Author: "Ahmed Idbaih" / Topic: medicine.disease - Searchworks@Jio Institute Digital Library Search Results

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189 results on '"Ahmed Idbaih"'

1. Histiocytosis and the nervous system: from diagnosis to targeted therapies

Author: Jean-François Emile, Fleur Cohen Aubart, Eli L. Diamond, Julien Haroche, Zahir Amoura, Benjamin H. Durham, Ahmed Idbaih, Omar Abdel-Wahab, Service de médecine interne [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), Service de neurologie 1 [CHU Pitié-Salpétrière], Hôpital Ambroise Paré [AP-HP], Memorial Sloane Kettering Cancer Center [New York], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Neurologie [CHU Pitié-Salpêtrière], and IFR70-CHU Pitié-Salpêtrière [AP-HP]
Subjects: Central Nervous System, Cancer Research, Pathology, medicine.medical_specialty, Erdheim-Chester Disease, [SDV]Life Sciences [q-bio], Reviews, Disease, 03 medical and health sciences, 0302 clinical medicine, Rosai-Dorfman-Destombes disease, Langerhans cell histiocytosis, medicine, AcademicSubjects/MED00300, Humans, Rosai–Dorfman disease, Histiocyte, business.industry, CD68, MAPK pathway, medicine.disease, Prognosis, 3. Good health, Histiocytosis, Histiocytosis, Langerhans-Cell, Oncology, 030220 oncology & carcinogenesis, Histiocytoses, Erdheim–Chester disease, AcademicSubjects/MED00310, Neurology (clinical), Histiocytosis, Sinus, business, 030215 immunology
Abstract: Histiocytoses are heterogeneous hematopoietic diseases characterized by the accumulation of CD68(+) cells with various admixed inflammatory infiltrates. The identification of the pivotal role of the mitogen-activated protein kinase (MAPK) pathway has opened new avenues of research and therapeutic approaches. We review the neurologic manifestations of 3 histiocytic disorders with frequent involvement of the brain and spine: Langerhans cell histiocytosis (LCH), Erdheim-Chester disease (ECD), and Rosai-Dorfman-Destombes disease (RDD). Central nervous system (CNS) manifestations occur in 10%-25% of LCH cases, with both tumorous or neurodegenerative forms. These subtypes differ by clinical and radiological presentation, pathogenesis, and prognosis. Tumorous or degenerative neurologic involvement occurs in 30%-40% of ECD patients and affects the hypothalamic-pituitary axis, meninges, and brain parenchyma. RDD lesions are typically tumorous with meningeal or parenchymal masses with strong contrast enhancement. Unlike LCH and ECD, neurodegenerative lesions or syndromes have not been described with RDD. Familiarity with principles of evaluation and treatment both shared among and distinct to each of these 3 diseases is critical for effective management. Refractory or disabling neurohistiocytic involvement should prompt the consideration for use of targeted kinase inhibitor therapies.
Published: 2021

2. Objective neurocognitive functioning and neurocognitive complaints in patients with high-grade glioma

Author: Martin J. van den Bent, Martin Klein, Andrew Bottomley, Wolfgang Wick, Jos W. R. Twisk, Jaap C. Reijneveld, A Josephine Drijver, Ahmed Idbaih, Madeline Pe, Ivan Caramanna, Neurology, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Vrije Universiteit Amsterdam [Amsterdam] (VU), European Organisation for Research and Treatment of Cancer [Bruxelles] (EORTC), European Cancer Organisation [Bruxelles] (ECCO), VU University Medical Center [Amsterdam], Erasmus University Medical Center [Rotterdam] (Erasmus MC), 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), Heidelberg University Hospital [Heidelberg], Clinical Neuropsychology, Medical psychology, Epidemiology and Data Science, APH - Health Behaviors & Chronic Diseases, APH - Methodology, CCA - Cancer Treatment and quality of life, Gestionnaire, HAL Sorbonne Université 5, Unité de recherche de l'institut du thorax (ITX-lab), 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], and 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)
Subjects: 0301 basic medicine, Male, Health Knowledge, Attitudes, Practice, Cancer Research, Cognition Disorders/etiology, Health-related quality of life, Neuropsychological Tests, Correlation, High-grade glioma, 0302 clinical medicine, Quality of life, Surveys and Questionnaires, Medicine, Practice, Brain Neoplasms, Health Knowledge, Cognition, Glioma, Middle Aged, Mental Status and Dementia Tests, Prognosis, humanities, 3. Good health, Europe, Oncology, 030220 oncology & carcinogenesis, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Female, Clinical psychology, Cognitive awareness, Concordance, [SDV.CAN]Life Sciences [q-bio]/Cancer, Glioma/complications, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, SDG 3 - Good Health and Well-being, Humans, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Cognitive skill, business.industry, Cancer, medicine.disease, Clinical trial, Neurocognitive functioning, 030104 developmental biology, Cross-Sectional Studies, Brain Neoplasms/complications, Attitudes, Quality of Life, PROs, Cognition Disorders, business, Neurocognitive, Follow-Up Studies
Abstract: BACKGROUND: Neurocognitively impaired patients with brain tumour are presumed to have reduced cognitive awareness preventing them from adequately valuing and reporting their own functioning, for instance, when providing patient-reported outcomes (PROs) such as health-related quality of life instruments. In this cross-sectional study, we aimed at assessing the concordance of neurocognitive complaints (NCCs) and objective neurocognitive functioning (NCF) as a measure of cognitive awareness.METHODS: NCF was assessed using an internationally accepted clinical trial battery. NCC was assessed using the cognitive functioning questionnaire from the Medical Outcome Study (MOS) and the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire cognitive functioning subscale. Patients were divided in cognitively impaired and unimpaired groups, based on their NCF performance. Pearson's correlation coefficients between NCF and NCCs were calculated. The same procedure was used to evaluate the correlation of NCF and QLQ-C30 CF subscale.RESULTS: Data from EORTC trials 26091 and 26101 were pooled into a data set of 546 patients. Twenty percent of patients could be characterised as unimpaired (109) and 80% as impaired (437). Impaired patients reported more cognitive complaints on the MOS scale than unimpaired patients. Correlations between NCF and NCCs were weak but significant for impaired patients and non-significant for unimpaired ones. Similar results were found for the correlation between NCF test performance and the QLQ-C30 CF subscale.CONCLUSION: Correlations between NCF test scores and complaints were weak but suggesting that neurocognitive impairment in patients with HGG does not preclude cognitive awareness. However, considering the findings of this study, we would suggest not to use PROs as a surrogate of performance-based neurocognitive evaluation.
Published: 2021

3. Immune checkpoint inhibitors for progressive multifocal leukoencephalopathy: a new gold standard?

Author: Amélie Guihot, Madalina Uzunov, Sophie Demeret, Agnès Bellanger, David Saadoun, Damien Roos-Weil, Claire Deback, Valérie Pourcher, Ahmed Idbaih, Nicolas Weiss, Natalia Shor, Veronique Leblond, Damien Galanaud, Caroline Houillier, Bruno Eymard, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre d'Immunologie et des Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut de Myologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)
Subjects: Oncology, medicine.medical_specialty, Neurology, business.industry, medicine.drug_class, Progressive multifocal leukoencephalopathy, medicine.medical_treatment, Immunosuppression, Context (language use), medicine.disease, Monoclonal antibody, Myasthenia gravis, Immune system, Internal medicine, medicine, Neurology (clinical), business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Encephalitis
Abstract: Progressive multifocal leukoencephalopathy (PML) is a very rare and opportunistic encephalitis caused by JC polyomavirus that is linked to profound immunosuppression and is usually fatal unless immune function can be restored. Immune checkpoint inhibitors (ICI) are monoclonal antibodies (mAbs) that block either CTLA-4 or PD-1 inhibitor receptors, thus enhancing antiviral T-cell activity. Successful treatment of PML by ICI has recently generated some enthusiasm in case reports/small series of patients. However, the initial enthusiasm was mitigated by some individual case reports that did not show any benefit. More data are thus warranted about efficacy of immune checkpoint inhibitors in the specific context of PML. We report here the outcomes of six PML patients treated by ICI between 2017 and 2019. Underlying causes of immunosuppression consisted in hematologic malignancies (n = 4), primary immune deficiency (n = 1) and use of immunosuppressive therapies for myasthenia gravis (n = 1). Three patients were alive with a mean follow-up of 21 months (14–33) after first ICI infusion, including one patient with frank clinical response, one with stabilization, and one with initial worsening and further stabilization of PML. The three other patients rapidly died from PML. Our data suggest that ICI may be effective for PML treatment but were less impressive than the ones previously reported. Larger studies are thus warranted to confirm this efficacy and to identify the predictive factors of response.
Published: 2021

4. Mechanisms and therapeutic implications of hypermutation in gliomas

Author: Florence Coulet, Jill S. Barnholtz-Sloan, Marc Sanson, Adam Boynton, Aniket Shetty, Yvonne Y. Li, Tracy T. Batchelor, Marine Giry, Garrett M. Frampton, Alexandre Carpentier, Peter J. Park, Franck Bielle, Eudocia Q. Lee, Khê Hoang-Xuan, Jean-Yves Delattre, Leon Taquet, Philippe Cornu, Erell Guillerm, Andrew D. Cherniack, Liam F. Spurr, Robert E. Jones, Mehdi Touat, Rameen Beroukhim, Patrick Y. Wen, J. Bryan Iorgulescu, David Meredith, Kristine Pelton, Caroline Dehais, Radwa Sharaf, Sandro Santagata, Alex Duval, Kenin Qian, Nadia Younan, Florence Laigle-Donadey, Patricia Ho, J Ricardo McFaline-Figueroa, Juliana Bonardi, Mary Jane Lim-Fat, David A. Reardon, Capucine Baldini, Naomi Currimjee, Shakti H. Ramkissoon, Caroline Houillier, Katie Pricola Fehnel, Seth Malinowski, Dimitri Psimaras, Cristina Birzu, Charlotte Bellamy, Isidro Cortes-Ciriano, Keith L. Ligon, Jack Geduldig, Karima Mokhtari, Maite Verreault, Lee A. Albacker, Pratiti Bandopadhayay, Bertrand Mathon, Susan N. Chi, E. Antonio Chiocca, Agusti Alentorn, Dean Pavlick, Frank Dubois, Sangita Pal, Samy Ammari, Brian M. Alexander, Arnab Chakravarti, Azra H. Ligon, Sanda Alexandrescu, Ahmed Idbaih, Frédéric Beuvon, Lakshmi Nayak, Laurent Capelle, Aurélien Marabelle, Daphne A. Haas-Kogan, Raymond Y. Huang, Craig L. Bohrson, Wenya Linda Bi, Ruben Ferrer-Luna, and Kin-Hoe Chow
Subjects: Male, 0301 basic medicine, Genome instability, medicine.medical_treatment, Programmed Cell Death 1 Receptor, Somatic hypermutation, Biology, DNA Mismatch Repair, Article, Mice, 03 medical and health sciences, 0302 clinical medicine, Gene Frequency, Cancer immunotherapy, Glioma, Temozolomide, medicine, Animals, Humans, Antineoplastic Agents, Alkylating, Multidisciplinary, Brain Neoplasms, Genome, Human, Microsatellite instability, Cancer, Sequence Analysis, DNA, Prognosis, medicine.disease, Xenograft Model Antitumor Assays, Phenotype, 030104 developmental biology, Mutagenesis, 030220 oncology & carcinogenesis, Mutation, Cancer research, DNA mismatch repair, Immunotherapy, Microsatellite Repeats, medicine.drug
Abstract: A high tumour mutational burden (hypermutation) is observed in some gliomas1–5; however, the mechanisms by which hypermutation develops and whether it predicts the response to immunotherapy are poorly understood. Here we comprehensively analyse the molecular determinants of mutational burden and signatures in 10,294 gliomas. We delineate two main pathways to hypermutation: a de novo pathway associated with constitutional defects in DNA polymerase and mismatch repair (MMR) genes, and a more common post-treatment pathway, associated with acquired resistance driven by MMR defects in chemotherapy-sensitive gliomas that recur after treatment with the chemotherapy drug temozolomide. Experimentally, the mutational signature of post-treatment hypermutated gliomas was recapitulated by temozolomide-induced damage in cells with MMR deficiency. MMR-deficient gliomas were characterized by a lack of prominent T cell infiltrates, extensive intratumoral heterogeneity, poor patient survival and a low rate of response to PD-1 blockade. Moreover, although bulk analyses did not detect microsatellite instability in MMR-deficient gliomas, single-cell whole-genome sequencing analysis of post-treatment hypermutated glioma cells identified microsatellite mutations. These results show that chemotherapy can drive the acquisition of hypermutated populations without promoting a response to PD-1 blockade and supports the diagnostic use of mutational burden and signatures in cancer. Temozolomide therapy seems to lead to mismatch repair deficiency and hypermutation in gliomas, but not to an increase in response to immunotherapy.
Published: 2020

5. Dissecting the role of crosstalk between glioblastoma subpopulations in tumor cell spreading

Author: Ibukun Adesoji Adejumobi, Ahmed Idbaih, Maxim Mogilevsky, Maite Verreault, Ariel Rubinstein, Maria R Jubran, Irina Cojocari, Rotem Karni, Ronit Vogt Sionov, Nataly Kravchenko-Balasha, Sama Tibi, The Hebrew University of Jerusalem (HUJ), The Hebrew University Hadassah Medical School, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service de neurologie 2 [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)
Subjects: 0301 basic medicine, Cancer Research, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Tumour heterogeneity, [SDV.CAN]Life Sciences [q-bio]/Cancer, lcsh:RC254-282, Article, 03 medical and health sciences, Paracrine signalling, 0302 clinical medicine, Neurosphere, medicine, Cell migration, Epidermal growth factor receptor, Molecular Biology, biology, medicine.disease, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, 3. Good health, Cellular infiltration, Dasatinib, Crosstalk (biology), 030104 developmental biology, 030220 oncology & carcinogenesis, Cancer cell, Cancer research, biology.protein, medicine.drug, Proto-oncogene tyrosine-protein kinase Src
Abstract: Glioblastoma (GBM) is a highly infiltrative brain cancer, which is thus difficult to operate. GBM cells frequently harbor Epidermal Growth Factor Receptor amplification (EGFRwt) and/or activating mutation (EGFRvIII), generating at least two different cellular subpopulations within the tumor. We examined the relationship between the diffusive architectures of GBM tumors and the paracrine interactions between those subpopulations. Our aim was to shed light on what drives GBM cells to reach large cell–cell distances, and whether this characteristic can be manipulated. We established a methodology that quantifies the infiltration abilities of cancer cells through computation of cell–cell separation distance distributions in 3D. We found that aggressive EGFRvIII cells modulate the migration and infiltrative properties of EGFRwt cells. EGFRvIII cells secrete HGF and IL6, leading to enhanced activity of Src protein in EGFRwt cells, and rendering EGFRwt cells higher velocity and augmented ability to spread. Src inhibitor, dasatinib, at low non-toxic concentrations, reduced the infiltrative properties of EGFRvIII/EGFRwt neurospheres. Furthermore, dasatinib treatment induced compact multicellular microstructure packing of EGFRvIII/EGFRwt cells, impairing their ability to spread. Prevention of cellular infiltration or induction of compact microstructures may assist the detection of GBM tumors and tumor remnants in the brains and improve their surgical removal.
Published: 2020

6. New hints towards a precision medicine strategy for IDH wild-type glioblastoma

Author: Manuela Salvucci, Roel G.W. Verhaak, Annette T. Byrne, Maite Verreault, Alice C. O’Farrell, Markus Rehm, Simone P. Niclou, Kate Connor, Kirsten White, James Clerkin, Brona M. Murphy, Donncha F. O’Brien, Martine L.M. Lamfers, J.H.M. Prehn, Ahmed Idbaih, Anna Golebiewska, and Neurosurgery
Subjects: 0301 basic medicine, Adult, Disease, Computational biology, 03 medical and health sciences, 0302 clinical medicine, medicine, Tumor Microenvironment, Humans, Precision Medicine, business.industry, Brain Neoplasms, Wild type, Primary malignancy, Hematology, DNA Methylation, Precision medicine, medicine.disease, Subtyping, Isocitrate Dehydrogenase, 3. Good health, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, DNA methylation, Mutation, Multi omics, business, Glioblastoma
Abstract: Glioblastoma represents the most common primary malignancy of the central nervous system in adults and remains a largely incurable disease. The elucidation of disease subtypes based on mutational profiling, gene expression and DNA methylation has so far failed to translate into improved clinical outcomes. However, new knowledge emerging from the subtyping effort in the IDH-wild-type setting may provide directions for future precision therapies. Here, we review recent learnings in the field, and further consider how tumour microenvironment differences across subtypes may reveal novel contexts of vulnerability. We discuss recent treatment approaches and ongoing trials in the IDH-wild-type glioblastoma setting, and propose an integrated discovery stratagem incorporating multi-omics, single-cell technologies and computational approaches.
Published: 2020

7. Efficacy and Safety of Tumor Treating Fields (TTFields) in Elderly Patients with Newly Diagnosed Glioblastoma: Subgroup Analysis of the Phase 3 EF-14 Clinical Trial

Author: Zvi Ram, Garth Nicholas, Chae-Yong Kim, Andreas F. Hottinger, Jay-Jiguang Zhu, Ahmed Idbaih, Tel Aviv Sourasky Medical Center [Te Aviv], Seoul National University Hospital, Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), 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), University of Ottawa [Ottawa], The University of Texas Health Science Center at Houston (UTHealth), Gestionnaire, HAL Sorbonne Université 5, 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], and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Oncology, Cancer Research, medicine.medical_specialty, Randomization, TTFields, Tumor Treating Fields, efficacy and safety, elderly patients, newly diagnosed glioblastoma, phase 3 clinical trial, quality-of-life, temozolomide, Phases of clinical research, Subgroup analysis, [SDV.CAN]Life Sciences [q-bio]/Cancer, 03 medical and health sciences, 0302 clinical medicine, Quality of life, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, medicine, Adverse effect, RC254-282, Temozolomide, business.industry, Cancer, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, medicine.disease, Clinical Trial, 3. Good health, Clinical trial, 030220 oncology & carcinogenesis, business, 030217 neurology & neurosurgery, medicine.drug
Abstract: BackgroundUnderstudied elderly patients comprise a large segment of high-risk patients with glioblastoma (GBM) that are challenging to treat. Tumor Treating Fields (TTFields) is a locoregional, noninvasive, antimitotic therapy delivering low-intensity, intermediate-frequency alternating electric fields to the tumor. In the phase 3 EF-14 clinical trial, TTFields (200 kHz) improved median progression-free survival (PFS) and median overall survival (OS) in patients with newly diagnosed GBM (ndGBM) when added concomitantly to maintenance temozolomide (TMZ). This EF-14 subgroup analysis evaluated the safety and efficacy of TTFields in elderly patients.MethodsAll 134 patients who are ≥65 years of age were included (TTFields/TMZ combination, n=89; TMZ monotherapy, n=45; 2:1 ratio of randomization). PFS and OS were analyzed using Kaplan–Meier methodology (α=0.05). Health-related quality-of-life (HRQoL) was assessed using the European Organisation for Research and Treatment of Cancer (EORTC) quality-of-life questionnaire QLQ-C30 supplemented with the brain tumor module (QLQ-BN20). Adverse events (AEs) were evaluated using Common Terminology Criteria for AEs (CTCAE) v4.0.ResultsThe PFS was 6.5 months in patients randomized to the treatment group with TTFields/TMZ combination versus 3.9 months in patients treated with TMZ monotherapy (HR, 0.47; 95% CI, 0.30–0.74; P=0.0236). The OS was 17.4 months in patients treated with TTFields/TMZ combination versus 13.7 months in patients treated with TMZ monotherapy (HR, 0.51; 95% CI, 0.33–0.77; P=0.0204). Annual survival rates with TTFields/TMZ versus TMZ monotherapy were 39% (95% CI, 29–50%) versus 27% (95% CI, 15–41%; P=0.072) at 2 years, 19% (95% CI, 11–29%) versus 11% (95% CI, 4–23%; P=0.135) at 3 years, and 15% (95% CI, 7–25%) versus 0% at 5 years, respectively. There were no significant differences between groups in the preselected items of HRQoL assessment. Grade ≥3 systemic AEs were 46% in the TTFields/TMZ group versus 40% in the TMZ monotherapy group, without statistically significant difference between the two groups. The only TTFields-related AEs were reversible scalp skin reactions, with grades 1–2 and grade 3 skin reactions reported by 51% and 2% of patients, respectively.ConclusionsCombining TTFields with maintenance TMZ significantly improved PFS and OS in elderly patients with ndGBM in the phase 3 EF-14 clinical trial, without significant increases in systemic toxicity or negatively affecting patient HRQoL. TTFields-related skin AEs were low-grade and manageable.Clinical Trial Registrationhttps://clinicaltrials.gov/ct2/show/NCT00916409, identifier: NCT00916409.
Published: 2021

8. PAK3 is a key signature gene of the glioma proneural subtype and affects its proliferation, differentiation and growth

Author: Charlotte Schmitt, Nathalie Magne, Sandrine Poëa-Guyon, Jean-Vianney Barnier, Alexandre Mutel, Hélène Castel, Véronique Rousseau, Marc Sanson, Vincent Gleize, Ahmed Idbaih, Kévin Duarte, Emmanuelle Huillard, Institut des Neurosciences Paris-Saclay (NeuroPSI), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), 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-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Différenciation et communication neuronale et neuroendocrine (DC2N), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and Barnier, Jean-Vianney
Subjects: Cancer Research, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Small hairpin RNA, 0302 clinical medicine, PAK1, Gene expression, Gliomas, RNA, Small Interfering, p21-activated kinases, Patient-derived cell line, Glioma tumor growth, Neurons, 0303 health sciences, [SDV.NEU.PC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior, Kinase, [SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, Cell Differentiation, General Medicine, Glioma, Isocitrate Dehydrogenase, Gene Expression Regulation, Neoplastic, Oncology, 030220 oncology & carcinogenesis, Molecular Medicine, Female, Proliferation and neuronal differentiation, Chromosome Deletion, Oligodendroglioma, Mice, Nude, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, p21-activated kinase, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Cell Line, Tumor, medicine, Biomarkers, Tumor, Animals, Proneural signature, 030304 developmental biology, Cell Proliferation, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Cancer, medicine.disease, Survival Analysis, p21-Activated Kinases, Cell culture, Mutation, Cancer research
Abstract: International audience; Purpose Gliomas are the most lethal adult primary brain cancers. Recent advances in their molecular characterization have contributed to a better understanding of their pathophysiology, but there is still a need to identify key genes controlling glioma cell proliferation and differentiation. The p21-activated kinases PAK1 and PAK2 play essential roles in cell division and brain development and are well-known oncogenes. In contrast, the role of PAK3 in cancer is poorly understood. It is known, however that this gene is involved in brain ontogenesis and has been identified as a gene of the proneural subtype signature in glioblastomas. Methods To better understand the role of PAK kinases in the pathophysiology of gliomas, we conducted expression analyses by querying multiple gene expression databases and analyzing primary human glioma samples. We next studied PAK3 expression upon differentiation in patient-derived cell lines (PDCLs) and the effects of PAK3 inhibition by lentiviral-mediated shRNA on glioma cell proliferation, differentiation and tumor growth. Results We show that contrary to PAK1 and PAK2, high PAK3 expression positively correlates with a longer survival of glioma patients. We also found that PAK3 displays differential expression patterns between glioma subgroups with a higher expression in 1p/19q-codeleted oligodendrogliomas, and is highly expressed in tumors and PDCLs of the proneural subtype. In PDCLs, high PAK3 expression negatively correlated with proliferation and positively correlated with neuronal differentiation. Inhibition of PAK3 expression increased PDCL proliferation and glioma tumor growth in nude mice. Conclusions Our results indicate that PAK3 plays a unique role among PAKs in glioma development and may represent a potential therapeutic target.
Published: 2021

9. SLIT2/ROBO signaling in tumor-associated microglia and macrophages drives glioblastoma immunosuppression and vascular dysmorphia

Author: Joost Dejaegher, Anne Eichmann, Maite Verreault, Flavia Regina Souza Lima, Andreas Bikfalvi, Marc Sanson, Thomas Mathivet, Q. Richard Lu, Corinne Lesaffre, Yunling Xu, Luiz Henrique Medeiros Geraldo, Lien Solie, Ahmed Idbaih, Justine Rudewicz, Jean-Leon Thomas, Thomas Viel, Camille Knosp, Laurent Jacob, Rohit Rao, Bertrand Tavitian, Nolwenn Lemaire, Nawal Maïssa, Thomas Daubon, Steven De Vleeschouwer, Laurence Pibouin-Fragner, Institut de biochimie et génétique cellulaires (IBGC), and Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS)
Subjects: [SDV]Life Sciences [q-bio], medicine.medical_treatment, Nerve Tissue Proteins, Biology, Brain cancer, Macrophage chemotaxis, Mice, 03 medical and health sciences, 0302 clinical medicine, Vascular Biology, Glioma, Immune Tolerance, Tumor Microenvironment, medicine, Animals, Humans, Macrophage, Receptors, Immunologic, ComputingMilieux_MISCELLANEOUS, PI3K/AKT/mTOR pathway, 030304 developmental biology, 0303 health sciences, Tumor microenvironment, Gene knockdown, Microglia, Brain Neoplasms, Macrophages, General Medicine, Immunotherapy, Prognosis, medicine.disease, 3. Good health, Gene Expression Regulation, Neoplastic, Mice, Inbred C57BL, medicine.anatomical_structure, Oncology, Gene Knockdown Techniques, 030220 oncology & carcinogenesis, Disease Progression, Cancer research, Heterografts, Intercellular Signaling Peptides and Proteins, Glioblastoma, Research Article, Signal Transduction
Abstract: SLIT2 is a secreted polypeptide that guides migration of cells expressing Roundabout 1 and 2 (ROBO1 and ROBO2) receptors. Herein, we investigated SLIT2/ROBO signaling effects in gliomas. In patients with glioblastoma (GBM), SLIT2 expression increased with malignant progression and correlated with poor survival and immunosuppression. Knockdown of SLIT2 in mouse glioma cells and patient-derived GBM xenografts reduced tumor growth and rendered tumors sensitive to immunotherapy. Tumor cell SLIT2 knockdown inhibited macrophage invasion and promoted a cytotoxic gene expression profile, which improved tumor vessel function and enhanced efficacy of chemotherapy and immunotherapy. Mechanistically, SLIT2 promoted microglia/macrophage chemotaxis and tumor-supportive polarization via ROBO1- and ROBO2-mediated PI3K-γ activation. Macrophage Robo1 and Robo2 deletion and systemic SLIT2 trap delivery mimicked SLIT2 knockdown effects on tumor growth and the tumor microenvironment (TME), revealing SLIT2 signaling through macrophage ROBOs as a potentially novel regulator of the GBM microenvironment and immunotherapeutic target for brain tumors. ispartof: JOURNAL OF CLINICAL INVESTIGATION vol:131 issue:16 ispartof: location:United States status: published
Published: 2021

10. BRAF mutation in overlapping forms of Erdheim-Chester and Rosai-Dorfman diseases: A unique case restricted to the central nervous system

Author: Mehdi Touat, Ahmed Idbaih, Bertrand Mathon, Khê Hoang-Xuan, Karima Mokhtari, Juliette Dufour, Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale (SESSTIM - U1252 INSERM - Aix Marseille Univ - UMR 259 IRD), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Neurochirurgie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de neurologie 2 [CHU Pitié-Salpêtrière], French National Research Agency : ANR-10-IAIHU-06, 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), Gestionnaire, HAL Sorbonne Université 5, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)
Subjects: Central Nervous System, Proto-Oncogene Proteins B-raf, Pathology, medicine.medical_specialty, Central nervous system, Case Report, Physical examination, Lesion, 03 medical and health sciences, 0302 clinical medicine, Biopsy, medicine, Humans, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Emperipolesis, PET-CT, medicine.diagnostic_test, business.industry, Neurosarcoidosis, Isolated brain, medicine.disease, 3. Good health, medicine.anatomical_structure, Neurology, Cerebellar peduncle, 030220 oncology & carcinogenesis, Mutation, Erdheim-Chester disease, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Rosai-Dorfman disease, Neurology (clinical), Histiocytosis, Sinus, medicine.symptom, business, Histiocytosis, 030215 immunology
Abstract: Histiocytosis is an uncommon disease characterized by excessive accumulation of histiocytes. Here, we report a rare case of non-Langerhans-cell histiocytosis in a 51-year-old woman who presented with severe symptoms of pericardial effusion. Radiologic investigation also detected multiple bone (lower limbs, vertebrae, ribs, and ilium) lesions. Resected pericardium showed abundant mono- or multi-nucleated non-foamy histiocytes (CD68+/CD163+/S-100+/CD1α−/langerin−) in a fibroinflammatory background. The histiocytes demonstrated emperipolesis of lymphocytes, a hallmark feature of Rosai-Dorfman disease (RDD). However, molecular analysis revealed a BRAF V600E mutation of the proliferating histiocytes, highlighting the neoplastic features frequently observed in another non-Langerhans-cell histiocytosis known as Erdheim-Chester Disease (ECD). We consider this case to be a unique presentation of ECD harboring some RDD-like cells with emperipolesis, but not a case of RDD with a BRAF mutation concerning its clinical manifestation (involvement of the heart and bones) and neoplastic features.
Published: 2021

11. Vemurafenib for Refractory Multisystem Langerhans Cell Histiocytosis in Children: An International Observational Study

Author: Johannes Visser, Anne Lutun, Elena Sieni, Fleur Cohen, Nabil Kabbara, Olga Slater, Jean-François Emile, Mathilde Jehanne, Alina Ferster, Michael Maschan, Houda Boudiaf, Pascale Schneider, Sarah Elitzur, Nathalie Aladjidi, Milen Minkov, Ahmed Idbaih, Matthew Collin, Michal Golan, Alexandra Kolenova, François Chalard, Karel Svojgr, Jean Donadieu, Anne Pagnier, Laurence Blanc, Nicolas Simon, Jean-Claude Alvarez, Islam Amine Larabi, Fanette Bernard, James Nicholson, Mohamed Barkaoui, Anne Sonntagbauer, Anne Lambilliote, Thomas Lehrnbecher, Dmitriy Evseev, Viktoria Efremova, Geneviève Plat, Martina Ahlmann, Jean Miron, Valérie Taly, Caroline Hutter, Julien Haroche, Zofia Hélias-Rodzewicz, Paul Milne, Sébastien Héritier, Andrej Lissat, Mathilde Tardieu, Service d'hématologie-immunologie-oncologie pédiatrique [CHU Trousseau], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital Raymond Poincaré [AP-HP], Centre Hospitalier Universitaire [Grenoble] (CHU), Cambridge University Hospitals - NHS (CUH), University of Cambridge [UK] (CAM), Medizinische Universität Wien = Medical University of Vienna, Department Pediatric Hematology Oncology, Azienda Ospedaliero-Universitaria Meyer, Florence, Departments of Hematology, Université Paris Diderot - Paris 7 (UPD7), Groupe d'Etude des Histiocytoses (GEH), Groupe d'Etude des Histiocytoses, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Radiologie [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Newcastle University [Newcastle], Centre National de Référence du Lupus Systémique, Syndrome des Anticorps Anti-phospholipides et Maladies Auto-immunes Systémiques Rares [CHU Pitié Salpêtrière], Service de Médecine Interne 2, maladies auto-immunes et systémiques [CHU Pitié-Salpêtrière], Institut E3M [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Institut E3M [CHU Pitié-Salpêtrière], 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)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Biomarqueurs et essais cliniques en Cancérologie et Onco-Hématologie (BECCOH), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay, Hôpital Sainte-Marguerite [CHU - APHM] (Hôpitaux Sud ), Centre Hospitalier Universitaire Félix-Guyon [Saint-Denis, La Réunion, France], Comenius University Children's Hospital Limbova 1 [Bratislava, Slovakia], Service Immuno Hémato-Onco Pédiatrique, CHU Grenoble, Service d'Hémato-oncologie Pédiatrique, CHU Bordeaux [Bordeaux]-Hôpital Pellegrin, Service de pédiatrie médicale et médecine de l'adolescent [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), CHU Toulouse [Toulouse], CHU Amiens-Picardie, Universitätsklinikum Frankfurt, Hôpital Universitaire des Enfants Reine Fabiola [Bruxelles, Belgique] (HUDERF), University Hospital [Minsk, Belarus], Universitätsklinikum Münster Klinik für Kinder [Münster, Germany], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Hôpital Jeanne de Flandre [Lille], Hôpital Mustapha [Mustapha, Algeria], Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], University Hospital Motol [Prague, Czech Republic], Hôpitaux Universitaires de Genève (HUG), Schneider Children’s Medical Center of Israel [Petah Tikva], The Edmond and Lily Safra Children's Hospital [Tel-Hahsomer, Israel], Dmitriy Rogachev National Center for Pediatric Hematology, Oncology and Immunology [Moscow, Russia], Sorbonne Université - Département de neurologie 2 - Mazarin, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Great Ormond Street Hospital for Children [London] (GOSH), Sant'Anna Children's Hospital, Médecine Personnalisée, Pharmacogénomique, Optimisation Thérapeutique (MEPPOT - U1147), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institute of Cellular Medicine [Newcastle], Service de Pharmacologie Toxicologie [Garches], Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Comenius University in Bratislava, Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Service d'Onco-neurologie = Département de neurologie 2 [CHU Pitié Salpêtrière], TALY, Valerie, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-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)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut E3M [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), 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), and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Subjects: Male, Proto-Oncogene Proteins B-raf, Cancer Research, medicine.medical_specialty, Time Factors, Adolescent, Treatment outcome, Drug Resistance, [SDV.CAN]Life Sciences [q-bio]/Cancer, Severity of Illness Index, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Langerhans cell histiocytosis, Refractory, medicine, Humans, Child, Vemurafenib, Protein Kinase Inhibitors, 030304 developmental biology, 0303 health sciences, Childhood Langerhans Cell Histiocytosis, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, business.industry, Age Factors, Infant, ORIGINAL REPORTS, medicine.disease, Dermatology, 3. Good health, Europe, Histiocytosis, Langerhans-Cell, Histiocytosis, Treatment Outcome, Oncology, Multicenter study, Pediatric Oncology, Child, Preschool, 030220 oncology & carcinogenesis, Mutation, Female, Observational study, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Signal Transduction, medicine.drug
Abstract: PURPOSE Off-label use of vemurafenib (VMF) to treat BRAFV600E mutation–positive, refractory, childhood Langerhans cell histiocytosis (LCH) was evaluated. PATIENTS AND METHODS Fifty-four patients from 12 countries took VMF 20 mg/kg/d. They were classified according to risk organ involvement: liver, spleen, and/or blood cytopenia. The main evaluation criteria were adverse events (Common Terminology Criteria for Adverse Events [version 4.3]) and therapeutic responses according to Disease Activity Score. RESULTS LCH extent was distributed as follows: 44 with positive and 10 with negative risk organ involvement. Median age at diagnosis was 0.9 years (range, 0.1 to 6.5 years). Median age at VMF initiation was 1.8 years (range, 0.18 to 14 years), with a median follow-up of 22 months (range, 4.3 to 57 months), whereas median treatment duration was 13.9 months (for 855 patient-months). At 8 weeks, 38 complete responses and 16 partial responses had been achieved, with the median Disease Activity Score decreasing from 7 at diagnosis to 0 ( P < .001). Skin rash, the most frequent adverse event, affected 74% of patients. No secondary skin cancer was observed. Therapeutic plasma VMF concentrations (range, 10 to 20 mg/L) seemed to be safe and effective. VMF discontinuation for 30 patients led to 24 LCH reactivations. The blood BRAFV600E allele load, assessed as circulating cell-free DNA, decreased after starting VMF but remained positive (median, 3.6% at diagnosis, and 1.6% during VMF treatment; P < .001) and was associated with a higher risk of reactivation at VMF discontinuation. None of the various empirical therapies (hematopoietic stem-cell transplantation, cladribine and cytarabine, anti-MEK agent, vinblastine, etc) used for maintenance could eradicate the BRAFV600E clone. CONCLUSION VMF seemed safe and effective in children with refractory BRAFV600E-positive LCH. Additional studies are needed to find effective maintenance therapy approaches.
Published: 2019

12. Molecular Profiling Reclassifies Adult Astroblastoma into Known and Clinically Distinct Tumor Entities with Frequent Mitogen-Activated Protein Kinase Pathway Alterations

Author: Franck Bielle, Mehdi Touat, Karima Mokhtari, Aurélien Nouet, Yannick Marie, Philipp Euskirchen, Audrey Rousseau, Luc Taillandier, William Boisseau, Justine Guegan, Marc Sanson, Caroline Dehais, Carine Karachi, Ahmed Idbaih, Nadine Martin-Duverneuil, Laurent Capelle, Khê Hoang-Xuan, Jean-Yves Delattre, Sorbonne Université - Département de neurologie 2 - Mazarin, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Berlin Institute of Health (BIH), German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Service de Neuropathologie [CHU Pitié Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Neurochirurgie [CHU Pitié-Salpêtrière], Service de Neuroradiologie [CHU Pitié-Salpêtrière], Service de neurologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), and UNICANCER
Subjects: Adult, Male, Cancer Research, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Astroblastoma, Brain tumor, MN1‐BEND2, [SDV.CAN]Life Sciences [q-bio]/Cancer, DNA sequencing, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Humans, Medicine, Neuro‐Oncology, Next‐generation sequencing, Aged, 030304 developmental biology, 0303 health sciences, biology, Brain Neoplasms, business.industry, Middle Aged, medicine.disease, Neoplasms, Neuroepithelial, 3. Good health, BRAF mutation, Oncology, Mitogen-activated protein kinase, Cancer research, biology.protein, Female, Mitogen-Activated Protein Kinases, business, 030217 neurology & neurosurgery, Recurrent Meningioma
Abstract: BackgroundAstroblastoma (ABM) is a rare glial brain tumor. Recurrent meningioma 1 (MN1) alterations have been recently identified in most pediatric cases. Adolescent and adult cases, however, remain molecularly poorly defined.Materials and MethodsWe performed clinical and molecular characterization of a retrospective cohort of 14 adult and 1 adolescent ABM.ResultsStrikingly, we found that MN1 fusions are a rare event in this age group (1/15). Using methylation profiling and targeted sequencing, most cases were reclassified as either pleomorphic xanthoastrocytomas (PXA)-like or high-grade glioma (HGG)-like. PXA-like ABM show BRAF mutation (6/7 with V600E mutation and 1/7 with G466E mutation) and CD34 expression. Conversely, HGG-like ABM harbored specific alterations of diffuse midline glioma (2/5) or glioblastoma (GBM; 3/5). These latter patients showed an unfavorable clinical course with significantly shorter overall survival (p = .021). Mitogen-activated protein kinase pathway alterations (including FGFR fusion, BRAF and NF1 mutations) were present in 10 of 15 patients and overrepresented in the HGG-like group (3/5) compared with previously reported prevalence of these alterations in GBM and diffuse midline glioma.ConclusionWe suggest that gliomas with astroblastic features include a variety of molecularly sharply defined entities. Adult ABM harboring molecular features of PXA and HGG should be reclassified. Central nervous system high-grade neuroepithelial tumors with MN1 alterations and histology of ABM appear to be uncommon in adults. Astroblastic morphology in adults should thus prompt thorough molecular investigation aiming at a clear histomolecular diagnosis and identifying actionable drug targets, especially in the mitogen-activated protein kinase pathway.Implications for PracticeAstroblastoma (ABM) remains a poorly defined and controversial entity. Although meningioma 1 alterations seem to define a large subset of pediatric cases, adult cases remain molecularly poorly defined. This comprehensive molecular characterization of 1 adolescent and 14 adult ABM revealed that adult ABM histology comprises several molecularly defined entities, which explains clinical diversity and identifies actionable targets. Namely, pleomorphic xanthoastrocytoma-like ABM cases show a favorable prognosis whereas high-grade glioma (glioblastoma and diffuse midline gliome)-like ABM show significantly worse clinical courses. These results call for in-depth molecular analysis of adult gliomas with astroblastic features for diagnostic and therapeutic purposes.
Published: 2019

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

Author: Ben Kinnersley, Julian Jacob, Wolf Mueller, Flavie Bompaire, Giulia Berzero, Yannick Marie, Robert Terziev, Damien Ricard, Caroline Dehais, Marc Sanson, Loïc Feuvret, Ahmed Idbaih, Khê Hoang-Xuan, Jean-Yves Delattre, Dimitri Psimaras, Terziev, R., Psimaras, D., Marie, Y., Feuvret, L., Berzero, G., Jacob, J., Dehais, C., Bompaire, F., Mueller, W., Kinnersley, B., Delattre, J. -Y., Idbaih, A., Hoang-Xuan, K., Sanson, M., Ricard, D., Sorbonne Université - Département de neurologie 2 - Mazarin, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Leipzig University, University hospital of Zurich [Zurich], Hôpital d'instruction des Armées Percy, Service de Santé des Armées, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service de Radiothérapie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), CB - Centre Borelli - UMR 9010 (CB), Service de Santé des Armées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Ecole Normale Supérieure Paris-Saclay (ENS Paris Saclay)-Université de Paris (UP), The institute of cancer research [London], École du Val de Grâce (EVDG), CHU Pitié-Salpêtrière [AP-HP], Gestionnaire, Hal Sorbonne Université, Service d'Onco-neurologie = Département de neurologie 2 [CHU Pitié Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service d'Oncologie Radiothérapie [CHU Pitié Salpétrière], and Service de Santé des Armées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Ecole Normale Supérieure Paris-Saclay (ENS Paris Saclay)-Université Paris Cité (UPCité)
Subjects: Oncology, Male, Cancer therapy, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Urinary incontinence, Leukoencephalopathy, 0302 clinical medicine, Cancer Survivors, Leukoencephalopathies, Risk Factors, White matter disease, Cumulative incidence, Survivors, Multidisciplinary, Molecular medicine, Brain Neoplasms, Incidence (epidemiology), Medical record, Incidence, Smoking, Age Factors, Glioma, Middle Aged, Magnetic Resonance Imaging, Progression-Free Survival, 3. Good health, [SDV] Life Sciences [q-bio], 030220 oncology & carcinogenesis, Medicine, Female, medicine.symptom, Adult, medicine.medical_specialty, Adolescent, Science, Single-nucleotide polymorphism, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Young Adult, Neurotoxicity syndromes, Internal medicine, medicine, Humans, Radiation Injuries, Aged, Retrospective Studies, Radiotherapy, business.industry, medicine.disease, Radiation therapy, CNS cancer, business, 030217 neurology & neurosurgery
Abstract: The incidence and risk factors associated with radiation-induced leukoencephalopathy (RIL) in long-term survivors of high-grade glioma (HGG) are still poorly investigated. We performed a retrospective research in our institutional database for patients with supratentorial HGG treated with focal radiotherapy, having a progression-free overall survival > 30 months and available germline DNA. We reviewed MRI scans for signs of leukoencephalopathy on T2/FLAIR sequences, and medical records for information on cerebrovascular risk factors and neurological symptoms. We investigated a panel of candidate single nucleotide polymorphisms (SNPs) to assess genetic risk. Eighty-one HGG patients (18 grade IV and 63 grade III, 50M/31F) were included in the study. The median age at the time of radiotherapy was 48 years old (range 18–69). The median follow-up after the completion of radiotherapy was 79 months. A total of 44 patients (44/81, 54.3%) developed RIL during follow-up. Twenty-nine of the 44 patients developed consistent symptoms such as subcortical dementia (n = 28), gait disturbances (n = 12), and urinary incontinence (n = 9). The cumulative incidence of RIL was 21% at 12 months, 42% at 36 months, and 48% at 60 months. Age > 60 years, smoking, and the germline SNP rs2120825 (PPARg locus) were associated with an increased risk of RIL. Our study identified potential risk factors for the development of RIL (age, smoking, and the germline SNP rs2120825) and established the rationale for testing PPARg agonists in the prevention and management of late-delayed radiation-induced neurotoxicity.
Published: 2021

14. SLIT2-ROBO signaling in tumor-associated microglia/macrophages drives glioblastoma immunosuppression and vascular dysmorphia

Author: Lien Solie, Maite Verreault, Q. R. Lu, S. De Vleeschouwer, Camille Knosp, Joost Dejaegher, N. Lemaire, Ahmed Idbaih, Bertrand Tavitian, Luiz H. Geraldo, Anne Eichmann, Thomas Viel, Thomas Daubon, Thomas Mathivet, Marc Sanson, Justine Rudewicz, Nawal Maïssa, Jean-Leon Thomas, Laurence Pibouin-Fragner, Flavia Regina Souza Lima, Laurent Jacob, Rohit Rao, Andreas Bikfalvi, Corinne Lesaffre, and Y. Xu
Subjects: Tumor microenvironment, Gene knockdown, Microglia, business.industry, medicine.medical_treatment, Immunotherapy, medicine.disease, Macrophage chemotaxis, medicine.anatomical_structure, Glioma, Cancer research, Medicine, Cytotoxic T cell, Macrophage, business
Abstract: SLIT2 is a secreted polypeptide that guides migration of cells expressing ROBO1&2 receptors. Herein, we investigated SLIT2/ROBO signaling effects in gliomas. In patients with glioblastoma (GBM), SLIT2 expression increased with malignant progression and correlated with poor survival and immunosuppression. Knockdown of SLIT2 in mouse glioma cells and patient derived GBM xenografts reduced tumor growth and synergized with immunotherapy to prolong survival. Tumor cell SLIT2 knockdown inhibited macrophage invasion and promoted a cytotoxic gene expression profile, which improved tumor vessel function and enhanced efficacy of chemotherapy and immunotherapy. Mechanistically, SLIT2 promoted microglia/macrophage chemotaxis and tumor-supportive polarization via ROBO1&2-mediated PI3Kγ activation. Macrophage Robo1&2 deletion and systemic SLIT2 trap delivery mimicked SLIT2 knockdown effects on tumor growth and the tumor microenvironment (TME), revealing SLIT2 signaling through macrophage ROBOs as a novel regulator of the GBM microenvironment and a potential immunotherapeutic target for brain tumors.
Published: 2021

15. P13.11 Transcriptional CDK inhibitors, CYC065 and THZ1 promote apoptosis in preclinical models of primary and recurrent GBM tumour cells and glioma stem cells

Author: Viktorija Juric, Ahmed Idbaih, Ann M Hopkins, Maite Verreault, Markus Rehm, Brona M. Murphy, H Duessmann, Jochen H M Prehn, Hanne Jahns, and Martine L.M. Lamfers
Subjects: Cancer Research, Primary (chemistry), Oncology, Apoptosis, Cyclin-dependent kinase, Glioma, medicine, Cancer research, biology.protein, Neurology (clinical), Biology, Stem cell, medicine.disease
Abstract: BACKGROUND Activation of cyclin-dependent kinases (CDKs) contributes to the uncontrolled proliferation of tumour cells. Genomic alterations that lead to the constitutive activation of CDKs are a feature of many tumours including glioblastoma (GBM), the most common and aggressive primary brain tumour. Patient resistance to the current standard of care, temozolomide and radiotherapy, is common and highlights the need to discover more effective treatment strategies. Additionally, glioma stem cells (GSCs), tumour initiating cells contribute to treatment resistance in GBM. Targeting GBM tumour cells and GSCs using transcriptional CDK inhibitors, CYC065 and THZ1 is a potential novel treatment to prevent relapse of the tumour. MATERIAL AND METHODS The therapeutic efficacy of two CDK inhibitors (CKIs) was tested in a panel of ten low-passage GBM patient-derived gliomasphere cultures and semi-in vivo chick embryo xenograft models. Specifically, transcriptional inhibitors targeting CDK9/2 (CYC065) and CDK7 (THZ1) were used. Mechanism of cell death was examined following CKI treatment. Additionally, dependence on anti-apoptotic proteins was studied using genetic depletion and BH3 profiling. Fluorescence activated cell sorting (FACS) and light-sheet fluorescence microscopy (LSFM) were employed to study stem cell populations in recurrent GBM and evaluation of CKI efficacy against GSCs. RESULTS We here demonstrate that CYC065 and THZ1 treatments cause loss of cell viability and induce caspase-dependent apoptosis in primary and recurrent patient-derived gliomaspheres while sparing primary cortical neurons. Importantly, apoptosis responses manifested across a range of time points that significantly correlated with the cell doubling time. Mechanistically, CYC065 and THZ1 downregulate the anti-apoptotic protein Mcl-1, which suffices to sensitise gliomasphere cultures to treatment-induced apoptosis in a Bim-dependent manner. Additionally, high expression levels of chemo- and radio-resistant GSCs were found in recurrent gliomaspheres. CKIs induced apoptosis in isolated CD133 and CD44 biomarker-positive cells while TMZ was ineffective, highlighting the potential of these drugs to overcome resistance to conventional chemotherapy. Additionally, using LSFM we shown that CD133, CD44 GSC biomarker-negative cells convert into GSC biomarker-positive cells and contribute to the enrichment in GSCs in recurrent GBM which could potentially explain the TMZ ineffectiveness. Finally, CKIs reduced proliferation and promoted apoptosis in chick embryo xenograft models of primary and recurrent GBM. CONCLUSION Collectively, these data demonstrate that CYC065 and THZ1 display high anti-cancer activity in primary and recurrent GBM and provide scientific rationale for the further development of CDK inhibitors to potentiate their clinical utilization in the future.
Published: 2021

16. Descriptive and retrospective analysis of diffuse glioma patients with symptomatic SARS-CoV2 infection during the first wave of the pandemic

Author: Fernando Lozano-Sanchez, Matthieu Groh, Mehdi Touat, Anna Luisa Di-Stefano, François Ducray, Renata Ursu, Jean-Yves Delattre, Hanane Agguini, Antoine F. Carpentier, Nadia Younan, Ahmed Idbaih, Catherine Belin, and Luois Garnier
Subjects: medicine.medical_specialty, Population, diffuse glioma, Asymptomatic, 03 medical and health sciences, Diffuse Glioma, 0302 clinical medicine, Internal medicine, Glioma, Pandemic, AcademicSubjects/MED00300, Medicine, education, Pathological, education.field_of_study, business.industry, COVID-19, Retrospective cohort study, medicine.disease, 3. Good health, 030220 oncology & carcinogenesis, Basic and Translational Investigations, SARS-CoV2, Cohort, outcome, AcademicSubjects/MED00310, prognosis, medicine.symptom, business, 030217 neurology & neurosurgery
Abstract: Background Little is known about diffuse glioma patients infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV2). Methods We performed a descriptive and retrospective analysis of 41 diffuse glioma patients with symptomatic SARS-CoV2 infection during the first wave of the COVID-19 pandemic. Results Confusion with or without fever was the most common neurological symptom (32%) supporting SARS-CoV2 testing in glioma patients with acute and unexplained confusion. Sixteen patients (39%) died after a median delay of 13 days. While multiple clinical, biological, and pathological features, COVID-19- or diffuse glioma-related, at hospital admission appeared to have a pejorative prognostic impact, none was significantly associated with death. Oncological treatments were interrupted at COVID-19 diagnosis and re-initiated with a median delay of 30 days after the end of COVID-19 symptoms. Conclusions Interestingly, our retrospective study describes for the first time the characteristics of a cohort of diffuse glioma patients with symptomatic COVID-19. Diffuse glioma patients with poorly symptomatic COVID-19 did not come to the attention of physicians and were not enrolled in the study skewing the denominator for prognostic analysis. Further studies are warranted to specify prognosis of overall population of diffuse glioma patients with COVID-19, including asymptomatic patients, and interactions of prognostic factors of both COVID-19 and diffuse gliomas.
Published: 2021

17. SARS-CoV-2 infection in patients with primary central nervous system lymphoma

Author: Agusti Alentorn, Franck Bielle, Valérie Pourcher, Caroline Houillier, Nadine Martin-Duverneuil, Basma Abdi, Renata Ursu, Fernando Lozano, Ahmed Idbaih, Bertrand Mathon, Mehdi Touat, Alice Laurenge, Lila Sirven-Villaros, Anne-Geneviève Marcelin, Jean Yves Delattre, Karima Mokhtari, Khê Hoang-Xuan, Gianpiero Tebano, Sylvain Choquet, Antoine F. Carpentier, Cyril Quemeneur, Alberto Duran-Peña, Andrea Morales, Roberta Di Blasi, Véronique Leblond, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de neurologie 2 [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service des maladies infectieuses et tropicales [CHU Pitié-Salpêtrière], Service d'Anesthésie réanimation [CHU Pitié-Salpêtrière], Service de Neurochirurgie [CHU Pitié-Salpêtrière], Service de Neuroradiologie [CHU Pitié-Salpêtrière], Service d'Hématologie clinique [CHU Pitié-Salpêtrière], Gestionnaire, HAL Sorbonne Université 5, 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), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), and Service de Maladies Infectieuses et Tropicales [CHU Pitié-Salpêtrière]
Subjects: Central Nervous System, medicine.medical_specialty, Lymphoma, medicine.medical_treatment, law.invention, 03 medical and health sciences, 0302 clinical medicine, law, Internal medicine, medicine, Humans, 030212 general & internal medicine, PCNSL, Retrospective Studies, Mechanical ventilation, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Chemotherapy, Original Communication, business.industry, SARS-CoV-2, Mortality rate, Primary central nervous system lymphoma, COVID-19, Retrospective cohort study, medicine.disease, Intensive care unit, 3. Good health, Neurology, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, RNA, Viral, Neurology (clinical), Complication, business, 030217 neurology & neurosurgery
Abstract: Background Cancer patients may be at higher risk for severe coronavirus infectious disease-19 (COVID-19); however, the outcome of Primary Central Nervous System Lymphoma (PCNSL) patients with SARS-CoV-2 infection has not been described yet. Methods We conducted a retrospective study within the Lymphomes Oculo-Cérébraux national network (LOC) to assess the clinical characteristics and outcome of SARS-CoV-2 infection in PCNSL patients (positive real-time polymerase chain reaction of nasopharyngeal swab or evocative lung computed tomography scan). We compared clinical characteristics between patients with severe (death and/or intensive care unit admission) and mild disease. Results Between March and May 2020, 13 PCNSL patients were diagnosed with SARS-CoV-2 infection, 11 (85%) of whom were undergoing chemotherapy at the time of infection. The mortality rate was 23% (3/13), and two additional patients (15%) required mechanical ventilation. Two patients (15%) had no COVID-19 symptoms. History of diabetes mellitus was more common in severe patients (3/5 vs 0/8, p = 0.03). Two patients recovered from COVID-19 after mechanical ventilation during more than two weeks and resumed chemotherapy. In all, chemotherapy was resumed after COVID-19 recovery in nine patients (69%) after a median delay of 16 days (range 3–32), none of whom developed unusual chemotherapy complication nor SARS-Cov2 reactivation. Conclusion This preliminary analysis suggests that, while being at higher risk be for severe illness, PCNSL patients with COVID-19 might be treated maximally especially if they achieved oncological response at the time of SARS-CoV-2 infection. Chemotherapy might be resumed without prolonged delay in PCNSL patients with COVID-19. Electronic supplementary material The online version of this article (10.1007/s00415-020-10311-w) contains supplementary material, which is available to authorized users.
Published: 2021

18. Risk factors for Coronavirus Disease 2019 (COVID-19) severity and mortality among solid cancer patients and impact of the disease on anticancer treatment: A French nationwide cohort study (GCO-002 CACOVID-19)

Author: Astrid Lièvre, Anthony Turpin, Isabelle Ray-Coquard, Karine Le Malicot, Juliette Thariat, Guido Ahle, Cindy Neuzillet, Xavier Paoletti, Olivier Bouché, Kais Aldabbagh, Pierre Michel, Didier Debieuvre, Anthony Canellas, Marie Wislez, Lucie Laurent, May Mabro, Raphael Colle, Anne-Claire Hardy-Bessard, Laura Mansi, Emeline Colomba, Jean Bourhis, Philippe Gorphe, Yoann Pointreau, Ahmed Idbaih, Renata Ursu, Anna Luisa Di Stefano, Gérard Zalcman, Thomas Aparicio, Solenne Moulin, Olivier Leleu, Sylvie Leparree, Henri Goasdoue, Christine Piprot, Gerald Tourneur, Vincent Bayart, Delphine Lignier, Emma Lachaier, Marwa Khamari, Alexandre Coutte, Nicolas Siembida, Aline Houessinon, Jean Marc Regimbeau, Bruno Chauffert, Aurélie Moreira, Vincent Hautefeuille, Christine Hee, Mathieu Boone, Céline Bihan, Emilie Chive, Stéphane Poulet-Potriquier, Rachida Fahem, Dominique Luet, Guillaume Roquin, Carole Vitellius, Nathanaëlle Cornet-Trichereau, François-Xavier Caroli-Bosc, Anne Thirot-Bidault, Stanislas Ropert, Julie Gachet - Masson, Mélanie Dehais, Gwen-Ael L'helgoualc'h, Ibrahim Ali-Mahamadou, Safia Talfi, Laure Belmont, Dieudonné Kilendo, Nasro Benrezzak, Emeline Dubief, Guillaume Conroy, Laurence Delique, Maud Basso, Isabelle Pons, Karine Salignon, Anne-Laure Villing, Emmanuelle Mougenot, Cassandra Porebski, Asma Guiatni, Nicolas Cloarec, Laurent Mineur, Marie Bouchaud, Céleste David, Annie Peytier, Thomas Greletty, Franck Audemar, Emanuelle Vignes, Floriane Minne, Guillaume Goldzak, Fabienne Huysman, Fayçal Hocine, Zaher Lakkis, Guillaume Meynard, Hamadi Almotlak, Elodie Klajer, Xu-Shan Sun, Julie Wasselin, Pascale Catala, Claire Mazuy, Hélène Vandamme, Jean-Briac Prevost, Aurélie Fadin, Laurent Basson, Jean-Baptiste Huguet, Emmanuelle Dos Santos, Bérangère Jany, Alain Saad, Frédéric Goutorbe, Eric Oziol, Mohamed Ramdani, Ouafae Kadiri, Delphine Garbay, Clotilde Huet, Etienne Giroux Leprieur, Wen Teng, Justine Monvoisin, Patrick Arnaud Coffin, Sylvie Roux, Hubert Orfeuvre, Mélanie Chagros, Didier Pillon, Agathe Rassoul, Pierre Guillaume Poureau, Cécile Novello, François Ducray, Cécile Trouba, Vianney Bastit, Emmanuel Babin, Vincent Leon, Anne-Catherine Courtecuisse, Julie Vambre, Vincent Tack, Christophe Desauw, Fatima Meniai, Christina Peres, Aurélie Esparcieux, Hervé Perrier, Nathalie Doux, Régis Kaphan, Bertrand Roques, Christine Rebischung, Dominique Mille, Gaëlle Fernandes, Naceur Abdelli, Natacha Jousset, Pierre Combe, Eric Jonveaux, Patrick Dumont, Marc Kanaan, Corinne Berthelot Gras, Valérie Panis, Laure Kaluzinski, Marjolène Venant-Valery, You-Heng Lam, Laura Vallee, Frédéric Riviere, Muriel Durand, Dihya Benghadid, Emilie Villeneuve, Olivia Hentic Dhome, Zedjiga Bounouar, Louis De Mestier, Jacqueline Dubois, Magali Eyriey, Lionel Moreau, Dib Baihas, Kaïs Aldabbagh, Dominique Degriffolet, Virginie Sebbagh, Jean-Christophe Seghezzi, Marion Lozach-Brugirard, Julie Mandrou, Loubna Mavier, Florence Hennetier, Jean-Philippe Wagner, Elisabeth Carola, Karthiga Chandirakumaran, Sandrine Loutski, Isabelle Cojean-Zelek, Amina Bouras, Sandrine Lacour, Fahem Froura, Hadjer Ben Nadji, Sophie Cattelain, Franck Darloy, Geneviève Jolimoy Boilleau, Cyrielle Maissiat, Ariane Darut-Jouve, Véronique Lorgis, Ikram Charifi-Alaoui, François Ghiringhelli, Antoine Drouillard, Marie Chaix, Sylvain Manfredi, Côme Lepage, Alice Gagnaire, Marianne Latournerie, Sofia jourdan, Nora Perrot, Mireille folia, Anne Minello, Jean-Louis Jouve, Marielle Fery, Alain Landau, Diane Evrard, Bruno Valenza, Jean-François Paitel, Laetitia Chablais, Thomas Kreitmann, Laurence Lancry-Lecomte, Adrien Monard, Eve Faugeras, Paul Boucheret, Cécile Glommeau, Christine Tchikladze, Claire Garnier Tixidre, Jérôme Long, Manel Zaidi, Véronique Delabarre, Juliette Meyzenc, Loïc Ferrand, Denis Moro-Sibilot, Paul Bouheret, Cécile Leyronnas, Camille Herve, Audrey Thoor, Emanuelle Jacquet, Gaël Roth, Videsheka Madapathage-Senanyake, Peggy Chupeau, Elsa Bieber, Maud Rosso, Isabelle Lepage, Frank Priou, Margot Laly, Sylvie Aprelon, Natacha Sobolak, Helen Homokos, Fabienne Watelle, Alice Pham-Becker, Géraldine Lauridant, Charlotte Dujardin, Etienne Lenglin, Aimée Nienguet Tsota, Sophie Dominguez, Alexandra Forestier, Franck Nouvel, Justine Lerooy, Céline Ratajczak, Olivier Romano, Dorothéee Brzyski, Aurélien Barriere, Dominique Genet, Julien Tisse, Xavier Zasadny, Adeline Grelet, Amélie Hennion-Imbault, Eglantine Haustraete, Samy Louafi, Manal Awad, Younes Zekri, Caroline Cheneau, Nolwen Leissen, Joëlle Egreteau, Alexandra Breant, Matthieu Sarabi, Stéphanie Labonne, Julien Forestier, Céline Leclercq, Florence Prunier-Bossion, Isabelle Ray Coquard, Marielle Guillet, Aurélie Theillaumas, Emilie Prome, Thomas Walter, Pierre Philouze, Melody Lawo, Solène De Talhouet, Johanne Beuvelot, Yann Molin, Marie Bellecoste Martin, Maud Saussereau, Lauren Agnelli, Nicolas Fakhry, Christophe Laplace, Emmanuelle Norguet Monnereau, Céline Boucard, Kahina Djenad, Catherine Fontaine, Jean-François Seitz, Laétitia Dahan, Julie Sigrand, Muriel Duluc, Christophe Locher, Marjory Fleury, Ange Brou Marie, Ramdane Berkane, Séverine Poupblanc, Dominique Auby, Daniela Petran, Patrick Texereau, Elodie Guerineau, Morgan Andre, Linda Mahjoubi, Fanny Sarrazin, Sonia Jeanson, Anthony Gschwend, Virginie Birr, Mathieu Fore, Monique Noirclerc, Sihem Dahou, Dominique Spaeth, Mélanie Lambotin, Thomas Lelu, Benjamin Linot, Nathalie Hugon, Dominique Rousseau, Hélène Castanie, Carole Lenne, Alain Lortholary, Anatole Cessot, Messaouda Merzoug, Cécile Naudin, Jean-Michel Vannetzel, Ghina Aziz, Yacine Hadj Arab, Stéphanie Pernes, Isabelle Roche-Lachaise, Frédéric Fiteni, Hadjer Yahiaoui, Gwendoline Marel Lopez, Jeanne Oddoz, Fabienne Peira, Olivier Michel, Jérôme Meunier, Brahim Ouahrani, Antoine Roger, Sonia Branco, Van Nguyen, Mathilde Gisselbrecht, Ghania Hammad, Pierre Mordant, Magda Stroksztejn, Marc Pocard, Luc Nlo Meyengue, Emmanuelle Sacco, Sophie Simon Anne, Elizabeth Fabre-Guillevin, Marine Slim, Aziz Zaanan, Jacques Cadranel, Johan Pluvy, Rénata Ursu, Amyrath Geraldo, Rime Lihi, Maryline Vo, Zohra Brouk, Raphaël Colle, Mostefa Bennamoun, Fabrice Lacan, Christophe Louvet, Soraya Mebarki, Marianne Veyri, Elena Paillaud, Christelle Lucas, Olivier Dubreuil, Jamila Lyamani, Hanane Agguini, Emilie Soularue, Clément Jourdaine, Benjamin Verillaud, Hakima Herzine, Eric Raymond, Nathalie Mathiot, Lola Jade Palmieri, Christian Epanya, Julien Taieb, Eliane Bertrand, Gaël Goujon, Céline Namour, Benoit Gazeau, Biljana Zafirova, Haitham Mirghani, Catherine Belin, Kahina Belkhir, Myriam Gharib, Aurore Vozy, Karim Amrane, Jean-Philippe Spano, Johanna Wassermann, Loic Feuvret, Jean-Baptiste Bachet, Sara Philonenko, Laetitia Guillot, Marion Zabbe, Stéphanie Gibiat, Camille Baylot, Aude Jouinot, Nicolas Leduc, Sabine Vieillot, Laurie James, Camille Ducerf, Jean-Frédéric Blanc, Claire Falandry Leger, Virginie Wautot, Marion Chauvenet, Aude Vincent, David Tougeron, Sandrine Goulvent, Etienne Suc, Anne-Pascale Laurenty, Eric Marquis, Margaux Bonnaire, Maxime Dewolf, Esteban Brenet, Delphine Billard, Claude-Fabien Litre, Antoine Dumazet, Damien Botsen, Marion Vazel, Claire Carlier, David Bonnerave, Charles Marchand-Crety, Olivier Bouche, Patricia Fosse, David Sefrioui, Sarah Watson, Fatah Torche, Thierry Muron, Stéphane Natur, Romain Desgrippes, Véronique Bihel, François-Régis Ferrand, Caroline Leiterer, Julie Lavole, Claire Moquet, Nathalie Pressoir, Catherine Dziukala, Catherine Ligeza Poisson, Abdelhalim Naji, Nicolas Williet, Jean-Marc Phelip, Fabrice Di Palma, Amina Kherrour Mehdi, Julien Langrand-Escure, Pierre Fournel, Grégoire Pigne, Léa Saban-Roche, Nicolas Magne, Cécile Vassal, Jean-Philippe Jacquin, Carole Ramirez, Alexis Vallard, Olivier Collard, Romain Rivoirard, Ivan Graber, Stéphanie Trager Maury, Elodie Duboisset, Jorge Ayllon Ugarte, Dalilia Rami, Christine Saler, Manon Reinbolt, Clara Le Fevre, Meher Ben Abdelghani, Louis-Marie Dourthe, Joffrey Perruisseau-Carrier, Marlène Nguimpi-Tambou, Flavie Barret, Luisa Di Stefano Anna, Annie Balthazard, Camille Vassord-Dang, Mathilde Le Marchand, Julien Vergniol, Iulia Pripon, Axelle Daemaegdt, Vanessa Latry, Muna Larrieu, Gaëlle Landry, Laetitia Touihri Maximin, Francesco Del Piano, Agnès Barlet, Mylène Vernisse, Sophie Lafond, Charline Genin, Camille Sibertin-Blanc, Emilien Chabrillac, Caroline Gregoire, Sébastien Vergez, Quentin Panouille, Rosine Guimbaud, Floriane Richa, Loïc Lebellec, Sophie Gounin, Guillaume Buiret, Marine Baudin, Hervé Hamon, Anne-Claire Deshorgue, Eduardo Barrascout, Stéphanie Legrand, Morgane Houlze, Linda Cambula, Anthony Lopez, Guillaume Fouquet, Kahina Touabi, Adeline GermaIn, Benoit Godbert, Florence Voivret, Julie Perrin, Rosa Da Silva, Emilie Bernichon, GCO-002 CACOVID-19 collaborators/investigators, Moulin, S., Leleu, O., Leparree, S., Goasdoue, H., Piprot, C., Tourneur, G., Bayart, V., Lignier, D., Lachaier, E., Khamari, M., Coutte, A., Siembida, N., Houessinon, A., Regimbeau, J.M., Chauffert, B., Moreira, A., Hautefeuille, V., Hee, C., Boone, M., Bihan, C., Chive, E., Poulet-Potriquier, S., Fahem, R., Luet, D., Roquin, G., Vitellius, C., Cornet-Trichereau, N., Caroli-Bosc, F.X., Thirot-Bidault, A., Ropert, S., Gachet-Masson, J., Dehais, M., L'helgoualc'h, G.A., Ali-Mahamadou, I., Talfi, S., Belmont, L., Kilendo, D., Benrezzak, N., Dubief, E., Conroy, G., Delique, L., Basso, M., Pons, I., Salignon, K., Villing, A.L., Mougenot, E., Porebski, C., Guiatni, A., Cloarec, N., Mineur, L., Bouchaud, M., David, C., Peytier, A., Greletty, T., Audemar, F., Vignes, E., Minne, F., Goldzak, G., Huysman, F., Hocine, F., Lakkis, Z., Mansi, L., Meynard, G., Almotlak, H., Klajer, E., Sun, X.S., Wasselin, J., Catala, P., Mazuy, C., Vandamme, H., Prevost, J.B., Fadin, A., Basson, L., Huguet, J.B., Dos Santos, E., Jany, B., Saad, A., Goutorbe, F., Oziol, E., Ramdani, M., Kadiri, O., Garbay, D., Huet, C., Giroux Leprieur, E., Teng, W., Monvoisin, J., Arnaud Coffin, P., Roux, S., Orfeuvre, H., Chagros, M., Pillon, D., Rassoul, A., Poureau, P.G., Novello, C., Ducray, F., Trouba, C., Bastit, V., Babin, E., Thariat, J., Leon, V., Courtecuisse, A.C., Vambre, J., Tack, V., Desauw, C., Meniai, F., Peres, C., Esparcieux, A., Perrier, H., Doux, N., Kaphan, R., Roques, B., Rebischung, C., Mille, D., Fernandes, G., Abdelli, N., Jousset, N., Combe, P., Jonveaux, E., Dumont, P., Kanaan, M., Berthelot Gras, C., Panis, V., Kaluzinski, L., Venant-Valery, M., Lam, Y.H., Vallee, L., Riviere, F., Durand, M., Benghadid, D., Villeneuve, E., Hentic Dhome, O., Laurent, L., Bounouar, Z., De Mestier, L., Dubois, J., Eyriey, M., Moreau, L., Ahle, G., Baihas, D., Aldabbagh, K., Degriffolet, D., Sebbagh, V., Seghezzi, J.C., Lozach-Brugirard, M., Mandrou, J., Mavier, L., Hennetier, F., Wagner, J.P., Carola, E., Chandirakumaran, K., Loutski, S., Cojean-Zelek, I., Bouras, A., Lacour, S., Froura, F., Ben Nadji, H., Cattelain, S., Darloy, F., Jolimoy Boilleau, G., Maissiat, C., Darut-Jouve, A., Lorgis, V., Charifi-Alaoui, I., Ghiringhelli, F., Drouillard, A., Chaix, M., Manfredi, S., Lepage, C., Gagnaire, A., Latournerie, M., Jourdan, S., Perrot, N., Folia, M., Minello, A., Jouve, J.L., Fery, M., Landau, A., Evrard, D., Valenza, B., Paitel, J.F., Chablais, L., Kreitmann, T., Lancry-Lecomte, L., Monard, A., Faugeras, E., Boucheret, P., Glommeau, C., Tchikladze, C., Garnier Tixidre, C., Long, J., Zaidi, M., Delabarre, V., Meyzenc, J., Ferrand, L., Moro-Sibilot, D., Bouheret, P., Leyronnas, C., Herve, C., Thoor, A., Jacquet, E., Roth, G., Madapathage-Senanyake, V., Chupeau, P., Bieber, E., Rosso, M., Lepage, I., Priou, F., Laly, M., Aprelon, S., Sobolak, N., Homokos, H., Pointreau, Y., Watelle, F., Pham-Becker, A., Lauridant, G., Turpin, A., Dujardin, C., Lenglin, E., Nienguet Tsota, A., Dominguez, S., Forestier, A., Nouvel, F., Lerooy, J., Ratajczak, C., Romano, O., Brzyski, D., Barriere, A., Genet, D., Tisse, J., Zasadny, X., Grelet, A., Hennion-Imbault, A., Haustraete, E., Louafi, S., Awad, M., Zekri, Y., Cheneau, C., Leissen, N., Egreteau, J., Breant, A., Sarabi, M., Labonne, S., Forestier, J., Leclercq, C., Prunier-Bossion, F., Ray Coquard, I., Guillet, M., Theillaumas, A., Prome, E., Walter, T., Philouze, P., Lawo, M., De Talhouet, S., Beuvelot, J., Molin, Y., Bellecoste Martin, M., Saussereau, M., Agnelli, L., Fakhry, N., Laplace, C., Norguet Monnereau, E., Boucard, C., Djenad, K., Fontaine, C., Seitz, J.F., Dahan, L., Sigrand, J., Duluc, M., Locher, C., Fleury, M., Brou Marie, A., Berkane, R., Poupblanc, S., Auby, D., Petran, D., Texereau, P., Guerineau, E., Andre, M., Mahjoubi, L., Sarrazin, F., Jeanson, S., Gschwend, A., Birr, V., Debieuvre, D., Fore, M., Noirclerc, M., Dahou, S., Spaeth, D., Lambotin, M., Lelu, T., Linot, B., Hugon, N., Rousseau, D., Castanie, H., Lenne, C., Lortholary, A., Cessot, A., Merzoug, M., Naudin, C., Vannetzel, J.M., Aziz, G., Hadj Arab, Y., Pernes, S., Roche-Lachaise, I., Fiteni, F., Yahiaoui, H., Marel Lopez, G., Oddoz, J., Peira, F., Michel, O., Meunier, J., Ouahrani, B., Roger, A., Branco, S., Nguyen, V., Gisselbrecht, M., Hammad, G., Mordant, P., Stroksztejn, M., Pocard, M., Nlo Meyengue, L., Aparicio, T., Sacco, E., Simon Anne, S., Fabre-Guillevin, E., Wislez, M., Slim, M., Zaanan, A., Cadranel, J., Pluvy, J., Ursu, R., Geraldo, A., Lihi, R., Vo, M., Brouk, Z., Colle, R., Bennamoun, M., Lacan, F., Louvet, C., Mebarki, S., Veyri, M., Paillaud, E., Lucas, C., Dubreuil, O., Lyamani, J., Idbaih, A., Agguini, H., Soularue, E., Canellas, A., Zalcman, G., Jourdaine, C., Verillaud, B., Herzine, H., Raymond, E., Mathiot, N., Palmieri, L.J., Epanya, C., Taieb, J., Bertrand, E., Goujon, G., Namour, C., Gazeau, B., Zafirova, B., Mirghani, H., Belin, C., Belkhir, K., Gharib, M., Vozy, A., Amrane, K., Spano, J.P., Wassermann, J., Feuvret, L., Bachet, J.B., Philonenko, S., Guillot, L., Zabbe, M., Gibiat, S., Baylot, C., Jouinot, A., Leduc, N., Vieillot, S., James, L., Ducerf, C., Blanc, J.F., Falandry Leger, C., Wautot, V., Chauvenet, M., Vincent, A., Tougeron, D., Goulvent, S., Suc, E., Laurenty, A.P., Marquis, E., Bonnaire, M., Dewolf, M., Brenet, E., Billard, D., Litre, C.F., Dumazet, A., Botsen, D., Vazel, M., Carlier, C., Bonnerave, D., Marchand-Crety, C., Bouche, O., Fosse, P., Sefrioui, D., Michel, P., Watson, S., Neuzillet, C., Torche, F., Muron, T., Natur, S., Desgrippes, R., Bihel, V., Ferrand, F.R., Leiterer, C., Lavole, J., Moquet, C., Pressoir, N., Dziukala, C., Ligeza Poisson, C., Naji, A., Williet, N., Phelip, J.M., Di Palma, F., Kherrour Mehdi, A., Langrand-Escure, J., Fournel, P., Pigne, G., Saban-Roche, L., Magne, N., Vassal, C., Jacquin, J.P., Ramirez, C., Vallard, A., Collard, O., Rivoirard, R., Graber, I., Trager Maury, S., Duboisset, E., Ayllon Ugarte, J., Rami, D., Saler, C., Reinbolt, M., Le Fevre, C., Ben Abdelghani, M., Dourthe, L.M., Perruisseau-Carrier, J., Nguimpi-Tambou, M., Barret, F., Di Stefano Anna, L., Balthazard, A., Mabro, M., Vassord-Dang, C., Le Marchand, M., Vergniol, J., Pripon, I., Daemaegdt, A., Latry, V., Larrieu, M., Landry, G., Touihri Maximin, L., Del Piano, F., Barlet, A., Vernisse, M., Lafond, S., Genin, C., Sibertin-Blanc, C., Chabrillac, E., Gregoire, C., Vergez, S., Panouille, Q., Guimbaud, R., Richa, F., Lebellec, L., Gounin, S., Buiret, G., Baudin, M., Hamon, H., Deshorgue, A.C., Barrascout, E., Legrand, S., Houlze, M., Cambula, L., Lopez, A., Fouquet, G., Touabi, K., GermaIn, A., Godbert, B., Voivret, F., Perrin, J., Da Silva, R., Bernichon, E., Chemistry, Oncogenesis, Stress and Signaling (COSS), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pontchaillou [Rennes], Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 (CANTHER), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Centre Léon Bérard [Lyon], Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), CH Colmar, Institut Curie [Paris], Centre Hospitalier Universitaire de Reims (CHU Reims), 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), Centre Hospitalier Emile Muller [Mulhouse] (CH E.Muller Mulhouse), Groupe Hospitalier de Territoire Haute Alsace (GHTHA), CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Beaujon, Hôpital Foch [Suresnes], CHU Saint-Antoine [AP-HP], ARCAGY-GINECO, Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (RIGHT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS BFC)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Institut Gustave Roussy (IGR), Département de médecine nucléaire [Rennes], CRLCC Eugène Marquis (CRLCC), Département de médecine oncologique [Gustave Roussy], Département de cancérologie cervico-faciale [Gustave Roussy] (CCF), Centre Jean Bernard [Institut Inter-régional de Cancérologie - Le Mans], 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), Hopital Saint-Louis [AP-HP] (AP-HP), Unité de génétique et biologie des cancers (U830), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), AbbVie, Merck, Carthera, Transgene, Nutritheragene, Roche, Air Liquide, Eli Lilly Japan, LEO Pharma Research Foundation, Bayer, Novartis, Sanofi, Biogen, Institut National de la Santé et de la Recherche Médicale (INSERM)-CRLCC Eugène Marquis (CRLCC)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC), 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], 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)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, 0301 basic medicine, Cancer Research, medicine.medical_treatment, Disease, law.invention, Cohort Studies, 0302 clinical medicine, Mechanical ventilation, Risk Factors, law, Neoplasms, Medicine, Prospective Studies, Prospective cohort study, Original Research, Cancer, Intensive care unit, 3. Good health, Death, Oncology, 030220 oncology & carcinogenesis, Female, France, Immunotherapy, Cohort study, medicine.medical_specialty, chemotherapy. radiotherapy, Antineoplastic Agents, [SDV.CAN]Life Sciences [q-bio]/Cancer, 03 medical and health sciences, Internal medicine, Humans, Chemotherapy, Mortality, Pandemics, Aged, Retrospective Studies, Radiotherapy, SARS-CoV-2, business.industry, COVID-19, Retrospective cohort study, Odds ratio, medicine.disease, Antineoplastic Agents/adverse effects, Antineoplastic Agents/therapeutic use, COVID-19/mortality, France/epidemiology, Neoplasms/mortality, Neoplasms/therapy, Neoplasms/virology, SARS-CoV-2/isolation & purification, 030104 developmental biology, business
Abstract: Background Cancer patients are thought to have an increased risk of developing severe Coronavirus Disease 2019 (COVID-19) infection and of dying from the disease. In this work, predictive factors for COVID-19 severity and mortality in cancer patients were investigated. Patients and Methods In this large nationwide retro-prospective cohort study, we collected data on patients with solid tumours and COVID-19 diagnosed between March 1 and June 11, 2020. The primary endpoint was all-cause mortality and COVID-19 severity, defined as admission to an intensive care unit (ICU) and/or mechanical ventilation and/or death, was one of the secondary endpoints. Results From April 4 to June 11, 2020, 1289 patients were analysed. The most frequent cancers were digestive and thoracic. Altogether, 424 (33%) patients had a severe form of COVID-19 and 370 (29%) patients died. In multivariate analysis, independent factors associated with death were male sex (odds ratio 1.73, 95%CI: 1.18-2.52), ECOG PS ≥ 2 (OR 3.23, 95%CI: 2.27-4.61), updated Charlson comorbidity index (OR 1.08, 95%CI: 1.01-1.16) and admission to ICU (OR 3.62, 95%CI 2.14-6.11). The same factors, age along with corticosteroids before COVID-19 diagnosis, and thoracic primary tumour site were independently associated with COVID-19 severity. None of the anticancer treatments administered within the previous 3 months had any effect on mortality or COVID-19 severity, except cytotoxic chemotherapy in the subgroup of patients with detectable SARS-CoV-2 by RT-PCR, which was associated with a slight increase of the risk of death (OR 1.53; 95%CI: 1.00-2.34; p = 0.05). A total of 431 (39%) patients had their systemic anticancer treatment interrupted or stopped following diagnosis of COVID-19. Conclusions Mortality and COVID-19 severity in cancer patients are high and are associated with general characteristics of patients. We found no deleterious effects of recent anticancer treatments, except for cytotoxic chemotherapy in the RT-PCR-confirmed subgroup of patients. In almost 40% of patients, the systemic anticancer therapy was interrupted or stopped after COVID-19 diagnosis., Highlights • A total of 1289 patients with solid tumours and COVID-19 were analysed. • Mortality and COVID-19 severity were mainly driven by patient general characteristics. • Overall, we found no deleterious effects of recent anticancer treatments on mortality. . • Systemic anticancer treatment was interrupted or stopped in 39% of patients.
Published: 2020

19. IDH-wildtype lower-grade diffuse gliomas: the importance of histological grade and molecular assessment for prognostic stratification

Author: Bertrand Mathon, Khê Hoang-Xuan, Jean-Yves Delattre, Marine Giry, Susanna Ronchi, Alice Laurenge, Marc Sanson, Laurent Capelle, Karima Mokhtari, Chiara Villa, Franck Bielle, Giulia Berzero, Yannick Marie, Yohann Schmitt, Anna Luisa Di Stefano, Ahmed Idbaih, Erell Guillerm, Berzero, G., Di Stefano, A. L., Ronchi, S., Bielle, F., Villa, C., Guillerm, E., Capelle, L., Mathon, B., Laurenge, A., Giry, M., Schmitt, Y., Marie, Y., Idbaih, A., Hoang-Xuan, K., Delattre, J. -Y., Mokhtari, K., and Sanson, M.
Subjects: Oncology, diffuse low grade gliomas, Cancer Research, medicine.medical_specialty, molecular markers, IDH-wildtype, Prognostic stratification, Fusion gene, Internal medicine, Glioma, Medicine, Humans, Telomerase reverse transcriptase, Grading (tumors), Retrospective Studies, business.industry, Brain Neoplasms, Wild type, gene fusion, Astrocytoma, medicine.disease, Prognosis, Isocitrate Dehydrogenase, Isocitrate dehydrogenase, Editorial, FGFR3, Mutation, Neurology (clinical), Neoplasm Grading, business
Abstract: Background Isocitrate dehydrogenase (IDH) wildtype (wt) grade II gliomas are a rare and heterogeneous entity. Survival and prognostic factors are poorly defined. Methods We searched retrospectively all patients diagnosed with diffuse World Health Organization (WHO) grades II and III gliomas at our center (1989–2020). Results Out of 517 grade II gliomas, 47 were “diffuse astrocytomas, IDHwt.” Tumors frequently had fronto-temporo-insular location (28/47, 60%) and infiltrative behavior. We found telomerase reverse transcriptase (TERT) promoter mutations (23/45, 51%), whole chromosome 7 gains (10/37, 27%), whole chromosome 10 losses (10/41, 24%), and EGFR amplifications (4/43, 9%), but no TP53 mutations (0/22, 0%). Median overall survival (OS) was 59 months (vs 19 mo for IDHwt grade III gliomas) (P < 0.0001). Twenty-nine patients (29/43, 67%) met the definition of molecular glioblastoma according to cIMPACT-NOW update 3. Median OS in this subset was 42 months, which was shorter compared with patients with IDHwt grade II gliomas not meeting this definition (median OS: 57 mo), but substantially longer compared with IDHwt grade III gliomas meeting the definition for molecular glioblastoma (median OS: 17 mo, P < 0.0001). Most patients with IDHwt grade II gliomas met cIMPACT criteria because of isolated TERT promoter mutations (16/26, 62%), which were not predictive of poor outcome (median OS: 88 mo). Actionable targets, including 5 gene fusions involving FGFR3, were found in 7 patients (24%). Conclusions Our findings highlight the importance of histological grading and molecular profiling for the prognostic stratification of IDHwt gliomas and suggest some caution when assimilating IDHwt grade II gliomas to molecular glioblastomas, especially those with isolated TERT promoter mutation.
Published: 2020

20. TAMI-51. IDENTIFYING NEW TUMOR MICROENVIRONMENT (TME) CONTEXTS OF VULNERABILITY IN GLIOBLASTOMA

Author: Franck Bielle, Kate Connor, Maite Verreault, Catherine Sautès-Fridman, Ahmed Idbaih, Annette T. Byrne, Wolf H. Fridman, Antoine Bougoüin, Maxime Meylan, Jochen H. M. Prehn, Manuela Salvucci, and Kieron White
Subjects: Cancer Research, Tumor microenvironment, Oncology, Cancer research, Vulnerability, medicine, Tumor Microenvironment/Angiogenesis/Metabolism/Invasion, Neurology (clinical), sense organs, Biology, medicine.disease, Glioblastoma
Abstract: Glioblastoma (GBM) is the most frequent and aggressive adult brain tumor with 85% of patients dying within two years. New effective precision medicine therapies are urgently required, especially for isocitrate dehydrogenase wild-type (IDHwt) disease. Despite efforts to subtype patients based on molecular profiles, this approach has yet failed to direct treatment strategies. Further interrogation of the tumor microenvironment (TME) across molecular subtypes and identification of new TME specific subtypes may guide new directions for future therapies. Here, we analysed transcriptomic data from selected GLIOTRAIN(www.gliotrain.eu)(n=120) and TCGA(n=69) IDHwt patients. Firstly, the microenvironment cell population (MCP)-counter method (a gene-expression-based TME deconvolution tool) was validated for use in the brain tumor setting using quantitative multiplex immunohistochemistry. In this context, immune markers (CD20/CD3/CD68/CD8) were significantly correlated with MCP-counter scores. We are currently optimizing and validating a vessel-density and microglial RNA-signature to provide a more robust representation of brain TME. Next, using MCP-counter, the TME composition of IDHwt tumors was assessed within proneural (24%), classical (38%) and mesenchymal (38%) subtypes. We initially classified the GLIOTRAIN cohort into 3 novel clusters characterised by differences in TME composition and validated our findings in the TCGA cohort. A TME-high group (37%) is characterized by elevated presence of lymphocytes and myeloid cells, and presents a high level of immune checkpoint genes: PDCD1(PD1) and CTLA4. In addition, the presence of tertiary lymphoid structures (TLS) is a feature of TMEhigh/mesenchymal+ patients. This finding has been validated by IHC and RNA-signature. TME-med (38%) displayed heterogenous immune populations and the TME-low (25%) represented an ‘immune-desert’ group. There was no significant difference in OS based on these TME subtypes(p=0.50). We hypothesise that PD1/CTLA4 blockade might be an effective treatment strategy in TME-high patients. These hypotheses will be tested (in the adjuvant setting) using appropriate syngeneic disease models which incorporate surgical resection.
Published: 2020

21. Leptomeningeal spread in glioblastoma: diagnostic and therapeutic challenges

Author: Karima Mokhtari, Nadia Younan, M. Sanson, Dimitri Psimaras, Ahmed Idbaih, Mehdi Touat, Franck Bielle, Khê Hoang-Xuan, Jean-Yves Delattre, Cristina Birzu, Suzanne Tran, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service de Neuropathologie [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), CIC Pitié BT, Service de Neurophysiologie [CHU Pitié-Salpêtrière], 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), 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 d'investigation clinique Biothérapie [CHU Pitié-Salpêtrière] (CIC-BTi), Centre d'investigation clinique pluridisciplinaire [CHU Pitié Salpêtrière] (CIC-P 1421), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], and Gestionnaire, HAL Sorbonne Université 5
Subjects: Cancer Research, medicine.medical_specialty, medicine.medical_treatment, MEDLINE, Intrathecal, 03 medical and health sciences, Therapeutic approach, 0302 clinical medicine, Leptomeningeal spread, Medicine, Humans, Neuro‐Oncology, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Diagnostic, Intensive care medicine, Retrospective Studies, business.industry, Brain Neoplasms, Cytotoxic chemotherapy, medicine.disease, Prognosis, Magnetic Resonance Imaging, 3. Good health, Clinical trial, Radiation therapy, Treatment, Oncology, 030220 oncology & carcinogenesis, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Complication, business, Glioblastoma, 030217 neurology & neurosurgery
Abstract: BackgroundGlioblastoma (GBM) is the most common and aggressive primary malignant brain tumor. Leptomeningeal spread (LMS) is a severe complication of GBM, raising diagnostic and therapeutic challenges in clinical routine.MethodsWe performed a review of the literature focused on LMS in GBM. MEDLINE and EMBASE databases were queried from 1989 to 2019 for articles describing diagnosis and therapeutic options in GBM LMS, as well as risk factors and pathogenic mechanisms.ResultsWe retrieved 155 articles, including retrospective series, case reports, and early phase clinical trials, as well as preclinical studies. These articles confirmed that LMS in GBM remains (a) a diagnostic challenge with cytological proof of LMS obtained in only 35% of cases and (b) a therapeutic challenge with a median overall survival below 2 months with best supportive care alone. For patients faced with suggestive clinical symptoms, whole neuroaxis magnetic resonance imaging and cerebrospinal fluid analysis are both recommended. Liquid biopsies are under investigation and may help prompt a reliable diagnosis. Based on the literature, a multimodal and personalized therapeutic approach of LMS, including surgery, radiotherapy, systemic cytotoxic chemotherapy, and intrathecal chemotherapies, may provide benefits to selected patients. Interestingly, molecular targeted therapies appear promising in case of actionable molecular target and should be considered.ConclusionAs the prognosis of glioblastoma is improving over time, LMS becomes a more common complication. Our review highlights the need for translational studies and clinical trials dedicated to this challenging condition in order to improve diagnostic and therapeutic strategies.Implications for PracticeThis review summarizes the diagnostic tools and applied treatments for leptomeningeal spread, a complication of glioblastoma, as well as their outcomes. The importance of exhaustive molecular testing for molecular targeted therapies is discussed. New diagnostic and therapeutic strategies are outlined, and the need for translational studies and clinical trials dedicated to this challenging condition is highlighted.
Published: 2020

22. One-year survival of patients with high-grade glioma discharged alive from the intensive care unit

Author: Isabelle Rivals, Khê Hoang-Xuan, Martin Dres, Sophie Demeret, Nicolas Weiss, Ahmed Idbaih, Elise Morawiec, Julien Mayaux, Nicolas Gatulle, Maxens Decavèle, Alexandre Demoule, and Thomas Similowski
Subjects: medicine.medical_specialty, Critical Care, One-year survival, law.invention, 03 medical and health sciences, 0302 clinical medicine, law, Intensive care, Glioma, Internal medicine, medicine, Humans, Intensive care unit, 030212 general & internal medicine, Hospital Mortality, Retrospective Studies, Original Communication, Performance status, business.industry, Mortality rate, Anticancer therapy, Cancer, Odds ratio, medicine.disease, Malignant brain tumors, Patient Discharge, Intensive Care Units, Neurology, Neurology (clinical), business, 030217 neurology & neurosurgery, Cohort study
Abstract: Introduction Only limited data are available regarding the long-term prognosis of patients with high-grade glioma discharged alive from the intensive care unit. We sought to quantify 1-year mortality and evaluate the association between mortality and (1) functional status, and (2) management of anticancer therapy in patients with high-grade glioma discharged alive from the intensive care unit. Patients and methods Retrospective observational cohort study of patients with high-grade glioma admitted to two intensive care units between January 2009 and June 2018. Functional status was assessed by the Karnofsky Performance Status. Anticancer therapy after discharge was classified as (1) continued (unchanged), (2) modified (changed or stopped), or (3) initiated (for newly diagnosed disease). Results Ninety-one high-grade glioma patients (73% of whom had glioblastoma) were included and 78 (86%) of these patients were discharged alive from the intensive care unit. Anticancer therapy was continued, modified, and initiated in 41%, 42%, and 17% of patients, respectively. Corticosteroid therapy at the time of ICU admission [odds ratio (OR) 0.07] and cancer progression (OR 0.09) was independently associated with continuation of anticancer therapy. The mortality rate 1 year after ICU admission was 73%. On multivariate analysis, continuation of anticancer therapy (OR 0.18) and Karnofsky performance status on admission (OR 0.90) were independently associated with lower 1-year mortality. Conclusion The presence of high-grade glioma is not sufficient to justify refusal of intensive care unit admission. Performance status and continuation of anticancer therapy are associated with higher survival after intensive care unit discharge. Previous presentation Preliminary results were presented at the most recent congress of the French Intensive Care Society, Paris, 2019. Electronic supplementary material The online version of this article (10.1007/s00415-020-10191-0) contains supplementary material, which is available to authorized users.
Published: 2020

23. Rare Primary Central Nervous System Tumors in Adults: An Overview

Author: Enrico Franceschi, Didier Frappaz, Roberta Rudà, Peter Hau, Matthias Preusser, Caroline Houillier, Giuseppe Lombardi, Sofia Asioli, Caroline Dehais, Franck Bielle, Vincenzo Di Nunno, Martin van den Bent, Alba A. Brandes, Ahmed Idbaih, EURACAN Domain 10, Paul Clement Radek, Lakomý Nicolai El-Hindy, Jean-Yves Delattre, Ville Vuorinen, Silvia Scoccianti, Riccardo SoffiettiLucia Monti, Andrea Pace, Gaetano Finocchiaro, Arimantas TamasauskasMark ter Laan, Anja Gijtenbeek, Michiel Wagemakers, David NoskeUroš Smrdel, Puneet Plaha, Naomi Fersht, Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS), Institut d'hématologie et d'oncologie pédiatrique [CHU - HCL] (IHOPe), Hospices Civils de Lyon (HCL), Centre Léon Bérard [Lyon], University of Turin, University Hospital Regensburg, Medizinische Universität Wien = Medical University of Vienna, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université - Département de neurologie 2 - Mazarin, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Neuropathologie [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), Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), Erasmus University Medical Center [Rotterdam] (Erasmus MC), Neurology, Gestionnaire, Hal Sorbonne Université, Università degli studi di Torino = University of Turin (UNITO), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service d'Onco-neurologie = Département de neurologie 2 [CHU Pitié Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Franceschi E., Frappaz D., Ruda R., Hau P., Preusser M., Houillier C., Lombardi G., Asioli S., Dehais C., Bielle F., Di Nunno V., van den Bent M., Brandes A.A., and Idbaih A.
Subjects: 0301 basic medicine, Oncology, Ependymoma, Cancer Research, medicine.medical_specialty, glioneural tumor, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV.CAN]Life Sciences [q-bio]/Cancer, Review, pituitary tumor, lcsh:RC254-282, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, pineal tumors, medicine, media_common.cataloged_instance, germ cell tumors, European union, mesenchymal non meningothelial intracranial tumor, media_common, Medulloblastoma, Grade III Meningioma, business.industry, CNS lymphoma, mesenchymal non meningothelial intracranial tumors, Pituitary tumors, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Primary central nervous system lymphoma, germ cell tumor, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, medicine.disease, 3. Good health, embryonal tumor of central nervous system, 030104 developmental biology, 030220 oncology & carcinogenesis, medullobalstoma, Germ cell tumors, business, pineal tumor, Rare disease
Abstract: International audience; Overall, tumors of primary central nervous system (CNS) are quite common in adults with an incidence rate close to 30 new cases/100,000 inhabitants per year. Significant clinical and biological advances have been accomplished in the most common adult primary CNS tumors (i.e., diffuse gliomas). However, most CNS tumor subtypes are rare with an incidence rate below the threshold defining rare disease of 6.0 new cases/100,000 inhabitants per year. Close to 150 entities of primary CNS tumors have now been identified by the novel integrated histomolecular classification published by the World Health Organization (WHO) and its updates by the c-IMPACT NOW consortium (the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy). While these entities can be better classified into smaller groups either by their histomolecular features and/or by their location, assessing their treatment by clinical trials and improving the survival of patients remain challenging. Despite these tumors are rare, research, and advances remain slower compared to diffuse gliomas for instance. In some cases (i.e., ependymoma, medulloblastoma) the understanding is high because single or few driver mutations have been defined. The European Union has launched European Reference Networks (ERNs) dedicated to support advances on the clinical side of rare diseases including rare cancers. The ERN for rare solid adult tumors is termed EURACAN. Within EURACAN, Domain 10 brings together the European patient advocacy groups (ePAGs) and physicians dedicated to improving outcomes in rare primary CNS tumors and also aims at supporting research, care and teaching in the field. In this review, we discuss the relevant biological and clinical characteristics, clinical management of patients, and research directions for the following types of rare primary CNS tumors: medulloblastoma, pineal region tumors, glioneuronal and rare glial tumors, ependymal tumors, grade III meningioma and mesenchymal tumors, primary central nervous system lymphoma, germ cell tumors, spinal cord tumors and rare pituitary tumors.
Published: 2020

24. Buparlisib plus carboplatin or lomustine in patients with recurrent glioblastoma: a phase Ib/II, open-label, multicentre, randomised study

Author: Valerie Donnet, David Mills, Miguel Gil-Gil, Jeffrey Raizer, Mona El-Hashimy, Mark Rosenthal, Hui K Gan, Patrick Y. Wen, Olivier Chinot, Estela Pineda, Ahmed Idbaih, Paul Clement, W. Mason, John DeGroot, Mario Campone, Institut de neurophysiopathologie (INP), and Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Oncology, Male, Cancer Research, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Buparlisib, Aminopyridines, Carboplatin, chemistry.chemical_compound, DOUBLE-BLIND, Phosphatidylinositol 3-Kinases, 0302 clinical medicine, CONCOMITANT, Lomustine, Recurrence, Antineoplastic Combined Chemotherapy Protocols, Clinical endpoint, BRAIN, Original Research, 0303 health sciences, Area under the curve, PI3 KINASE INHIBITOR, Middle Aged, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, NVP-BKM120, 3. Good health, rGBM, 030220 oncology & carcinogenesis, Female, Life Sciences & Biomedicine, medicine.drug, RADIOTHERAPY, recurrent glioblastoma, medicine.medical_specialty, buparlisib, Morpholines, lcsh:RC254-282, MULTIFORME, 03 medical and health sciences, Glioma, Internal medicine, medicine, Humans, neoplasms, 030304 developmental biology, Aged, Temozolomide, Science & Technology, IDENTIFICATION, business.industry, Bayes Theorem, medicine.disease, ADJUVANT TEMOZOLOMIDE, nervous system diseases, BKM120, Radiation therapy, chemistry, business, Glioblastoma
Abstract: BACKGROUND: Glioblastoma relapse is associated with activation of phosphatidylinositol 3-kinase (PI3K) signalling pathway. In preclinical studies, the pan-PI3K inhibitor buparlisib showed antitumour activity in glioma models. METHODS: This was a two-part, multicentre, phase Ib/II study in patients with recurrent glioblastoma pretreated with radiotherapy and temozolomide standard of care. Patients received buparlisib (80 mg or 100 mg once daily) plus carboplatin (area under the curve (AUC)=5 every 3 weeks), or buparlisib (60 mg once daily) plus lomustine (100 mg/m2 every 6 weeks). The primary endpoint was to determine the maximum tolerable dose (MTD) and/or recommended phase II dose of buparlisib plus carboplatin or lomustine. RESULTS: Between 28 February 2014 and 7 July 2016, 35 patients were enrolled and treated with buparlisib plus carboplatin (n=17; buparlisib (80 mg) plus carboplatin, n=3; and buparlisib (100 mg) plus carboplatin, n=14), or buparlisib (60 mg) plus lomustine (n=18). The MTD of buparlisib was determined to be 100 mg per day in combination with carboplatin at an AUC of 5 every 3 weeks. The MTD of buparlisib in combination with lomustine could not be determined as it did not satisfy the MTD criteria per the Bayesian logistic regression model. CONCLUSION: The overall safety profile of buparlisib remained unchanged, and no new or unexpected safety findings were reported in this study. Preliminary assessment for both combinations did not demonstrate sufficient antitumour activity compared with historical data on single-agent carboplatin or lomustine. TRIAL REGISTRATION NUMBER: NCT01934361. ispartof: ESMO OPEN vol:5 issue:4 ispartof: location:England status: published
Published: 2020

25. A new landscape for systemic pharmacotherapy of recurrent glioblastoma?

Author: Emilie Le Rhun, Ahmed Idbaih, Pim J. French, Giuseppe Lombardi, Matthias Preusser, Vittorina Zagonel, Neurology, Veneto Institute of Oncology IOV-IRCCS [Padua, Italy], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Universität Zürich [Zürich] = University of Zurich (UZH), Medizinische Universität Wien = Medical University of Vienna, Erasmus University Medical Center [Rotterdam] (Erasmus MC), INSERM, Université de Lille, 146992|||Universität Zürich [Zürich] = University of Zurich [UZH], Erasmus University Medical Center [Rotterdam] [Erasmus MC], Protéomique, Réponse Inflammatoire, Spectrométrie de Masse (PRISM) - U 1192 (PRISM), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)
Subjects: 0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, [SDV]Life Sciences [q-bio], Malignant brain tumor, lcsh:RC254-282, 03 medical and health sciences, 0302 clinical medicine, Pharmacotherapy, Internal medicine, Medicine, neoplasms, Adult patients, business.industry, Recurrent glioblastoma, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, medicine.disease, nervous system diseases, n/a, 030104 developmental biology, Editorial, 030220 oncology & carcinogenesis, business, Glioblastoma
Abstract: International audience; Glioblastoma is the most common and aggressive primary malignant brain tumor in adult patients. Despite multimodal treatment with maximal safe surgical resection followed by concurrent radiochemotherapy and adjuvant chemotherapy with temozolomide, the prognosis remains poor with a median survival of 1 year. The survival rate at 5 years is 5% and, theoretically, all glioblastomas relapse [1]. Once tumors progress, treatment options are limited, and the management of recurrent glioblastoma remains challenging. The standard of care for second-line treatment has not been defined; options include surgery, re-irradiation, systemic pharmacotherapy, and, in Europe, mostly lomustine [2,3]. The general and neurological health status of the patient, the molecular findings, the time to first recurrence, the pattern of recurrence, and previous treatment have to be considered. Nitrosoureas or temozolomide rechallenge show limited efficacy. Anti-vascular endothelial growth factor (VEGF) bevacizumab prolonged progression-free survival (PFS), but did not improve overall survival (OS) [4].Because the treatment of recurrent glioblastoma remains a highly unmet clinical need, deeper mechanistic insight into the molecular changes present in these tumors is required. The enrollment of recurrent glioblastoma patients in clinical trials investigating new therapeutic options should be considered carefully whenever possible. In this Special Issue, we present some of the exciting updates on recurrent glioblastomas, which may help shape future treatment options.
Published: 2020

26. Central nervous system involvement in Erdheim-Chester disease: An observational cohort study

Author: Damien Galanaud, Danielle Seilhean, Khê Hoang-Xuan, Philippe Maksud, J. Donadieu, Jean-François Emile, Bruno Law-Ye, Fleur Cohen Aubart, Ahmed Idbaih, Zahir Amoura, Julien Haroche, Frédéric Charlotte, Biomarqueurs et essais cliniques en Cancérologie et Onco-Hématologie (BECCOH), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), 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)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Adult, Male, Proto-Oncogene Proteins B-raf, medicine.medical_specialty, Longitudinal study, Erdheim-Chester Disease, medicine.medical_treatment, Physical examination, Disease, Targeted therapy, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Cerebellum, medicine, Humans, Longitudinal Studies, Protein Kinase Inhibitors, Aged, Retrospective Studies, Cerebral Cortex, medicine.diagnostic_test, business.industry, Age Factors, Middle Aged, medicine.disease, Prognosis, Magnetic Resonance Imaging, 3. Good health, Treatment Outcome, Spinal Cord, 030220 oncology & carcinogenesis, Erdheim–Chester disease, Cohort, Diabetes insipidus, Female, Neurology (clinical), France, Atrophy, business, 030217 neurology & neurosurgery, Diabetes Insipidus, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Cohort study, Brain Stem
Abstract: ObjectiveCNS involvement in Erdheim-Chester disease (ECD) leads to substantial morbidity and mortality. To assess CNS manifestations in a French cohort of 253 patients with ECD, we determined clinical characteristics and outcomes, including those under targeted therapies.MethodsThis was a retrospective longitudinal study. CNS manifestations were determined by clinical examination and brain or spine MRI. Targeted therapy efficacy was assessed using global assessment from a physician and a radiologist. The study was approved by the ethics committee Comité de Protection des Personnes Ile de France III.ResultsNinety-seven of 253 patients (38%) with ECD had CNS involvement. CNS involvement was significantly associated with a younger age at diagnosis (mean 55.5 years) and at symptom onset (mean 50.5 years), as well as with the presence of the BRAFV600E mutation (in 77% of cases), xanthelasma (34%), and diabetes insipidus (36%). Median survival among patients with CNS involvement was significantly lower than that of patients with ECD without CNS involvement (124 months vs 146 months, p = 0.03). Seventy-four CNS MRIs were centrally reviewed, which showed 3 patterns: tumoral in 66%, pseudo-degenerative in 50%, and vascular in 18%. Targeted therapy (BRAF or MEK inhibitors) was associated with improved symptoms in 43% of patients and MRI improvement in 45%.ConclusionsCNS manifestations are typically associated with poor prognosis in patients with ECD. Three distinct patterns can be recognized: tumoral, pseudodegenerative, and vascular.Classification of evidenceThis study provides Class III evidence that targeted therapy leads to clinical or imaging improvement in almost 50% of patients.
Published: 2020

27. Biodegraded magnetosomes with reduced size and heating power maintain a persistent activity against intracranial U87-Luc mouse GBM tumors

Author: Jean-Yves Delattre, Charlotte Schmitt, Florence Gazeau, Clovis Adam, Ahmed Idbaih, Imène Chebbi, Edouard Alphandéry, François Guyot, Institut de minéralogie, de physique des matériaux et de cosmochimie (IMPMC), Muséum national d'Histoire naturelle (MNHN)-Institut de recherche pour le développement [IRD] : UR206-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université (SU), Muséum national d'Histoire naturelle (MNHN), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service d'Onco-neurologie = Département de neurologie 2 [CHU Pitié Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Matière et Systèmes Complexes (MSC (UMR_7057)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Université Paris Diderot - Paris 7 (UPD7), Institut Universitaire de France (IUF), Ministère de l'Education nationale, de l’Enseignement supérieur et de la Recherche (M.E.N.E.S.R.), Laboratoire de recherche en Génie Logiciel, Applications distribuées, Systèmes décisionnels et Imagerie intelligente [Manouba] (RIADI), École Nationale des Sciences de l'Informatique [Manouba] (ENSI), Université de la Manouba [Tunisie] (UMA)-Université de la Manouba [Tunisie] (UMA), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université - Département de neurologie 2 - Mazarin, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), 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), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Matière et Systèmes Complexes (MSC)
Subjects: [SDV]Life Sciences [q-bio], Cell, Pharmaceutical Science, Medicine (miscellaneous), 02 engineering and technology, Applied Microbiology and Biotechnology, Theranostic Nanomedicine, Mice, Magnetotactic bacteria, U87-Luc, Tissue Distribution, Magnetite Nanoparticles, Internalization, media_common, 0303 health sciences, Alternating magnetic field, Brain Neoplasms, Chemistry, 021001 nanoscience & nanotechnology, medicine.anatomical_structure, Nanomedicine, lcsh:R855-855.5, Oncology, Antitumor efficacy, Molecular Medicine, Female, Nanooncology, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], 0210 nano-technology, Hyperthermia, lcsh:Medical technology, Cell Survival, lcsh:Biotechnology, media_common.quotation_subject, Magnetosome, Biomedical Engineering, Mice, Nude, Antineoplastic Agents, Bioengineering, Heating, 03 medical and health sciences, In vivo, Cell Line, Tumor, lcsh:TP248.13-248.65, Thermotherapy, medicine, Animals, Humans, Magnetic hyperthermia, Magnetospirillum, Particle Size, 030304 developmental biology, Research, fungi, Hyperthermia, Induced, medicine.disease, In vitro, Magnetic Fields, Biophysics, Magnetosomes, Chains of magnetosomes, Glioblastoma, Nanotherapy, [SDU.STU.MI]Sciences of the Universe [physics]/Earth Sciences/Mineralogy
Abstract: BackgroundAn important but rarely addressed question in nano-therapy is to know whether bio-degraded nanoparticles with reduced sizes and weakened heating power are able to maintain sufficient anti-tumor activity to fully eradicate a tumor, hence preventing tumor re-growth. To answer it, we studied magnetosomes, which are nanoparticles synthesized by magnetotactic bacteria with sufficiently large sizes (~ 30 nm on average) to enable a follow-up of nanoparticle sizes/heating power variations under two different altering conditions that do not prevent anti-tumor activity, i.e. in vitro cellular internalization and in vivo intra-tumor stay for more than 30 days.ResultsWhen magnetosomes are internalized in U87-Luc cells by being incubated with these cells during 24 h in vitro, the dominant magnetosome sizes within the magnetosome size distribution (DMS) and specific absorption rate (SAR) strongly decrease from DMS ~ 40 nm and SAR ~ 1234 W/gFebefore internalization to DMS ~ 11 nm and SAR ~ 57 W/gFe after internalization, a behavior that does not prevent internalized magnetosomes to efficiently destroy U87-Luc cell, i.e. the percentage of U87-Luc living cells incubated with magnetosomes decreases by 25% between before and after alternating magnetic field (AMF) application. When 2 µl of a suspension containing 40 µg of magnetosomes are administered to intracranial U87-Luc tumors of 2 mm3and exposed (or not) to 15 magnetic sessions (MS), each one consisting in 30 min application of an AMF of 27 mT and 198 kHz, DMS and SAR decrease between before and after the 15 MS from ~ 40 nm and ~ 4 W/gFedown to ~ 29 nm and ~ 0 W/gFe. Although the magnetosome heating power is weakened in vivo, i.e. no measurable tumor temperature increase is observed after the sixth MS, anti-tumor activity remains persistent up to the 15th MS, resulting in full tumor disappearance among 50% of treated mice.ConclusionHere, we report sustained magnetosome anti-tumor activity under conditions of significant magnetosome size reduction and complete loss of magnetosome heating power.
Published: 2019

28. EANO–EURACAN clinical practice guideline for diagnosis, treatment, and follow-up of post-pubertal and adult patients with medulloblastoma

Author: Martin J. van den Bent, Benedikt Wiestler, Didier Frappaz, Florence Laigle-Donadey, Matthias Preusser, Stephanie E. Combs, Walter Stummer, Elke Hattingen, Dagmar Beier, Michael A. Grotzer, Clemens Seidel, Felice Giangaspero, Nathalie Boddaert, Peter Hau, Michael Weller, Kristian W. Pajtler, Steven C. Clifford, Ahmed Idbaih, Alba A. Brandes, Enrico Franceschi, Ana Guerreiro Stucklin, Rolf-Dieter Kortmann, Volodia Dangouloff-Ros, Jacoline E C Bromberg, Martin G. McCabe, Stefan M. Pfister, Silvia Hofer, Torsten Pietsch, Dominique Figarella-Branger, Raphael Guzman, Christine Haberler, Department of Medical Oncology (AUSL di Bologna), Azienda Unità Sanitaria Locale di Bologna (AUSL), Luzerner Kantonsspital, Surgical oncology Centre Léon Bérard, Centre Léon Bérard [Lyon], Neuroimagerie en psychiatrie (U1000), 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), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-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), Aix Marseille Université (AMU), Service d’Anatomie Pathologique et de Neuropathologie, APHM, Hôpital de la Timone, Hôpital de la Timone [CHU - APHM] (TIMONE), Pédiatrie et oncologie pédiatrique [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Departments of Neurosurgery and Biomedicine, University Hospital Basel [Basel], University of Manchester [Manchester], University hospital of Zurich [Zurich], 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 du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), Department of Neurology, Erasmus University Medical Center [Rotterdam] (Erasmus MC), 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), Neurology, 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)-Aix Marseille Université (AMU), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Subjects: Adult, medicine.medical_specialty, Adolescent, [SDV]Life Sciences [q-bio], MEDLINE, 03 medical and health sciences, 0302 clinical medicine, Multidisciplinary approach, medicine, Post-pubertal, Humans, Cerebellar Neoplasms, Intensive care medicine, ComputingMilieux_MISCELLANEOUS, Medulloblastoma, Adult patients, business.industry, Puberty, Guideline, medicine.disease, European Association of Neuro-Oncology (EANO), EUropean RAre CANcer (EURACAN), guideline, medulloblastoma, post-pubertal, adult, 3. Good health, Europe, Clinical Practice, Oncology, Diagnosis treatment, 030220 oncology & carcinogenesis, Practice Guidelines as Topic, business, 030217 neurology & neurosurgery, Follow-Up Studies
Abstract: The European Association of Neuro-Oncology (EANO) and EUropean RAre CANcer (EURACAN) guideline provides recommendations for the diagnosis, treatment, and follow-up of post-pubertal and adult patients with medulloblastoma. The guideline is based on the 2016 WHO classification of tumours of the CNS and on scientific developments published since 1980. It aims to provide direction for diagnostic and management decisions, and for limiting unnecessary treatments and cost. In view of the scarcity of data in adults with medulloblastoma, we base our recommendations on adult data when possible, but also include recommendations derived from paediatric data if justified. Our recommendations are a resource for professionals involved in the management of post-pubertal and adult patients with medulloblastoma, for patients and caregivers, and for health-care providers in Europe. The implementation of this guideline requires multidisciplinary structures of care, and defined processes of diagnosis and treatment.
Published: 2019

29. Interactions between tumor-associated macrophages and tumor cells in glioblastoma: unraveling promising targeted therapies

Author: Marc Sanson, Ahmed Idbaih, Stéphanie Jouannet, Mony Chenda Morisse, and Margarita Dominguez-Villar
Subjects: 0301 basic medicine, Tumor microenvironment, Microglia, Brain Neoplasms, business.industry, Macrophages, General Neuroscience, Central nervous system, Tumor cells, medicine.disease, nervous system diseases, 03 medical and health sciences, 030104 developmental biology, medicine.anatomical_structure, Cancer research, Overall survival, Humans, Medicine, Pharmacology (medical), Neurology (clinical), Glioblastoma, business
Abstract: Glioblastoma (GBM) is the deadliest primary malignant central nervous system (CNS) tumor with a median overall survival of 15 months despite a very intensive therapeutic regimen including maximal safe surgery, radiotherapy, and chemotherapy. Therefore, GBM treatment still raises major biological and therapeutic challenges. Areas covered: One of the hallmarks of the GBM is its tumor microenvironment including tumor-associated macrophages (TAM). TAM, accounting for approximately 30% of the GBM bulk cell population, may explain, at least in part, the immunosuppressive features of GBMs. The TAM are active and highly plastic immune cells and include two major ontogenetically different cell populations: (i) microglia and, (ii) monocytes-derived macrophages (MDM). TAM recruited to the tumor bulk can be reprogramed by GBM cells resulting in an ineffective anti-tumor response. Interestingly, interactions between TAM and GBM cells promote tumor oncogenesis (i.e. tumor cells proliferation and migration/invasion). This review aims to explore TAM targeting in GBM as a promising therapeutic option in the near future. Expert Commentary: A better understanding of TAM-GBM interactions and dynamics will certainly uncover new anti-GBM therapeutic avenues.
Published: 2018

30. Targeted therapies in 54 patients with Erdheim-Chester disease, including follow-up after interruption (the LOVE study)

Author: Jean-François Emile, Fleur Cohen Aubart, Zahir Amoura, Neila Benameur, Fabrice Carrat, Ahmed Idbaih, Jean Donadieu, Khê Hoang-Xuan, Stéphane Barete, Frédéric Charlotte, Julien Haroche, and Philippe Maksud
Subjects: Proto-Oncogene Proteins B-raf, 0301 basic medicine, Erdheim-Chester Disease, medicine.medical_specialty, Indoles, Immunology, Treatment outcome, MEDLINE, Biochemistry, Drug Administration Schedule, 03 medical and health sciences, 0302 clinical medicine, Piperidines, Positron Emission Tomography Computed Tomography, Oximes, Humans, Multicenter Studies as Topic, Medicine, Molecular Targeted Therapy, Registries, Vemurafenib, Protein Kinase Inhibitors, Retrospective Studies, Positron Emission Tomography-Computed Tomography, Sulfonamides, business.industry, Imidazoles, Follow up studies, Retrospective cohort study, Cell Biology, Hematology, medicine.disease, Treatment Outcome, 030104 developmental biology, 030220 oncology & carcinogenesis, Erdheim–Chester disease, Azetidines, France, Radiology, business, Follow-Up Studies, medicine.drug
Published: 2017

31. Targeting the immune system in glioblastoma

Author: Louis Royer-Perron, Agusti Alentorn, Khê Hoang-Xuan, Jean-Yves Delattre, Ahmed Idbaih, Marc Sanson, Maria Jose Ibañez-Julia, Ludovic Nguyen Them, and Alberto Duran-Peña
Subjects: Pharmacology, Oncology, medicine.medical_specialty, Temozolomide, business.industry, Adjuvant chemotherapy, medicine.medical_treatment, Brain tumor, Phases of clinical research, Immunotherapy, medicine.disease, Radiation therapy, Immune system, Internal medicine, Drug Discovery, Immunology, Genetics, medicine, Molecular Medicine, business, medicine.drug, Glioblastoma
Abstract: Introduction: Glioblastoma (GBM) is the most aggressive primary brain cancer in adults. The standard of care of newly diagnosed GBM, including radiotherapy with concurrent and adjuvant chemotherapy with temozolomide, was established more than 10 years ago. Despite this very intensive and multimodal therapeutic regimen, the prognosis of GBM patients remains grim. New treatments are urgently needed. Immunotherapy is changing perspectives in oncology and has raised of lot of hope for brain tumor patients.Areas covered: We will review molecular and cellular actors involved in immune response against GBM cells. Then, we will discuss the drugs modulating these immune molecular and cellular targets including passive and active immunotherapies.Expert commentary: Results obtained from studies using immunotherapy in GBM are encouraging and multiple promising phase III clinical trials are ongoing. Better outcomes with immunotherapies, alone or in combination, are expected in at least subpopulations of patien...
Published: 2017

32. Histiocytoses: emerging neoplasia behind inflammation

Author: Fleur Cohen-Aubart, Omar Abdel-Wahab, Jean-François Emile, Julien Haroche, Augusto Vaglio, Frédéric Charlotte, Zahir Amoura, Jean Donadieu, Ahmed Idbaih, and Barret J. Rollins
Subjects: Inflammation, business.industry, Molecular pathology, Disease, medicine.disease, Pathogenesis, Histiocytosis, Langerhans-Cell, 03 medical and health sciences, Histiocytosis, 0302 clinical medicine, Oncology, Langerhans cell histiocytosis, Neoplasms, 030220 oncology & carcinogenesis, Histiocytoses, Immunology, Animals, Humans, Medicine, Macrophage, business, Histiocyte, 030215 immunology
Abstract: Summary Histiocytoses are disorders characterised by inflammation and the accumulation of cells derived from the monocyte and macrophage lineages, which results in tissue damage. Although they are often considered rare disorders with protean clinical manifestations, considerable advances in the understanding of their genetics have led to increased clinical recognition of these conditions, and fuelled further insights into their pathogenesis. In this Review, we describe insights into the cells of origin, molecular pathology, clinical features, and treatment strategies for some of the most common histiocytic disorders, including Langerhans cell histiocytosis, Erdheim-Chester disease, and Rosai-Dorfman disease. With the discovery of recurrent mutations affecting the mitogen-activated protein kinase and mTOR–AKT pathways in some of these histiocytoses, our understanding of these diseases has now evolved from the concept of a primary inflammatory condition to that of a clonal neoplastic disease. This understanding has led to the development of effective mechanism-based therapeutic strategies for patients with histiocytic diseases.
Published: 2017

33. CNS inflammatory disorder after concurrent radiotherapy-temozolomide and nivolumab in a glioblastoma patient

Author: Anna Luisa Di Stefano, Dimitri Psimaras, Vincent Reina, Julien Savatovsky, Caroline Houillier, Micheline Pha, Ahmed Idbaih, Chiara Villa, Loïc Feuvret, Giulia Berzero, Di Stefano, A. L., Savatovsky, J., Feuvret, L., Villa, C., Reina, V., Pha, M., Houillier, C., Berzero, G., Idbaih, A., and Psimaras, D.
Subjects: Adult, Oncology, Cancer Research, medicine.medical_specialty, encephalitis, medicine.medical_treatment, Central Nervous System Neoplasms, CNS inflammatory disorder, 03 medical and health sciences, 0302 clinical medicine, Text mining, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, Temozolomide, Humans, Medicine, Letters to the Editor, immune checkpoint inhibitors (ICIs), Inflammation, immune-related adverse events (irAEs), business.industry, glioblastoma, Chemoradiotherapy, Prognosis, medicine.disease, Radiation therapy, Nivolumab, 030220 oncology & carcinogenesis, Female, Neurology (clinical), Glioblastoma, business, 030217 neurology & neurosurgery, medicine.drug, Inflammatory disorder
Published: 2018

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

Author: Pierre Verrelle, Nathalie Grandin, Bruno Pereira, Ahmed Idbaih, Delphine Poncet, François Ducray, Franck Bielle, Pauline Billard, Patrick Lomonte, Jean-Yves Delattre, Dominique Figarella-Branger, Marc Sanson, Caroline Dehais, Catherine Carpentier, Camille Cohen, Michel Charbonneau, Génétique, Reproduction et Développement (GReD), Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Clermont-Ferrand, Université Paris Descartes - Faculté de Médecine (UPD5 Médecine), Université Paris Descartes - Paris 5 (UPD5), Université de Caen Normandie (UNICAEN), Normandie Université (NU), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 (UPMC), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de neurophysiopathologie (INP), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de génétique et de physiologie moléculaire et cellulaire (CGPhiMC), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Cancer Resistance Exploring and Targeting (CREaT), Université d'Auvergne - Clermont-Ferrand I (UdA), Institut Armand Frappier (INRS-IAF), Institut National de la Recherche Scientifique [Québec] (INRS)-Réseau International des Instituts Pasteur (RIIP), Pola Network, Unité de Biostatistiques [CHU Clermont-Ferrand], Direction de la recherche clinique et de l’innovation [CHU Clermont-Ferrand] (DRCI), CHU Clermont-Ferrand-CHU Clermont-Ferrand, Institut NeuroMyoGène (INMG), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Charles Foix [AP-HP], Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Hôpital de la Timone [CHU - APHM] (TIMONE), Chimie, Modélisation et Imagerie pour la Biologie [Orsay], Université Paris-Sud - Paris 11 (UP11)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université - Département de neurologie 2 - Mazarin, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP]-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [APHP], Centre de Recherche en Cancérologie de Lyon (CRCL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Réseau International des Instituts Pasteur (RIIP)-Institut National de la Recherche Scientifique [Québec] (INRS), and LOMONTE, PATRICK
Subjects: Male, Telomerase, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV]Life Sciences [q-bio], [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], lcsh:RC346-429, MESH: Isocitrate Dehydrogenase, Cohort Studies, 0302 clinical medicine, ATRX loss of expression, Medicine, MESH: Cohort Studies, ComputingMilieux_MISCELLANEOUS, MESH: Aged, 0303 health sciences, MESH: Middle Aged, MESH: X-linked Nuclear Protein, Brain Neoplasms, MESH: Gene Expression Regulation, Neoplastic, Middle Aged, Isocitrate Dehydrogenase, 3. Good health, Gene Expression Regulation, Neoplastic, Secondary glioblastoma, 030220 oncology & carcinogenesis, MESH: Brain Neoplasms, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Female, Anaplastic astrocytoma, Adult, X-linked Nuclear Protein, IDH1, MESH: Mutation, [SDV.CAN]Life Sciences [q-bio]/Cancer, Neuropathology, Astrocytoma, Pathology and Forensic Medicine, MESH: Telomere Homeostasis, 03 medical and health sciences, Cellular and Molecular Neuroscience, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Alternative lengthening of telomeres, Humans, lcsh:Neurology. Diseases of the nervous system, ATRX, Aged, 030304 developmental biology, IDH1/2 mutations, MESH: Humans, business.industry, Research, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Telomere Homeostasis, Cancer, MESH: Adult, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease, MESH: Male, Telomere, MESH: Astrocytoma, Mutation, Cancer cell, Cancer research, Neurology (clinical), business, MESH: Female
Abstract: All cancer cells need to maintain functional telomeres to sustain continuous cell division and proliferation. In human diffuse gliomas, functional telomeres are maintained due either to reactivation of telomerase expression, the main pathway in most cancer types, or to activation of a mechanism called the alternative lengthening of telomeres (ALT). The presence of IDH1/2 mutations (IDH-mutant) together with loss of ATRX expression (ATRX-lost) are frequently associated with ALT in diffuse gliomas. However, detection of ALT, anda fortioriits quantification, are rarely, if ever, measured in neuropathology laboratories. We measured the level of ALT activity using the previously described quantitative “C-circle” assay and analyzed it in a well characterized cohort of 104 IDH-mutant and ATRX-lost adult diffuse gliomas. We report that in IDH-mutant ATRX-lost anaplastic astrocytomas, the intensity of ALT was inversely correlated with age (p
Published: 2019

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

Author: Bryan Iorgulescu, Mehdi Touat, Andrew D. Cherniack, Agusti Alentorn, David A. Reardon, Caroline Dehais, Rameen Beroukhim, Capucine Baldini, Khê Hoang-Xuan, Karima Mokhtari, Aurélien Marabelle, Alexandre Carpentier, Raymond Y. Huang, Alex Duval, Marc Sanson, Sangita Pal, Adam Boynton, Maite Verreault, Franck Bielle, Azra H. Ligon, Brian M. Alexander, Pratiti Bandopadhayay, Ennio Antonio Chiocca, David Meredith, Frédéric Beuvon, Erell Guillerm, Patrick Y. Wen, Lakshmi Nayak, Nadia Younan, Sandro Santagata, Florence Laigle-Donadey, Daphne A. Haas-Kogan, Ruben Ferrer-Luna, Florence Coulet, Jack Geduldig, Eudocia Q. Lee, Susan N. Chi, Sanda Alexandrescu, Jean-Yves Delattre, Wenya Bi, Christina Birzu, Samy Ammari, Ahmed Idbaih, Keith L. Ligon, Bertrand Mathon, Philippe Cornu, Liam F. Spurr, Yvonne Y. Li, Caroline Houiller, and Charlotte Bellamy
Subjects: Cancer Research, Standard of care, business.industry, Cancer therapy, Drug Resistance, Somatic hypermutation, medicine.disease, Oncology, Glioma, Cancer research, medicine, Clinical significance, Neurology (clinical), business
Abstract: BACKGROUND Hypermutation is an emerging biomarker for predicting response to immunotherapy in cancer patients, however its clinical value in gliomas is not established. We sought to assess the determinants of hypermutation in gliomas, and its value for predicting response to standard of care and immune checkpoint blockade (ICB). METHODS We performed comprehensive genomic characterization of 2,420 clinically annotated gliomas. We assessed the clinical and molecular characteristics associated with hypermutation and relationships between hypermutation and response to cancer treatments. RESULTS Hypermutation occurred predominantly as an adaptive resistance mechanism to temozolomide in gliomas and was most prevalent in recurrent gliomas with MGMTpromoter methylation (33.8%), IDH1/2mutation (41.0%) or 1p/19q co-deletion (59.5%). Hypermutation was almost always associated with molecular defects in DNA mismatch repair (MMR), and was associated with shorter survival after its appearance based on multivariate analysis (hazard ratio 1.91; 95% CI 1.24–2.94; P=0.004). The molecular mechanisms whereby gliomas undergo hypermutation during therapy with alkylating agents were dissected using patient-derived glioma models in vitro and in vivo. Outcomes of hypermutated gliomas treated with immune checkpoint blockade or with standard of care agents will be presented at the conference. CONCLUSIONS Using the largest set of hypermutated gliomas described to date, this study establishes that mutational burden and mutation signatures are clinically and biologically significant biomarkers that can be used to predict therapy response and guide treatment decisions in gliomas
Published: 2019

36. P05.05 Safety and feasibility of temporary blood-brain barrier disruption with the SonoCloud-1/3 implantable ultrasound device in recurrent glioblastoma

Author: Antoine F. Carpentier, Guillaume Bouchoux, Jean-Yves Chapelon, Cyril Lafon, Jean Yves Delattre, Ahmed Idbaih, Alexandre Vignot, Lisa Belin, Carole Desseaux, and Michael Canney
Subjects: Cancer Research, medicine.medical_specialty, Ultrasound device, medicine.diagnostic_test, business.industry, Recurrent glioblastoma, Magnetic resonance imaging, Low-intensity pulsed ultrasound, Blood–brain barrier, medicine.disease, Poster Presentations, medicine.anatomical_structure, Oncology, medicine, Microbubbles, Neurology (clinical), Blood-brain barrier disruption, Radiology, business, Glioblastoma
Abstract: BACKGROUND The blood-brain barrier (BBB) limits penetration of drug therapies to the brain and may account for the limited effectiveness of chemotherapies in patients with primary brain cancer. An implantable ultrasound (US) device, SonoCloud, was developed to temporarily disrupt the BBB in patients with recurrent glioblastoma (rGBM) prior to carboplatin chemotherapy administration to enhance brain drug concentrations. BBB disruption was investigated with a single emitter device, SonoCloud-1 (SC1) and a three-emitter device, SonoCloud-3 (SC3) in a safety and feasibility study in rGBM patients at the Hôpitaux Universitaires La Pitié Salpêtrière in Paris, France (NCT02253212). MATERIAL AND METHODS The SC1 implant consisted of a 1 MHz, 10-mm diameter ultrasound transducer encapsulated in a biocompatible housing while the SC3 consisted of (3) separate SC1 emitters implanted in a triangular pattern to disrupt the BBB over a 3x larger volume. Patients were implanted with the SonoCloud device during tumor debulking or in a dedicated surgical procedure. The devices were activated monthly by connecting the device to an external generator via a transdermal needle. Intravenous injection of SonoVue® microbubbles was performed with device activation to temporarily disrupt the BBB. Magnetic resonance imaging (MRI) was performed after sonications with gadolinium contrast to verify BBB disruption followed by carboplatin infusion at AUC4-6. Patients received treatments until disease progression. RESULTS Between 2014 and 2016, 21 patients were registered for the study and implanted with the SC1; 19 patients received at least one sonication. Six additional patients were implanted and received sonications with the SC3. A total of 89 US sessions were performed to disrupt the BBB - 65 with the SC1 and 24 with the SC3. Treatment-related adverse events observed were transient and manageable. No carboplatin-related neurotoxicity was observed. SC1 patients with no or poor BBB disruption (n=8) visible on MRI had a median progression-free survival (PFS) of 2.73 months, and a median overall survival (OS) of 8.64 months. SC1 patients with clear BBB disruption (n=11) had a median PFS of 4.11 months, and a median OS of 12.94 months. The SC3 device was as well-tolerated as the SC1 device, with SC3 patients receiving between 1–12 monthly sonications. CONCLUSION These results provide the first safety data on the effects of disrupting the BBB in rGBM patients prior to carboplatin chemotherapy using an implantable low intensity pulsed ultrasound device on enlarged areas of brain. This study has now been completed. A new safety study with a larger device, SonoCloud-9, that covers the tumor and surrounding infiltrative regions, has started in France in early 2019 (NCT03744026). Work supported by CarThera and APHP.
Published: 2019

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

Author: Jean-Yves Delattre, Ahmed Idbaih, Dominique Figarella-Branger, Caroline Dehais, Fabienne Escande, Emeline Tabouret, Agusti Alentorn, Nesrine Trabelsi, Romain Appay, Claude-Alain Maurage, François Ducray, Karima Mokhtari, Catherine Carpentier, Yannick Marie, Emmanuelle Uro-Coste, Carole Colin, Aurélie Kamoun, Institut de neurophysiopathologie (INP), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Service d’Anatomie Pathologique et de Neuropathologie, APHM, Hôpital de la Timone, Hôpital de la Timone [CHU - APHM] (TIMONE), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 (UPMC), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), biology and pathological laboratory, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), (le programme) Cartes d'identité des tumeurs (CIT), Ligue Nationales Contre le Cancer (LNCC), Biologie des Interactions Neurones / Glie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Département de neurooncologie, Service d'anatomie pathologique et histologie-cytologie [Rangueil], Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Service de neurologie 1 [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital de Rangueil, CHU Toulouse [Toulouse], Service de Neurologie [CHU Pitié-Salpêtrière], and IFR70-CHU Pitié-Salpêtrière [AP-HP]
Subjects: Male, Cancer Research, Necrosis, [SDV]Life Sciences [q-bio], Cohort Studies, 0302 clinical medicine, CDKN2A, Medicine, ComputingMilieux_MISCELLANEOUS, Sequence Deletion, Aged, 80 and over, Kinase, Retinoblastoma, Brain Neoplasms, Homozygote, Glioma, Middle Aged, Prognosis, Combined Modality Therapy, Isocitrate Dehydrogenase, 3. Good health, Survival Rate, Isocitrate dehydrogenase, Oncology, Chromosomes, Human, Pair 1, 030220 oncology & carcinogenesis, Female, medicine.symptom, Adult, Adolescent, 03 medical and health sciences, Young Adult, Biomarkers, Tumor, Humans, Progression-free survival, neoplasms, Cyclin-Dependent Kinase Inhibitor p16, Aged, business.industry, Editorials, medicine.disease, Mutation, Cancer research, Neurology (clinical), business, Chromosomes, Human, Pair 19, 030217 neurology & neurosurgery, Anaplastic astrocytoma, Follow-Up Studies
Abstract: Background The 2016 WHO classification of the central nervous system tumors stratifies IDH-mutant gliomas into two major groups depending on the presence or absence of 1p/19q-codeletion. However, the grading system remains unchanged and it is now controversial whether it can be still applied to this updated molecular classification. Methods In a large cohort of 911 high grade IDH-mutant gliomas from the French national POLA network (including 428 IDH-mutant gliomas without 1p/19q-codeletion and 483 anaplastic oligodendrogliomas, IDH-mutant and 1p/19q-codeleted), we investigated the prognostic value of CDKN2A gene homozygous deletion as well as WHO grading criteria (mitoses, microvascular proliferation and necrosis). In addition, we also searched for other retinoblastoma pathway gene alterations (CDK4 amplification and RB1 homozygous deletion) in a subset of patients. CDKN2A homozygous deletion was also searched in an independent series of 40 grade II IDH-mutant gliomas. Results CDKN2A homozygous deletion was associated with dismal outcome among IDH-mutant gliomas lacking 1p/19q-codeletion (p Conclusions Our study pointed out the utmost relevance of CDKN2A homozygous deletion as an adverse prognostic factor in the two broad categories of IDH-mutant gliomas stratified on 1p/19q-codeletion and suggest to refine the grading of these tumors.
Published: 2019

38. Diabetes Mellitus, Extreme Insulin Resistance, and Hypothalamic-Pituitary Langerhans Cells Histiocytosis

Author: Corinne Vigouroux, Marie Bastin, Mathilde Sollier, Fabrizio Andreelli, Ahmed Idbaih, Jean Donadieu, Agnès Hartemann, Fleur Cohen Aubart, Chloé Amouyal, Philippe Touraine, Martine Auclair, M. Halbron, Olivier Bourron, G. Bera, Jacques Young, and Héléna Mosbah
Subjects: Pathology, medicine.medical_specialty, Langerin, Endocrinology, Diabetes and Metabolism, Case Report, lcsh:Diseases of the endocrine glands. Clinical endocrinology, 03 medical and health sciences, 0302 clinical medicine, Langerhans cell histiocytosis, Diabetes mellitus, Biopsy, medicine, 030212 general & internal medicine, Cladribine, Histiocyte, lcsh:RC648-665, biology, medicine.diagnostic_test, business.industry, medicine.disease, Histiocytosis, 030220 oncology & carcinogenesis, Diabetes insipidus, biology.protein, business, medicine.drug
Abstract: Background. Langerhans Cell Histiocytosis (LCH) is a rare inflammatory neoplasm characterized by an infiltration of organs by Langerin + (CD207+) and CD1a+ histiocytes. Diabetes insipidus is a frequent manifestation of the disease, while diabetes mellitus is very rare. We report the first case of a 20-year-old man suffering from hypothalamopituitary histiocytosis and diabetes mellitus with serum anti-insulin receptor antibodies. Case Presentation. A 20-year-old patient was admitted for the evaluation of growth delay and hyperphagia. HbA1c level and fasting blood glucose were in the normal range. The diagnosis of hypothalamopituitary histiocytosis was based on histological features after biopsy of a large suprachiasmatic lesion identified on magnetic resonance imaging (MRI). Association of vinblastine and purinethol was started followed by a second-line therapy by cladribine. During the follow-up, the patient was admitted for recurrence of hyperglycemic states and extreme insulin resistance. The screening for serum anti-insulin receptor antibodies was positive. Each episode of hyperglycemia appeared to be correlated with tumoral activity and increase in serum anti-insulin receptor antibodies and appeared to be improved when the disease was controlled by chemotherapy. Conclusion. We report the first description of a hypothalamopituitary histiocytosis associated with serum anti-insulin receptor antibodies, extreme insulin resistance, and diabetes. Parallel evolution of glucose levels and serum anti-insulin receptor antibodies seemed to be the consequence of immune suppressive properties of cladribine.
Published: 2019

39. Endocrine manifestations in a cohort of 63 adulthood and childhood onset patients with Langerhans cell histiocytosis

Author: Philippe Touraine, Fleur Cohen, Joseph Y Drabo, Abdellatif Tazi, Carine Courtillot, Ahmed Idbaih, Jean Donadieu, Zahir Amoura, Julien Haroche, Yempabou Sagna, Gestionnaire, Hal Sorbonne Université, Centre Hospitalier Universitaire Yalgado Ouédraogo (CHUYO), Service d'Endocrinologie et Médecine de la Reproduction [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de pneumologie [Saint-Louis], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'hématologie-immunologie-oncologie pédiatrique [CHU Trousseau], CHU Trousseau [APHP], Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service d'Onco-neurologie = Département de neurologie 2 [CHU Pitié Salpêtrière], Service de médecine interne [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Service d’endocrinologie et médecine de la reproduction [CHU Pitié-Salpêtrière], Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université - Département de neurologie 2 - Mazarin, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: Male, Pediatrics, Endocrinology, Diabetes and Metabolism, [SDV]Life Sciences [q-bio], Cohort Studies, 0302 clinical medicine, Endocrinology, Langerhans cell histiocytosis, Age of Onset, Child, Aged, 80 and over, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, General Medicine, Middle Aged, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 3. Good health, [SDV] Life Sciences [q-bio], Histiocytosis, Child, Preschool, 030220 oncology & carcinogenesis, Cohort, Female, France, Thyroid function, Adult, Thyroid Hormones, medicine.medical_specialty, Adolescent, Endocrine System, 030209 endocrinology & metabolism, Endocrine System Diseases, Young Adult, 03 medical and health sciences, Internal medicine, medicine, Humans, Endocrine system, Aged, Retrospective Studies, business.industry, Retrospective cohort study, medicine.disease, Histiocytosis, Langerhans-Cell, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Gonadotropins, Pituitary, Diabetes insipidus, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Age of onset, business, Follow-Up Studies
Abstract: Objective Langerhans cell histiocytosis (LCH) is a rare inflammatory myeloid neoplasm which can infiltrate any organ or tissue. Endocrine involvement has mostly been described in case reports and small retrospective studies. We aimed to describe endocrine manifestations in a large cohort of adulthood onset (AO) and childhood onset (CO) patients with LCH. Design Single-center observational study conducted between January 2002 and December 2017 at Pitié-Salpêtrière University Hospital (Paris, France), a tertiary care hospital. Method Clinical, biological and morphological evaluations of pituitary, gonadal, adrenal and thyroid function evaluations performed in 63 consecutive patients with LCH (AO patients: 40, CO patients: 23). Fifty-eight patients underwent follow-up assessments. Results Complete pituitary evaluation was performed in 38/63 patients (60.3%); at least one anterior pituitary dysfunction (APD) was found in 63.2% of them. In this subgroup of patients, the most prevalent deficiencies were diabetes insipidus (DI) and GHD (55.3% each), followed by gonadotropin deficiency (34.2%) and thyrotropin deficiency (23.7%). In the subgroup of the 25 incompletely evaluated patients, we found DI in 44%, GHD in 50%, gonadotropin deficiency in 30.4% and thyrotropin deficiency in 16%. APD was more common in CO patients (P = 0.003) but was not systematically associated with DI regardless of the age of onset. Endocrine dysfunction was most often permanent; moreover, occurrence of new deficiencies has been described during follow-up. Conclusion The spectrum of endocrine disorders appears to be large in LCH (both in AO and CO patients) and should be evaluated carefully at diagnosis and during follow-up. APD was not always associated with DI.
Published: 2019

40. Safety and Feasibility of Repeated and Transient Blood–Brain Barrier Disruption by Pulsed Ultrasound in Patients with Recurrent Glioblastoma

Author: Alexandre Carpentier, Marc Sanson, Caroline Houillier, Bruno Law-Ye, Anne Bissery, Alexandre Vignot, Khê Hoang-Xuan, Bertrand Mathon, Jean-Yves Delattre, Jean-Yves Chapelon, Cyril Lafon, Nicolas Asquier, Arthur André, Carole Desseaux, Ahmed Idbaih, Clementine Trosch, Guillaume Bouchoux, Caroline Dehais, Delphine Leclercq, Michael Canney, Laurent Capelle, Lisa Belin, Yann De Rycke, and Florence Laigle-Donadey
Subjects: Drug, Cancer Research, medicine.medical_specialty, medicine.medical_treatment, media_common.quotation_subject, Urology, Blood–brain barrier, Article, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Humans, Medicine, In patient, Adverse effect, media_common, Chemotherapy, medicine.diagnostic_test, business.industry, Neurotoxicity, Magnetic resonance imaging, medicine.disease, Magnetic Resonance Imaging, Carboplatin, 3. Good health, medicine.anatomical_structure, Ultrasonic Waves, Oncology, chemistry, Blood-Brain Barrier, 030220 oncology & carcinogenesis, Feasibility Studies, Neoplasm Recurrence, Local, Glioblastoma, business, 030217 neurology & neurosurgery
Abstract: Purpose: The blood–brain barrier (BBB) limits the efficacy of drug therapies for glioblastoma (GBM). Preclinical data indicate that low-intensity pulsed ultrasound (LIPU) can transiently disrupt the BBB and increase intracerebral drug concentrations. Patients and Methods: A first-in-man, single-arm, single-center trial (NCT02253212) was initiated to investigate the transient disruption of the BBB in patients with recurrent GBM. Patients were implanted with a 1-MHz, 11.5-mm diameter cranial ultrasound device (SonoCloud-1, CarThera). The device was activated monthly to transiently disrupt the BBB before intravenous carboplatin chemotherapy. Results: Between 2014 and 2016, 21 patients were registered for the study and implanted with the SonoCloud-1; 19 patients received at least one sonication. In 65 ultrasound sessions, BBB disruption was visible on T1w MRI for 52 sonications. Treatment-related adverse events observed were transient and manageable: a transient edema at H1 and at D15. No carboplatin-related neurotoxicity was observed. Patients with no or poor BBB disruption (n = 8) visible on MRI had a median progression-free survival (PFS) of 2.73 months, and a median overall survival (OS) of 8.64 months. Patients with clear BBB disruption (n = 11) had a median PFS of 4.11 months, and a median OS of 12.94 months. Conclusions: SonoCloud-1 treatments were well tolerated and may increase the effectiveness of systemic drug therapies, such as carboplatin, in the brain without inducing neurotoxicity. See related commentary by Sonabend and Stupp, p. 3750
Published: 2019
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41. EORTC 1709/CCTG CE.8: A phase III trial of marizomib in combination with temozolomide-based radiochemotherapy versus temozolomide-based radiochemotherapy alone in patients with newly diagnosed glioblastoma

Author: James Perry, Warren P. Mason, Michael Weller, Martin J. van den Bent, Emilie Le Rhun, Ahmed Idbaih, Filip de Vos, Pierre Freres, Laura Masucci, Maureen Vanlancker, José Manuel Sepulveda Sánchez, Jean-Sebastien Frenel, Anna Maria Elisabeth Walenkamp, Clemens Seidel, Hal W. Hirte, Frédéric Dhermain, Jaap C. Reijneveld, Thierry Gorlia, Patrick Roth, and Christopher J. O'Callaghan
Subjects: Oncology, Cancer Research, medicine.medical_specialty, Temozolomide, business.industry, medicine.medical_treatment, Newly diagnosed, medicine.disease, Radiation therapy, Internal medicine, Concomitant, medicine, In patient, business, Standard therapy, medicine.drug, Glioblastoma
Abstract: 2004 Background: Patients with newly diagnosed glioblastoma receive postoperative standard therapy with radiotherapy (RT), and concomitant and up to six cycles of maintenance temozolomide (TMZ) chemotherapy (TMZ/RT→TMZ). Marizomib is a novel, irreversible and brain-penetrant pan-proteasome inhibitor with encouraging findings in preclinical models and early-stage clinical trials for patients with newly diagnosed and recurrent glioblastoma. Therefore, a phase 3 trial was designed to explore the activity of marizomib in addition to TMZ/RT→TMZ. ClinicalTrials.gov Identifier: NCT03345095 Methods: EORTC 1709/CCTG CE.8 is a multicenter, randomized, controlled, open label phase 3 superiority trial. Eligibility criteria included histologically confirmed newly diagnosed glioblastoma and a Karnofsky performance status (KPS) > 70. Eligible patients were stratified for institution, age, KPS as well as extent of surgery, and centrally randomized in a 1:1 ratio. The primary objective of this study is to compare overall survival (OS) in patients receiving marizomib in addition to standard treatment with patients receiving standard treatment only. Secondary endpoints include progression-free survival (PFS), safety, neurocognitive function, and quality of life. Results: The study was opened at 49 EORTC sites in Europe, 23 CCTG sites in Canada, and 8 sites in the US. Patient enrolment started in June 2018 and was close to completion at the time of a planned interim analysis in September 2020. A total of 749 patients (of the planned 750) were randomized when the IDMC recommended to discontinue enrollment. Age, KPS and extent of resection were well balanced between the 2 study arms. No difference in median OS was observed between the standard arm (15.9 months) and the marizomib arm (15.7 months; HR = 0.99). Median PFS was 6.1 vs. 6.2 months (HR = 1.02). Patients in the marizomib group had more often grade 3/4 treatment-emergent adverse events (TEAE) compared to the standard therapy group (42.6% vs. 20.5%), including ataxia, hallucinations and headache. Conclusions: The addition of marizomib to standard radiochemotherapy did not improve OS or PFS in patients with newly diagnosed glioblastoma. Final survival analyses including determination of MGMT promoter methylation status and analyses of other secondary endpoints are ongoing. Clinical trial information: NCT03345095.
Published: 2021

42. Dural and osteolytic sarcomatoid relapse of a secondary gliosarcoma with tryptase immunoreactivity

Author: Franck Bielle, Ahmed Idbaih, Charles Duyckaerts, Damien Galanaud, Ana Laura Calderón-Garcidueñas, Universidad Veracruzana, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Algorithms, models and methods for images and signals of the human brain (ARAMIS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Inria de Paris, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Service de neurologie 2 [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), 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), Service de Neuroradiologie [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), 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)-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)-Inria de Paris, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Inria de Paris, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Inria de Paris
Subjects: Pathology, medicine.medical_specialty, Gliosarcoma, [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Tryptase, Pathology and Forensic Medicine, 03 medical and health sciences, 0302 clinical medicine, Text mining, [INFO.INFO-IM]Computer Science [cs]/Medical Imaging, medicine, ComputingMilieux_MISCELLANEOUS, biology, business.industry, [INFO.INFO-CV]Computer Science [cs]/Computer Vision and Pattern Recognition [cs.CV], General Medicine, medicine.disease, 3. Good health, Neurology, [INFO.INFO-TI]Computer Science [cs]/Image Processing [eess.IV], biology.protein, Neurology (clinical), business, [SPI.SIGNAL]Engineering Sciences [physics]/Signal and Image processing, 030217 neurology & neurosurgery
Abstract: International audience
Published: 2016

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

Author: Anne Jouvet, Karima Mokhtari, Marc Sanson, Eric Letouzé, François Ducray, Ahmed Idbaih, Aurélien de Reyniès, Nadine Martin-Duverneuil, Emmanuelle Uro-Coste, Caroline Dehais, Aurélie Kamoun, Dominique Figarella-Branger, Catherine Carpentier, Carole Colin, Jean-Yves Delattre, Nabila Elarouci, (le programme) Cartes d'identité des tumeurs (CIT), Ligue Nationales Contre le Cancer (LNCC), Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de Recherches en Oncologie biologique et Oncopharmacologie (CRO2), Aix Marseille Université (AMU)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Neuropathologie Raymond Escourolle [CHU Pitié-Salpétriêre], Université Pierre et Marie Curie - Paris 6 (UPMC)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital neurologique et neurochirurgical Pierre Wertheimer [CHU - HCL], Hospices Civils de Lyon (HCL), Faculté de Médecine [Rangueil], Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), OncoNeuroTek [Paris], Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Neuro-Oncologie [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), UPMC - Département de neurologie 2 - Mazarin, Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Laboratoire de Neuropathologie Raymond Escourolle, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Université Pierre et Marie Curie - Paris 6 (UPMC), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse], Service de Neuroradiologie [CHU Pitié-Salpêtrière], Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), and HAL UPMC, Gestionnaire
Subjects: Male, 0301 basic medicine, General Physics and Astronomy, Transcriptome, Cluster Analysis, Aged, 80 and over, Neurons, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Multidisciplinary, Stem Cells, Genomics, Glioma, Middle Aged, 3. Good health, Oligodendroglia, medicine.anatomical_structure, Chromosomes, Human, Pair 1, DNA methylation, Female, Chromosome Deletion, Signal Transduction, Adult, Cell type, Science, Oligodendroglioma, Biology, Article, General Biochemistry, Genetics and Molecular Biology, Proto-Oncogene Proteins c-myc, Young Adult, 03 medical and health sciences, medicine, Humans, Survival analysis, Aged, Gene Expression Profiling, General Chemistry, DNA Methylation, medicine.disease, Survival Analysis, Oligodendrocyte, Gene expression profiling, 030104 developmental biology, Cancer research, Chromosomes, Human, Pair 19, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Oligodendroglial tumours (OT) are a heterogeneous group of gliomas. Three molecular subgroups are currently distinguished on the basis of the IDH mutation and 1p/19q co-deletion. Here we present an integrated analysis of the transcriptome, genome and methylome of 156 OT. Not only does our multi-omics classification match the current classification but also reveals three subgroups within 1p/19q co-deleted tumours, associated with specific expression patterns of nervous system cell types: oligodendrocyte, oligodendrocyte precursor cell (OPC) and neuronal lineage. We confirm the validity of these three subgroups using public datasets. Importantly, the OPC-like group is associated with more aggressive clinical and molecular patterns, including MYC activation. We show that the MYC activation occurs through various alterations, including MYC genomic gain, MAX genomic loss, MYC hypomethylation and microRNA-34b/c down-regulation. In the lower grade glioma TCGA dataset, the OPC-like group is associated with a poorer outcome independently of histological grade. Our study reveals previously unrecognized heterogeneity among 1p/19q co-deleted tumours., Oligodendroglial tumours are characterized into three different molecular subtypes. Here, the authors use genomic data to identify a further three subgroups of 1p/19q co-deleted tumours and demonstrate an association with an aggressive phenotype.
Published: 2016

44. Multi-platform molecular profiling of a large cohort of glioblastomas reveals potential therapeutic strategies

Author: Joanne Xiu, Jeremy Rudnick, Ahmed Idbaih, Todd Maney, Jethro Hu, David Spetzler, Tiffany Juarez, Michael Glantz, Sandeep K. Reddy, Sandeep C. Pingle, Karen Fink, David Piccioni, Nader Sanai, Santosh Kesari, Ryan Bender, Anatole Ghazalpour, and Zoran Gatalica
Subjects: 0301 basic medicine, Gerontology, Gene mutation, 0302 clinical medicine, Gene duplication, 80 and over, Medicine, Promoter Regions, Genetic, Cancer, Aged, 80 and over, Tumor, Brain Neoplasms, Age Factors, Astrocytoma, Middle Aged, Prognosis, tumor profiling, Oncology, 030220 oncology & carcinogenesis, DNA methylation, Immunohistochemistry, IDH1, Research Paper, Adult, EGFRvIII, MGMT promoter methylation, Oncology and Carcinogenesis, and over, Promoter Regions, Young Adult, 03 medical and health sciences, Rare Diseases, Genetic, Biomarkers, Tumor, Genetics, Humans, neoplasms, Survival analysis, Aged, business.industry, Tumor Suppressor Proteins, Human Genome, Neurosciences, Gene Amplification, glioblastoma, DNA Methylation, medicine.disease, Survival Analysis, Brain Disorders, Brain Cancer, Clinical trial, Good Health and Well Being, 030104 developmental biology, Mutation, Cancer research, business, Biomarkers
Abstract: Glioblastomas (GBM) are the most aggressive and prevalent form of gliomas with abysmal prognosis and limited treatment options. We analyzed clinically relevant molecular aberrations suggestive of response to therapies in 1035 GBM tumors. Our analysis revealed mutations in 39 genes of 48 tested. IHC revealed expression of PD-L1 in 19% and PD-1 in 46%. MGMT-methylation was seen in 43%, EGFRvIII in 19% and 1p19q co-deletion in 2%. TP53 mutation was associated with concurrent mutations, while IDH1 mutation was associated with MGMT-methylation and TP53 mutation and was mutually exclusive of EGFRvIII mutation. Distinct biomarker profiles were seen in GBM compared with WHO grade III astrocytoma, suggesting different biology and potentially different treatment approaches. Analysis of 17 metachronous paired tumors showed frequent biomarker changes, including MGMT-methylation and EGFR aberrations, indicating the need for a re-biopsy for tumor profiling to direct subsequent therapy. MGMT-methylation, PR and TOPO1 appeared as significant prognostic markers in sub-cohorts of GBM defined by age. The current study represents the largest biomarker study on clinical GBM tumors using multiple technologies to detect gene mutation, amplification, protein expression and promoter methylation. These data will inform planning for future personalized biomarker-based clinical trials and identifying effective treatments based on tumor biomarkers.
Published: 2016

45. Initial surgical resection and long time to occurrence from initial diagnosis are independent prognostic factors in resected recurrent IDH wild-type glioblastoma

Author: Khê Hoang-Xuan, Jean-Yves Delattre, Yannick Marie, Fernando Lozano-Sanchez, Alexandre Carpentier, Marine Giry, François Ducray, Bertrand Mathon, Ahmed Idbaih, Jérôme Honnorat, Antoine Seyve, Matthieu Peyre, Suzanne Tran, Loïc Feuvret, Laurent Capelle, Karima Mokhtari, Alice Thomas, Marc Sanson, Hospices Civils de Lyon, Departement de Neurologie (HCL), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université - Département de neurologie 2 - Mazarin, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Paul Strauss, CRLCC Paul Strauss, Service de Neurochirurgie [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), Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), Service de Neuropathologie [CHU Pitié Salpêtrière], Service de Radiothérapie [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), Institut NeuroMyoGène (INMG), 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), Hospices Civils de Lyon (HCL), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (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), Service d'Oncologie Radiothérapie [CHU Pitié Salpétrière], 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, Reoperation, Surgical resection, medicine.medical_specialty, Time Factors, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, medicine.medical_treatment, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.MHEP.CHI]Life Sciences [q-bio]/Human health and pathology/Surgery, IDH wild-type, Time-to-Treatment, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Recurrent glioblastoma, Overall survival, Humans, Medicine, Progression-free survival, First Recurrence, Aged, Retrospective Studies, Chemotherapy, Tumor size, Brain Neoplasms, business.industry, General Medicine, Middle Aged, Prognosis, medicine.disease, Isocitrate Dehydrogenase, 3. Good health, Surgery, 030220 oncology & carcinogenesis, Female, Neurology (clinical), Glioblastoma, business, 030217 neurology & neurosurgery
Abstract: International audience; Objective: IDH wild-type glioblastoma is the most common and aggressive primary brain cancer in adults. At tumor recurrence, treatment decision-making is not standardized; several options include second surgery, reirradiation, and a second line of chemotherapy. In this retrospective monocentric study conducted at the era of WHO 2016 classification, we investigated IDH wild-type glioblastoma patients below the age of 70 to see (i) the clinical benefit of second surgery at recurrence and (ii) the prognostic factors in resected recurrent glioblastoma patients.Methods: 229 newly diagnosed IDH wild-type glioblastoma patients below the age of 70 treated with the standard of care (SOC) were enrolled in the current study and stratified into two subgroups according to treatment at recurrence: re-resection and no re-resection.Results: All experienced tumor recurrence with a median progression-free survival of 11 months. 25 % of patients were reoperated. Patients reoperated at recurrence had longer post-progression median overall survival compared to their non-reoperated counterparts (14 versus 9 months, p < .05). Initial surgical resection and a long time from the initial diagnosis to the first recurrence were independent prognostic factors for good outcomes in resected recurrent IDH-wild-type glioblastoma patients; however, tumor size before and after surgery did not impact post-surgical survival.Conclusion: Our study supports surgical resection at recurrence as therapeutic in IDH wild-type glioblastoma patients aged below 70 and in good clinical condition regardless of preoperative tumor size, particularly in patients who experienced a longer time before first recurrence and surgery at initial diagnosis. Further prospective and larger studies are warranted to validate our findings.
Published: 2020

46. Abstract 5705: Mechanisms and therapeutic implications of hypermutation in gliomas

Author: Brian M. Alexander, Shakti H. Ramkissoon, Mehdi Touat, Seth Malinowski, Arnab Chakravarti, Philippe Cornu, Andrew D. Cherniack, Agusti Alentorn, Karima Mokhtari, Caroline Dehais, Jack Geduldig, Kenin Qian, Florence Laigle-Donadey, Maite Verreault, Kin-Hoe Chow, Jill S. Barnholtz-Sloan, Marc Sanson, Adam Boynton, Ahmed Idbaih, Dimitri Psimaras, Bertrand Mathon, Aniket Shetty, Sangita Pal, Yvonne Y. Li, Franck Bielle, Caroline Houillier, Laurent Capelle, Garrett M. Frampton, Craig L. Bohrson, Samy Ammari, Frank Dubois, David A. Reardon, Aurélien Marabelle, Liam F. Spurr, Mary J. Lim-Fat, Isidro Cortes-Ciriano, Erell Guillerm, Alexandre Carpentier, Pratiti Bandopadhayay, Frédéric Beuvon, Charlotte Bellamy, Kristine Pelton, Bryan Iorgulescu, Wenya Linda Bi, Peter J. Park, Patrick Y. Wen, Rameen Beroukhim, Naomi Currimjee, and Keith L. Ligon
Subjects: Cancer Research, Temozolomide, Somatic hypermutation, Cancer, Microsatellite instability, Biology, MMR Deficiency, medicine.disease, Acquired resistance, Oncology, Glioma, medicine, Cancer research, DNA mismatch repair, medicine.drug
Abstract: High tumor mutational burden (hypermutation) is observed in some gliomas; however, its mechanisms of development and whether it predicts immunotherapy response are poorly understood. Here, we comprehensively analyze the molecular determinants of mutational burden and signatures in 10,294 gliomas including AACR Project GENIE and institutional datasets. We delineate two main pathways to hypermutation: a de novo pathway associated with constitutional defects in DNA polymerase and mismatch repair (MMR) genes, and a more common post-treatment pathway associated with acquired resistance driven by MMR defects in chemotherapy-sensitive gliomas that recur after temozolomide treatment. Experimentally, the mutational signature of post-treatment hypermutated gliomas was only recapitulated by temozolomide-induced damage in cells harboring MMR deficiency. MMR-deficient gliomas exhibited unique features including the lack of prominent T-cell infiltrates, extensive intratumoral heterogeneity, poor survival and low response rate to PD-1 blockade. Moreover, while microsatellite instability in MMR-deficient gliomas was not detected by bulk analyses, single-cell whole-genome sequencing of post-treatment hypermutated glioma cells demonstrated microsatellite mutations. This study shows that chemotherapy can drive acquisition of hypermutated populations without promoting response to PD-1 blockade and supports diagnostic use of mutational burden and signatures in cancer. Citation Format: Mehdi Touat, Yvonne Y. Li, Adam N. Boynton, Liam F. Spurr, Bryan Iorgulescu, Craig L. Bohrson, Isidro Cortes-Ciriano, Jack E. Geduldig, Kristine Pelton, Mary J. Lim-Fat, Sangita Pal, Shakti H. Ramkissoon, Frank Dubois, Charlotte Bellamy, Naomi Currimjee, Kenin Qian, Seth Malinowski, Aniket Shetty, Kin-Hoe Chow, Maïté Verreault, Erell Guillerm, Samy Ammari, Frédéric Beuvon, Karima Mokhtari, Agusti Alentorn, Caroline Dehais, Caroline Houillier, Florence Laigle-Donadey, Dimitri Psimaras, Alexandre Carpentier, Philippe Cornu, Laurent Capelle, Bertrand Mathon, Jill S. Barnholtz-Sloan, Arnab Chakravarti, Wenya L. Bi, Garrett M. Frampton, Marc Sanson, Brian M. Alexander, Andrew Cherniack, Patrick Y. Wen, David A. Reardon, Aurelien Marabelle, Peter J. Park, Ahmed Idbaih, Rameen Beroukhim, Pratiti Bandopadhayay, Franck Bielle, Keith L. Ligon. Mechanisms and therapeutic implications of hypermutation in gliomas [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5705.
Published: 2020

47. Long-term outcome of 117 patients with Erdheim-Chester disease and mixed histiocytosis receiving targeted therapies (BRAF and MEK inhibitors): A monocentric experience

Author: NeLa Benameur, Fleur Cohen-Aubart, Jean-Philippe Spano, Stéphane Barete, Zahir Amoura, Ahmed Idbaih, Jean-François Emile, Frédéric Charlotte, and Julien Haroche
Subjects: Cancer Research, Histiocytosis, medicine.medical_specialty, Oncology, business.industry, Erdheim–Chester disease, medicine, Disease, medicine.disease, business, Infiltration (medical), Dermatology, Myeloid Neoplasm
Abstract: 7560 Background: Erdheim–Chester disease (ECD), an inflammatory myeloid neoplasm from the L group, is an histiocytosis associated with multisystem infiltration. Around 1500 cases have been reported worldwide since 1930. In 15% of cases, ECD is associated with another histiocytosis corresponding to mixed histiocytosis. Before 2004, 60% of patients died within 3 years after diagnosis. The targetable BRAFV600Emutation is present in as much as 70% of all ECD cases. Targeted therapies (BRAF inhibitors in April 2012, followed by MEK inhibitors after 2015) have revolutionized the therapeutic options and prognosis of refractory ECD and mixed histiocytosis. Methods: This retrospective study was conducted between April 2012 and December 2019 on 117 ECD patients who received targeted therapies in the French National Referral Center for Histiocytosis at Pitié-Salpêtrière Hospital in Paris, France. 28 patients (pts) (24%) had a mixed histiocytosis. Results: 43 (36.7%) pts were female and 95/116 exploitable pts (81.9%) had a BRAF V600E mutation. 12 (10.3%) pts had a co-ocurring hemopathy (myeloproliferative neoplasm or myelodysplastic syndrom). Age at diagnosis was 57.2 yr (+/- 13.8). The main sites of involvement were: vascular (“coated aorta”) in 85 pts (73%), heart in 83 pts (71%), xanthelasma in 30 pts (26%), central nervous system in 56 pts (48%) and peri-renal (“hairy kidney”) in 84 pts (72%). 34 pts (29%) had previously received corticosteroids, and 63 pts (54%) interferon alpha regimen (mainly PEG interferon). 86 (74%) pts received the BRAF inhibitor vemurafenib, and 42 (36%) pts the MEK inhibitor cobimetinib (some patients receiving both). 25 pts died during follow-up. The median survival of patients with targeted therapies in december 2019 was undefined, whereas the patients with no targeted therapies had a median survival of 133 months (HR 0.64 (0.42-0.99); p = 0.04). Among the 117 pts, only 2 had a progression of VAF of mutations within genes frequently mutated in myeloid neoplasms. The most serious adverse events were cutaneous (squamous cell carcinoma, basocellular carcinoma, DRESS) and acute pancreatitis with BRAF inhibitors, whereas chorioretinitis and left ventricular dysfunction were seen with MEK inhibitors. None of the patients receiving targeted therapies progressed. Conclusions: Targeted therapies (BRAF and/or MEK inhibitors) were found dramatically efficacious in 117 patients with severe and refractory ECD and mixed histiocytosis, improving survival of patients.
Published: 2020

48. PATH-16. MOLECULAR PATHOLOGY AND CLINICAL CHARACTERISTICS OF MMR DEFICIENCY (MMRd) IN DIFFUSE GLIOMAS

Author: Shannon Block, David A. Reardon, Alexandre Carpentier, Rameen Beroukhim, Mehdi Touat, Jean-Yves Delattre, Wenya Bi, Justine Guegan, Frédéric Beuvon, Marc Sanson, Ahmed Idbaih, Keith L. Ligon, Alex Duval, Pratiti Bandopadhayay, Sandro Santagata, Patrick Y. Wen, Florence Coulet, Karima Mokhtari, Marine Giry, Franck Bielle, and Erell Guillerm
Subjects: Cancer Research, Pathology, medicine.medical_specialty, congenital, hereditary, and neonatal diseases and abnormalities, business.industry, Molecular pathology, Microsatellite instability, Signs and symptoms, MMR Deficiency, medicine.disease, digestive system diseases, Abstracts, Oncology, Glioma, medicine, Neurology (clinical), Msh2 gene, business
Abstract: BACKGROUND: MMR deficiency (MMRd) is found in a subset of gliomas. Emerging evidence indicates that MMRd could serve as predictive biomarker for both response to immunotherapy and resistance to alkylating agents. However, the molecular epidemiology, outcome, and the optimal diagnostic method of MMRd are poorly defined in gliomas. METHODS: A cohort of 350 adult gliomas was characterized as to WHO 2016 diagnosis, IDH1/2 sequencing, MGMT promoter methylation, prior treatment and outcome. Immunohistochemistry of MMR proteins (MSH2, MSH6, MLH1, PMS2) was performed in 260 tumors with available tissue. 100 tumors were analyzed with next generation targeted exome sequencing (NGS, Oncopanel) of 447 cancer genes, including full exon coverage of MMR genes. Comparisons between results from IHC, NGS and microsatellite instability (MSI) testing using pentaplex PCR amplification testing were incorporated to inform best practices. RESULTS: 53/260 tumors showed immunohistochemical (ie MMR protein staining loss) and/or molecular (ie presence of MMR pathogenic mutation with hypermutation) evidence of MMRd. No MSI was found by pentaplex PCR. 38/260 tumors harbored loss of protein expression of one or two MMR proteins: 15 showed loss of MSH6 protein (with/without concomitant MSH2 loss) and 23 had loss of PMS2 (with/without MLH1 loss). Analysis of 201 consecutive recurrent tumors from alkylator pre-treated patients showed significant association between MMRd and the presence of IDH1/2 mutation: MMRd in 20/90 (22.2%) of IDH1/2-mutant tumors vs 2/111 (1.8%) of IDH1/2-wild-type tumors (p
Published: 2018

49. Etiology and prognosis of acute respiratory failure in patients with primary malignant brain tumors admitted to the intensive care unit

Author: Léa Lemasle, Thomas Similowski, Isabelle Rivals, Marie Cantier, Alexandre Demoule, Ahmed Idbaih, Clémence Marois, Khê Hoang-Xuan, Maxens Decavèle, Hélène Prodanovic, and Nicolas Weiss
Subjects: Male, Cancer Research, medicine.medical_specialty, Acute infectious pneumonia, Aspiration pneumonia, Pneumocystis pneumonia, Pneumonia, Aspiration, law.invention, 03 medical and health sciences, 0302 clinical medicine, law, Internal medicine, medicine, Humans, Aged, Retrospective Studies, business.industry, Brain Neoplasms, Pneumonia, Pneumocystis, Cancer, Middle Aged, medicine.disease, Prognosis, Intensive care unit, Pulmonary embolism, Survival Rate, Intensive Care Units, Neurology, Oncology, Respiratory failure, 030220 oncology & carcinogenesis, Case-Control Studies, Etiology, Female, Neurology (clinical), business, Respiratory Insufficiency, 030217 neurology & neurosurgery
Abstract: Acute respiratory failure (ARF) is common and potentially fatal in patients with primary malignant brain tumors (PMBT). However, few data are available regarding its precipitating factors and prognosis. We sought to: (1) compare the causes of ARF and the outcome between patients with PMBT and patients with other peripheral solid tumors (PST), (2) identify the factors influencing ICU survival in PMBT patients. Two-center retrospective case-control study from March 1996 to May 2014. Primary central nervous system lymphomas were also included. Eighty-four patients with PMBT and 133 patients with PST were included. Acute infectious pneumonia was more frequent in PMBT than PST patients (77 vs. 36%, p
Published: 2018

50. Vemurafenib and cobimetinib overcome resistance to vemurafenib in BRAF-mutant ganglioglioma

Author: Anna Luisa Di Stefano, Julie Gratieux, Marc Sanson, Mehdi Touat, Chiara Villa, Hélène Blons, Géraldine Perkins, Karine Sejean, Pierre Laurent-Puig, Sorin Aldea, Julien Savatovsky, Keith L. Ligon, Stephanie Condette Auliac, Ahmed Idbaih, Anne-Paule Gimenez-Roqueplo, and Antoine Hollebecque
Subjects: 0301 basic medicine, Neuroblastoma RAS viral oncogene homolog, Adult, Male, Proto-Oncogene Proteins B-raf, Antineoplastic Agents, medicine.disease_cause, Ganglioglioma, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Piperidines, Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, Vemurafenib, neoplasms, Clinical/Scientific Notes, Cobimetinib, business.industry, Brain Neoplasms, Melanoma, MEK inhibitor, medicine.disease, digestive system diseases, 030104 developmental biology, chemistry, Drug Resistance, Neoplasm, 030220 oncology & carcinogenesis, Anaplastic Ganglioglioma, Mutation, Cancer research, Azetidines, Neurology (clinical), KRAS, business, medicine.drug
Abstract: V-raf murine sarcoma viral oncogene homolog B1 ( BRAF V600E) mutations are found in more than half of pleomorphic xanthoastrocytomas (PXA) and gangliogliomas, 2 rare primary brain tumors mainly affecting children and young adults.1 While patients with low-grade PXA and ganglioglioma typically carry a relatively favorable prognosis, clinicopathologic features such as older age, malignant histopathologic characteristics, as well as loss of p16/ CDKN2A are associated with aggressive behavior and unfavorable outcome.2 The BRAF inhibitor (BRAFi) vemurafenib showed activity in patients with BRAF V600E-mutant anaplastic PXA and ganglioglioma,3 representing one of the most significant successes of targeted therapy in gliomas over the past years. However, and as expected from experience in other cancers, acquired resistance to vemurafenib invariably develops. To date, there is no satisfactory therapeutic option for patients that have progressed on vemurafenib. Studies in BRAF V600E-mutant melanoma showed that a subset of tumors develop resistance to BRAFi through molecular events reactivating the mitogen-activated protein kinase (MAPK) pathway, such as NRAS , KRAS , or MEK mutations.4 This provided rationale for combined BRAF/MEK inhibition, which demonstrated superior outcomes in comparison to BRAFi monotherapy in BRAF V600E-mutant melanoma.5 We hypothesized that acquired resistance to vemurafenib may result from persistent MAPK activation in anaplastic ganglioglioma, and that combined BRAF/MEK inhibition could overcome resistance. In support of this, we report that combined treatment with vemurafenib and the MEK inhibitor cobimetinib resulted in major clinical benefit in a patient with refractory BRAF V600E-mutant anaplastic ganglioglioma who had progressed while receiving single-agent vemurafenib.
Published: 2018

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