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1,165 results on '"Laboratoire d'anatomie pathologique"'

1. Thoracic manifestations of <scp>IgG4</scp> ‐related disease

Author: Romain Muller, Mikael Ebbo, Paul Habert, Laurent Daniel, Antoine Briantais, Pascal Chanez, Jean Yves Gaubert, Nicolas Schleinitz, Hôpital de la Timone [CHU - APHM] (TIMONE), Laboratoire d'Imagerie Interventionnelle Expérimentale (LIIE), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Nord [CHU - APHM], Laboratoire d'anatomie pathologique - [Hôpital Nord - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital Nord [CHU - APHM], Service de Pneumologie-Allergologie [Hôpital de la Timone - APHM], and Université de la Méditerranée - Aix-Marseille 2-Assistance Publique - Hôpitaux de Marseille (APHM)-Hôpital Sainte-Marguerite [CHU - APHM] (Hôpitaux Sud )
Subjects: IgG4, interstitial lung disease, Pulmonary and Respiratory Medicine, thoracic, [SDV]Life Sciences [q-bio], immunoglobulin G4-related disease, rare systemic fibroinflammatory disease
Abstract: International audience; Immunoglobulin G4-related disease (IgG4-RD) is a recently described rare systemic fibroinflammatory disease with an estimated incidence of less than 1 in 100,000 persons per year. The disease can affect virtually any organ and is characterized by unifying histopathological findings. Recently, four subgroups of patients have been characterized: hepatobiliary, head and neck, Mikulicz syndrome and retroperitoneal fibrosis, who illustrate the mainly abdominal and ENT tropism of the disease. Yet, thoracic involvement is not uncommon. It can be detected in up to 30% of patients with systemic IgG4-RD and is the exclusive manifestation of the disease in about 10% of cases. Clinical symptoms are nonspecific and may include dyspnoea, cough or chest pain. Chest CT findings are heterogeneous and primarily include peribronchovascular thickening, nodules, ground-glass opacities and lymphadenopathy. There is no specific diagnostic test for IgG4-RD thoracic involvement, which may mimic malignancy or vasculitis. Therefore, a cautious approach is needed to make an accurate diagnosis: a search for extra-thoracic manifestations, elevated serum IgG4 levels, circulating levels of plasmablasts and pathologic evidence of disease is warranted. Although very suggestive, neither the presence of a polyclonal IgG4 lymphoplasmacytic infiltrate, storiform fibrosis or obliterative phlebitis are sufficient to confirm the histological diagnosis. Steroids are recommended as first-line therapy. Rituximab or disease-modifying antirheumatic drugs may be used in relapsed or rare cases of steroid-refractory disease. In this review, we summarize current knowledge regarding the pathophysiology, epidemiology, diagnostic modalities (clinical-biological-imaging-histopathology) and treatment of IgG4-RD thoracic involvement.
Published: 2022
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2. Papillary glioneuronal tumors: histological and molecular characteristics and diagnostic value of SLC44A1-PRKCA fusion

Author: Ludovic Lacroix, Felipe Andreiuolo, Fabrice Chrétien, Frédéric Fina, Pascale Varlet, Arnault Tauziède-Espariat, Stéphanie Puget, Julia A. Bridge, David Castel, Emmanuèle Lechapt-Zalcman, Xiao Qiong Liu, Estelle Daudigeos-Dubus, Vita Ridola, Marc Polivka, Nathalie Boddaert, Mélanie Pagès, Jacques Grill, Sophie Gilles, Neuroimagerie en psychiatrie (U1000), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Centre Hospitalier Sainte Anne [Paris], Département de biologie et pathologie médicales [Gustave Roussy], Institut Gustave Roussy (IGR), Vectorologie et thérapeutiques anti-cancéreuses [Villejuif] (UMR 8203), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Département de cancérologie de l'enfant et de l'adolescent [Gustave Roussy], Hôpital Lariboisière, Imagerie et Stratégies Thérapeutiques des pathologies Cérébrales et Tumorales (ISTCT), 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), Laboratoire d'Anatomie Pathologique [CHU Caen], Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), CHU Necker - Enfants Malades [AP-HP], University of Nebraska Medical Center, University of Nebraska System, Histopathologie humaine et Modèles animaux, Institut Pasteur [Paris], Institut de psychiatrie et neurosciences (U894 / UMS 1266), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Lariboisière-Fernand-Widal [APHP], Institut Pasteur [Paris] (IP), Centre de Psychiatrie et Neurosciences (U894), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Sud - Paris 11 (UP11), Centre National de la Recherche Scientifique (CNRS)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Université de Caen Normandie (UNICAEN), Normandie Université (NU), Neuroimagerie en psychiatrie ( U1000 ), Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ), Institut Gustave Roussy ( IGR ), Vectorologie et thérapeutiques anti-cancéreuses [Villejuif] ( UMR 8203 ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Centre National de la Recherche Scientifique ( CNRS ), Imagerie et Stratégies Thérapeutiques des pathologies Cérébrales et Tumorales ( ISTCT ), 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 ), Laboratoire d'Anatomie Pathologique [Caen], Normandie Université ( NU ) -Normandie Université ( NU ) -CHU Caen, Centre de Psychiatrie et Neurosciences ( CPN - U894 ), and Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM )
Subjects: Male, Pathology, [SDV]Life Sciences [q-bio], Antigens, CD34, medicine.disease_cause, Ganglioglioma, 0302 clinical medicine, KIAA-BRAF, Child, ganglioglioma, Mutation, medicine.diagnostic_test, Brain Neoplasms, Kinase, Glioma, Magnetic Resonance Imaging, Neoplasms, Neuroepithelial, 3. Good health, angiocentric neuroepithelial tumors, SLC44A1-PRKCA, Child, Preschool, 030220 oncology & carcinogenesis, Immunohistochemistry, Female, Oncogene Fusion, Adult, medicine.medical_specialty, Protein Kinase C-alpha, Adolescent, Organic Cation Transport Proteins, MAP Kinase Signaling System, Papillary glioneuronal tumor, Nerve Tissue Proteins, BRAF, Pathology and Forensic Medicine, Young Adult, 03 medical and health sciences, Cellular and Molecular Neuroscience, Western blot, Antigens, CD, medicine, Humans, Receptor, Fibroblast Growth Factor, Type 1, rosette-forming glioneuronal tumors of the fourth ventricle, [ SDV ] Life Sciences [q-bio], business.industry, Research, medicine.disease, MAPK, FGFR1, Neurology (clinical), business, 030217 neurology & neurosurgery, Fluorescence in situ hybridization
Abstract: International audience; INTRODUCTION:Papillary Glioneuronal Tumor (PGNT) is a grade I tumor which was classified as a separate entity in the World Health Organization Classification of the Central Nervous System 2007 in the group of mixed glioneuronal tumors. This tumor is rare and subclassifying PGNT represents a challenge. Recently, a fusion between SLC44A1 and PRKCA which encodes a protein kinase C involved in MAPK signaling pathway has been described in two studies (five cases). The current study aimed at raising the cytogenetic, histological and molecular profiles of PGNT and to determine if SLC44A1-PRKCA fusion represented a specific diagnostic marker to distinguish it from other glioneuronal tumors.RESULTS:We report on four pediatric cases of PGNT, along with clinico-radiologic and immunohistological features for which SLC44A1-PRKCA fusion assessment by fluorescence in situ hybridization, BRAF V600E and FGFR1 mutation by immunohistochemistry and direct DNA sequencing and KIAA1549-BRAF fusion by RT-PCR were performed. MAPK signaling pathway activation was investigated using phospho-ERK immunohistochemistry and western blot. We analyzed fifteen cases of tumors with challenging histological or clinical differential diagnoses showing respectively a papillary architecture or periventricular location (PGNT mimics). fluorescence in situ hybridization analysis revealed a constant SLC44A1-PRKCA fusion signal in all PGNTs. None of PGNT mimics showed the SLC44A1-PRKCA fusion signal pattern. All PGNTs were negative for BRAF V600E and FGFR1 mutation, and KIAA1549-BRAF fusion. Phospho-ERK analysis provides arguments for the activation of the MAPK signaling pathway in these tumors.CONCLUSIONS:Here we confirmed and extended the molecular data on PGNT. These results suggest that PGNT belong to low grade glioma with MAPK signaling pathway deregulation. SLC44A1-PRKCA fusion seems to be a specific characteristic of PGNT with a high diagnostic value and detectable by FISH.
Published: 2015
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3. Evidence for BRAF V600E and H3F3A K27M double mutations in paediatric glial and glioneuronal tumours

Author: Dominique Figarella-Branger, François Labrousse, Anh Tuan Nguyen, Emmanuelle Uro-Coste, Laetitia Padovani, Isabelle Nanni-Metellus, Catherine Miquel, Anne Jouvet, Catherine Godfraind, Carole Colin, Claude-Alain Maurage, Pascale Varlet, Emmanuelle Lechapt-Zalcman, Guillaume Gauchotte, Karen Silva, Service d’Anatomie Pathologique et de Neuropathologie, APHM, Hôpital de la Timone, 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 de Transfert d’Oncologie Biologique, APHM, Hôpital Nord, Hôpital Nord [CHU - APHM], Service de Radiothérapie, APHM, Hôpital de la Timone, Marseille, Institut de Pathologie, Centre de Biologie Pathologie Génétique, CS 70001, CHRU de Lille, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Service de Neuropathologie [Hôpital Sainte-Anne, Paris], Hôpital Sainte Anne, Université Paris Descartes - Paris 5 (UPD5), Centre de Recherches en Cancérologie de Toulouse (CRCT), 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), nserm U823, Institut Albert-Bonniot, Département de Pathologie, Université Joseph-Fourier, Grenoble, Institut National de la Santé et de la Recherche Médicale (INSERM), Hypoxie, physiopathologies cérébrovasculaire et tumorale (CERVOxy), Imagerie et Stratégies Thérapeutiques des pathologies Cérébrales et Tumorales (ISTCT), 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)-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), Laboratoire d'Anatomie Pathologique [CHU Caen], Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Service d'Anatomie Pathologique [CHU Limoges], CHU Limoges, 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), 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), Centre de Pathologie et de Neuropathologie Est, Hospices civils de Lyon, Lyon, Franc, Hospices Civils de Lyon (HCL), 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 ), Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Inserm, U837, Université Lille – Nord-de-France, Lille, Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service de Neuropathologie, Hôpital Sainte-Anne, Université Paris Descartes - Paris 5 ( UPD5 ), Centre de Recherche en Cancérologie de Toulouse ( CRCT ), Université Toulouse III - Paul Sabatier ( UPS ), 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 ), Hypoxie, physiopathologies cérébrovasculaire et tumorale ( CERVOxy ), Imagerie et Stratégies Thérapeutiques des pathologies Cérébrales et Tumorales ( ISTCT ), 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 ) -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 ), Laboratoire d'Anatomie Pathologique [Caen], Normandie Université ( NU ) -Normandie Université ( NU ) -CHU Caen, 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 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 ), Hospices Civils de Lyon ( HCL ), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer (JPArc - U837 Inserm), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université Lille 2 - Faculté de Médecine, 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), 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), 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), Institut National de la Santé et de la Recherche Médicale (INSERM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Aix Marseille Université (AMU), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Université de Caen Normandie (UNICAEN), and Normandie Université (NU)
Subjects: Pathology, medicine.medical_specialty, Histology, [ SDV ] Life Sciences [q-bio], business.industry, [SDV]Life Sciences [q-bio], Pathology and Forensic Medicine, BRAF V600E, Text mining, Neurology, Physiology (medical), DNA Mutational Analysis, Mutation (genetic algorithm), Cancer research, Medicine, Neurology (clinical), business, ComputingMilieux_MISCELLANEOUS
Abstract: CERVOXY COLL; International audience
Published: 2015
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4. Adult H3K27M mutated thalamic glioma patients display a better prognosis than unmutated patients

Author: Stéphan Grimaldi, Vincent Harlay, Romain Appay, Céline Bequet, Grégorio Petrirena, Chantal Campello, Maryline Barrié, Didier Autran, Sébastien Boissonneau, Thomas Graillon, Dominique Figarella-Branger, Isabelle Nanni, Olivier Chinot, Emeline Tabouret, Laboratoire d'Anatomie Pathologique-Neuropathologique [AP-HM Hôpital La Timone], Hôpital de la Timone [CHU - APHM] (TIMONE), 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: Adult, Cancer Research, Brain Neoplasms, [SDV]Life Sciences [q-bio], Glioma, Prognosis, Histones, Thalamus, Neurology, Oncology, Mutation, Humans, Neurology (clinical), Retrospective Studies
Abstract: Adult thalamic gliomas are a rare entity whose management is challenging for physicians. The aim of this study is to describe the characteristics and prognostic factors of thalamic gliomas in adult patients.We retrospectively analyzed the clinical, neuro-radiological, histological, and molecular characteristics of all cases of adult thalamic glioma in our regional center.We included 38 adult patients. Median age at diagnosis was 56.5 years old (range, 24-80). Median KPS at diagnosis was 70%. Two-thirds of patients presented with tumor necrosis on MRI. Bithalamic lesions were present in four patients. The median volume of enhancement associated with lesions was relatively small (14 mmThalamic adult glioma differs from bithalamic glioma in children with regards to its clinical, radiological and molecular profiles. Long-term survival is observed in young patients with limited symptoms and H3K27M mutation. A larger prospective cohort is needed to validate these findings.
Published: 2022
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5. 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
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6. Meningiomas in patients with long-term exposition to progestins: Characteristics and outcome

Author: Frederic Castinetti, Thomas Cuny, Sébastien Boissonneau, Mohamed Boucekine, Dominique Figarella-Branger, Stéphane Fuentes, Thierry Brue, Thomas Graillon, Kaissar Farah, Romain Appay, Hadrien Peyrière, Frédérique Albarel, Isabelle Morange, Henry Dufour, Mikael Meyer, Institut de neurophysiopathologie (INP), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Anatomie Pathologique-Neuropathologique [AP-HM Hôpital La Timone], Hôpital de la Timone [CHU - APHM] (TIMONE), and Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)
Subjects: Nomegestrol acetate, medicine.medical_specialty, Proliferation index, medicine.drug_class, [SDV]Life Sciences [q-bio], education, Population, Urology, Acétate de nomegestrol, Progesterone receptor, Meningioma, 03 medical and health sciences, Chlormadinone acetate, chemistry.chemical_compound, 0302 clinical medicine, Acétate de chlormadinone, otorhinolaryngologic diseases, Meningeal Neoplasms, medicine, Humans, Cyproterone Acetate, neoplasms, Skull Base, education.field_of_study, business.industry, Acétate de cyprotérone, Cyproterone acetate, Méningiome, medicine.disease, nervous system diseases, 3. Good health, Discontinuation, Progestin, chemistry, 030220 oncology & carcinogenesis, Progestatif, Surgery, Neurology (clinical), Progestins, business, hormones, hormone substitutes, and hormone antagonists, Récepteur à la progesterone, 030217 neurology & neurosurgery
Abstract: Objective The aim of this study was to describe progestin-associated meningiomas’ characteristics, outcome and management. Material and methods We included 53 patients operated on and/or followed in the department for meningioma with progestin intake longer than one year and with recent drug discontinuation. Results Cyproterone acetate (CPA), nomegestrol acetate (NomA), and chlormadinone acetate (ChlA) were involved in most cases. Mean duration of progestin drugs intake was 17.5 years. Tumors were multiple in 66% of cases and were located in the anterior and the medial skull base in 71% of cases. Transitional subtype represented 16/25 tumors; 19 meningiomas were WHO grade I and 6 were grade II. The rate of transitional subtype and skull base location was significantly higher compared to matched operated meningioma general population. No difference was observed given WHO classification. But Ki67 proliferation index tends to be lower and 5/6 of the WHO grade II meningiomas were classified as WHO grade II because of brain invasion. Strong progesterone receptors expression was observed in most cases. After progestin discontinuation, a spontaneous visual recovery was observed in 6/10 patients. Under CPA (n = 24) and ChlA/NomA (n = 11), tumor volume decreased in 71% and 18% of patients, was stabilized in 25% and 64% of patients, and increased in 4% and 18% of patients, respectively. Volume outcome was related to meningioma location. Conclusions Outcome at progestins discontinuation is favorable but different comparing CPA versus ChlA-NomA and comparing tumor location. Long-term follow-up is required. In most cases, simple observation is recommended and surgery should be avoided.
Published: 2021
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7. Cross-species genomics reveals oncogenic dependencies in ZFTA/C11orf95 fusion-positive supratentorial ependymomas

Author: Daisuke Kawauchi, Mikio Hoshino, Tuyu Zheng, David T.W. Jones, Julia Benzel, Toma Adachi, Philipp Sievers, Andrew M. Donson, Ryo Shiraishi, Till Milde, Matija Snuderl, Shinichiro Taya, Amir Arabzade, Kendra K. Maass, Johannes Gojo, Marina Ryzhova, Patricia Benites Goncalves da Silva, Martin Sill, Stefan Rutkowski, Gudrun Fleischhack, Jonas Ecker, Pablo Hernáiz Driever, Ulrich Schüller, David R Ghasemi, Kristian W. Pajtler, Marcel Kool, Johan M. Kros, Richard J. Gilbertson, Felix Sahm, Christel Herold-Mende, David W. Ellison, Vijay Ramaswamy, Robert Kupp, Guido Reifenberger, Christine Haberler, Andreas von Deimling, Damian Stichel, Stefan M. Pfister, Andrey Korshunov, Richard Grundy, Dominique Figarella-Branger, Sebastian Brandner, Florian Selt, David Capper, Stephen C. Mack, Nicolas U. Gerber, Dominik Sturm, Konstantin Okonechnikov, Rebecca Chapman, Pathology, Institut de neurophysiopathologie (INP), 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), and Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Somatic cell, [SDV]Life Sciences [q-bio], Medizin, Biology, medicine.disease_cause, Fusion gene, Mice, 03 medical and health sciences, 0302 clinical medicine, Cell Line, Tumor, GLI2, medicine, Animals, Humans, Gene, Proteins, Supratentorial Neoplasms, Genomics, Methylation, Subependymoma, medicine.disease, DNA-Binding Proteins, Disease Models, Animal, 030104 developmental biology, Oncology, Ependymoma, 030220 oncology & carcinogenesis, DNA methylation, Cancer research, Carcinogenesis, Transcription Factors
Abstract: Molecular groups of supratentorial ependymomas comprise tumors with ZFTA–RELA or YAP1-involving fusions and fusion-negative subependymoma. However, occasionally supratentorial ependymomas cannot be readily assigned to any of these groups due to lack of detection of a typical fusion and/or ambiguous DNA methylation–based classification. An unbiased approach with a cohort of unprecedented size revealed distinct methylation clusters composed of tumors with ependymal but also various other histologic features containing alternative translocations that shared ZFTA as a partner gene. Somatic overexpression of ZFTA-associated fusion genes in the developing cerebral cortex is capable of inducing tumor formation in vivo, and cross-species comparative analyses identified GLI2 as a key downstream regulator of tumorigenesis in all tumors. Targeting GLI2 with arsenic trioxide caused extended survival of tumor-bearing animals, indicating a potential therapeutic vulnerability in ZFTA fusion–positive tumors. Significance: ZFTA–RELA fusions are a hallmark feature of supratentorial ependymoma. We find that ZFTA acts as a partner for alternative transcriptional activators in oncogenic fusions of supratentorial tumors with various histologic characteristics. Establishing representative mouse models, we identify potential therapeutic targets shared by ZFTA fusion–positive tumors, such as GLI2. This article is highlighted in the In This Issue feature, p. 2113
Published: 2021
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8. Long-term Impact of Subclinical Inflammation Diagnosed by Protocol Biopsy One Year After Renal Transplantation

Author: Jean-Michel Goujon, Luc Marcellin, Sandrine Girardot-Seguin, Guy Touchard, Arnaud François, Antoine Thierry, François Comoz, Marie-Christine Machet, Laure-Hélène Noël, Nathalie Rioux-Leclercq, Carole Cordonnier, Eric Thervet, Vincent Vuiblet, Ischémie - Reperfusion en transplatation rénale, Université de Poitiers-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de néphrologie - hémodialyse et transplantation rénale, Centre hospitalier universitaire de Poitiers (CHU Poitiers), Service de néphrologie et transplantation, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [AP-HP], Hôpital Maison Blanche, Centre Hospitalier Universitaire de Reims (CHU Reims), Laboratoire d'anatomopathologie, Service d'Anatomopathologie [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-CHU Trousseau [APHP], Service d'anatomie pathologique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], 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], 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), Service d'anatomie et cytopathologie, CHU Amiens-Picardie, Service d'Anatomie et Cytologie Pathologique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Département de Pathologie, CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], Laboratoire Roche, Laboratoire Roche SAS, Roche SAS, France, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Poitiers, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'anatomie et cytologie pathologiques [Rennes] = Anatomy and Cytopathology [Rennes], CHU Pontchaillou [Rennes], CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Université de Caen Normandie (UNICAEN), Service d'Anatomie et Cytologie Pathologique [CHU Rouen], Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université, Université de Poitiers-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université de Poitiers-Centre hospitalier universitaire de Poitiers ( CHU Poitiers ), Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Descartes - Paris 5 ( UPD5 ) -CHU Necker - Enfants Malades [AP-HP], Centre Hospitalier Universitaire de Reims ( CHU Reims ), Centre hospitalier universitaire de Poitiers ( CHU Poitiers ), CHRU Tours-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Laboratoire d'anatomie pathologique, CHU Caen-Hôpital côte de nacre, CHU Rouen-Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ), and De Villemeur, Hervé
Subjects: [ SDV.MHEP.UN ] Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, Protocol biopsy, medicine.medical_specialty, [SDV.IMM] Life Sciences [q-bio]/Immunology, [SDV.MHEP.CHI] Life Sciences [q-bio]/Human health and pathology/Surgery, Biopsy, 030232 urology & nephrology, Renal function, [SDV.MHEP.CHI]Life Sciences [q-bio]/Human health and pathology/Surgery, 030230 surgery, Kidney, Gastroenterology, [SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, 03 medical and health sciences, 0302 clinical medicine, subclinical inflammation, Internal medicine, medicine, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, Immunology and Allergy, Humans, Pharmacology (medical), [ SDV.MHEP.CHI ] Life Sciences [q-bio]/Human health and pathology/Surgery, Kidney transplantation, Survival analysis, Subclinical infection, Inflammation, Transplantation, medicine.diagnostic_test, business.industry, Incidence (epidemiology), Graft Survival, renal function, renal transplantation, medicine.disease, [SDV.MHEP.UN] Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, Kidney Transplantation, Survival Analysis, 3. Good health, Surgery, Sirolimus, [SDV.IMM]Life Sciences [q-bio]/Immunology, business, Immunosuppressive Agents, medicine.drug
Abstract: International audience; The long-term impact of subclinical acute rejection (SCAR) on renal graft function remains poorly understood. Furthermore, the interpretation of borderline lesions is difficult and their incidence is variable. The aim of this study was to analyze the characteristics of subclinical inflammation (SCI) in protocol biopsies performed 1-year after renal transplantation. SCI was defined as the presence of borderline lesions or SCAR according to the Banff 2005 classification. The patients included were a subpopulation of the CONCEPT study in which patients were randomized 3 months after transplantation to receive either sirolimus (SRL) or cyclosporine A (CsA) in combination with mycophenolate mofetil. At 1 year, we observed SCI in 37 of the 121 patients observed with an evaluable biopsy. The incidence was more frequent in the SRL group (SRL 45.2% vs. CsA 15.3%). At 30 months , SCI was associated with a significantly lower level of estimated glomerular filtration rate (mean MDRD 50.8 [±13.3] vs. 57.7 [±16.3] mL/min/1.73 m(2) , p = 0.035). In conclusion, SCI at 1-year posttransplantation is associated with worsening renal function and is more frequent in SRL-treated patients. Therefore, evaluation of SCI may be a valuable tool to allow the optimization of immunosuppressive regimens.
Published: 2011
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9. Genomic expression and single-nucleotide polymorphism profiling discriminates chromophobe renal cell carcinoma and oncocytoma

Author: Min-Han Tan, Jun Sugimura, Jonathon A. Ditlev, Annick Vieillefond, Tomoaki Fujioka, Puay Hoon Tan, Ximing J. Yang, Daisuke Matsuda, Delphine Amsellem-Ouazana, Eric J. Kort, Nicolas Thiounn, Chin Fong Wong, Sophie Giraud, Philippe Vielh, Thierry Flam, Bin Tean Teh, Bernard Debré, Stéphane Richard, Sophie Ferlicot, Marc Zerbib, Kyle A. Furge, Sok Kean Khoo, Hwei Ling Tan, Gérard Benoit, Vincent Molinié, Stéphane Droupy, BMC, Ed., Laboratory of Cancer Genetics, Van Andel Institute [Grand Rapids], NCCS-VARI Translational Cancer Research Laboratory, National Cancer Centre Singapore, Department of Medical Oncology, Department of Epidemiology and Public Health, National University of Singapore (NUS), Department of Pathology, Singapore General Hospital, Northwestern University Feinberg School of Medicine, Department of Urology, Iwate Medical University School of Medicine, Laboratory of Computational Biology, Laboratory of Molecular Epidemiology, Laboratoire de Génétique, Hôpital Herriot, Laboratoire d'Anatomie Pathologique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital de Bicêtre, Pathologie morphologique, Département de biologie et pathologie médicales [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Service d'urologie, Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Cytokines et Immunologie des Tumeurs Humaines (U753), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'anatomie pathologique, Hôpital Saint Joseph, Laboratoire d'anatomie pathologique, Consultation d'oncogénétique spécialisée, Hôpital de Bicêtre-Service d'Urologie, and We wish to thank the Fischer Family Foundation, the Singapore Cancer Society, the French National Cancer Institute (Kidney PNES, INCa), and the French League against Cancer (Comités du Cher et de l'Indre) for supporting this study. We would also like to thank the Hauenstein Foundation and the Van Andel Foundation for their continued support. We thank the Cooperative Human Tissue Network (CHTN) of the National Cancer Institute for providing samples for analysis. Min-Han Tan is supported by the Singapore Millenium Foundation and the National Kidney Foundation.
Subjects: Pathology, Cancer Research, Chromophobe Renal Cell Carcinoma, Gene Dosage, Chromophobe cell, urologic and male genital diseases, MESH: Gene Dosage, 0302 clinical medicine, Odds Ratio, Adenoma, Oxyphilic, Oncocytoma, Gene Regulatory Networks, MESH: Nerve Tissue Proteins, Renal oncocytoma, MESH: Gene Regulatory Networks, Oligonucleotide Array Sequence Analysis, Synaptogyrins, 0303 health sciences, MESH: Genetic Testing, MESH: Polymorphism, Single Nucleotide, MESH: Carcinoma, Renal Cell, MESH: Gene Expression Regulation, Neoplastic, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Immunohistochemistry, MESH: Predictive Value of Tests, Kidney Neoplasms, MESH: Reproducibility of Results, Gene Expression Regulation, Neoplastic, Oncology, Chromosomes, Human, Pair 1, 030220 oncology & carcinogenesis, Cytogenetic Analysis, MESH: Membrane Proteins, Research Article, medicine.medical_specialty, MESH: Adenoma, Oxyphilic, MESH: Chromosomes, Human, Pair 1, [SDV.CAN]Life Sciences [q-bio]/Cancer, Nerve Tissue Proteins, Computational biology, Biology, Gene dosage, Polymorphism, Single Nucleotide, lcsh:RC254-282, Diagnosis, Differential, 03 medical and health sciences, MESH: Gene Expression Profiling, [SDV.CAN] Life Sciences [q-bio]/Cancer, MESH: Diagnosis, Differential, Predictive Value of Tests, medicine, Genetics, Biomarkers, Tumor, Humans, MESH: Tumor Suppressor Proteins, Genetic Testing, Carcinoma, Renal Cell, 030304 developmental biology, MESH: Humans, MESH: Cytogenetic Analysis, Gene Expression Profiling, Tumor Suppressor Proteins, MESH: Aquaporin 6, Membrane Proteins, Reproducibility of Results, MESH: Immunohistochemistry, Gene signature, medicine.disease, MESH: Odds Ratio, Aquaporin 6, Gene expression profiling, Clear cell renal cell carcinoma, MESH: Tumor Markers, Biological, MESH: Oligonucleotide Array Sequence Analysis, MESH: Kidney Neoplasms
Abstract: Background Chromophobe renal cell carcinoma (chRCC) and renal oncocytoma are two distinct but closely related entities with strong morphologic and genetic similarities. While chRCC is a malignant tumor, oncocytoma is usually regarded as a benign entity. The overlapping characteristics are best explained by a common cellular origin, and the biologic differences between chRCC and oncocytoma are therefore of considerable interest in terms of carcinogenesis, diagnosis and clinical management. Previous studies have been relatively limited in terms of examining the differences between oncocytoma and chromophobe RCC. Methods Gene expression profiling using the Affymetrix HGU133Plus2 platform was applied on chRCC (n = 15) and oncocytoma specimens (n = 15). Supervised analysis was applied to identify a discriminatory gene signature, as well as differentially expressed genes. High throughput single-nucleotide polymorphism (SNP) genotyping was performed on independent samples (n = 14) using Affymetrix GeneChip Mapping 100 K arrays to assess correlation between expression and gene copy number. Immunohistochemical validation was performed in an independent set of tumors. Results A novel 14 probe-set signature was developed to classify the tumors internally with 93% accuracy, and this was successfully validated on an external data-set with 94% accuracy. Pathway analysis highlighted clinically relevant dysregulated pathways of c-erbB2 and mammalian target of rapamycin (mTOR) signaling in chRCC, but no significant differences in p-AKT or extracellular HER2 expression was identified on immunohistochemistry. Loss of chromosome 1p, reflected in both cytogenetic and expression analysis, is common to both entities, implying this may be an early event in histogenesis. Multiple regional areas of cytogenetic alterations and corresponding expression biases differentiating the two entities were identified. Parafibromin, aquaporin 6, and synaptogyrin 3 were novel immunohistochemical markers effectively discriminating the two pathologic entities. Conclusions Gene expression profiles, high-throughput SNP genotyping, and pathway analysis effectively distinguish chRCC from oncocytoma. We have generated a novel transcript predictor that is able to discriminate between the two entities accurately, and which has been validated both in an internal and an independent data-set, implying generalizability. A cytogenetic alteration, loss of chromosome 1p, common to renal oncocytoma and chRCC has been identified, providing the opportunities for identifying novel tumor suppressor genes and we have identified a series of immunohistochemical markers that are clinically useful in discriminating chRCC and oncocytoma.
Published: 2010
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10. Array-CGH analysis indicates a high prevalence of genomic rearrangements in holoprosencephaly: an updated map of candidate loci

Author: Jaqueline Vigneron, Isabelle Gicquel, Jonathan Seguin, Caroline Rouleau, Annie Laquerrière, Véronique David, Claude Bendavid, Jean Mosser, Sylvie Jaillard, Christèle Dubourg, Sylvie Odent, Corinne Jeanne-Pasquier, Pascale Marcorelles, Lucie Rochard, Laurent Pasquier, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS), Service de biologie moléculaire, Hôpital Pontchaillou, Service de génétique clinique, hôpital Sud, Consultation de Génétique, Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Endothélium microcirculatoire cérébral et lésions du système nerveux central au cours du développement (Néovasc), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Anatomie Pathologique, Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), 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), Laboratoire d'anatomie pathologique, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Lapeyronie, Service de Cytogénétique et de Biologie Cellulaire, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Plate-forme transcriptome, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), This work was funded by PHRC interrégional 2004, GIS maladies rares (GISMR0701), FMO (Fédération des Maladies Orphelines)., Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS), Service de génétique clinique [Rennes], Université de Rennes (UR)-CHU Pontchaillou [Rennes]-hôpital Sud, Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rennes (UR)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Université de Rennes (UR), and De Villemeur, Hervé
Subjects: musculoskeletal diseases, Candidate gene, congenital, hereditary, and neonatal diseases and abnormalities, MESH: Gene Rearrangement, [SDV.GEN] Life Sciences [q-bio]/Genetics, Biology, ZIC2, CGH array, Cohort Studies, MESH: Nucleic Acid Hybridization, 03 medical and health sciences, Holoprosencephaly, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [SDV.BDD] Life Sciences [q-bio]/Development Biology, Genetics, medicine, Humans, Point Mutation, rearrangements, candidate loci, Gene, MESH: Cohort Studies, [SDV.BDD]Life Sciences [q-bio]/Development Biology, Genetics (clinical), 030304 developmental biology, MESH: Point Mutation, Gene Rearrangement, 0303 health sciences, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, Genetic heterogeneity, Point mutation, 030305 genetics & heredity, Chromosome Mapping, Nucleic Acid Hybridization, Karyotype, medicine.disease, Subtelomere, holoprosencephaly, MESH: Karyotyping, MESH: Gene Deletion, Karyotyping, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], MESH: Chromosome Mapping, MESH: Holoprosencephaly, Gene Deletion
Abstract: International audience; Holoprosencephaly (HPE) is the most frequent malformation of the brain. To date, 12 different HPE loci and 8 HPE genes have been identified from recurrent chromosomal rearrangements or from the sequencing of genes from Nodal and SHH pathways. Our cohort of HPE patients presents a high genetic heterogeneity. Point mutations were found in SHH, ZIC2, SIX3, and TGIF genes in about 20% of cases (with 10% in SHH). Deletions in these same genes were found in 7.5% of the patients and 4.4% presented with other subtelomeric gain or losses. Consequently, the molecular basis of HPE remains unknown in 70% of our cohorts. To detect new HPE candidate genes, we used array-CGH to refine the previous karyotype based HPE loci map. We analyzed 111 HPE patients with high-performance Agilent oligonucleotidic arrays and found that 28 presented anomalies involving known or new potential HPE loci located on different chromosomes but with poor redundancy. This study showed an impressive rate of 19 patients among 111 with de novo chromosomal anomalies giving evidence that microrearrangements could be a major molecular mechanism in HPE. Additionally, this study opens new insights on HPE candidate genes identification giving an updated HPE candidate loci map.
Published: 2009
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11. KBA.62: a useful marker for primary and metastatic melanomas

Author: Sophie Le Guellec, Philippe Rochaix, Paul Carle, Pierre Payoux, Séverine Valmary-Degano, Talal Al Saati, François Launay, Laurence Lamant, Serge Boulinguez, Frédéric Lauwers, Pierre Brousset, Cécile Pages, Laboratoire d'Anatomie Pathologique [Purpan], CHU Toulouse [Toulouse], Institut Claudius Regaud, CRLCC Institut Claudius Regaud, Plateau technique d'Histopathologie Expérimentale, Institut Claude de Préval (ICP), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Service de dermatologie, Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse], Service de chirurgie plastique et maxillo-faciale, CHU Purpan, Toulouse, Service de Médecine Nucléaire [Toulouse], CHU Toulouse [Toulouse]-Hôpital Rangueil, Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC ( CEF2P / CARCINO ), Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Université Bourgogne Franche-Comté ( UBFC ) -Université de Franche-Comté ( UFC ), Laboratoire d'anatomie pathologique [Besancon], Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Hôpital Jean Minjoz-Université de Franche-Comté ( UFC ), Institut de Physique Nucléaire d'Orsay ( IPNO ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut National de Physique Nucléaire et de Physique des Particules du CNRS ( IN2P3 ) -Centre National de la Recherche Scientifique ( CNRS ), Imagerie cérébrale et handicaps neurologiques, Université Paul Sabatier - Toulouse 3 ( UPS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service d'anatomie pathologique et histologie-cytologie [Rangueil], Université Paul Sabatier - Toulouse 3 ( UPS ) -CHU Toulouse [Toulouse]-Hôpital de Rangueil, Université Sciences et Technologies - Bordeaux 1, Centre de Recherche en Cancérologie de Toulouse ( CRCT ), and Université Paul Sabatier - Toulouse 3 ( UPS ) -CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse]-Institut National de la Santé et de la Recherche Médicale ( INSERM )
Subjects: MESH: Neoplasm Proteins, Pathology, Skin Neoplasms, MESH : Immunohistochemistry, MESH: Lymphatic Metastasis, MESH : S100 Proteins, MESH: Antigens, Neoplasm, MESH: Lymph Nodes, MESH : Antigens, Neoplasm, Metastasis, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, MESH: Antibodies, Monoclonal, 030207 dermatology & venereal diseases, 0302 clinical medicine, MESH : Tumor Markers, Biological, Lymph node, Melanoma, MESH : Lymph Nodes, Micrometastasis, S100 Proteins, Antibodies, Monoclonal, MESH : Lymphatic Metastasis, Immunohistochemistry, 3. Good health, Neoplasm Proteins, medicine.anatomical_structure, 030220 oncology & carcinogenesis, MESH : Antibodies, Monoclonal, Lymphatic Metastasis, Lymph, MESH : Sensitivity and Specificity, MESH: S100 Proteins, Melanoma-Specific Antigens, medicine.medical_specialty, MESH: Melanoma, Sentinel lymph node, MESH : Melanoma, [SDV.CAN]Life Sciences [q-bio]/Cancer, Sensitivity and Specificity, Pathology and Forensic Medicine, 03 medical and health sciences, MESH : Neoplasm Proteins, Antigens, Neoplasm, medicine, Biomarkers, Tumor, Humans, Desmoplastic melanoma, MESH: Humans, business.industry, MESH: Skin Neoplasms, MESH : Skin Neoplasms, MESH : Humans, MESH : Melanoma-Specific Antigens, MESH: Immunohistochemistry, medicine.disease, MESH: Sensitivity and Specificity, MESH: Melanoma-Specific Antigens, MESH: Tumor Markers, Biological, Lymph Nodes, business
Abstract: International audience; We previously described a novel antimelanoma antibody, designated KBA.62. However, review of the literature showed that only a few studies have reported on this antibody. We report our experience in the diagnosis of melanoma using KBA.62 and its value in both primary and metastatic conditions. In addition to conventional melanomas, we included desmoplastic and spindle cell melanomas, whose diagnosis can be challenging. We also focus on identification of malignant cells in sentinel lymph node biopsies using KBA.62, by comparison with anti-S-100 protein and HMB-45 antibodies, because discrepancies in sensitivity and specificity of melanoma markers have given rise to numerous studies aiming to determine the best panel for the evaluation of sentinel lymph node from patients with melanoma. Overall, KBA.62 was positive in 93% of primary and metastatic melanomas. Interestingly, the 12 cases of desmoplastic and spindle cell melanomas had strongly positive results. In addition, the results of our study performed on a series of 215 sentinel lymph nodes showed that the sensitivity of anti-S-100 protein and KBA.62 antibodies in detecting occult metastasis was similar. Moreover, KBA.62 identified 6 patients (3%) who had confirmed sentinel lymph node metastasis but were negative for HMB-45. The resolution was higher with KBA.62 than that observed with anti-S-100 protein antibody, as the nonmelanocytic positive cells for KBA.62 in lymph nodes were only represented by endothelial cells, which therefore constituted an intrinsic positive control. We conclude that KBA.62 antibody is a useful additional marker for melanoma, specifically in desmoplastic/spindle cell cases and in the context of micrometastasis in sentinel lymph node.
Published: 2008
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12. The Use of Pro-Angiogenic and/or Pro-Hypoxic miRNAs as Tools to Monitor Patients with Diffuse Gliomas

Author: Guénaëlle Levallet, Fatéméh Dubois, Arthur Leclerc, Edwige Petit, Lien Bekaert, Maxime Faisant, Christian Creveuil, Evelyne Emery, Gérard Zalcman, Emmanuèle Lechapt-Zalcman, Département de Pathologie [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 pour les Cancers et Tissus cérébraux (ISTCT), Normandie Université (NU)-Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS), Service de Neurochirurgie [CHU Caen], CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Unité de génétique et biologie des cancers (U830), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'investigation Clinique [CHU Bichat] - Épidémiologie clinique (CIC 1425), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Laboratoire d'Anatomie Pathologique [CHU Caen], Molecular virology and immunology – Physiopathology and therapeutic of chronic viral hepatitis (Team 18) (Inserm U955), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Département de pathologie [Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), and APRI 2012
Subjects: Brain Neoplasms, hypoxia, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Organic Chemistry, [SDV.CAN]Life Sciences [q-bio]/Cancer, General Medicine, Isocitrate Dehydrogenase, Catalysis, Computer Science Applications, Inorganic Chemistry, MicroRNAs, angiogenesis, glioma, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Mutation, Humans, miRNA, Physical and Theoretical Chemistry, Molecular Biology, Spectroscopy
Abstract: CERVOXY; International audience; IDH (isocitrate dehydrogenase) mutation, hypoxia, and neo-angiogenesis, three hallmarks of diffuse gliomas, modulate the expression of small non-coding RNAs (miRNA). In this paper, we tested whether pro-angiogenic and/or pro-hypoxic miRNAs could be used to monitor patients with glioma. The miRNAs were extracted from tumoral surgical specimens embedded in the paraffin of 97 patients with diffuse gliomas and, for 7 patients, from a blood sample too. The expression of 10 pro-angiogenic and/or pro-hypoxic miRNAs was assayed by qRT-PCR and normalized to the miRNA expression of non-tumoral brain tissues. We confirmed in vitro that IDH in hypoxia (1% O2, 24 h) alters pro-angiogenic and/or pro-hypoxic miRNA expression in HBT-14 (U-87 MG) cells. Then, we reported that the expression of these miRNAs is (i) strongly affected in patients with glioma compared to that in a non-tumoral brain; (ii) correlated with the histology/grade of glioma according to the 2016 WHO classification; and (iii) predicts the overall and/or progression-free survival of patients with glioma in univariate but not in a multivariate analysis after adjusting for sex, age at diagnosis, and WHO classification. Finally, the expression of miRNAs was found to be the same between the plasma and glial tumor of the same patient. This study highlights a panel of seven pro-angiogenic and/or pro-hypoxic miRNAs as a potential tool for monitoring patients with glioma.
Published: 2022
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13. Prognostic value of circulating lymphocyte subsets in primary central nervous system lymphoma

Author: Axel Berthelot, Celine Bequet, Vincent Harlay, Gregorio Petrirena, Chantal Campello, Maryline Barrié, Romain Appay, Olivier Chinot, Emeline Tabouret, Institut de neurophysiopathologie (INP), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Anatomie Pathologique-Neuropathologique [AP-HM Hôpital La Timone], Hôpital de la Timone [CHU - APHM] (TIMONE), 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: Central Nervous System, Cancer Research, [SDV]Life Sciences [q-bio], Prognosis, Lymphocyte Subsets, Neurology, Oncology, Lymphopenia, Antineoplastic Combined Chemotherapy Protocols, Humans, Neurology (clinical), Lymphocyte Count, Lymphoma, Large B-Cell, Diffuse, Rituximab, Retrospective Studies
Abstract: Immunity plays an important role in CNS-DLBCL development. CNS-DLBCL predictive factors need to be improved.To evaluate the predictive value of circulating lymphocyte subsets in PCNSL patients.We prospectively analyzed blood lymphocyte immunophenotyping (LIP) in newly CNS-DLBCL referred to our institution between December 2013 and January 2020. LIP analysis was performed before rituximab and chemotherapy administration. The clinical, radiological, histological, biological and treatment data were retrospectively collected.Fifty-three patients were included with a median age of 69.7 (range 21.7-87.5). Median KPS was 60 (range 30-100). Thirty-three patients (64%) presented with one or several lymphopenias: 21 (40%), 24 (46%) and 9 (17%) NK, T and B lymphopenias respectively. Only 11 patients (21%) had normal LIP. Median CD4+/CD8+ ratio was 2.11 (range 0.54-9.11). This ratio was normal, low or high in 27%, 28% and 44% of patients respectively. The presence of steroids did not impact LIP results. Complete, partial responses, stable and progressive disease (PD) were observed in 24 (50%), 10 (21%), 4 (8%), and 10 (21%) patients respectively. CD4+/CD8+ ratio tended to be different between refractory (PD patients) and non-refractory patients (p = 0.077, ROC AUC: 0.684). Median progression-free survival (PFS) and overall survival (OS) were 14.7 (95%CI 6.5-22.9) and 43.2 (95%CI 21.6-64.9) months, respectively. In multivariate analyses, adjusted by KPS, a CD4+/CD8+ ratio 1.97 was associated with poor PFS [p = 0.043, HR = 3.32 (1.02-4.88)] and tended to be associated with worse OS (p = 0.064).LIP at baseline may predict refractory disease and exhibits a prognostic value in CNS-DLBCL patients.
Published: 2022
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14. Characteristics of IDH-mutant gliomas with non-canonical IDH mutation

Author: Poetsch, L., Bronnimann, C., Loiseau, H., Frénel, J., Siegfried, A., Seizeur, R., Gauchotte, G., Cappellen, D., Carpentier, C., Figarella‑Branger, Dominique, Eimer, S., Meyronet, D., Ducray, F., Network, POLA, Rigaud, V., CHU Bordeaux [Bordeaux], Imagerie moléculaire et thérapies innovantes en oncologie (IMOTION), Université de Bordeaux (UB), CRLCC René Gauducheau, Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de neurochirurgie [Brest], Hôpital de la Cavale Blanche - CHRU Brest (CHU - BREST ), 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), Biothérapies des maladies génétiques et cancers, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), 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 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), Institut de neurophysiopathologie (INP), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Anatomie Pathologique-Neuropathologique [AP-HM Hôpital La Timone], Hôpital de la Timone [CHU - APHM] (TIMONE), Service de pathologie [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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 Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pitié-Salpêtrière [AP-HP], 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), and Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Adult, Male, Cancer Research, medicine.medical_specialty, IDH1, [SDV]Life Sciences [q-bio], Mutant, IDH2, Gastroenterology, 03 medical and health sciences, 0302 clinical medicine, Glioma, Internal medicine, medicine, Genetic predisposition, Humans, Genetic Predisposition to Disease, Family history, neoplasms, ComputingMilieux_MISCELLANEOUS, Brain Neoplasms, business.industry, Cancer, Prognosis, medicine.disease, Combined Modality Therapy, Isocitrate Dehydrogenase, nervous system diseases, 3. Good health, Idh mutation, Survival Rate, Neurology, Oncology, 030220 oncology & carcinogenesis, Mutation, Female, Neurology (clinical), business, 030217 neurology & neurosurgery, Follow-Up Studies
Abstract: Approximately 10% of IDH-mutant gliomas harbour non-canonical IDH mutations (non-p.R132H IDH1 and IDH2 mutations). The aim of this study was to analyse the characteristics of non-canonical IDH-mutant gliomas. We retrospectively analysed the characteristics of 166 patients with non-canonical IDH mutant gliomas and compared them to those of 155 consecutive patients with IDH1 p.R132H mutant gliomas. The median age at diagnosis was 38 years in patients with non-canonical IDH mutant gliomas and 43 years in glioma patients with IDH1 p.R132H-mutant tumours. Family history of cancer was more frequent among glioma patients harbouring non-canonical IDH mutations than in patients with IDH1 p.R132H mutations (22.2% vs 5.1%; P
Published: 2020
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15. Difficultés diagnostiques de la bérylliose pulmonaire chronique en France

Author: B. Guillaud Segard, M. Ghanem, Romain Lazor, Dominique Israel-Biet, V. Bonneterre, Sylvain Marchand-Adam, J.P. L’huillier, Vincent Cottin, M.F. Marquignon, Abdellatif Tazi, Anne Gondouin, Jean-Marc Naccache, Dominique Valeyre, CHU Grenoble, Service de pneumologie, Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Pneumologie, oncologie thoracique et allergologie respiratoire [CHRU Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Université de Paris - UFR Médecine Paris Centre [Santé] (UP Médecine Paris Centre), Université de Paris (UP), 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), 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), Centre d’Etude des Pathologies Respiratoires (CEPR), UMR 1100 (CEPR), Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Pulmonary and Respiratory Medicine, Gynecology, 03 medical and health sciences, medicine.medical_specialty, 0302 clinical medicine, 030228 respiratory system, business.industry, Granulomatous disease, [SDV]Life Sciences [q-bio], Medicine, 030212 general & internal medicine, business, 3. Good health
Abstract: Resume Introduction Il existe peu de donnees concernant l’epidemiologie de la berylliose pulmonaire chronique (BPC) en France. L’objectif de cette etude etait de denombrer les cas de BPC prevalents en France pendant la periode allant de 2010 a 2014. Methodes Une enquete nationale a ete realisee en France a l’aide d’un questionnaire specifique diffuse aupres des services de pneumologie et de pathologie professionnelle. Resultats Nous avons identifie 33 cas de BPC en France qui avaient ete diagnostiques entre 1982 et 2014. L’exposition etait professionnelle dans 28/33 cas (85 %) et concernait majoritairement les metiers de la fonderie (39 % des cas). Un diagnostic de certitude etait pose chez 29/33 cas (88 %) avec l’association d’une hypersensibilite au Be et d’une granulomatose, les 4 cas restant etaient des BPC probables. Le diagnostic de granulomatose survenait en moyenne 4 ans apres la fin de l’exposition. Le delai median entre le diagnostic de granulomatose et le diagnostic de berylliose etait de 2 ans (0 a 38 ans). Nous retrouvions une predisposition genetique chez 14 des 17 patients testes (82 %). Conclusion Cette etude a permis de recenser 33 cas de BPC suivis en France entre 2010 et 2014. La meconnaissance de la BPC et des expositions favorisantes, l’apparition tardive apres l’arret des expositions, la complexite du diagnostic et les similitudes avec la sarcoidose pourraient expliquer le faible nombre de cas recenses.
Published: 2020
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16. Exome sequencing identifies the first genetic determinants of sirenomelia in humans

Author: Marianne Begorre, Daniel Cailliez, Claire Beneteau, Pierre Chenal, Thierry Frebourg, Guillaume Benoist, François Lecoquierre, Raphaele Mangione, Florence Petit, Nicolas Gruchy, Louise Devisme, Sophie Patrier, Juliette Coursimault, Fanny Pelluard, Hubert Journel, Bénédicte Gérard, Marion Gérard, Pascale Saugier-Veber, Valérie Layet, Alain Liquier, Corinne Jeanne, Mirjam M. de Jong, Nadia Tillouche, Anne Bazin, Gaël Nicolas, Conny M. A. van Ravenswaaij-Arts, Anne-Claire Brehin, Wilfrid Finck, Sophie Coutant, Sophie Degre, Christine Francannet, Madeleine Joubert, Hélène Laurichesse Delmas, Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire CERBA [Saint Ouen l'Aumône], Service d'Anatomie Pathologique [CHU Clermont-Ferrand], CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Université de Lausanne = University of Lausanne (UNIL), Service de Gynécologie-Obstétrique et Médecine de la Reproduction [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 génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Groupe Hospitalier du Havre, University of Groningen [Groningen], Institut de Pathologie [CHU Lille], Pôle de Biologie Pathologie Génétique [CHU Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Clermont-Ferrand, Service d'hématologie et immunologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Génétique Médicale, Centre hospitalier Bretagne Atlantique (Morbihan) (CHBA)-Hôpital Chubert, Unité de Cytogénétique et Génétique Médicale, Groupe Hospitalier du Havre-Hôpital Gustave Flaubert, Service d'Anatomie et Cytologie Pathologique [CHU Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Laboratoire d'anatomie pathologique, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Institut méditerranéen de biodiversité et d'écologie marine et continentale (IMBE), Avignon Université (AU)-Aix Marseille Université (AMU)-Institut de recherche pour le développement [IRD] : UMR237-Centre National de la Recherche Scientifique (CNRS), Laboratoire de cytogénétique prénatale [CHU Caen], UNIROUEN - UFR Santé (UNIROUEN UFR Santé), Normandie Université (NU)-Normandie Université (NU), Service de Génétique [CHU Caen], Clinical Cognitive Neuropsychiatry Research Program (CCNP), Université de Lausanne (UNIL), Université Paris Diderot - Paris 7 (UPD7)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Subjects: Male, Genotype, audal dysgenesis, Ectromelia, [SDV]Life Sciences [q-bio], REQUIREMENT, Malformation sequence, Biology, Sirenomelia, CAUDAL REGRESSION, Frameshift mutation, 03 medical and health sciences, Genetics, medicine, Humans, CDX2 Transcription Factor, Genetic Predisposition to Disease, CDX2, Gene, Alleles, Genetic Association Studies, Genetics (clinical), Exome sequencing, Adaptor Proteins, Signal Transducing, 030304 developmental biology, 0303 health sciences, Calcium-Binding Proteins, 030305 genetics & heredity, Wnt signaling pathway, Heterozygote advantage, DEFECTS, medicine.disease, caudal dysgenesis, de novo mutation, Pedigree, Phenotype, Amino Acid Substitution, GROWTH, Female, CDX2 de novo mutation, exome sequencing
Abstract: Full access; International audience; Sirenomelia is a rare severe malformation sequence of unknown cause characterized by fused legs and severe visceral abnormalities. We present a series of nine families including two rare familial aggregations of sirenomelia investigated by a trio‐based exome sequencing strategy. This approach identified CDX2 variants in the two familial aggregations, both fitting an autosomal dominant pattern of inheritance with variable expressivity. CDX2 is a major regulator of caudal development in vertebrate and mouse heterozygotes are a previously described model of sirenomelia. Remarkably, the p.(Arg237His) variant has already been reported in a patient with persistent cloaca. Analysis of the sporadic cases revealed six additional candidate variants including a de novo frameshift variant in the genetically constrained NKD1 gene, encoding a known interactor of CDX2 . We provide the first insights for a genetic contribution in human sirenomelia and highlight the role of Cdx and Wnt signaling pathways in the development of this disorder.
Published: 2020
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17. Reliability Criteria of Two-Dimensional Shear Wave Elastography: Analysis of 4277 Measurements in 788 Patients

Author: Gilles Hunault, Valérie Vilgrain, Sylvain Lemoine, Victor de Ledinghen, Maxime Ronot, Brigitte Le Bail, Jérôme Lebigot, Marie-Christine Rousselet, Christophe Aubé, Anita Paisant, Valérie Paradis, Clémence M. Canivet, Jérôme Boursier, Anne Crouan, Sophie Michalak, Pierre-Emmanuel Rautou, Christophe Cassinotto, Marie Irles-Depe, BOURGEAIS, Véronique, Hémodynamique, Interaction Fibrose et Invasivité tumorales Hépatiques (HIFIH), Université d'Angers (UA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), SFR UA 4208 Interactions Cellulaires et Applications Thérapeutiques (ICAT), Hôpital Saint Eloi (CHRU Montpellier), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Hôpital Pellegrin, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Département d'hépatologie (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Laboratoire de Pathologie Cellulaire et Tissulaire, CERCOPAN, Laboratoire d'anatomie pathologique, Service d’Hépatologie [Hôpital Beaujon], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Subjects: Liver Cirrhosis, Cirrhosis, Coefficient of variation, [SDV]Life Sciences [q-bio], Population, Chronic liver disease, Standard deviation, 03 medical and health sciences, 0302 clinical medicine, 2D-SWE, Region of interest, Medicine, Humans, education, Reliability (statistics), ComputingMilieux_MISCELLANEOUS, education.field_of_study, Hepatology, medicine.diagnostic_test, business.industry, Liver Diseases, Gastroenterology, Reproducibility of Results, medicine.disease, Reliability, Liver Stiffness, 3. Good health, [SDV] Life Sciences [q-bio], Liver, 030220 oncology & carcinogenesis, Liver biopsy, Elasticity Imaging Techniques, Liver Fibrosis, 030211 gastroenterology & hepatology, business, Nuclear medicine
Abstract: International audience; Background & aims: Two-dimensional shear wave elastography (2D-SWE) is an accurate method for the non-invasive evaluation of liver fibrosis. We aimed to determine the reliability criteria and the number of necessary reliable measurements for 2D-SWE.Methods: 788 patients with chronic liver disease underwent liver biopsy and 2D-SWE examination in three centers. The 4277 2D-SWE measurements performed were 2:1 randomly divided into derivation (n = 2851) and validation (n = 1426) sets. Reliability criteria for a 2D-SWE measurement were defined in the derivation set from the intrinsic characteristics given by the device (mean liver stiffness, standard deviation, diameter of the region of interest), with further evaluation in the validation set.Results: In the whole population of 4277 measurements, AUROC for bridging fibrosis was 0.825 ± 0.006 and AUROC for cirrhosis was 0.880 ± 0.006. Mean stiffness and coefficient of variation (CV) were independent predictors of bridging fibrosis or cirrhosis. From these two parameters, new criteria were derived to define a reliable 2D-SWE measurement: stiffness
Published: 2022
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18. Cartographie simultanée de la vascularisation, de l'hypoxie et de la prolifération à l'aide de l’IRM de perfusion, la TEP au 18F-FMISO et au 18F-FLT, en relation avec la prise de contraste dans les glioblastomes

Author: Cécile Perrio, Myriam Bernaudin, Stéphane Guillouet, David Hassanein Berro, J M Derlon, Samuel Valable, Mathieu Hatt, Solène Collet, Jean-Sébastien Guillamo, Jean-Marc Constans, Ararat Chakhoyan, Emmanuèle Lechapt-Zalcman, Dimitris Visvikis, Imagerie et Stratégies Thérapeutiques des pathologies Cérébrales et Tumorales (ISTCT), 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 Neurochirurgie [CHU Caen], CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Université de Caen Normandie (UNICAEN), Normandie Université (NU), Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), Service de Neurologie [CHU Caen], 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 [CHU Nimes] (Pôle NIRR), Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes)-Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Départment de Neuroradiologie [CHU Caen], Laboratoire d'Anatomie Pathologique [CHU Caen], Service de Neuropathologie [Paris], Centre Hospitalier Sainte Anne [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-GHU Paris Psychiatrie et Neurosciences, Laboratoire de Traitement de l'Information Medicale (LaTIM), Institut National de la Santé et de la Recherche Médicale (INSERM)-IMT Atlantique Bretagne-Pays de la Loire (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Centre Hospitalier Régional Universitaire de Brest (CHRU Brest)-Université de Brest (UBO)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), 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), and Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)
Subjects: 03 medical and health sciences, 0302 clinical medicine, Radiological and Ultrasound Technology, [SDV]Life Sciences [q-bio], Radiology, Nuclear Medicine and imaging, Neurology (clinical), 030217 neurology & neurosurgery, 030218 nuclear medicine & medical imaging
Abstract: CERVOXY-LDM TEP; International audience; Introduction L'IRM conventionnelle joue un rôle clé dans la prise en charge des patients atteints de glioblastomes, cependant, l’IRM multiparamétrique et la TEP pourraient fournir des informations supplémentaires en identifiant les régions à haut risque de récidive. Dans cette étude, nous nous sommes intéressés à la prolifération, l'hypervascularisation et l'hypoxie, considérées comme des facteurs de mauvais pronostic. Elles ont été évaluées en mesurant respectivement la captation du 18F-FLT, le rCBV et la captation du 18F-FMISO et comparées à la prise de contraste (PC) sur la séquence T1w-Gd.Méthodes Une IRM de perfusion (31 patients), une TEP au 18F-FLT (20 patients) et/ou une TEP 18F-FMISO (20 patients, dont 9 ayant eu les deux radiotraceurs), ont été réalisées en préopératoire. Les volumes et les hotspots (5% max de chaque volume) ont été segmentés semi-automatiquement sur les SUV des TEP 18F-FLT et 18F-FMISO, ainsi que sur les rCBV. Le pourcentage des volumes et des hotspots en dehors de la PC, a été calculé.Résultats Toutes les tumeurs ont montré une prolifération, une hypervascularisation et des régions hypoxiques élevées. Les volumes superposés sur les images T1w-Gd ont montré que certaines régions prolifératives, d'hypervascularisation et d'hypoxie s'étendaient au-delà de la PC, mais avec des différences marquées entre les patients. Les plages de volume périphérique en dehors de la PC étaient [1,6% - 155,5%], [1,5% - 89,5%] et [3,1% - 78,0%] pour 18F-FLT, rCBV et 18F-FMISO respectivement. Tous les patients avaient des hotspots hyperprolifératifs en dehors de la PC, tandis que les hotspots d'hypervascularisation et d'hypoxie étaient principalement détectés dans la PC.Conclusion L'analyse spatiale des cartographies multimodales avec les volumes segmentés et les hotspots fournit des informations précieuses pour optimiser la prise en charge et le traitement des glioblastomes.
Published: 2021

19. Traitement des néoplasies intraépithéliales génitales par laser CO2 : étude rétrospective

Author: F. Comoz, S. Pédaillès, H. Lefranc, E. Joly, F. Lefort, Anne Dompmartin, J.-M. Chevallier, Université de Caen Normandie - UFR Santé (UNICAEN Santé), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU), Laboratoire d'Anatomie Pathologique [CHU Caen], Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Département d'information médicale [CHU CAEN] (DIM), Hôpital Côte de Nacre [CHU Caen], CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), and Centre Hospitalier Intercommunal Alençon-Mamers (CHICAM)
Subjects: Gynecology, 030207 dermatology & venereal diseases, 03 medical and health sciences, medicine.medical_specialty, 0302 clinical medicine, Co2 laser, business.industry, [SDV]Life Sciences [q-bio], Medicine, Dermatology, business, ComputingMilieux_MISCELLANEOUS, 3. Good health
Abstract: Resume Introduction Les neoplasies intraepitheliales (NIE) genitales sont des precurseurs de carcinomes epidermoides. Le traitement ideal doit etre efficace, conservateur et bien tolere. Le laser CO2 est un des traitements recommandes, mais son efficacite et sa tolerance n’ont fait l’objet que de peu d’etudes. Patients et methodes Il s’agit d’une etude retrospective monocentrique. Seize patients (8 femmes et 8 hommes) traites par laser CO2 pour une NIE genitale, de haut grade ou differenciee, ont ete inclus. Les marges laterales prises macroscopiquement lors du traitement etaient de 3 a 5 mm. La seance de laser CO2, l’evaluation de la reponse therapeutique et le suivi etaient effectues par un dermatologue du CHU de Caen. Resultats L’âge moyen des patients etait de 68,1 ans et le delai de suivi moyen de 52,7 mois (5 a 130). Les lesions etaient uniques pour 87,5 % des patients. Les taux de recidive des NIE genitales apres traitement par laser CO2 etaient de 58 % pour les femmes et 40 % pour les hommes. Chez plus de 90 % des patients, il n’existait pas d’alteration de la qualite de vie ni de modifications de l’activite sexuelle. Conclusion Quels que soient les traitements recommandes, les recidives des NIE sont frequentes. Le laser CO2 est une option therapeutique conservatrice, efficace et bien toleree. Il permet d’obtenir rapidement une remission clinique mais, comme avec tous les traitements disponibles, un suivi dermatologique au long cours reste necessaire.
Published: 2019
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20. NDR2 kinase contributes to cell invasion and cytokinesis defects induced by the inactivation of RASSF1A tumor-suppressor gene in lung cancer cells

Author: Emmanuel Bergot, Alexandre P. J. Martin, Fatéméh Dubois, Alexander Hergovich, Maureen Keller, Elodie Maille, Jérôme Levallet, Sylvain Teulier, Gérard Zalcman, Jacques Camonis, Solenn Brosseau, Nicolas Elie, Guénaëlle Levallet, Unité de recherche interdisciplinaire pour la prévention et le traitement des cancers (ANTICIPE), 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)-Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM), Œstrogènes, reproduction, cancer (OeReCa), Normandie Université (NU)-Normandie Université (NU), 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), Laboratoire d'Anatomie Pathologique [CHU Caen], CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Université de Caen Normandie (UNICAEN), Normandie Université (NU), Unité de génétique et biologie des cancers (U830), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), CIC Hôpital Bichat, Institut National de la Santé et de la Recherche Médicale (INSERM)-UFR de Médecine-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Interactions Cellules Organismes Environnement (ICORE), Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), University College of London [London] (UCL), Service de pneumologie [CHU Caen], Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-UFR de Médecine, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN)-Centre Régional de Lutte contre le Cancer François Baclesse (CRLC François Baclesse ), Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM), and AP-HP - Hôpital Bichat - Claude Bernard [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-UFR de Médecine
Subjects: 0301 basic medicine, Cancer Research, Lung Neoplasms, RHOB, [SDV]Life Sciences [q-bio], Cell Cycle Proteins, environment and public health, Small hairpin RNA, Mice, 0302 clinical medicine, Cell Movement, Neoplasm Metastasis, Phosphorylation, Genes, Suppressor, rhoB GTP-Binding Protein, 10. No inequality, Chemistry, Kinase, Nuclear Proteins, Prognosis, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, 3. Good health, Cell biology, Phenotype, Oncology, 030220 oncology & carcinogenesis, Heterografts, YAP, Lung cancer, endocrine system, Epithelial-Mesenchymal Transition, Tumor suppressor gene, [SDV.CAN]Life Sciences [q-bio]/Cancer, Protein Serine-Threonine Kinases, lcsh:RC254-282, 03 medical and health sciences, Cell Line, Tumor, Biomarkers, Tumor, Animals, Humans, Gene silencing, Gene Silencing, GEF-H1, Cytokinesis, NDR2 kinase, Tumor Suppressor Proteins, Research, RASSF1A, Disease Models, Animal, enzymes and coenzymes (carbohydrates), 030104 developmental biology, Apoptosis, Transcription Factors
Abstract: Background RASSF1A, a tumor suppressor gene, is frequently inactivated in lung cancer leading to a YAP-dependent epithelial-mesenchymal transition (EMT). Such effects are partly due to the inactivation of the anti-migratory RhoB GTPase via the inhibitory phosphorylation of GEF-H1, the GDP/GTP exchange factor for RhoB. However, the kinase responsible for RhoB/GEF-H1 inactivation in RASSF1A-depleted cells remained unknown. Methods NDR1/2 inactivation by siRNA or shRNA effects on epithelial-mesenchymal transition, invasion, xenograft formation and growth in SCID−/− Beige mice, apoptosis, proliferation, cytokinesis, YAP/TAZ activation were investigated upon RASSF1A loss in human bronchial epithelial cells (HBEC). Results We demonstrate here that depletion of the YAP-kinases NDR1/2 reverts migration and metastatic properties upon RASSF1A loss in HBEC. We show that NDR2 interacts directly with GEF-H1 (which contains the NDR phosphorylation consensus motif HXRXXS/T), leading to GEF-H1 phosphorylation. We further report that the RASSF1A/NDR2/GEF-H1/RhoB/YAP axis is involved in proper cytokinesis in human bronchial cells, since chromosome proper segregation are NDR-dependent upon RASSF1A or GEF-H1 loss in HBEC. Conclusion To summarize, our data support a model in which, upon RASSF1A silencing, NDR2 gets activated, phosphorylates and inactivates GEF-H1, leading to RhoB inactivation. This cascade induced by RASSF1A loss in bronchial cells is responsible for metastasis properties, YAP activation and cytokinesis defects. Electronic supplementary material The online version of this article (10.1186/s13046-019-1145-8) contains supplementary material, which is available to authorized users.
Published: 2019
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21. Complex Management of Nephrotic Syndrome and Kidney Failure during Pregnancy in a Type 1 Diabetes Patient: A Challenging Case

Author: Leo Drapeau, Mathilde Beaumier, Julie Esbelin, François Comoz, Lucile Figueres, Giorgina Piccoli, Delphine Kervella, Centre hospitalier universitaire de Nantes (CHU Nantes), Nantes Université (Nantes Univ), Service de Néphrologie [CHPC - Site Louis Pasteur], Site Louis Pasteur [CHPC], CH Centre Hospitalier Public du Cotentin (CHPC)-CH Centre Hospitalier Public du Cotentin (CHPC), 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), Centre Hospitalier Le Mans (CH Le Mans), Team 3 : Integrative transplantation, HLA, Immunology and genomics of kidney injury (U1064 Inserm - CR2TI), Centre de Recherche en Transplantation et Immunologie - Center for Research in Transplantation and Translational Immunology (U1064 Inserm - CR2TI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), Institut de transplantation urologie-néphrologie (ITUN), Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), and KERANDEL-DION, Céline
Subjects: [SDV] Life Sciences [q-bio], acute kidney injury, type 1 diabetes, nephrotic syndrome, [SDV]Life Sciences [q-bio], pregnancy, General Medicine
Abstract: International audience; Pregnancy with chronic kidney disease is challenging, and patients with diabetic nephropathy are at particular risk of a rapid kidney function decline during pregnancy. While indications for the management of pregnant patients with initial diabetic nephropathy are widely available in the literature, data on patients with severe nephrotic syndrome and kidney function impairment are lacking, and the decision on whether and when dialysis should be initiated is not univocal. We report a type 1 diabetes patient who started pregnancy with a severe nephrotic syndrome and shifted from CKD stage 3b to stage 5 during pregnancy. The management was complicated by a fetal heart malformation and by poorly controlled diabetes. The evidence for and against starting dialysis was carefully evaluated, and the choice of strict nephrological and obstetrical monitoring, nutritional management, and diuretic treatment made it possible to avoid dialysis in pregnancy, after ruling out pre-eclampsia. This experience enables examination of some open issues and contributes to the discussion of when to start dialysis in pregnancy.
Published: 2022
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22. P18.07.A Hippo signaling pathway is strongly involved in meningioma tumorigenesis

Author: Mougel, Gregory, Mondielli, Grégoire, Appay, R, Querdray, Adeline, Roche, C, Jijon, A, Konstantinova, I, Soude, A, Graillon, Thomas, Barlier, Anne, 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), Institut Marseille Maladies Rares (MarMaRa), Aix Marseille Université (AMU), Laboratoire de Biochimie et de Biologie Moléculaire [Hôpital de la Conception - APHM], Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), Laboratoire d'Anatomie Pathologique-Neuropathologique [AP-HM Hôpital La Timone], Hôpital de la Timone [CHU - APHM] (TIMONE), Université Lille Nord de France (COMUE), and Département de Neurochirurgie [CHU Timone]
Subjects: Cancer Research, Oncology, [SDV]Life Sciences [q-bio], Neurology (clinical)
Abstract: Background Recurrent and aggressive meningiomas remain an unmet medical need in neuro-oncology. In mammals, Hippo signaling pathway is responsible for the growth of organs by regulating cell proliferation and apoptosis. The tumor suppressor NF2 protein belongs to the core of the Hippo pathway and a defect of its gene is present in 50% of meningiomas. Absence of NF2 keeps Hippo pathway inactive allowing the translocation of YAP/TAZ to the nucleus and the formation of a complex with TEADs. This complex then promotes the transcription of anti-apoptotic and proliferative genes such as CTGF, CYR61 and AXL. Here we present experimental results on human meningioma fragments and primary cell cultures supporting that Hippo pathway plays a critical role in meningioma tumorigenesis. Material and Methods The role of the Hippo pathway was studied on 57 meningiomas, well characterized at clinical, histological and molecular level. The genomic profile, target transcripts of the complex YAP/TAZ-TEADs, cell viability, and cell proliferation were analyzed after siRNA transfection targeting YAP, TAZ, YAP+TAZ and TEADs. Results Fifty-seven meningiomas were randomly selected including 27 WHO grade II and III tumors. Thirty (53%) presented a defect on the NF2 gene (NF2def) including 19(65%) grade II/III. NF2def meningiomas presented a significant increase of expression levels of Hippo pathway target transcripts CTGF, CYR61 and AXL in comparison with NF2 wild-type tumors (p Conclusion Our experimental results strongly support the importance of the Hippo pathway in meningioma tumorigenesis, supporting its relevance as a new target in meningioma therapy. A.Barlier reports receiving research grants from Inventiva Pharma. No potential conflicts of interest were disclosed by the other authors.
Published: 2022
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23. Severe and Irreversible Pancytopenia Associated With SARS-CoV-2 Bone Marrow Infection in a Patient With Waldenstrom Macroglobulinemia

Author: Mélanie Velier, Stéphane Priet, Gilles Kaplanski, Françoise Dignat-George, Arthur Varoquaux, Romain Appay, Antoine Tichadou, Hubert Lepidi, Yael Berda-Haddad, Xavier de Lamballerie, Julian Touati, Robin Arcani, Marie Koubi, Anne Laure Couderc, Régis Costello, Geoffroy Venton, Pierre André Jarrot, Thérèse Atieh, Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Theories and Approaches of Genomic Complexity (TAGC), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de neurophysiopathologie (INP), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Anatomie Pathologique-Neuropathologique [AP-HM Hôpital La Timone], and Hôpital de la Timone [CHU - APHM] (TIMONE)
Subjects: Cancer Research, 2019-20 coronavirus outbreak, Coronavirus disease 2019 (COVID-19), Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Case Report, Aplasia.COVID-19.Indirect immunofluorescence.Lymphoproliferative disorder.Monoclonal immunoglobulin, 03 medical and health sciences, 0302 clinical medicine, medicine, Aplasia, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, Indirect immunofluorescence, business.industry, COVID-19, Waldenstrom macroglobulinemia, Hematology, medicine.disease, Virology, Pancytopenia, 3. Good health, medicine.anatomical_structure, Lymphoproliferative disorder, Oncology, 030220 oncology & carcinogenesis, Monoclonal immunoglobulin, Bone marrow, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience
Published: 2021
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24. Association of inoperable glioblastoma with a heterogeneous functional and survival outcome

Author: Chantal Campello, Olivier Chinot, Gregorio Petrirena, Dominique Figarella, Celine Boucard, Karine Baumstarck, Laetitia Padovani, Vincent Harlay, Emeline Tabouret, Anderson Loundou, Didier Autran, Henry Dufour, Sébastien Boissonneau, Maryline Barrie, Institut de neurophysiopathologie (INP), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Anatomie Pathologique-Neuropathologique [AP-HM Hôpital La Timone], Hôpital de la Timone [CHU - APHM] (TIMONE), 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: Oncology, Cancer Research, medicine.medical_specialty, business.industry, Internal medicine, [SDV]Life Sciences [q-bio], medicine, Biopsy only, medicine.disease, business, Survival outcome, Glioblastoma
Abstract: e14036 Background: “Biopsy only” GBM patients is an understudied group of patients associated to a poor outcome, which has been reported to represent 21% of histologically confirmed GBM in the US National Cancer Data Base. Pattern of care included radiotherapy-temozolomide (RT-TMZ) standard regimen completed in 15% of patients, any other form of oncologic treatment in 60%, and supportive care alone in 25% of patients (Kole, Cancer 2016). Our objective was to explore heterogeneity of inoperable GBM patients group, both for patients characteristics, pattern of care planned and completed, functional and survival outcome. Methods: Patients with inoperable GBM included in a prospective regional glioma cohort initiated in 2014 were retrospectively reviewed for patients characteristics, MRI finding, treatment allocation and delivery. Functional independency analyzed as a cumulative time of KPS≥70, PFS and OS were analyzed. Results: Of 535 patients referred to our center, 449 patients were included at initial surgery, of which 158 patients (35%) underwent biopsy only. 18 patients were excluded for missing data leaving 139 patients for the present analysis. 54 (39%) were referred to RT-TMZ (50 patients completed concomitant treatment), 68 (49%) considered unfitted for RT received chemotherapy upfront (CT-UF) (of which 3 were subsequently referred to RT), 17 (12%) referred to palliative care only (PC). Groups differed at baseline for age (mean 60, 68, 69y for RT-TMZ, CT-UF, PC respectively); for KPS (70, 60, 50 for RT-TMZ, CT-UF, PC respectively); for mean tumor surface (793, 1420, 1412 cm2 for RT-TMZ, CT-UF, PC); for tumor extension (bilateral in 6.4% and 29.3% for RT-CT and CT-UF respectively); for steroid intake (45, 60, 100 mg daily respectively). Median OS was 14 months (95% CI, 9.65-18.71), 8 months (95% CI, 4.62-7.67), 2 months (95% CI, 0.67-3.33) for RT-TMZ, CT-UF, PC respectively. Of importance, mean duration of functional independence was of 8.3 months, 2.1 months, and 0.1 month for RT-TMZ, CT-UF, and PC respectively; 33/139 (24%) of the patients experienced functional independency for more than 40% of their life time. Conclusions: Inoperable GBM constitute a large and heterogeneous population in which more than 1/3 of the patients are amenable to standard of care, with survival outcome similar to the one of patients who underwent surgery. Patients considered unfit for RT-CT at diagnosis fail to be referred subsequently to RT after CT and exhibit a poor survival outcome that deserve new effective treatments. Cumulative duration of functional independence is limited and should be considered as part of treatment evaluation.
Published: 2021
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25. Simultaneous mapping of vasculature, hypoxia and proliferation using DSC-MRI, 18F-FMISO PET, and 18F-FLT PET in relation to contrast enhancement in newly diagnosed glioblastoma

Author: Collet, Solène, Guillamo, Jean Sébastien, Berro, David Hassanein, Chakhoyan, Ararat, Constans, Jean-Marc, Lechapt-Zalcman, Emmanuèle, Derlon, Jean-Michel, Hatt, Mathieu, Visvikis, Dimitris, Guillouet, Stéphane, Perrio, Cécile, Bernaudin, Myriam, Samuel, Valable, Hypoxie, physiopathologies cérébrovasculaire et tumorale (CERVOxy), Imagerie et Stratégies Thérapeutiques des pathologies Cérébrales et Tumorales (ISTCT), 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)-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), Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Service de Neurochirurgie [CHU Caen], Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Department of Neurology [UCLA], University of California [Los Angeles] (UCLA), University of California (UC)-University of California (UC)-David Geffen School of Medicine [Los Angeles], University of California (UC)-University of California (UC), CHU Amiens-Picardie, Laboratoire d'Anatomie Pathologique [CHU Caen], 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), Laboratoire de Développements Méthodologiques en Tomographie par Emission de Positons (LDM-TEP), Service Hospitalier Frédéric Joliot (SHFJ), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Imagerie et Stratégies Thérapeutiques des pathologies Cérébrales et Tumorales (ISTCT), Normandie Université (NU)-Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS), Couteau, Florence, UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Université de Caen Normandie (UNICAEN), Normandie Université (NU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), University of California-University of California-David Geffen School of Medicine [Los Angeles], University of California-University of California, Institut National de la Santé et de la Recherche Médicale (INSERM)-IMT Atlantique Bretagne-Pays de la Loire (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Centre Hospitalier Régional Universitaire de Brest (CHRU Brest)-Université de Brest (UBO)-Institut Brestois Santé Agro Matière (IBSAM), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Imagerie et Stratégies Thérapeutiques des pathologies Cérébrales et Tumorales (ISTCT)
Subjects: [SDV] Life Sciences [q-bio], Glioblastoma, PET, Vascular, [SDV]Life Sciences [q-bio], Proliferation, [CHIM] Chemical Sciences, Vasculature, [CHIM]Chemical Sciences, Oncology: Brain, Hypoxia, MRI
Abstract: CERVOXY/LDM TEP COLL; International audience; Conventional MRI plays a key role in the management of patients with high grade glioma but multiparametric MRI and PET tracers could provide further information to better characterize the tumor metabolism and heterogeneity, by identifying the regions having a high risk of recurrence. In this study, we focused on the proliferation, hypervascularization and hypoxia, all factors considered as factors of poor prognosis. They were assessed by measuring the uptake of 18F-FLT, the rCBV maps and the uptake of 18F-FMISO, respectively. For each modality, the volumes and high uptake sub-volumes (hotspots) were semi-automatically segmented and compared to contrast enhancement (CE) volume on T1w-Gd images, commonly used in the management of patient with glioblastoma. Methods: DSC MRI (31 patients), 18F-FLT PET (20 patients) and/or 18F-FMISO PET (20 patients), for a total of 31 patients, were performed on pre-operative glioblastoma patients. Volumes and hotspots were segmented on SUV maps for 18F-FLT (using FLAB) and 18F-FMISO (using mean contralateral + 3.3 SD) PET and on rCBV maps (using mean contralateral + 1.96 SD) for DSC MRI and overlaid on T1w-Gd images. For each modality, the percentage of peripheral volumes and the peripheral hotspot outside the CE volume were calculated. Results: All tumors showed high proliferation, hypervascularization and hypoxic regions. Images also showed pronounced heterogeneity of both tracers uptake and rCBV maps, within each individual case. Overlaid volumes on T1w-Gd images showed that some proliferative, hypervascularization and hypoxic regions extended beyond the CE volume but with marked differences between patients. The ranges of peripheral volume outside the CE volume were [1.6% - 155.5 %], [1.5% - 89.5%] and [3.1% - 78.0%] for 18F-FLT, rCBV and 18F-FMISO respectively. All patients had hyperproliferative hotspots outside CE volume, whereas hotspots of hypervasculature and hypoxia were mainly detected within the enhancing region. Conclusion: The spatial analysis of the multiparametric maps with the segmented volumes and hotspots provides valuable information to optimize the management and treatment of the patients with glioblastoma.
Published: 2021
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26. TEMOBIC : Phase II Trial of Neoadjuvant Chemotherapy for Unresectable Anaplastic Gliomas: An ANOCEF Study

Author: Anderson Loundou, Luc Taillandier, Marc Sanson, Olivier Chinot, Jean-Yves Delattre, Dominique Figarella-Branger, Rémy Guillevin, Michel Fabbro, Maryline Barrie, Khê Hoang-Xuan, Didier Autran, Karima Mokhtari, François Ducray, Christine Kerr, Stéphanie Cartalat-Carel, Emeline Tabouret, Institut de neurophysiopathologie (INP), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Service d’Oncologie Médicale [Hôpital de la Timone - APHM], Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Laboratoire d'Anatomie Pathologique-Neuropathologique [AP-HM Hôpital La Timone], Hôpital de la Timone [CHU - APHM] (TIMONE), and Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)
Subjects: Adult, Oncology, Cancer Research, medicine.medical_specialty, IDH1, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Anaplastic oligodendroglioma, World health, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Glioma, medicine, Humans, Antineoplastic Agents, Alkylating, ComputingMilieux_MISCELLANEOUS, Aged, Chemotherapy, Temozolomide, Brain Neoplasms, business.industry, Clinical Trial Results, Middle Aged, medicine.disease, Neoadjuvant Therapy, Confidence interval, 3. Good health, Dacarbazine, Radiation therapy, 030220 oncology & carcinogenesis, business, 030217 neurology & neurosurgery, medicine.drug
Abstract: Lessons Learned Background The optimal treatment for unresectable large anaplastic gliomas remains debated. Methods Adult patients with histologically proven unresectable anaplastic oligodendroglioma or mixed gliomas (World Health Organization [WHO] 2007) were eligible. Treatment consisted of BCNU (150 mg/m2) and temozolomide (110 mg/m2 for 5 days) every 6 weeks for six cycles before radiotherapy. Results Between December 2005 and December 2009, 55 patients (median age of 53.1 years; range, 20.5–70.2) were included. Forty percent of patients presented with wild-type IDH1 gliomas, and 30% presented with methylated MGMT promoter. Median progression-free survival (PFS), centralized PFS, and overall survival (OS) were 16.6 (95% confidence interval [CI], 12.8–20.3), 15.4 (95% CI, 10.0–20.8), and 25.4 (95% CI, 17.5–33.2) months, respectively. Complete and partial responses under chemotherapy were observed for 28.3% and 17% of patients, respectively. Radiotherapy completion was achieved for 75% of patients. Preservation of functional status and self-care capability (Karnofsky performance status [KPS] ≥70) were preserved until disease progression for 69% of patients. Grade ≥ 3 toxicities were reported for 52% of patients, and three deaths were related to treatment. By multivariate analyses including age and KPS, IDH mutation was associated with better prognostic for both PFS and OS, whereas MGMT promoter methylation was associated with better OS. Conclusion The association of BCNU and temozolomide upfront is active for patients with unresectable anaplastic gliomas, but toxicity limits its use.
Published: 2021
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27. Specific and Sensitive Diagnosis of BCOR-ITD in Various Cancers by Digital PCR

Author: Doriane Barets, Romain Appay, Marie Heinisch, Maxime Battistella, Corinne Bouvier, Guillaume Chotard, François Le Loarer, Nicolas Macagno, Romain Perbet, Daniel Pissaloux, Audrey Rousseau, Arnaud Tauziède-Espariat, Pascale Varlet, Alexandre Vasiljevic, Carole Colin, Frédéric Fina, Dominique Figarella-Branger, Laboratoire d'Anatomie Pathologique-Neuropathologique [AP-HM Hôpital La Timone], Hôpital de la Timone [CHU - APHM] (TIMONE), Institut de neurophysiopathologie (INP), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), 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), Service d'Anatomo-Cyto-Pathologie et de NeuroPathologie [Hôpital de la Timone - APHM] (ACPNP), and Aix Marseille Université (AMU)- Hôpital de la Timone [CHU - APHM] (TIMONE)
Subjects: Cancer Research, Clear-cell sarcoma of the kidney, HGNET-BCOR, [SDV]Life Sciences [q-bio], [SDV.CAN]Life Sciences [q-bio]/Cancer, digital PCR assay, Computational biology, Biology, Undifferentiated Round Cell Sarcoma, lcsh:RC254-282, 03 medical and health sciences, Exon, 0302 clinical medicine, medicine, Coding region, FFPE tissue, Digital polymerase chain reaction, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Gene, 030304 developmental biology, Original Research, 0303 health sciences, [SDV.GEN]Life Sciences [q-bio]/Genetics, Endometrial stromal sarcoma, diagnostic marker, medicine.disease, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, 3. Good health, Oncology, 030220 oncology & carcinogenesis, Tandem exon duplication, BCOR-internal tandem duplication, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: BCOR is an epigenetic regulator altered by various mechanisms including BCOR-internal tandem duplication (BCOR-ITD) in a wide range of cancers. Six different BCOR-ITD in the 3’-part of the coding sequence of exon 15 have been reported ranging from 89 to 114 bp in length. BCOR-ITD is a common genetic alteration found in clear cell sarcoma of the kidney and primitive myxoid mesenchymal tumor of infancy (PMMTI) and it characterizes a new type of central nervous system tumor: “CNS tumor with BCOR-ITD”. It can also be detected in undifferentiated round cell sarcoma (URCS) and in high-grade endometrial stromal sarcoma (HGESS). Therefore, it is of utmost importance to search for this genetic alteration in these cancers with the most frequent technique being RNA-sequencing. Here, we developed a new droplet PCR assay (dPCR) to detect the six sequences characterizing BCOR-ITD. To achieve this goal, we used a single colored probe to detect both the duplicated region and the normal sequence that acts as a reference. We first generated seven synthetic DNA sequences: ITD0 (the normal sequence) and ITD1 to ITD6 (the duplicated sequences described in the literature) and then we set up the optima dPCR conditions. We validated our assay on 19 samples from a representative panel of human tumors (9 HGNET-BCOR, 5 URCS, 3 HGESS, and 2 PMMTI) in which BCOR-ITD status was known using at least one other method including RNA sequencing, RT-PCR or DNA-methylation profiling for CNS tumors. Our results showed that our technique was 100% sensitive and specific. DPCR detected BCOR-ITD in 13/19 of the cases; in the remaining 6 cases additional RNA-sequencing revealed BCOR gene fusions. To conclude, in the era of histomolecular classification of human tumors, our modified dPCR assay is of particular interest to detect BCOR-ITD since it is a robust and less expensive test that can be applied to a broad spectrum of cancers that share this alteration.
Published: 2021
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28. Pharmacokinetics and tolerance of repeated oral administration of 5-fluorocytosine in healthy dogs

Author: Bernard Klonjkowski, Frédérique Degorce, Jérémy Béguin, Philippe Erbs, Matthias Kohlhauer, Eve Laloy, Baptiste Moreau, Eric Quemeneur, Christelle Maurey, Malbec, Odile, École nationale vétérinaire - Alfort (ENVA), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Transgene SA [Illkirch], Virologie UMR1161 (VIRO), École nationale vétérinaire - Alfort (ENVA)-Laboratoire de santé animale, sites de Maisons-Alfort et de Normandie, Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Laboratoire d'Anatomie Pathologique Vétérinaire du Sud-Ouest [Toulouse] (LAPVSO), École nationale vétérinaire d'Alfort (ENVA), École nationale vétérinaire d'Alfort (ENVA)-Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), and École nationale vétérinaire - Alfort (ENVA)-Laboratoire de santé animale, sites de Maisons-Alfort et de Dozulé
Subjects: Male, Drug-Related Side Effects and Adverse Reactions, 040301 veterinary sciences, Veterinary medicine, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Administration, Oral, Flucytosine, Pharmacokinetic, Pharmacology, 0403 veterinary science, 03 medical and health sciences, Dogs, 0302 clinical medicine, Pharmacotherapy, Pharmacokinetics, Oral administration, SF600-1100, Antineoplastic agents, medicine, Dog, Animals, Targeted chemotherapy, Dog Diseases, Adverse effect, Cytosine analog, Chemotherapy, General Veterinary, business.industry, Research, Cytosine deaminase, 04 agricultural and veterinary sciences, General Medicine, 3. Good health, [SDV] Life Sciences [q-bio], 030220 oncology & carcinogenesis, Toxicity, Drug-related side effects, Female, Drug Eruptions, Fluorouracil, business, Adverse reactions
Abstract: Background 5-fluorocytosine is a pyrimidine and a fluorinated cytosine analog mainly used as an antifungal agent. It is a precursor of 5-fluorouracil, which possesses anticancer properties. To reduce systemic toxicity of 5-fluorouracil during chemotherapy, 5- fluorocytosine can be used as a targeted anticancer agent. Expression of cytosine deaminase by a viral vector within a tumor allows targeted chemotherapy by converting 5-fluorocytosine into the cytotoxic chemotherapeutic agent 5-fluorouracil. However, little is known about the tolerance of 5-fluorocytosine in dogs after prolonged administration. Results In three healthy Beagle dogs receiving 100 mg/kg of 5-fluorocytosine twice daily for 14 days by oral route, non-compartmental pharmacokinetics revealed a terminal elimination half-life of 164.5 ± 22.5 min at day 1 and of 179.2 ± 11.5 min, after 7 days of administration. Clearance was significantly decreased between day 1 and day 7 with 0.386 ± 0.031 and 0.322 ± 0.027 ml/min/kg, respectively. Maximal plasma concentration values were below 100 µg/ml, which is considered within the therapeutic margin for human patients. 5-fluorouracil plasma concentration was below the limit of detection at all time points. The main adverse events consisted of depigmented, ulcerated, exudative, and crusty cutaneous lesions 10 to 13 days after beginning 5-fluorocytosine administration. The lesions were localized to the nasal planum, the lips, the eyelids, and the scrotum. Histological analyses were consistent with a cutaneous lupoid drug reaction. Complete healing was observed 15 to 21 days after cessation of 5-fluorocytosine. No biochemical or hematological adverse events were noticed. Conclusions Long term administration of 5-fluorocytosine was associated with cutaneous toxicity in healthy dogs. It suggests that pharmacotherapy should be adjusted to reduce the toxicity of 5-fluorocytosine in targeted chemotherapy.
Published: 2021
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29. Radiotherapy‐PCV versus radiotherapy‐temozolomide for IDH ‐mutant anaplastic astrocytoma: a retrospective multicentre analysis of the French POLA cohort

Author: Esteyrie, Vincent, Dehais, Caroline, Martin, Elodie, Carpentier, Catherine, Uro‐Coste, Emmanuelle, Figarella‑Branger, Dominique, Bronniman, Charlotte, Pouessel, Damien, Ciron, Delphine Larrieu, Ducray, François, Moyal, Elizabeth Cohen‐Jonathan, Institut de neurophysiopathologie (INP), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Anatomie Pathologique-Neuropathologique [AP-HM Hôpital La Timone], and Hôpital de la Timone [CHU - APHM] (TIMONE)
Subjects: [SDV]Life Sciences [q-bio], ComputingMilieux_MISCELLANEOUS
Abstract: International audience
Published: 2021
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30. Therapeutic implications of improved molecular diagnostics for rare CNS embryonal tumor entities: results of an international, retrospective study

Author: Christelle Dufour, Johannes Gojo, Sandra Jacobs, Barry Pizer, Dominik Sturm, Torsten Pietsch, Stefan Rutkowski, Christine Haberler, Nicolas U. Gerber, Teresa de Rojas, Peter Hauser, Ulrich Schüller, Peter C. Burger, Marta Perek-Polnik, Martin Mynarek, Jaeho Cho, Matija Snuderl, Bernward Zeller, Michal Zapotocky, Maura Massimino, Robert Kwiecien, Dominique Figarella-Branger, Andrey Golanov, Charles G. Eberhart, Stefan M. Pfister, Daniel Alderete, Thomas S. Jacques, Ella Kumirova, Konstantin Okonechnikov, Astrid Sehested, Ofelia Cruz, Andrey Korshunov, Björn Ole Juhnke, Niels Bovenschen, Jessica C Pickles, David Sumerauer, Cynthia Hawkins, David Scheie, Eugene Hwang, Pieter Wesseling, Barbara von Zezschwitz, Felice Giangaspero, Marcel Kool, Elizabeth Schepke, Andreas von Deimling, Marco Gessi, Dannis G. van Vuurden, Maximilian Wechsung, Miklós Garami, David Capper, Katja von Hoff, Maria Joao Gil-da-Costa, Maria Łastowska, Felix Schmitt-Hoffner, Olga Zheludkova, Lucas Moreno, Michael A. Grotzer, Frank Konietschke, Marina Ryzhova, Elisabeth J. Rushing, Irene Slavc, Institut de neurophysiopathologie (INP), 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), Pediatric surgery, CCA - Imaging and biomarkers, CCA - Cancer Treatment and quality of life, Pathology, and Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Oncology, Cancer Research, genetics [Central Nervous System Neoplasms], medicine.medical_treatment, [SDV]Life Sciences [q-bio], diagnosis [Central Nervous System Neoplasms], Central Nervous System Neoplasms, 0302 clinical medicine, CNS-PNET, Medicine, Neuroectodermal Tumors, Primitive, genetics [Neoplasms, Germ Cell and Embryonal], Pathology, Molecular, diagnosis [Brain Neoplasms], Brain Neoplasms, genetics [Neuroectodermal Tumors, Primitive], CNS embryonal tumor, Forkhead Transcription Factors, Neoplasms, Germ Cell and Embryonal, 3. Good health, therapy [Brain Neoplasms], therapy [Neoplasms, Germ Cell and Embryonal], 030220 oncology & carcinogenesis, DNA methylation, DNA methylation profiling, therapy [Central Nervous System Neoplasms], medicine.medical_specialty, CNS NB-FOXR2, ETMR, FOXR2 protein, human, 03 medical and health sciences, Glioma, Internal medicine, Neuroblastoma, Humans, ddc:610, diagnosis [Neuroectodermal Tumors, Primitive], Retrospective Studies, Chemotherapy, business.industry, Retrospective cohort study, medicine.disease, Molecular diagnostics, therapy [Neuroectodermal Tumors, Primitive], genetics [Brain Neoplasms], CNS Embryonal Tumor, Regimen, diagnosis [Neoplasms, Germ Cell and Embryonal], Neurology (clinical), business, Pediatric Neuro-Oncology, 030217 neurology & neurosurgery
Abstract: Background Only few data are available on treatment-associated behavior of distinct rare CNS embryonal tumor entities previously treated as “CNS-primitive neuroectodermal tumors” (CNS-PNET). Respective data on specific entities, including CNS neuroblastoma, FOXR2 activated (CNS NB-FOXR2), and embryonal tumors with multilayered rosettes (ETMR) are needed for development of differentiated treatment strategies. Methods Within this retrospective, international study, tumor samples of clinically well-annotated patients with the original diagnosis of CNS-PNET were analyzed using DNA methylation arrays (n = 307). Additional cases (n = 66) with DNA methylation pattern of CNS NB-FOXR2 were included irrespective of initial histological diagnosis. Pooled clinical data (n = 292) were descriptively analyzed. Results DNA methylation profiling of “CNS-PNET” classified 58 (19%) cases as ETMR, 57 (19%) as high-grade glioma (HGG), 36 (12%) as CNS NB-FOXR2, and 89(29%) cases were classified into 18 other entities. Sixty-seven (22%) cases did not show DNA methylation patterns similar to established CNS tumor reference classes. Best treatment results were achieved for CNS NB-FOXR2 patients (5-year PFS: 63% ± 7%, OS: 85% ± 5%, n = 63), with 35/42 progression-free survivors after upfront craniospinal irradiation (CSI) and chemotherapy. The worst outcome was seen for ETMR and HGG patients with 5-year PFS of 18% ± 6% and 22% ± 7%, and 5-year OS of 24% ± 6% and 25% ± 7%, respectively. Conclusion The historically reported poor outcome of CNS-PNET patients becomes highly variable when tumors are molecularly classified based on DNA methylation profiling. Patients with CNS NB-FOXR2 responded well to current treatments and a standard-risk CSI-based regimen may be prospectively evaluated. The poor outcome of ETMR across applied treatment strategies substantiates the necessity for evaluation of novel treatments.
Published: 2021
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31. Prognostic relevance of clinical and molecular risk factors in children with high-risk medulloblastoma treated in the phase II trial PNET HR+5

Author: Christelle Dufour, Léa Guerrini-Rousseau, Julien Masliah-Planchon, Franck Bourdeaut, Pascale Schneider, Dominique Figarella-Branger, Pascal Chastagner, Emilie De Carli, Anne Geoffray, Valérie Bernier-Chastagner, Cécile Faure-Conter, Claire Berger, Céline Chappé, Natacha Entz-Werle, Laetitia Padovani, Julien Lejeune, Celine Icher, Anne-Isabelle Bertozzi, Marie-Bernadette Delisle, Pierre Leblond, Nicolas André, Christine Soler, Stéphanie Foulon, Tasnime Akbaraly, Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Institut de neurophysiopathologie (INP), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Anatomie Pathologique-Neuropathologique [AP-HM Hôpital La Timone], Hôpital de la Timone [CHU - APHM] (TIMONE), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Bioimagerie et Pathologies (LBP), and Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Medulloblastoma, Oncology, Cancer Research, medicine.medical_specialty, Temozolomide, business.industry, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Induction chemotherapy, [SDV.CAN]Life Sciences [q-bio]/Cancer, ThioTEPA, medicine.disease, Chemotherapy regimen, Carboplatin, Radiation therapy, chemistry.chemical_compound, chemistry, Internal medicine, medicine, Neurology (clinical), business, Survival rate, medicine.drug
Abstract: Background High-risk medulloblastoma is defined by the presence of metastatic disease and/or incomplete resection and/or unfavorable histopathology and/or tumors with MYC amplification. We aimed to assess the 3-year progression-free survival (PFS) and define the molecular characteristics associated with PFS in patients aged 5–19 years with newly diagnosed high-risk medulloblastoma treated according to the phase II trial PNET HR+5. Methods All children received postoperative induction chemotherapy (etoposide and carboplatin), followed by 2 high-dose thiotepa courses (600 mg/m2) with hematological stem cell support. At the latest 45 days after the last stem cell rescue, patients received risk-adapted craniospinal radiation therapy. Maintenance treatment with temozolomide was planned to start between 1–3 months after the end of radiotherapy. The primary endpoint was PFS. Outcome and safety analyses were per protocol (all patients who received at least one dose of induction chemotherapy). Results Fifty-one patients (median age, 8 y; range, 5–19) were enrolled. The median follow-up was 7.1 years (range: 3.4–9.0). The 3 and 5-year PFS with their 95% confidence intervals (95% CI) were 78% (65–88) and 76% (63–86), and the 3 and 5-year OS were 84% (72–92) and 76% (63–86), respectively. Medulloblastoma subtype was a statistically significant prognostic factor (P-value = 0.039) with large-cell/anaplastic being of worse prognosis, as well as a molecular subgroup (P-value = 0.012) with sonic hedgehog (SHH) and group 3 being of worse prognosis than wingless (WNT) and group 4. Therapy was well tolerated. Conclusions This treatment based on high-dose chemotherapy and conventional radiotherapy resulted in a high survival rate in children with newly diagnosed high-risk medulloblastoma.
Published: 2020
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32. Hyperplasie lymphoïde associée au VIH : une localisation orbitaire exceptionnelle

Author: Jean-Claude Quintyn, Marie-Alice Laville, Marie-Laure Quintyn, Camille Linard, Pierre Branger, Arthur Leclerc, Françoise Chapon, Evelyne Emery, Service de Neurochirurgie [CHU Caen], CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Université de Caen Normandie (UNICAEN), Normandie Université (NU), Université de Caen Normandie - UFR Santé (UNICAEN Santé), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU), Laboratoire d'Anatomie Pathologique [CHU Caen], Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Service d'Ophthalmologie [CHU CAEN], Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), and Service de Neurologie [CHU Caen]
Subjects: 0301 basic medicine, Pathology, medicine.medical_specialty, business.industry, [SDV]Life Sciences [q-bio], Human immunodeficiency virus (HIV), medicine.disease_cause, medicine.disease, Lymphoid hyperplasia, 3. Good health, Pathology and Forensic Medicine, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, 030220 oncology & carcinogenesis, medicine, Pseudolymphoma, Benign Lymphoid Hyperplasia, Intracranial lesions, Lymph, medicine.symptom, business
Abstract: HIV-related lymphoid hyperplasia has been exceptionally described outside lymph nodes. To our knowledge, 3 cases of nasopharyngeal localisation have been described in the literature. We report here an intracranial localisation with an important ophthalmological clinical impact. Our observation allows us to approach the differential diagnoses of intracranial lesions in the HIV-positive patient, to analyse the differential diagnoses of benign lymphoid hyperplasia and to discuss the therapeutic options.
Published: 2020
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33. Characterization of the ability of a, second-generation SST-DA chimeric molecule, TBR-065, to suppress GH secretion from human GH-secreting adenoma cells

Author: Henry Dufour, Heather A. Halem, Michael D. Culler, Shengwen Zhang, Alexandru Saveanu, Thomas Graillon, Anne Barlier, Célines Defilles, Rakesh Datta, Grégory Mougel, Thierry Brue, Tanya Landsman, Thomas Cuny, Dominique Figarella-Branger, Institut de neurophysiopathologie (INP), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Anatomie Pathologique-Neuropathologique [AP-HM Hôpital La Timone], Hôpital de la Timone [CHU - APHM] (TIMONE), and Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)
Subjects: Adenoma, medicine.medical_specialty, endocrine system, Cabergoline, Endocrinology, Diabetes and Metabolism, [SDV]Life Sciences [q-bio], Dopamine, 030209 endocrinology & metabolism, TBR-065, Octreotide, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, fluids and secretions, Internal medicine, Acromegaly, parasitic diseases, medicine, Tumor Cells, Cultured, Somatostatin receptor 2, Humans, Secretion, Pituitary Neoplasms, Receptors, Somatostatin, Receptor, business.industry, Human Growth Hormone, Receptors, Dopamine D2, fungi, Dopastatin, medicine.disease, Prolactin, Growth hormone secretion, 3. Good health, Somatostatin, business, 030217 neurology & neurosurgery, hormones, hormone substitutes, and hormone antagonists
Abstract: Somatostatin (SST) and dopamine (DA) inhibit growth hormone (GH) secretion and proliferation of GH-secreting pituitary adenomas (GHomas) through binding to SSTR2 and D2R receptors. Chimeric SST-DA compounds (Dopastatins) display increased potency in inhibiting GH secretion, as compared with individual SST or DA analogs (alone or combined). To assess the efficacy of a second-generation dopastatin, TBR-065, in suppressing GH secretion from human GH- and GH/prolactin(PRL)-omas. We compared the ability of TBR-065 to inhibit GH secretion from primary cultures of human GH- or GH/PRLoma cells to that of the first generation dopastatin, TBR-760 (formerly BIM-23A760), octreotide (OCT) and cabergoline (CAB), the later either alone or combined. We investigated whether there was any impact of BIM-133, the metabolite of TBR-065, on the ability of TBR-065 to inhibit GH in these cultures. 17 GH- and GH/PRLomas were included in this study. Inhibition of GH secretion by TBR-065, TBR-760, OCT and CAB (0.1 pM to 0.1 µM) was assessed over a period of 8 h. All tumors expressed SSTR2 and D2R mRNAs. GH suppression was higher with TBR-065 as compared with TBR-760 (Emax = 57 ± 5.6% vs. 41.1 ± 12.5%, respectively, p
Published: 2020
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34. Perfusion-weighted techniques in MRI grading of pediatric cerebral tumors: efficiency of dynamic susceptibility contrast and arterial spin labeling

Author: A. Le Troter, Nadine Girard, Arthur Varoquaux, Romain Appay, Jan Patrick Stellmann, Benoit Testud, Gilles Brun, Jean-François Hak, Institut de neurophysiopathologie (INP), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Anatomie Pathologique-Neuropathologique [AP-HM Hôpital La Timone], and Hôpital de la Timone [CHU - APHM] (TIMONE)
Subjects: medicine.medical_specialty, Neurology, [SDV]Life Sciences [q-bio], Contrast Media, Blood volume, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, 0302 clinical medicine, Medicine, Humans, Radiology, Nuclear Medicine and imaging, Child, Grading (tumors), ComputingMilieux_MISCELLANEOUS, Neuroradiology, Retrospective Studies, Receiver operating characteristic, business.industry, Brain Neoplasms, Area under the curve, Blood flow, Magnetic Resonance Imaging, Perfusion, Cerebrovascular Circulation, Spin Labels, Neurology (clinical), Neoplasm Grading, Cardiology and Cardiovascular Medicine, business, Nuclear medicine, 030217 neurology & neurosurgery
Abstract: Dynamic susceptibility contrast (DSC) and arterial spin labeling (ASL) perfusion MRI are applied in pediatric brain tumor grading, but their value for clinical daily practice remains unclear. We explored the ability of ASL and DSC to distinguish low- and high-grade lesions, in an unselected cohort of pediatric cerebral tumors. We retrospectively compared standard perfusion outcomes including blood volume, blood flow, and time parameters from DSC and ASL at 1.5T or 3T MRI scanners of 46 treatment-naive patients by drawing ROI via consensus by two neuroradiologists on the solid portions of every tumor. The discriminant abilities of perfusion parameters were evaluated by receiver operating characteristic (ROC) over the entire cohort and depending on the tumor location and the magnetic field. ASL and DSC parameters showed overall low to moderate performances to distinguish low- and high-grade tumors (area under the curve: between 0.548 and 0.697). Discriminant abilities were better for tumors located supratentorially (AUC between 0.777 and 0.810) than infratentorially, where none of the metrics reached significance. We observed a better differentiation between low- and high-grade cancers at 3T than at 1.5-T. For infratentorial tumors, time parameters from DSC performed better than the commonly used metrics (AUC ≥ 0.8). DSC and ASL show moderate abilities to distinguish low- and high-grade brain tumors in an unselected cohort. Absolute value of K2, TMAX, tMIP, and normalized value of TMAX of the DSC appear as an alternative to conventional parameters for infratentorial tumors. Three Tesla evaluation should be favored over 1.5-Tesla.
Published: 2020
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35. Glycogenin-1 deficiency mimicking limb-girdle muscular dystrophy

Author: Robert-Yves Carlier, Françoise Chapon, Guillaume Nicolas, Valérie Biancalana, Pascal Laforêt, Maxime Fournier, Edoardo Malfatti, Claire Lefeuvre, Stéphane Schaeffer, Hôpital Raymond Poincaré [AP-HP], Service de Neurologie [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), Handicap neuromusculaire : Physiopathologie, Biothérapie et Pharmacologies appliquées (END-ICAP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'Anatomie Pathologique [CHU Caen], Laboratoire de Diagnostic Génétique [CHU Strasbourg], Université de Strasbourg (UNISTRA)-CHU Strasbourg, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg (UNISTRA), and Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)
Subjects: Pathology, medicine.medical_specialty, [SDV]Life Sciences [q-bio], Case Report, Gene mutation, Biceps, Glycogen storage disease type XV, GYG-1, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Deltoid muscle, Genetics, medicine, Muscular dystrophy, Molecular Biology, lcsh:QH301-705.5, lcsh:R5-920, 030219 obstetrics & reproductive medicine, Muscle biopsy, PBM-2, medicine.diagnostic_test, business.industry, Polyglucosan body myopathy-2, Muscle weakness, Neuromuscular disease, medicine.disease, 3. Good health, lcsh:Biology (General), Distal Myopathies, medicine.symptom, business, lcsh:Medicine (General), 030217 neurology & neurosurgery, Limb-girdle muscular dystrophy, Glycogenin-1, GSD XV
Abstract: Glycogen storage disease type XV (GSD XV) is a recently described muscle glycogenosis due to glycogenin-1 (GYG1) deficiency characterized by the presence of polyglucosan bodies on muscle biopsy (Polyglucosan body myopathy-2, PGBM2). Here we describe a 44 year-old man with limb-girdle muscle weakness mimicking a limb-girdle muscular dystrophy (LGMD), and early onset exertional myalgia. Neurologic examination revealed a waddling gait with hyperlordosis, bilateral asymmetric scapular winging, mild asymmetric deltoid and biceps brachii weakness, and pelvic-girdle weakness involving the gluteal muscles and, to a lesser extent, the quadriceps. Serum creatine kinase levels were slightly elevated. Electrophysiological examination showed a myopathic pattern. There was no cardiac or respiratory involvement. Whole-body muscle MRI revealed atrophy and fat replacement of the tongue, biceps brachii, pelvic girdle and erector spinae. A deltoid muscle biopsy showed the presence of PAS-positive inclusions that remained non-digested with alpha-amylase treatment. Electron microscopy studies confirmed the presence of polyglucosan bodies. A diagnostic gene panel designed by the Genetic Diagnosis Laboratory of Strasbourg University Hospital (France) for 210 muscular disorders genes disclosed two heterozygous, pathogenic GYG1 gene mutations (c.304G>C;p.(Asp102His) + c.164_165del). Considering the clinical heterogeneity found in the previously described 38 GYG-1 deficient patients, we suggest that GYG1 should be systematically included in targeted NGS gene panels for LGMDs, distal myopathies, and metabolic myopathies., Highlights • Glycogen storage disease type XV (GSD XV) is a recently described muscle glycogenosis due to glycogenin-1 (GYG1) deficiency characterized by the presence of polyglucosan bodies on muscle biopsy. • Here is the presentation of a 44 year-old man with limb-girdle muscle weakness mimicking a limb-girdle muscular dystrophy. • The large heterogeneity of phenotypic spectrum of GYG-1 deficiency suggests its inclusion in NGS gene panels targeted.
Published: 2020
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36. High-grade gliomas in adolescents and young adults highlight histomolecular differences from their adult and pediatric counterparts

Author: Arnault Tauziède-Espariat, Karima Mokhtari, Steven Knafo, Emmanuel Mandonnet, Pascale Varlet, Fabrice Chrétien, Marc Polivka, Clovis Adam, Johan Pallud, Marie-Anne Debily, Albane Gareton, Dominique Figarella-Branger, Thierry Faillot, Raphaël Saffroy, Marc Sanson, Alexandre Roux, Stéphanie Puget, Mathilde Desplanques, Frédéric Dhermain, Jacques Grill, François Doz, Franck Bourdeaut, Aurélie Dauta, Myriam Edjlali-Goujon, Nathalie Boddaert, Mélanie Pagès, Dominique Cazals-Hatem, Georges Dorfmüller, Institut de neurophysiopathologie (INP), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Anatomie Pathologique-Neuropathologique [AP-HM Hôpital La Timone], and Hôpital de la Timone [CHU - APHM] (TIMONE)
Subjects: Oncology, Cancer Research, medicine.medical_specialty, [SDV]Life Sciences [q-bio], World health, whole exome sequencing, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Glioma, glioma, medicine, Young adult, 10. No inequality, Exome sequencing, business.industry, glioblastoma, Retrospective cohort study, medicine.disease, humanities, 3. Good health, Isocitrate dehydrogenase, 030220 oncology & carcinogenesis, Immunohistochemistry, DNA-methylation analysis, Neurology (clinical), Oligodendroglioma, business, 030217 neurology & neurosurgery, integrated diagnosis
Abstract: Background Considering that pediatric high-grade gliomas (HGGs) are biologically distinct from their adult counterparts, the objective of this study was to define the landscape of HGGs in adolescents and young adults (AYAs). Methods We performed a multicentric retrospective study of 112 AYAs from adult and pediatric Ile-de-France neurosurgical units, treated between 1998 and 2013 to analyze their clinicoradiological and histomolecular profiles. The inclusion criteria were age between 15 and 25 years, histopathological HGG diagnosis, available clinical data, and preoperative and follow-up MRI. MRI and tumoral samples were centrally reviewed. Immunohistochemistry and complementary molecular techniques such as targeted/next-generation sequencing, whole exome sequencing, and DNA-methylation analyses were performed to achieve an integrated diagnosis according to the 2016 World Health Organization (WHO) classification. Results Based on 80 documented AYA patients, HGGs constitute heterogeneous clinicopathological and molecular groups, with a predominant representation of pediatric subtypes (histone H3-mutants, 40%) but also adult subtypes (isocitrate dehydrogenase [IDH] mutants, 28%) characterized by the rarity of oligodendrogliomas, IDH mutants, and 1p/19q codeletion and the relative high frequency of “rare adult IDH mutations” (20%). H3G34-mutants (14%) represent the most specific subgroup in AYAs. In the H3K27-mutant subgroup, non-brainstem diffuse midline gliomas are more frequent (66.7%) than diffuse intrinsic pontine gliomas (23.8%), contrary to what is observed in children. We found that WHO grade has no prognostic value, but molecular subgrouping has major prognostic importance. Conclusions HGGs in AYAs could benefit from a specific classification, driven by molecular subtyping rather than age group. Collaborative efforts are needed from pediatric and adult neuro-oncology teams to improve the management of HGGs in AYAs.
Published: 2020
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37. TP5, a Peptide Inhibitor of Aberrant and Hyperactive CDK5/p25: A Novel Therapeutic Approach against Glioblastoma

Author: Qi Song, Harish C. Pant, Zhengping Zhuang, Emeline Tabouret, Jinkyu Jung, Antonio Cardone, Jing Cui, Mark R. Gilbert, Herui Wang, Deric M. Park, Romain Appay, Niranjana D. Amin, Institut de neurophysiopathologie (INP), Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH), Laboratoire d'Anatomie Pathologique-Neuropathologique [AP-HM Hôpital La Timone], Hôpital de la Timone [CHU - APHM] (TIMONE), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), National Institute of Neurological Disorders and Stroke [Bethesda] (NINDS), University of Maryland Institute for Advanced Computer Studies, University of Maryland [College Park], University of Maryland System-University of Maryland System, and University of Chicago
Subjects: 0301 basic medicine, Cancer Research, DNA damage, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, medicine.medical_treatment, [SDV]Life Sciences [q-bio], CDK5, [SDV.CAN]Life Sciences [q-bio]/Cancer, chemotherapy, lcsh:RC254-282, Article, 03 medical and health sciences, 0302 clinical medicine, In vivo, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], medicine, Viability assay, radiotherapy, Chemotherapy, Temozolomide, Kinase, Chemistry, glioblastoma, Cell cycle, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, targeted therapy, 3. Good health, 030104 developmental biology, Oncology, nervous system, Apoptosis, 030220 oncology & carcinogenesis, ATM, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Cancer research, medicine.drug
Abstract: We examined the efficacy of selective inhibition of cyclin-dependent kinase 5 (CDK5) in glioblastoma by TP5. We analyzed its impact in vitro on CDK5 expression and activity, cell survival, apoptosis and cell cycle. DNA damage was analyzed using the expression of &gamma, H2A.X and phosphorylated ATM. Its tolerance and efficacy were assessed on in vivo xenograft mouse models. We showed that TP5 decreased the activity but not the expression of CDK5 and p35. TP5 alone impaired cell viability and colony formation of glioblastoma cell lines and induced apoptosis. TP5 increased DNA damage by inhibiting the phosphorylation of ATM, leading to G1 arrest. Whereas CDK5 activity is increased by DNA-damaging agents such as temozolomide and irradiation, TP5 was synergistic with either temozolomide or irradiation due to an accumulation of DNA damage. Concomitant use of TP5 and either temozolomide or irradiation reduced the phosphorylation of ATM, increased DNA damage, and inhibited the G2/M arrest induced by temozolomide or irradiation. TP5 alone suppressed the tumor growth of orthotopic glioblastoma mouse model. The treatment was well tolerated. Finally, alone or in association with irradiation or temozolomide, TP5 prolonged mouse survival. TP5 alone or in association with temozolomide and radiotherapy is a promising therapeutic option for glioblastoma.
Published: 2020
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38. Diagnostic and prognostic value of a 7-panel mutation testing in thyroid nodules with indeterminate cytology: the SWEETMAC study

Author: Dominique Vaur, Hervé Monpeyssen, Fabrice Menegaux, Virginie Saguet-Rysanek, Nicolas Goardon, Laurence Leenhardt, Camille Buffet, Renaud Ciappuccini, J. Lequesne, Alexandra Leconte, Audrey Lasne-Cardon, Bénédicte Clarisse, Stéphane Bardet, Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), Unité de recherche interdisciplinaire pour la prévention et le traitement des cancers (ANTICIPE), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-UNICANCER, Hôpital Américain de 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), Service d’Endocrinologie, Métabolisme et Prévention des Risques Cardio-Vasculaires [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), Gestionnaire, HAL Sorbonne Université 5, Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN)-Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Endocrinologie, Métabolisme et Prévention des Maladies Cardio-vasculaires [CHU Pitié-Salpêtrière], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: Proto-Oncogene Proteins B-raf, Thyroid nodules, medicine.medical_specialty, Carcinoma, Hepatocellular, Adenoma, endocrine system diseases, Endocrinology, Diabetes and Metabolism, Biopsy, Fine-Needle, DNA Mutational Analysis, 030209 endocrinology & metabolism, Gastroenterology, Thyroid cancer, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Thyroid lymphoma, Internal medicine, Diagnosis, medicine, Humans, Prospective Studies, Thyroid Neoplasms, Thyroid Nodule, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, business.industry, Liver Neoplasms, Thyroid, Cancer, Nodule (medicine), [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Prognosis, medicine.disease, 3. Good health, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Mutation, Original Article, medicine.symptom, PAX8, business
Abstract: Purpose The aim of this prospective study (ClinicalTrials.gov: NCT01880203) was to evaluate the diagnostic and prognostic value of a 7-panel mutation testing in the aspirates of thyroid nodules with indeterminate cytology (IC). Methods Eligible patients had a thyroid nodule ≥15 mm with IC (Bethesda III–V) for which surgery had been recommended. Detection of BRAF and RAS mutations was performed using pyrosequencing and RET/PTC and PAX8/PPARγ rearrangements using Real-Time quantitative reverse transcription‐polymerase chain reaction (RT-PCR). Results Among 131 nodules with IC, 21 (16%) were malignant including 20 differentiated cancers and one thyroid lymphoma. Molecular abnormalities were identified in 15 nodules with IC corresponding to 10 malignant and 5 benign tumours. BRAF mutation was detected in 4 nodules all corresponding to classic PTC, and PAX8/PPARγ rearrangement in 2 HCC. In contrast, RAS mutation was identified in eight nodules, of which four were malignant, and one RET/PTC3 rearrangement in a follicular adenoma. This data resulted in an accuracy of 88%, sensitivity of 48%, specificity of 95%, positive-predictive value of 67%, and negative-predictive value of 91%. After a 56 month’s follow-up, the proportion of excellent response was similar in patients with molecular alterations (67%) and those without (60%). Conclusions By increasing the overall risk of cancer from 16 to 67% in mutated nodules and by diminishing it to 9% in wild-type, this study confirms the relevance of the 7-panel mutation testing in the diagnostic of nodules with IC. Genetic testing, however, did not predict outcome in the cancer patient subgroup.
Published: 2020
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39. Early Phase of Primary Melanoma Growth from the Patient Point of view: A Prospective Cross Sectional Study on Melanoma over 1 mm in Thickness

Author: Caroline Gaudy-Marqueste, Jean-Jacques Grob, Florent Amatore, Nicolas Macagno, Safia Abed, Florent Grange, Anderson Loundou, N. Malissen, 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), Laboratoire d'Anatomie Pathologique-Neuropathologique [AP-HM Hôpital La Timone], and Hôpital de la Timone [CHU - APHM] (TIMONE)
Subjects: medicine.medical_specialty, Skin Neoplasms, Cross-sectional study, growth, Statistical difference, Dermatology, perception, Resection, Lesion, 030207 dermatology & venereal diseases, 03 medical and health sciences, 0302 clinical medicine, Surveys and Questionnaires, medicine, Humans, Prospective Studies, Pathological, Melanoma, ComputingMilieux_MISCELLANEOUS, business.industry, Tumor kinetics, General Medicine, medicine.disease, Cross-Sectional Studies, RL1-803, Radiology, patient, medicine.symptom, business, Early phase, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: A Nodular Pink Lesion with an Uncommon Diagnosis: A QuizMost melanomas are diagnosed by the patients themselves or by their partners or relatives; they alone can describe its history. We designed a prospective cross-sectional study to describe patients' perception of morphology, growth pattern and kinetics of their primary melanoma over 1 mm in thickness before resection. Patients were interviewed with a questionnaire, a grid representing 9 possible scenarios of melanoma growth, and a set of 87 photographs of potential aspects of melanomas and precursors. Most patients were able to describe the growth of their melanoma and select pictures representative of its successive aspects before resection. Among 453 patients, 60% reported a preexisting lesion present for years. Growth pattern scenarios concurred with tumor kinetics but with no statistical difference between nodular and superficial spreading subtypes. These subjective patient-reported indicators about melanoma growth over time could dynamically complement its objective pathological analysis otherwise static at a single time point.
Published: 2020
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40. cIMPACT‐NOW update 6: new entity and diagnostic principle recommendations of the cIMPACT‐Utrecht meeting on future CNS tumor classification and grading

Author: Uri Tabori, Torsten Pietsch, Cynthia Hawkins, Arie Perry, David N. Louis, Valerie A. White, Guido Reifenberger, Dominique Figarella-Branger, Christine Haberler, Chitra Sarkar, Johan M. Kros, David Capper, Brent A. Orr, Sung Hye Park, Pieter Wesseling, Felix Sahm, Brian Rous, Caterina Giannini, David A. Solomon, Maryam Fouladi, Daniel J. Brat, Werner Paulus, Marc K. Rosenblum, Ian A. Cree, Michael Weller, Kenneth Aldape, Ho Keung Ng, Takashi Komori, Andreas von Deimling, Martin J. van den Bent, Gregory N. Fuller, Charles G. Eberhart, David Ellison, Institut de neurophysiopathologie (INP), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Anatomie Pathologique-Neuropathologique [AP-HM Hôpital La Timone], Hôpital de la Timone [CHU - APHM] (TIMONE), CCA - Imaging and biomarkers, Pathology, Louis D.N., Wesseling P., Aldape K., Brat D.J., Capper D., Cree I.A., Eberhart C., Figarella-Branger D., Fouladi M., Fuller G.N., Giannini C., Haberler C., Hawkins C., Komori T., Kros J.M., Ng H.K., Orr B.A., Park S.-H., Paulus W., Perry A., Pietsch T., Reifenberger G., Rosenblum M., Rous B., Sahm F., Sarkar C., Solomon D.A., Tabori U., van den Bent M.J., von Deimling A., Weller M., White V.A., Ellison D.W., and Neurology
Subjects: 0301 basic medicine, medicine.medical_specialty, [SDV]Life Sciences [q-bio], Clinical Sciences, neoplasms, World health, Pathology and Forensic Medicine, Central Nervous System Neoplasms, 03 medical and health sciences, 0302 clinical medicine, Rare Diseases, Medicine, Humans, Medical physics, CNS TUMORS, Grading (tumors), Cancer, Neurology & Neurosurgery, business.industry, General Neuroscience, Neurosciences, central nervous system, 3. Good health, 030104 developmental biology, Cns neoplasms, classification, brain tumors, Neurology (clinical), Neoplasm Grading, business, 030217 neurology & neurosurgery, brain tumor
Abstract: International audience; cIMPACT-NOW (the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy) was established to evaluate and make practical recommendations on recent advances in the field of CNS tumor classification, particularly in light of the rapid progress in molecular insights into these neoplasms. For Round 2 of its deliberations, cIMPACT-NOW Working Committee 3 was reconstituted and convened in Utrecht, The Netherlands, for a meeting designed to review putative new CNS tumor types in advance of any future World Health Organization meeting on CNS tumor classification. In preparatory activities for the meeting and at the actual meeting, a list of possible entities was assembled and each type and subtype debated. Working Committee 3 recommended that a substantial number of newly recognized types and subtypes should be considered for inclusion in future CNS tumor classifications. In addition, the group endorsed a number of principles-relating to classification categories, approaches to classification, nomenclature, and grading-that the group hopes will also inform the future classification of CNS neoplasms.
Published: 2020
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41. Gliome de bas grade avec altération de MYBL1 : observation d’une nouvelle entité tumorale pédiatrique

Author: Romain, Appay, Arnault, Tauziède-Espariat, Karen, Silva, Radia, Fritih, Didier, Scavarda, Clémence, Delteil, Pascale, Varlet, Dominique, Figarella-Branger, Institut de neurophysiopathologie (INP), 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), and Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Pediatric, Epilepsy, Brain Neoplasms, Pédiatrie, [SDV]Life Sciences [q-bio], MYBL1, Supratentorial Neoplasms, Glioma, Astrocytoma, Young Adult, Proto-Oncogene Proteins, Diffuse glioma, Trans-Activators, Humans, Isomorphe, MYBL1: Isomorphic, Child, Gliome diffus, Épilepsie
Abstract: International audience; Diffuse gliomas with MYB or MYBL1 alterations are rare tumours mostly affecting children or young adults with long-term epilepsy. This category of glioma includes two morphological subtypes. The angiocentric subtype is characterized by an angiocentric pattern of growth and a frequent MYB:QKI fusion. The isomorphic subtype corresponds to a highly differentiated astrocytic glioma with low cellularity, low proliferation and no specific microscopic features. The diagnosis is based on the imaging, demonstrating a supratentorial tumor, associated with the confirmation of a MYB or MYBL1 rearrangement. Here, we report the case of a 7-year-old child who presented a right frontal brain lesion corresponding to an isomorphic diffuse glioma with MYBL1 alteration.
Published: 2020
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42. Diffuse leptomeningeal glioneuronal tumor: a double misnomer? A report of two cases

Author: Mélanie Pagès, David T.W. Jones, Pascale Varlet, Carole Colin, Romain Appay, Dominique Figarella-Branger, Institut de neurophysiopathologie (INP), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Anatomie Pathologique-Neuropathologique [AP-HM Hôpital La Timone], and Hôpital de la Timone [CHU - APHM] (TIMONE)
Subjects: Proto-Oncogene Proteins B-raf, Adult, medicine.medical_specialty, Pathology, Neurology, Class I Phosphatidylinositol 3-Kinases, [SDV]Life Sciences [q-bio], Oligodendroglioma, Misnomer, Case Report, DLGNT, Supratentorial, lcsh:RC346-429, Pathology and Forensic Medicine, 03 medical and health sciences, Cellular and Molecular Neuroscience, BRAFV600E mutation, 0302 clinical medicine, Glioneuronal tumor, Meningeal Neoplasms, medicine, 1p Deletion, Humans, lcsh:Neurology. Diseases of the nervous system, 030304 developmental biology, DNA-methylation profiling, 0303 health sciences, Brain Neoplasms, business.industry, Intraspinal Tumor, PIK3CA E545A, 3. Good health, BRAF V600E, Chromosomes, Human, Pair 1, Mutation, Female, Neurology (clinical), Chromosome Deletion, Who classification, business, Chromosomes, Human, Pair 19, 030217 neurology & neurosurgery
Abstract: Diffuse leptomeningeal glioneuronal tumor (DLGNT) was introduced, for the first time, as a provisional entity in the 2016 WHO classification of central nervous system tumors. DLGNT mainly occur in children and characterized by a widespread leptomeningeal growth occasionally associated with intraspinal tumor nodules, an oligodendroglial-like cytology, glioneuronal differentiation and MAP-Kinase activation associated with either solitary 1p deletion or 1p/19q codeletion in the absence of IDH mutation.We report here two unexpected DLGNTs adult cases, characterized by a unique supratentorial circumscribed intraparenchymal tumor without leptomeningeal involvement in spite of long follow-up. In both cases, the diagnosis of DLGNT was made after DNA-methylation profiling which demonstrated that one case belonged to the DLGNT class whereas the other remained not classifiable but showed on CNV the characteristic genetic findings recorded in DLGNT. Both cases harbored 1p/19q codeletion associated with KIAA1549:BRAF fusion in one case and with BRAF V600E and PIK3CA E545A mutations, in the other.Our study enlarges the clinical and molecular spectrum of DLGNTs, and points out that the terminology of DLGNTs is not fully appropriate since some cases could have neither diffuse growth nor leptomeningeal dissemination. This suggests that DLGNTs encompass a wide spectrum of tumors that has yet to be fully clarified.
Published: 2020
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43. Prenatal cannabinoid exposure alters the ovarian reserve in adult offspring of rats

Author: Hubert Lepidi, Anne-Laure Pelissier-Alicot, Beatrice Mandon-Pepin, Blandine Courbiere, Magalie Barbier, Elodie Poumerol, Pierre Castel, Olivier J. Manzoni, Virginie Tassistro, Service de gynécologie-obstétrique [Hôpital Nord - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital Nord [CHU - APHM], Institut méditerranéen de biodiversité et d'écologie marine et continentale (IMBE), Avignon Université (AU)-Aix Marseille Université (AMU)-Institut de recherche pour le développement [IRD] : UMR237-Centre National de la Recherche Scientifique (CNRS), Biologie de la Reproduction, Environnement, Epigénétique & Développement (BREED), Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-École nationale vétérinaire d'Alfort (ENVA)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Laboratoire d'anatomie pathologique - [Hôpital Nord - APHM], Hôpital Nord [CHU - APHM]-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM), Microbes évolution phylogénie et infections (MEPHI), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Institut de Neurobiologie de la Méditerranée [Aix-Marseille Université] (INMED - INSERM U1249), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), A*Midex Foundation of Aix-Marseille University, École nationale vétérinaire - Alfort (ENVA)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), and Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0301 basic medicine, Agonist, Endocannabinoid system, Drug Inverse Agonism, medicine.drug_class, Offspring, Health, Toxicology and Mutagenesis, medicine.medical_treatment, Morpholines, Gestational Age, 010501 environmental sciences, Biology, Naphthalenes, Toxicology, 01 natural sciences, Andrology, 03 medical and health sciences, Receptor, Cannabinoid, CB1, Pregnancy, Prenatal exposure, SR141716, medicine, Delta 9-tetrahydrocannabinol, Inverse agonist, Animals, Dronabinol, Young adult, Rats, Wistar, Ovarian reserve, Ovarian Reserve, Cannabinoid Receptor Antagonists, 0105 earth and related environmental sciences, Cannabinoid Receptor Agonists, [SDV.BA]Life Sciences [q-bio]/Animal biology, Ovary, General Medicine, Benzoxazines, 030104 developmental biology, Gene Expression Regulation, Prenatal Exposure Delayed Effects, Gestation, Female, Cannabinoid, Rimonabant, WIN55212, Endocannabinoids
Abstract: International audience; In animals, research in the past two decades has demonstrated the strong involvement of the endocannabinoid system (ECS) in numerous steps of the reproductive process, including ovarian physiology. Reproductive lifespan is closely related to the number of nongrowing ovarian follicles, called ovarian reserve (OR), which is definitively established during foetal life. Thus, OR damage may lead to poor reproductive outcomes and a shortened reproductive lifespan. We investigated whether prenatal ECS modulation had an effect on the OR at different ages in the rat offspring. Four groups of gestating female rats (F0) were exposed to the CB1-/CB2-receptor agonist WIN55212 (0.5 mg/kg), the CB1R inverse agonist SR141716 (3 mg/kg) or Δ9THC (5 mg/kg) and were compared to negative control groups. OR was histologically assessed at different postnatal timepoints (F1 individuals): postnatal day (PND) 6, PND40 and PND90. At PND6, prenatal exposure had no effect on OR. In the young adult group (PND90) exposed during gestation to WIN55212, we observed a CB1R-mediated delayed OR decrease, which was reversed by prenatal CB1R blockade by SR141716. Conversely, after prenatal SR141716 exposure, we observed higher OR counts at PND90. RT-PCR experiments also showed that prenatal ECS modulation perturbed the mRNA levels of ECS enzymes and OR regulation genes. Our findings support the role of the ECS in OR regulation during the foetal life of rats and highlight the need for further studies to elucidate its precise role in OR physiology.
Published: 2020
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44. Néphropathie associée à une vascularite urticarienne hypocomplémentémique : présentation d’un cas clinique et revue de la littérature

Author: Nicolas Gautier, Antoine Lanot, A. Boyer, Bruno Hurault de Ligny, F. Comoz, Achille Aouba, Centre Universitaire des Maladies Rénales [CHU Caen] (CUMR 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 de Caen Normandie - UFR Santé (UNICAEN Santé), Normandie Université (NU)-Normandie Université (NU), Laboratoire d'Anatomie Pathologique [CHU Caen], CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Université de Caen Normandie (UNICAEN), Normandie Université (NU), and Service de médecine interne [CHU Caen]
Subjects: Systemic disease, medicine.medical_specialty, medicine.diagnostic_test, business.industry, [SDV]Life Sciences [q-bio], 030232 urology & nephrology, Glomerulonephritis, Hydroxychloroquine, urologic and male genital diseases, medicine.disease, Dermatology, Sialadenitis, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Nephrology, Membranoproliferative glomerulonephritis, Biopsy, medicine, business, Nephritis, Systemic vasculitis, medicine.drug
Abstract: Hypocomplementemic urticarial vasculitis is a rare systemic vasculitis, affecting small vessels, characterised by chronicle urticaria, hypocomplementemia, and systemic manifestations. Renal involvement, whose prevalence varies between 9% and 60%, is mainly glomerular. We here report the case of a 59 years old woman presenting kidney failure, associated with chronicle urticaria and arthralgias. Laboratory investigation showed haematuria, proteinuria, hypocomplementemia and anti-SSa antibody positivity. A percutaneous kidney biopsy revealed focal and segmental glomerulonephritis associated with an acute interstitial nephritis. Hypocomplementemic urticarial vasculitis diagnosis was established after identifying anti-C1q antibodies. The lack of a dry syndrome, the negativity of a Schirmer test and the lack of sialadenitis on a salivary gland biopsy excluded an associated Gougerot-Sjogren Syndrome. The patient was treated with hydroxychloroquine and low-dose steroids, enabling a clinical and biological recovery. Of the 82 cases in the literature describing hypocomplementemic urticarial vasculitis associated nephropathies, 72 (88%) were a glomerular impairment, most frequently secondary to membranoproliferative glomerulonephritis. Only 6 (7%) tubulo-interstitial nephritis have been reported, 4 of them being associated with a glomerulonephritis. Patients were more likely to be women, aged in their third decade. The most frequent renal manifestations were haematuria (60%), and proteinuria (52%). Kidney failure was rarely observed (22%), with a fairly good renal prognosis. Hypocomplementemic urticarial vasculitis was associated with a systemic disease in 11 (13%) patients. In the absence of recommendations, the treatment strategy remains to be defined.
Published: 2020
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45. cIMPACT-NOW update 5: recommended grading criteria and terminologies for IDH-mutant astrocytomas

Author: Caterina Giannini, Catriona McLean, Howard Colman, Chitra Sarkar, Dominique Figrarella-Branger, Arie Perry, Gregory N. Fuller, David N. Louis, Kenneth Aldape, Robert B. Jenkins, Andreas von Deimling, Martin J. van den Bent, Roger Stupp, Guido Reifenberger, Johan M. Kros, Bette K. Kleinschmidt-DeMasters, Eric C. Holland, Takashi Komori, Daniel J. Brat, Michael Weller, National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH), Institut de neurophysiopathologie (INP), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Anatomie Pathologique-Neuropathologique [AP-HM Hôpital La Timone], Hôpital de la Timone [CHU - APHM] (TIMONE), Departments of Applied Physics [New Haven], Yale University [New Haven], Mayo Clinic [Rochester], Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Brat D.J., Aldape K., Colman H., Figrarella-Branger D., Fuller G.N., Giannini C., Holland E.C., Jenkins R.B., Kleinschmidt-DeMasters B., Komori T., Kros J.M., Louis D.N., McLean C., Perry A., Reifenberger G., Sarkar C., Stupp R., van den Bent M.J., von Deimling A., Weller M., Pathology, and Neurology
Subjects: business.industry, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV]Life Sciences [q-bio], Mutant, [SDV.CAN]Life Sciences [q-bio]/Cancer, Bioinformatics, IDH mutant astrocytoma, Article, Pathology and Forensic Medicine, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, 030220 oncology & carcinogenesis, Medicine, Neurology (clinical), business, Grading (tumors), 030217 neurology & neurosurgery, ComputingMilieux_MISCELLANEOUS
Abstract: International audience
Published: 2020
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46. EB1-dependent long survival of glioblastoma-grafted mice with the oral tubulin-binder BAL101553 is associated with inhibition of tumor angiogenesis

Author: Raphael Berges, Dominique Figarella-Branger, Aurélie Tchoghandjian, Heidi Lane, Arnauld Sergé, Diane Braguer, Felix Bachmann, Stéphane Honoré, Institut de neurophysiopathologie (INP), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Anatomie Pathologique-Neuropathologique [AP-HM Hôpital La Timone], Hôpital de la Timone [CHU - APHM] (TIMONE), and Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)
Subjects: 0301 basic medicine, cancer stem cells, [SDV]Life Sciences [q-bio], experimental cancer therapeutics, 03 medical and health sciences, 0302 clinical medicine, Cancer stem cell, medicine, Secretion, microtubule-targeting agent, business.industry, glioblastoma, Cancer, medicine.disease, Phenotype, In vitro, 3. Good health, Endothelial stem cell, 030104 developmental biology, Oncology, Mechanism of action, 030220 oncology & carcinogenesis, Cancer research, medicine.symptom, Stem cell, business, Research Paper
Abstract: International audience; Glioblastoma (GBM) are aggressive brain tumors with limited treatment options. Cancer stem-like cells (CSLCs) contribute to GBM invasiveness, representing promising targets. BAL101553, a prodrug of BAL27862, is a novel small molecule tubulin-binding agent, promoting tumor cell death through spindle assembly checkpoint activation, which is currently in Phase 1/2a in advanced solid tumor patients including GBM. This study aimed to evaluate long-term daily oral BAL101553 treatment of mice orthotopically grafted with GBM CSLCs (GBM6) according to EB1 expression-level, and to decipher its mechanism of action on GBM stem cells. Oral treatment with BAL101553 for 100 days provoked a large EB1 expression level-dependent survival benefit, together with a decrease in tumor growth and brain invasion. Formation of vascular structures by the fluorescent GBM6-GFP-sh0 cells, mimicking endothelial vascular networks, was observed in the brains of control grafted mice. Following BAL101553 treatment, vessels were no longer detectable, suggesting inhibition of the endothelial trans-differentiation of GBM stem cells. In vitro, BAL27862 treatment resulted in a switch to the endothelial-like phenotype of GBM6 towards an astrocytic phenotype. Moreover, the drug inhibited secretion of VEGF, thus preventing normal endothelial cell migration activated by CSLCs. The decrease in VEGF secretion was confirmed in a human GBM explant following drug treatment. Altogether, our data first confirm the potential of EB1 expression as a response-predictive biomarker of BAL101553 in GBM we previously published and add new insights in BAL101553 long-term action by counteracting CSLCs mediated tumor angiogenesis. Our results strongly support BAL101553 clinical studies in GBM patients.
Published: 2020
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47. Reverse transcriptase multiplex ligation-dependent probe amplification in endomyocardial biopsies for the diagnosis of cardiac allograft rejection

Author: Philippe Ruminy, Romain Guillemain, Jean-Paul Duong Van Huyen, Jean-Luc Taupin, Pierre-Julien Viailly, Philippe Rouvier, Nicolas Adam, Sabine Pattier, Claire Toquet, Patrick Bruneval, Ahmad Abdel Sater, Guillaume Coutance, Fanny Drieux, Eric Epailly, Arnaud François, Marie-Pierre Chenard, Marion Rabant, Shaida Varnous, Alexandre Loupy, Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (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), Laboratoire d'anatomie pathologique [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut de cardiologie [CHU Pitié-Salpêtrière], 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), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Anatomie et Cytologie Pathologique [CHU Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Equipe Traitement de l'information en Biologie Santé (TIBS - LITIS), Laboratoire d'Informatique, de Traitement de l'Information et des Systèmes (LITIS), Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Université Le Havre Normandie (ULH), Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), NANTES (NANTES - Ana Path), Centre hospitalier universitaire de Nantes (CHU Nantes), Equipe de Recherche sur les Rationalités Philosophiques et les Savoirs (ERRAPHIS), Université Toulouse - Jean Jaurès (UT2J), Service d'Anatomie Pathologique Générale, CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], Service de Chirurgie Cardio-Vasculaire, CHU Strasbourg-Nouvel Hôpital Civil, Department of Chest Medicine, Mont-Godinne Hospital-Catholic University of Louvain de Mont-Godinne, Service de transplantation cardiaque [CHU Nantes], Service de virologie et d'immunologie biologique, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Transplantation Rénale, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Laboratoire de Recherche en Imagerie : Méthodes d'imagerie des Échanges transcapillaires (LRI - EA4062), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), CCSD, Accord Elsevier, 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)-Université Paris Descartes - Paris 5 (UPD5)-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), Service de pathologie [CHU Strasbourg], CHU Strasbourg, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), and Hopital Saint-Louis [AP-HP] (AP-HP)
Subjects: Adult, Graft Rejection, Male, musculoskeletal diseases, Pulmonary and Respiratory Medicine, medicine.medical_specialty, Pathology, Biopsy, medicine.medical_treatment, [SDV]Life Sciences [q-bio], 030204 cardiovascular system & hematology, 030230 surgery, Allograft Rejection, 03 medical and health sciences, 0302 clinical medicine, GNLY, medicine, molecular biology, Humans, Multiplex, Multiplex ligation-dependent probe amplification, ComputingMilieux_MISCELLANEOUS, Retrospective Studies, Heart transplantation, class prediction analysis, Transplantation, business.industry, Myocardium, CCL18, Histology, Middle Aged, Allografts, Reverse transcriptase, 3. Good health, [SDV] Life Sciences [q-bio], Cross-Sectional Studies, endomyocardial biopsy, histopathology, Heart Transplantation, RNA, Female, Surgery, Histopathology, Cardiology and Cardiovascular Medicine, business, Multiplex Polymerase Chain Reaction
Abstract: International audience; Background: Molecular biology has emerged as a potential companion to histology for the diagnosis of rejection after heart transplantation. Reverse transcriptase multiplex ligation-dependent probe amplification (RT-MLPA) is a technique of targeted gene expression analysis suitable for formalin-fixed paraffin-embedded (FFPE) biopsies. Our aim was to assess RT-MLPA for the diagnosis of allograft rejection in heart transplantation.Methods: We performed a cross-sectional, case-control, multicenter study. After the selection of a 14-transcript panel (endothelial burden, Natural killer cells, interferon-γ pathway, effector T-cells, and antigen presentation), RT-MLPA was applied to 183 FFPE endomyocardial biopsies (EMB), randomized into a training (n = 113) and a validation (n = 70) series. A two-step class prediction analysis was developed (Linear prediction score-LPS1: rejection vs non-rejection; LPS2: antibody-mediated rejection [AMR] vs acute cellular rejection [ACR]). A study of the agreement between pathology and RT-MLPA was performed.Results: Overall, 48 ACR, 82 AMR, 5 mixed rejection, and 48 non-rejection EMBs were analyzed. Three molecular clusters were delineated by unsupervised hierarchical analysis (molecular non-rejection, ACR, and AMR). AMR was characterized by the high expression of CCL4, GNLY, FCGR3, CXCL11 and ACR by the high expression of CCL18 and ADAMdec. RT-MLPA and histopathology agreed in the final diagnosis in 82.2%, 67.7%, and 76.8% of the EMB in the test, validation, and overall cohort, respectively. Disagreement cases were more common in the case of histologic low-grade rejection and early post-transplant EMB.Conclusions: RT-MLPA is a suitable technique for targeted gene expression analysis on FFPE EMB with a good overall agreement with the histologic diagnosis of heart allograft rejection.
Published: 2020
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48. Medulloblastomas associated with an APC germline pathogenic variant share the good prognosis of CTNNB1-mutated medulloblastomas

Author: Marie-Bernadette Delisle, Anne-Isabelle Bertozzi-Salomon, Marc Polivka, Hélène Zattara, Aurore Surun, Laurence Brugières, Fabienne Prieur, Franck Bourdeaut, Alexandre Vasiljevic, Pierre Leblond, Pascale Varlet, Nicolas André, Françoise Desseigne, Dominique Figarella-Branger, Eric Sariban, Rosine Guimbaud, Christelle Dufour, Cécile Faure-Conter, Claire Alapetite, Florence Coulet, Léa Guerrini-Rousseau, Chrystelle Colas, François Doz, Sandra Raimbault, Claude-Alain Maurage, Brigitte Lacour, Claire Berger, Institut de neurophysiopathologie (INP), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Anatomie Pathologique-Neuropathologique [AP-HM Hôpital La Timone], and Hôpital de la Timone [CHU - APHM] (TIMONE)
Subjects: Adult, Male, Cancer Research, Adolescent, Adenomatous polyposis coli, [SDV]Life Sciences [q-bio], Adenomatous Polyposis Coli Protein, Context (language use), medulloblastoma, Germline, Thyroid carcinoma, WNT, 03 medical and health sciences, 0302 clinical medicine, Gardner Syndrome, Medicine, Humans, Cerebellar Neoplasms, Child, Gardner syndrome, Osteoma, neoplasms, Germ-Line Mutation, beta Catenin, 030304 developmental biology, Retrospective Studies, Medulloblastoma, 0303 health sciences, biology, business.industry, Wnt signaling pathway, Editorials, medicine.disease, familial adenomatosis polyposis, 3. Good health, nervous system diseases, APC, stomatognathic diseases, Oncology, Adenomatous Polyposis Coli, 030220 oncology & carcinogenesis, Cancer research, biology.protein, Female, Neurology (clinical), business
Abstract: Background Medulloblastomas may occur in a predisposition context, including familial adenomatosis polyposis. Medulloblastomas related to a germline pathogenic variant of adenomatous polyposis coli (APC) remain rare and poorly described. Their similarities with sporadic WNT medulloblastomas still require description. Methods We performed a multicentric retrospective review of 12 patients treated between 1988 and 2018 for medulloblastoma with an identified or highly suspected (personal or familial history) APC germline pathogenic variant. We report personal and familial history APC gene pathogenic variants whenever available: clinical and histologic characteristics of the medulloblastoma, treatments, and long-term outcome, including second tumor and late sequelae. Results Medulloblastomas associated with APC pathogenic variants are mainly classic (11/11 patients, 1 not available), nonmetastatic (10/12 patients) medulloblastomas, with nuclear immunoreactivity for ß-catenin (9/9 tested cases). Ten of 11 assessable patients are disease free with a median follow-up of 10.7 years (range, 1–28 y). Secondary tumors included desmoid tumors in 7 patients (9 tumors), 1 thyroid carcinoma, 2 pilomatricomas, 1 osteoma, 1 vertebral hemangioma, and 1 malignant triton in the radiation field, which caused the only cancer-related death in our series. Conclusions Medulloblastomas associated with an APC pathogenic variant have an overall favorable outcome, even for metastatic tumors. Yet, long-term survival is clouded by second tumor occurrence; treatment may play some role in some of these second malignancies. Our findings raise the question of applying a de-escalation therapeutic protocol to treat patients with APC germline pathogenic variants given the excellent outcome, and reduced intensity of craniospinal irradiation may be further evaluated.
Published: 2020
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49. WHO grade has no prognostic value in the pediatric high-grade glioma included in the HERBY trial

Author: Felice Giangaspero, Chris Jones, Christophe Deroulers, Dominique Figarella-Branger, Marie-Cécile Le Deley, Thomas S. Jacques, Gwénaël Le Teuff, Tim Jaspan, Torsten Pietsch, J. Grill, Pascale Varlet, Felipe Andreiuolo, Christine Haberler, Institut de neurophysiopathologie (INP), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Anatomie Pathologique-Neuropathologique [AP-HM Hôpital La Timone], Hôpital de la Timone [CHU - APHM] (TIMONE), Imagerie et Modélisation en Neurobiologie et Cancérologie (IMNC (UMR_8165)), and Université Paris-Sud - Paris 11 (UP11)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, Oncology, Cancer Research, [SDV]Life Sciences [q-bio], Datasets as Topic, MESH: Neoplasm Grading, Central Pathology Review, MESH: World Health Organization, MESH: Glioma, 0302 clinical medicine, MESH: Child, Multicenter Studies as Topic, MESH: Datasets as Topic, Child, Randomized Controlled Trials as Topic, MESH: Chemoradiotherapy, [PHYS]Physics [physics], biology, Brain Neoplasms, Chemoradiotherapy, Glioma, Prognosis, 3. Good health, Bevacizumab, Glioma grading, Child, Preschool, 030220 oncology & carcinogenesis, Ki-67, MESH: Brain Neoplasms, Female, MESH: Clinical Trials, Phase II as Topic, high-grade glioma, medicine.medical_specialty, Adolescent, Antineoplastic Agents, World Health Organization, World health, MESH: Prognosis, 03 medical and health sciences, Clinical Trials, Phase II as Topic, MESH: Bevacizumab, Internal medicine, grading criteria, pediatric, Temozolomide, medicine, Humans, Grading (tumors), MESH: Temozolomide, High-Grade Glioma, MESH: Adolescent, MESH: Humans, business.industry, MESH: Child, Preschool, Who grade, medicine.disease, MESH: Male, MESH: Randomized Controlled Trials as Topic, biology.protein, MESH: Multicenter Studies as Topic, MESH: Antineoplastic Agents, Neurology (clinical), Neoplasm Grading, business, Pediatric Neuro-Oncology, MESH: Female, 030217 neurology & neurosurgery
Abstract: Background The World Health Organization (WHO) adult glioma grading system is questionable in pediatric high-grade gliomas (pHGGs), which are biologically distinct from adult HGGs. We took advantage of the neuropathological review data obtained during one of the largest prospective randomized pHGG trials, namely HERBY (NCT01390948), to address this issue in children with newly diagnosed non-brainstem HGG. Methods HGG diagnosis was confirmed by pre-randomization, real-time central pathology review using WHO 2007 criteria, followed by a consensus review blinded to clinical factors and outcomes. We evaluated association between WHO 2007 grade and other clinical/radiological/biological characteristics and the prognostic value of WHO 2007 grade, midline location, and selected biomarkers (Ki-67 index/Olig2/CD34/EGFR/p53/H3F3A K27M mutation) on overall survival. Results Real-time central neuropathological review was feasible in a multicenter study, with a mean time of 2.4 days, and led to the rejection of HGG diagnosis in 20 of 163 cases (12.3%). The different grading criteria and resulting WHO grade were not significantly associated with overall survival in the entire population (n = 118) or in midline and non-midline subgroups. H3F3A K27M mutation was significantly associated with poor outcome. No significant prognostic value was observed for grade, even after regrading H3F3A K27M-mutated midline glioma as grade IV (WHO 2016). Midline location and a high Ki-67 index (≥20%) were associated with poor outcome (P = 0.004 and P = 0.04, respectively). A 10% increase in Ki-67 index was associated with a hazard ratio of 1.53 (95% CI: 1.27–1.83; P < 0.0001). Conclusion Our findings suggest that WHO grade III versus IV has no prognostic value in pediatric HGG.
Published: 2020
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50. Machine Learning for Better Prognostic Stratification and Driver Gene Identification Using Somatic Copy Number Variations in Anaplastic Oligodendroglioma

Author: Luc Bauchet, Denys Fontaine, D. Larrieu‐Ciron, M. Andraud, H. Aubriot‐Lorton, Fabien Forest, G. Runavot, Shai Rosenberg, I. Carpiuc, François Labrousse, Christine Desenclos, Annie Laquerrière, Georges Noël, Olivier Chinot, Catherine Godfraind, Patrick Beauchesne, Jean-Yves Delattre, Caroline Dehais, T. Cruel, Danchristian Chiforeanu, F. Dhermain, Dominique Cazals-Hatem, Claude Gaultier, W. Lahiani, Marie-Laure Tanguy, C. Dehais, S. Elouadhani‐Hamdi, Pomone Richard, François Ghiringhelli, Olivier Langlois, Ca. Maurage, Dominique Figarella-Branger, Ahmed Idbaih, Carole Ramirez, Philippe Menei, François Ducray, Benoit Lhermitte, Nabila Elarouci, M. Campone, F. Vandenbos‐Burel, Mj. Motso‐Fotso, C. Blechet, Nicolas Desse, Sandrine Eimer, Valérie Rigau, Agusti Alentorn, Anne Jouvet, Damien Ricard, Mc. Tortel, T. Khallil, Clovis Adam, Hugues Loiseau, L. Bekaert, Henri Sevestre, Chiara Villa, M. Fesneau, Isabelle Quintin-Roue, Antoine Petit, Philippe Colin, Elodie Vauleon, S. Lopez, S. Gaillard, Guillaume Gauchotte, Antoine F. Carpentier, Phong Dam-Hieu, Md. Diebold, Yannick Marie, Thierry Faillot, Serge Milin, Aurélien de Reyniès, Emmanuelle Lechapt-Zalcman, Fabrice Parker, E. Cohen‐Moyal, Delphine Loussouarn, Emmanuelle Uro-Coste, Em. Gueye, Audrey Rousseau, F. Ducray, M‐I Mihai, Aurelie Kamoun, Karima Mokhtari, 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], 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), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), (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), Institut de neurophysiopathologie (INP), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Anatomie Pathologique-Neuropathologique [AP-HM Hôpital La Timone], Hôpital de la Timone [CHU - APHM] (TIMONE), 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 Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: Male, 0301 basic medicine, Cancer Research, DNA Copy Number Variations, Survival, Somatic cell, [SDV]Life Sciences [q-bio], Oligodendroglioma, Machine learning, computer.software_genre, medicine.disease_cause, Cohort Studies, Loss of heterozygosity, 03 medical and health sciences, microRNA, medicine, Humans, Neuro‐Oncology, Copy-number variation, Gene, Pathological, business.industry, Genomics, Glioma, Middle Aged, Prognosis, Precision medicine, 3. Good health, 030104 developmental biology, Oncology, Female, Artificial intelligence, Carcinogenesis, business, computer
Abstract: Background 1p/19q-codeleted anaplastic gliomas have variable clinical behavior. We have recently shown that the common 9p21.3 allelic loss is an independent prognostic factor in this tumor type. The aim of this study is to identify less frequent genomic copy number variations (CNVs) with clinical importance that may shed light on molecular oncogenesis of this tumor type. Materials and Methods A cohort of 197 patients with anaplastic oligodendroglioma was collected as part of the French POLA network. Clinical, pathological, and molecular information was recorded. CNV analysis was performed using single-nucleotide polymorphism arrays. Computational biology and feature selection based on the random forests method were used to identify CNV events associated with overall survival and other clinical-pathological variables. Results Recurrent chromosomal events were identified in chromosomes 4, 9, and 11. Forty-six focal amplification events and 22 focal deletion events were identified. Twenty-four focal CNV areas were associated with survival, and five of them were significantly associated with survival after multivariable analysis. Nine out of 24 CNV events were validated using an external cohort of The Cancer Genome Atlas. Five of the validated events contain a cancer-related gene or microRNA: CDKN2A deletion, SS18L1 amplification, RHOA/MIR191 copy-neutral loss of heterozygosity, FGFR3 amplification, and ARNT amplification. The CNV profile contributes to better survival prediction compared with clinical-based risk assessment. Conclusion Several recurrent CNV events, detected in anaplastic oligodendroglioma, enable better survival prediction. More importantly, they help in identifying potential genes for understanding oncogenesis and for personalized therapy. Implications for Practice Genomic analysis of 197 anaplastic oligodendroglioma tumors reveals recurrent somatic copy number variation areas that may help in understanding oncogenesis and target identification for precision medicine. A machine learning multivariable model built using this genomic information enables better survival prediction.
Published: 2018
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