôme Honnorat, Caroline Dehais, Giulia Berzero, Jean-Yves Delattre, Francesc Graus, Virginie Fourchotte, Madeleine Scharf, Yael Hacohen, Berzero, G., Hacohen, Y., Komorowski, L., Scharf, M., Dehais, C., Leclercq, D., Fourchotte, V., Buecher, B., Honnorat, J., Graus, F., Delattre, J. -Y., and Psimaras, D.

Subjects
0301 basic medicine, Pathology, medicine.medical_specialty, biology, business.industry, Paraneoplastic cerebellar degeneration, medicine.disease, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Text mining, Neurology, biology.protein, Medicine, Neurology (clinical), Antibody, business, Clinical/Scientific Notes, 030217 neurology & neurosurgery
Published
2017

27. OS6.7 Early intravenous immunoglobulin treatment in paraneoplastic neurological syndromes with onconeural antibodies: results from the IasON trial

Author

Véronique Rogemond, Evgenia Karantoni, Géraldine Picard, Giulia Berzero, J. De Seze, Caroline Dehais, François Ducray, Dimitri Psimaras, J.-Y. Delattre, and Jérôme Honnorat

Subjects
OS6 Pediatric Brain Tumors, Cancer Research, Onconeural antibodies, Oncology, biology, business.industry, Immunology, biology.protein, Medicine, Neurology (clinical), Antibody, business
Published
2016

28. Prognostic impact of the 2016 WHO classification of diffuse gliomas in the French POLA cohort

Author

Dominique Figarella-Branger, Anh Tuan Nguyen, Hugues Loiseau, Jean-Yves Delattre, Claude-Alain Maurage, Olivier Chinot, François Ducray, Carole Colin, Ahmed Idbaih, Elisabeth Moyal, Emmanuelle Uro-Coste, Emmanuèle Lechapt-Zalcman, Caroline Dehais, Catherine Carpentier, Christine Desenclos, Emeline Tabouret, Karima Mokhtari, Anne Jouvet, David Meyronet, Marc Polivka, Neuro-Oncologie [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Centre de Recherches en Oncologie biologique et Oncopharmacologie (CRO2), Aix Marseille Université (AMU)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Anatomo-Cyto-Pathologie et de NeuroPathologie [Hôpital de la Timone - APHM] (ACPNP), Aix Marseille Université (AMU)- Hôpital de la Timone [CHU - APHM] (TIMONE), CHU Pitié-Salpêtrière [APHP], Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Centre National de la Recherche Scientifique (CNRS), Hôpital neurologique et neurochirurgical Pierre Wertheimer [CHU - HCL], Hospices Civils de Lyon (HCL), Centre de Recherche en Cancérologie de Lyon (CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Neuropathologie Raymond Escourolle, Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Laboratoire d'anatomie et de cytopathologie - Centre hospitalier Lyon Sud, CHU Toulouse [Toulouse], Faculté de Médecine [Rangueil], Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse], CHU de Bordeaux Pellegrin [Bordeaux], Institut Claudius Regaud, CRLCC Institut Claudius Regaud, Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées, Service de pathologie [CHU Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service de pathologie, AP-HP Hôpital Lariboisière [Paris], Laboratoire d'Anatomie Pathologique [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Imagerie et Stratégies Thérapeutiques des pathologies Cérébrales et Tumorales (ISTCT), Normandie Université (NU)-Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Service de neurochirurgie, Hôpital Nord - Amiens, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Laboratoire de Neuropathologie Raymond Escourolle [CHU Pitié-Salpétriêre], Université Pierre et Marie Curie - Paris 6 (UPMC)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Toulouse (UT), Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Pierre et Marie Curie - Paris 6 (UPMC)

Subjects
Oncology, Adult, Male, medicine.medical_specialty, Pathology, IDH1, Adolescent, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Oligodendroglioma, [SDV.CAN]Life Sciences [q-bio]/Cancer, 1p/19q Codeletion, Astrocytoma, World Health Organization, Disease-Free Survival, Pathology and Forensic Medicine, Cohort Studies, 03 medical and health sciences, Cellular and Molecular Neuroscience, Young Adult, 0302 clinical medicine, Internal medicine, medicine, Humans, Oligodendroglial Tumor, neoplasms, Pathological, Grading (tumors), Aged, Aged, 80 and over, business.industry, Brain Neoplasms, Glioma, Middle Aged, medicine.disease, Prognosis, 3. Good health, 030220 oncology & carcinogenesis, Cohort, Mutation, Female, Neurology (clinical), Who classification, business, 030217 neurology & neurosurgery, Anaplastic astrocytoma
Abstract

The new WHO classification of diffuse gliomas has been refined and now includes the 1p/19q codeletion, IDH1/2 mutation, and histone H3-K27M mutation. Our objective was to assess the prognostic value of the updated 2016 WHO classification in the French POLA cohort. All cases of high-grade oligodendroglial tumors sent for central pathological review and included into the French nationwide POLA cohort were reclassified according to the updated 4th WHO classification. In total, 1041 patients were included, with a median age at diagnosis of 50.4 years (range 17.1–84.4). Based on the new histomolecular classification, diagnoses included anaplastic oligodendroglioma IDH mutant and 1p/19q-codeleted (32.5 %), anaplastic astrocytoma IDH mutant (IDH mut) (11.0 %), anaplastic astrocytoma IDH wild type (IDH wt) (5.3 %), glioblastoma IDH mut (17.1 %), and glioblastoma IDH wt (33.2 %). Ten patients presented with a diffuse midline tumor, H3 K27M mutant. The new WHO classification was prognostic for progression-free survival (PFS) and overall survival (OS) (p

Published
2016

29. Mitotic index, microvascular proliferation, and necrosis define 3 groups of 1p/19q codeleted anaplastic oligodendrogliomas associated with different genomic alterations

Author

Dominique, Figarella-Branger, Karima, Mokhtari, Caroline, Dehais, Anne, Jouvet, Emmanuelle, Uro-Coste, Carole, Colin, Catherine, Carpentier, Fabien, Forest, Claude-Alain, Maurage, Jean-Michel, Vignaud, Marc, Polivka, Emmanuelle, Lechapt-Zalcman, Sandrine, Eimer, Gabriel, Viennet, Isabelle, Quintin-Roué, Marie-Hélène, Aubriot-Lorton, Marie-Danièle, Diebold, Delphine, Loussouarn, Catherine, Lacroix, Valérie, Rigau, Annie, Laquerrière, Fanny, Vandenbos, Sophie, Michalak, Henri, Sevestre, Michel, Peoch, François, Labrousse, Christo, Christov, Jean-Louis, Kemeny, Marie-Pierre, Chenard, Danchristian, Chiforeanu, François, Ducray, Ahmed, Idbaih, Frederic, Dhermain, Laboratoire d'anatomie pathologique - [Hôpital Nord - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital Nord [CHU - APHM], Centre de Recherches en Oncologie biologique et Oncopharmacologie (CRO2), Aix Marseille Université (AMU)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Pathologie et de Neuropathologie Est, Hospices Civils de Lyon (HCL), Service d'anatomie pathologique et histologie-cytologie [Rangueil], Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Centre de Recherches en Cancérologie de Toulouse (CRCT), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), INSERM, U975, Université Paris 06, Service d’Anatomie et Cytologie Pathologiques, Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Service d'Anatomie Pathologique, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service d’Anatomie Pathologique [CHRU Nancy], 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), Service d'anatomie et cytologie pathologiques, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Laboratoire d'Anatomie Pathologique [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Hypoxie, physiopathologies cérébrovasculaire et tumorale (CERVOxy), Imagerie et Stratégies Thérapeutiques des pathologies Cérébrales et Tumorales (ISTCT), Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Service de Pathologie-Neuropathologie, CHU de Bordeaux Pellegrin [Bordeaux], Histologie et Pathologie Moléculaire, Université Bordeaux Segalen - Bordeaux 2, Service Anatomie et Cytologie Pathologiques, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), CHRU Brest - Laboratoire d'Anatomo-Pathologie (CHU - AnaPath), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Service de Pathologie [CHU de Dijon], Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Laboratoire d'anatomie et cytologie pathologiques [Reims], Centre Hospitalier Universitaire de Reims (CHU Reims), Service d'Anatomie Pathologique B, Centre hospitalier universitaire de Nantes (CHU Nantes), Service d'Anatomie et Cytologie Pathologique, AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Laboratoire d'Anatomie et Cytologie Pathologiques, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service d'Anatomie et Cytologie Pathologique [CHU Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), chu de nice, Hôpital Pasteur, Laboratoire Central d’Anatomo Pathologie, Hôpital Pasteur [Nice] (CHU), Département de pathologie cellulaire et tissulaire, CHU d'Angers, 4, rue Larrey, 49100 Angers, France., Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Service d'Anatomie et Cytologie Pathologiques, CHU Amiens-Picardie, Service d'Anatomie Pathologique [CHU Limoges], CHU Limoges, Hôpital Henri Mondor, CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Laboratoire d'anatomie pathologique - Hôpital de Hautepierre Hôpitaux Universitaires de Strasbourg - Université de Strasbourg, Service d'anatomie et cytologie pathologiques [Rennes] = Anatomy and Cytopathology [Rennes], CHU Pontchaillou [Rennes], Service de neuro-oncologie [Hôpital Pierre Wertheimer - HCL], Hôpital neurologique et neurochirurgical Pierre Wertheimer [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), 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), Service de Neuropathologie Raymond Escourolle [CHU Pitié Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Service de neurologie 2 [CHU Pitié-Salpêtrière], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital de Rangueil, CHU Toulouse [Toulouse], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Saint-Etienne, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Lariboisière-Université Paris Diderot - Paris 7 (UPD7), Normandie Université (NU)-Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon), Centre Hospitalier Universitaire de Montpellier (CHU Montpellier ), Service d'Anatomie et Cytologie Pathologique [Rouen], AP-HP Hôpital Henri Mondor (Créteil), Service d'anatomie et cytologie pathologiques [Rennes], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Centre de recherche en neurosciences de Lyon (CRNL), 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), Université Paris Diderot - Paris 7 (UPD7)-Hôpital Lariboisière-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Service de Neuropathologie [CHU Pitié Salpêtrière], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital Nord [CHU - APHM]-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Aix Marseille Université (AMU), Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université

Subjects
Cancer Research, Pathology, medicine.medical_specialty, IDH1, Necrosis, Mitotic index, Proliferation index, [SDV]Life Sciences [q-bio], Oligodendroglioma, Biology, Disease-Free Survival, 03 medical and health sciences, 0302 clinical medicine, Chromosome instability, medicine, Mitotic Index, Humans, Progression-free survival, ComputingMilieux_MISCELLANEOUS, Neovascularization, Pathologic, Brain Neoplasms, Brain, medicine.disease, Isocitrate Dehydrogenase, 3. Good health, Oncology, Chromosomes, Human, Pair 1, 030220 oncology & carcinogenesis, Basic and Translational Investigations, Chromosome abnormality, Neurology (clinical), medicine.symptom, Chromosome Deletion, Chromosomes, Human, Pair 19, 030217 neurology & neurosurgery
Abstract

BACKGROUND: The aim of this study was to correlate histological features and molecular characteristics in anaplastic oligodendrogliomas (AO). METHODS: The histological characteristics of 203 AO patients enrolled in the French national network POLA were analyzed. The genomic profiles of 191 cases were studied using genomic arrays. IDH mutational status was assessed by immunohistochemistry and direct sequencing. RESULTS: 1p/19q co-deletion was present in 79% of cases and was associated with alpha-internexin expression (p < 10-4), IDH1/2 mutation (p < 10-4), chromosome 4 loss (p < 10-3), and better overall survival (p < 10-4). Based on mitotic index, microvascular proliferation (MVP) and necrosis, 3 groups of 1p/19q co-deleted AO were identified: AO with more than 5 mitoses per 10-HPF, no MVP and no necrosis, (1), AO with MVP and no necrosis (2) and AO with MVP and necrosis (3). Compared to group 1, group 2 and 3 AO had a higher mean Ki-67 proliferation index and a higher rate of 9p and 9q losses. Compared to group 2, group 3 AO had a higher number of chromosomal alterations including chromosome 4 loss. In the subgroup of 157 1p/19q co-deleted AO, chromosomal instability was associated with shorter progression free survival (p = 0.024) and shorter overall survival (p = 0.023). CONCLUSIONS: The present study shows that oligodendroglioma with classic histological features remains a molecularly heterogeneous entity and should be stratified according to 1p/19q status because of its major prognostic relevance. Moreover, 1p/19q co-deleted AO are also heterogeneous. Interestingly, mitotic index, MVP and necrosis help to classify them into three groups associated with distinct genomic alterations.

Published
2014

30. SNP array analysis reveals novel genomic abnormalities including copy neutral loss of heterozygosity in anaplastic oligodendrogliomas

Author

Emmanuelle Uro-Coste, Luc Bauchet, Jean-Yves Delattre, Caroline Le Guerinel, Phong Dam-Hieu, Christine Desenclos, Alexandra Benouaich-Amiel, Thierry Faillot, Catherine Carpentier, Delphine Loussouarn, Antoine F. Carpentier, Karima Mokhtari, François Labrousse, Georges Noël, Olivier Chinot, Jérôme Honnorat, Simon de Bernard, François Ghiringhelli, Ahmed Idbaih, Pierre Verelle, Selma Elouadhani-Hamdi, Sandrine Eimer, Emmanuelle Lechapt-Zalcman, Dominique Figarella-Branger, Marie Janette Motsuo Fotso, Patrick Beauchesne, Frédéric Dhermain, Joel Godard, Anne Jouvet, Caroline Dehais, Carole Ramirez, Philippe Menei, Célia Courdy, Philippe Colin, Elodie Vauleon, Olivier Langlois, François Ducray, Denys Fontaine, Fabrice Parker, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), UPMC - Département de neurologie 2 - Mazarin, Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de Référence Maladie Rare 'Syndromes neurologiques Paranéoplasiques', Hospices Civils de Lyon (HCL)-Hopital Neurologique, Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Recherches en Oncologie biologique et Oncopharmacologie (CRO2), Aix Marseille Université (AMU)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), AltraBio [Lyon], Service d'anatomie pathologique et histologie-cytologie [Rangueil], Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital de Rangueil, CHU Toulouse [Toulouse], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de recherche en neurosciences de Lyon (CRNL), 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), Clinique de Neurochirurgie [CHU Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service de Neuro-Oncologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Services de Neurologie [CHU Toulouse], CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], Service de Neurochirurgie [CHRU de Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Laboratoire d'Histologie et de Pathologie moléculaire des tumeurs, Université Bordeaux Segalen - Bordeaux 2-EA 2406, Service de neurochirurgie [Bicêtre], Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Laboratoire d'Anatomie Pathologique [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Université Paris Diderot - Paris 7 (UPD7), 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), Service de neurochirurgie, Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Service de neurochirurgie [Brest], Hôpital de la Cavale Blanche - CHRU Brest (CHU - BREST ), Service de neurochirurgie [AP-HP Hôpital Lariboisière], AP-HP Groupe Hospitalier Lariboisière, Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre d'Études Préhistoire, Antiquité, Moyen-Age (CEPAM), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), Hôpital Henri Mondor, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service de Neurochirurgie, Centre Hospitalier Universitaire de Nice (CHU Nice), CRLCC Eugène Marquis (CRLCC), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Micro et Nanomédecines Biomimétiques (MINT), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Bretagne Loire (UBL), Service de Neurochirurgie [CHU Saint-Etienne], Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne)-Hôpital Nord (Saint Etienne), Service de Neurochirurgie [CHU Amiens], CHU Amiens-Picardie, Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), Centre Paul Strauss, CRLCC Paul Strauss, Homéostasie Cellulaire et Pathologies (HCP), Université de Limoges (UNILIM)-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-CHU Limoges, Service d'Hématologie biologique [CHU Limoges], CHU Limoges, Université de Limoges (UNILIM), Département de radiothérapie [Gustave Roussy], Institut Gustave Roussy (IGR), Stéroides et système nerveux : physiopathologie moléculaire et clinique, Université Paris-Sud - Paris 11 (UP11)-IFR93-Institut National de la Santé et de la Recherche Médicale (INSERM), This work is funded by the French Institut National du Cancer (INCa) and part of the national program Cartes d’Identite´ des Tumeurs H (CIT) (http://cit.liguecancer.net/) funded and developed by the Ligue nationale contre le cancer., Sindou, Philippe, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), 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), Département Neurologie [CHU Toulouse], Pôle Neurosciences [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut des Neurosciences de Montpellier (INM), Université Nice Sophia Antipolis (1965 - 2019) (UNS), Université de Limoges (UNILIM)-CHU Limoges-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Service de Neurochirurgie [CHRU Besançon], 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), Service de neurochirurgie [CHU Angers], Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E)-Université Jean Monnet - Saint-Étienne (UJM), Service de neurologie 1 [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Institut National de la Santé et de la Recherche Médicale (INSERM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Aix Marseille Université (AMU), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]

Subjects
Male, MESH: Genes, p16, Pathology, Tumor Physiology, Loss of Heterozygosity, Loss of heterozygosity, 0302 clinical medicine, CDKN2A, Gene duplication, Molecular Cell Biology, Basic Cancer Research, MESH: Aged, Multidisciplinary, MESH: Middle Aged, Brain Neoplasms, MESH: Polymorphism, Single Nucleotide, Genomics, Middle Aged, 3. Good health, Neurology, Oncology, 030220 oncology & carcinogenesis, MESH: Brain Neoplasms, Medicine, Female, Research Article, Adult, medicine.medical_specialty, IDH1, Histology, MESH: Mutation, Science, Oligodendroglioma, Locus (genetics), [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, IDH2, Polymorphism, Single Nucleotide, 03 medical and health sciences, medicine, Genetics, Cancer Genetics, Humans, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, MESH: Oligodendroglioma, Aged, MESH: Loss of Heterozygosity, MESH: Humans, Genes, p16, Chromosome, MESH: Adult, medicine.disease, MESH: Male, MESH: Gene Deletion, Mutation, MESH: Female, 030217 neurology & neurosurgery, Gene Deletion, Neuroscience
Abstract

International audience; Anaplastic oligodendrogliomas (AOD) are rare glial tumors in adults with relative homogeneous clinical, radiological and histological features at the time of diagnosis but dramatically various clinical courses. Studies have identified several molecular abnormalities with clinical or biological relevance to AOD (e.g. t(1;19)(q10;p10), IDH1, IDH2, CIC and FUBP1 mutations).To better characterize the clinical and biological behavior of this tumor type, the creation of a national multicentric network, named "Prise en charge des OLigodendrogliomes Anaplasiques (POLA)," has been supported by the Institut National du Cancer (InCA). Newly diagnosed and centrally validated AOD patients and their related biological material (tumor and blood samples) were prospectively included in the POLA clinical database and tissue bank, respectively.At the molecular level, we have conducted a high-resolution single nucleotide polymorphism array analysis, which included 83 patients. Despite a careful central pathological review, AOD have been found to exhibit heterogeneous genomic features. A total of 82% of the tumors exhibited a 1p/19q-co-deletion, while 18% harbor a distinct chromosome pattern. Novel focal abnormalities, including homozygously deleted, amplified and disrupted regions, have been identified. Recurring copy neutral losses of heterozygosity (CNLOH) inducing the modulation of gene expression have also been discovered. CNLOH in the CDKN2A locus was associated with protein silencing in 1/3 of the cases. In addition, FUBP1 homozygous deletion was detected in one case suggesting a putative tumor suppressor role of FUBP1 in AOD.Our study showed that the genomic and pathological analyses of AOD are synergistic in detecting relevant clinical and biological subgroups of AOD.

Published
2012

31. Association of Clinical, Biological, and Brain Magnetic Resonance Imaging Findings With Electroencephalographic Findings for Patients With COVID-19

Author

Virginie, Lambrecq, Aurélie, Hanin, Esteban, Munoz-Musat, Lydia, Chougar, Salimata, Gassama, Cécile, Delorme, Louis, Cousyn, Alaina, Borden, Maria, Damiano, Valerio, Frazzini, Gilles, Huberfeld, Frank, Landgraf, Vi-Huong, Nguyen-Michel, Phintip, Pichit, Aude, Sangare, Mario, Chavez, Capucine, Morélot-Panzini, Elise, Morawiec, Mathieu, Raux, Charles-Edouard, Luyt, Pierre, Rufat, Damien, Galanaud, Jean-Christophe, Corvol, Catherine, Lubetzki, Benjamin, Rohaut, Sophie, Demeret, Nadya, Pyatigorskaya, Lionel, Naccache, Vincent, Navarro, Safia, Said, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service de Neurophysiologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Neuroradiologie [CHU Pitié-Salpêtrière], Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], Service de Pneumologie et Réanimation Médicale [CHU Pitié-Salpêtrière] (Département ' R3S '), Service d'Anesthésie réanimation [CHU Pitié-Salpêtrière], Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut de cardiologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Service de Cardiologie [CHU Pitié-Salpêtrière], Service de Département d'Information Médicale [CHU Pitié-Salpêtrière] (DIM), Unité fonctionnelle d'épilepsie [CHU Pitié-Salpêtrière], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-IFR70-CHU Pitié-Salpêtrière [AP-HP], Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Département Médico-Universitaire Neurosciences [Sorbonne Université] (DMU Neurosciences), CHU Charles Foix [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Rothschild [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU), Service de Pneumologie - R3S [CHU Pitié-Salpêtrière] (SPMIR-R3S), Département Médico-Universitaire réanimation anesthésie médecine péri-opératoire [Sorbonne Université] (DMU DREAM), CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Groupe de recherche clinique en anesthésie réanimation médecine périopératoire [CHU Pitié-Salpétrière] (GRC ARPE), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), Département de Biostatistique, Santé Publique et Information Médicale [CHU Pitié-Salpêtrière] (BIOSPIM ), Centre de référence des épilepsies rares [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-IFR70-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Service de Neurologie [CHU Pitié-Salpêtrière], Cohort COVID-19 Neurosciences (CoCo Neurosciences) Study Group: Jean-Yves Delattre, Stephanie Carvalho, Sandrine Sagnes, Bruno Dubois, Celine Louapre, Tanya Stojkovic, Ahmed Idbaih, Charlotte Rosso, David Grabli, Ana Zenovia Gales, Bruno Millet, Eleonore Bayen, Sophie Dupont, Gaelle Bruneteau, Stephane Lehericy, Danielle Seilhean, Alexandra Durr, Aurelie Kas, Foudil Lamari, Marion Houot, Vanessa Batista Brochard, Pascale Pradat-Diehl, Khe Hoang-Xuan, Bertrand Fontaine, Philippe Fossati, Isabelle Arnulf, Alexandre Carpentier, Yved Edel, Anna Luisa Di Stefano, Gilberte Robain, Philippe Thoumie, Bertrand Degos, Tarek Sharshar, Sonia Alamowitch, Emmanuelle Apartis-Bourdieu, Charles-Siegried Peretti, Renata Ursu, Nathalie Dzierzynski, Kiyoka Kinugawa Bourron, Joel Belmin, Bruno Oquendo, Eric Pautas, Marc Verny, Yves Samson, Sara Leder, Anne Leger, Sandrine Deltour, Flore Baronnet, Stéphanie Bombois, Mehdi Touat, Caroline Dehais, Caroline Houillier, Florence Laigle-Donadey, Dimitri Psimaras, Agusti Alentorn, Nadia Younan, Nicolas Villain, Maria Del Mar Amador, Louise-Laure Mariani, Nicolas Mezouar, Graziella Mangone, Aurélie Meneret, Andreas Hartmann, Clément Tarrano, David Bendetowicz, Pierre-Francois Pradat, Michel Baulac, Sara Sambin, Florence Chochon, Adele Hesters, Bastien Herlin, An Hung Nguyen, Valérie Procher, Alexandre Demoule, Julien Mayaux, Morgane Faure, Claire Ewenczyk, Giulia Coarelli, Anna Heinzmann, Perrine Charles, Marion Masingue, Guillaume Bassez, Isabelle An, Yulia Worbe, Rabab Debs, Timothee Lenglet, Natalia Shor, Delphine Leclercq, Albert Cao, Clémence Marois, Nicolas Weiss, Loic Le Guennec, Vincent Degos, Alice Jacquens, Thomas Similowski, Jean-Yves Rotge, Bertrand Saudreau, Victor Pitron, Nassim Sarni, Nathalie Girault, Redwan Maatoug, Smaranda Leu, Lionel Thivart, Karima Mokhtari, Isabelle Plu, Bruno Goncalves, Laure Bottin, Marion Yger, Gaelle Ouvrard, Rebecca Haddad, Flora Ketz, Carmelo Lafuente, Christel Oasi, Bruno Megarbane, Dominique Herve, Haysam Salman, Armelle Rametti-Lacroux, Alize Chalancon, Anais Herve, Hugo Royer, Florence Beauzor, Valentine Maheo, Christelle Laganot, Camille Minelli, Aurélie Fekete, Abel Grine, Marie Biet, Rania Hilab, Aurore Besnard, Meriem Bouguerra, Gwen Goudard, Saida Houairi, Saba Al-Youssef, Christine Pires, Anissa Oukhedouma, Katarzyna Siuda-Krzywicka, Tal Seidel Malkinson, Hanane Agguini, Hassen Douzane Agguini, Safia Said, Raux, Mathieu, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service de neurologie 1 [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), and HAL-SU, Gestionnaire

Subjects
Male, [SDV.MHEP.ME] Life Sciences [q-bio]/Human health and pathology/Emerging diseases, Brain Diseases, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, SARS-CoV-2, [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, Research, [SDV]Life Sciences [q-bio], COVID-19, Electroencephalography, Middle Aged, Magnetic Resonance Imaging, Cohort Studies, [SDV] Life Sciences [q-bio], Online Only, [SDV.IB.IMA] Life Sciences [q-bio]/Bioengineering/Imaging, Infectious Diseases, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Electronic Health Records, Humans, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Original Investigation
Abstract

Key Points Question Can electroencephalography (EEG), combined with clinical, biological, and magnetic resonance imaging (MRI) analyses, help to better characterize patients with neurologic coronavirus disease 2019 (COVID-19) and diagnose specific COVID-19–related encephalopathy? Findings Neurologic manifestations, biological findings, EEG findings, and brain MRI images were analyzed in a cohort study of 78 adult patients with COVID-19. Nine patients had no identified cause of brain injury, as revealed by biological and MRI findings; their injury was defined as COVID-19–related encephalopathy. Meaning This study suggests that, although neurologic manifestations, EEG findings, and MRI findings may appear heterogeneous and nonspecific, multimodal monitoring may better identify patients with COVID-19–related encephalopathy and guide treatment strategy., Importance There is evidence of central nervous system impairments associated with coronavirus disease 2019 (COVID-19) infection, including encephalopathy. Multimodal monitoring of patients with COVID-19 may delineate the specific features of COVID-19–related encephalopathy and guide clinical management. Objectives To investigate clinical, biological, and brain magnetic resonance imaging (MRI) findings in association with electroencephalographic (EEG) features for patients with COVID-19, and to better refine the features of COVID-19–related encephalopathy. Design, Setting, and Participants This retrospective cohort study conducted in Pitié-Salpêtrière Hospital, Paris, France, enrolled 78 hospitalized adults who received a diagnosis of severe acute respiratory syndrome coronavirus 2 (SARS-Cov2) and underwent EEG between March 30 and June 11, 2020. Exposures Detection of SARS-CoV-2 from a nasopharyngeal specimen using a reverse transcription–polymerase chain reaction assay or, in the case of associated pneumonia, on a computed tomography scan of the chest. Main Outcomes and Measures Data on the clinical and paraclinical features of the 78 patients with COVID-19 were retrieved from electronic patient records. Results Of 644 patients who were hospitalized for COVID-19, 78 (57 men [73%]; mean [SD] age, 61 [12] years) underwent EEG. The main indications for EEG were delirium, seizure-like events, and delayed awakening in the intensive care unit after stopping treatment with sedatives. Sixty-nine patients showed pathologic EEG findings, including metabolic-toxic encephalopathy features, frontal abnormalities, periodic discharges, and epileptic activities. Of 57 patients who underwent brain MRI, 41 showed abnormalities, including perfusion abnormalities, acute ischemic lesions, multiple microhemorrhages, and white matter–enhancing lesions. Fifty-five patients showed biological abnormalities, including dysnatremia, kidney failure, and liver dysfunction, the same day as the EEG. The results of cerebrospinal fluid analysis were negative for SARS-Cov-2 for all tested patients. Nine patients who had no identifiable cause of brain injury outside COVID-19 were further isolated; their brain injury was defined as COVID-19–related encephalopathy. They represented 1% (9 of 644) of patients with COVID-19 requiring hospitalization. Six of these 9 patients had movement disorders, 7 had frontal syndrome, 4 had brainstem impairment, 4 had periodic EEG discharges, and 3 had MRI white matter–enhancing lesions. Conclusions and Relevance The results from this cohort of patients hospitalized with COVID-19 suggest there are clinical, EEG, and MRI patterns that could delineate specific COVID-19–related encephalopathy and guide treatment strategy., This cohort study investigates clinical, biological, and brain magnetic resonance imaging (MRI) findings in association with electroencephalographic (EEG) features for patients with coronavirus disease 2019 (COVID-19) and refines the features of COVID-19–related encephalopathy.

Published
2021

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