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1. The colibactin-producing Escherichia coli alters the tumor microenvironment to immunosuppressive lipid overload facilitating colorectal cancer progression and chemoresistance

Author

Nilmara de Oliveira Alves, Guillaume Dalmasso, Darja Nikitina, Amaury Vaysse, Richard Ruez, Lea Ledoux, Thierry Pedron, Emma Bergsten, Olivier Boulard, Lora Autier, Sofian Allam, Laurence Motreff, Pierre Sauvanet, Diane Letourneur, Pragya Kashyap, Johan Gagnière, Denis Pezet, Catherine Godfraind, Michel Salzet, Emmanuel Lemichez, Mathilde Bonnet, Imène Najjar, Christophe Malabat, Marc Monot, Denis Mestivier, Nicolas Barnich, Pankaj Yadav, Isabelle Fournier, Sean Kennedy, Amel Mettouchi, Richard Bonnet, Iradj Sobhani, and Mathias Chamaillard

Subjects
Colibactin-producing Escherichia coli, land’s cycle, lipid droplet, right-sided colorectal cancer, Diseases of the digestive system. Gastroenterology, RC799-869
Abstract

ABSTRACTIntratumoral bacteria flexibly contribute to cellular and molecular tumor heterogeneity for supporting cancer recurrence through poorly understood mechanisms. Using spatial metabolomic profiling technologies and 16SrRNA sequencing, we herein report that right-sided colorectal tumors are predominantly populated with Colibactin-producing Escherichia coli (CoPEC) that are locally establishing a high-glycerophospholipid microenvironment with lowered immunogenicity. It coincided with a reduced infiltration of CD8+ T lymphocytes that produce the cytotoxic cytokines IFN-γ where invading bacteria have been geolocated. Mechanistically, the accumulation of lipid droplets in infected cancer cells relied on the production of colibactin as a measure to limit genotoxic stress to some extent. Such heightened phosphatidylcholine remodeling by the enzyme of the Land’s cycle supplied CoPEC-infected cancer cells with sufficient energy for sustaining cell survival in response to chemotherapies. This accords with the lowered overall survival of colorectal patients at stage III-IV who were colonized by CoPEC when compared to patients at stage I-II. Accordingly, the sensitivity of CoPEC-infected cancer cells to chemotherapies was restored upon treatment with an acyl-CoA synthetase inhibitor. By contrast, such metabolic dysregulation leading to chemoresistance was not observed in human colon cancer cells that were infected with the mutant strain that did not produce colibactin (11G5∆ClbQ). This work revealed that CoPEC locally supports an energy trade-off lipid overload within tumors for lowering tumor immunogenicity. This may pave the way for improving chemoresistance and subsequently outcome of CRC patients who are colonized by CoPEC.

Published
2024
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2. Cytotoxic necrotizing factor 1 hinders colon tumorigenesis induced by colibactin-producing Escherichia coli in ApcMin/+ mice

Author

Héloïse Chat, Guillaume Dalmasso, Catherine Godfraind, Virginie Bonnin, Racha Beyrouthy, Mathilde Bonnet, Nicolas Barnich, Amel Mettouchi, Emmanuel Lemichez, Richard Bonnet, and Julien Delmas

Subjects
Colorectal cancer, Escherichia coli, colibactin, CNF-1, CoPEC, Diseases of the digestive system. Gastroenterology, RC799-869
Abstract

ABSTRACTColorectal cancer (CRC) patients are frequently colonized by colibactin-producing Escherichia coli (CoPEC) (>40%), which enhances tumorigenesis in mouse models of CRC. We observed that 50% of CoPEC also contains the cnf1 gene, which encodes cytotoxic necrotizing factor-1 (CNF1), an enhancer of the eukaryotic cell cycle. The impact of its co-occurrence with colibactin (Clb) has not yet been investigated. We evaluated the impact of CNF1 on colorectal tumorigenesis using human colonic epithelial HT-29 cells and CRC-susceptible ApcMin/+ mice inoculated with the CoPEC 21F8 clinical strain (Clb+Cnf+) or 21F8 isogenic mutants (Clb+Cnf-, Clb-Cnf+ and Clb-Cnf-). Infection with the Clb+Cnf- strain induced higher levels of inflammatory cytokines and senescence markers both in vitro and in vivo compared to those induced by infection with the Clb+Cnf+ strain. In contrast, the Clb+Cnf- and Clb+Cnf+ strains generated similar levels of DNA damage in HT-29 cells and in colonic murine tissues. Furthermore, the ApcMin/+ mice inoculated with the Clb+Cnf- strain developed significantly more tumors than the mice inoculated with the Clb+Cnf+ strain or the isogenic mutants, and the composition of their microbiota was changed. Finally, rectal administration of the CNF1 protein in ApcMin/+ mice inoculated with the Clb+Cnf- strain significantly decreased tumorigenesis and inflammation. Overall, this study provides evidence that CNF1 decreases the carcinogenic effects of CoPEC in ApcMin/+ mice by decreasing CoPEC-induced cellular senescence and inflammation.

Published
2023
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3. Mast cell density and its clinical relevance in Waldenström's macroglobulinemia

Author

Richard Lemal, Stéphanie Poulain, Albane Ledoux‐Pilon, Lauren Veronese, Andrei Tchirkov, Benjamin Lebecque, Thomas Tassin, Jacques‐Olivier Bay, Frédéric Charlotte, Florence Nguyen‐Khac, Marc Berger, Catherine Godfraind, Loïc Ysebaert, Frédéric Davi, Bruno Pereira, Véronique Leblond, Olivier Hermine, Romain Guièze, Franck Pagès, and Olivier Tournilhac

Subjects
mast cells, tumor biology, Waldenström's macroglobulinemia, Diseases of the blood and blood-forming organs, RC633-647.5
Abstract

Abstract The presence of numerous mast cells (MCs) mixed with tumor cells in the bone marrow (BM) is a hallmark of the diagnosis of Waldenström's macroglobulinemia (WM). MCs have been shown to support lymphoplasmacytic cell growth, but there is thus far no demonstration of the prognostic impact of BM MC density in WM. We investigated BM MC density by sensitive and specific digital quantification, allowing the analysis of a large area infiltrated by BM tumor cells. A total of 65 WM patients were investigated, including 54 at diagnosis and 11 at relapse. Tryptase and CD20 immunohistochemisty staining was performed on contiguous sections of deparaffinized BM trephine biopsies. After numerization of each section, the BM surface area was manually marked out, excluding the bone framework and adipocytes to limit the analyses to only hematopoietic tissue. MCs were assessed using a digital tool previously used to quantify immune‐cell infiltrates on tumor‐tissue sections. Deep next‐generation sequencing and allele‐specific PCR were used to explore the MYD88 and CXCR4 mutational status. MC density was heterogeneous among the WM patients. An optimal MC density threshold (> 56 MC.mm–2) was defined according to ROC curve analysis of overall survival. A higher MC density (> 56 MC.mm–2) was associated with greater BM involvement by WM lymphoplasmacytic cells and less hepatosplenic involvement (p = 0.023). Furthermore, MC density significantly correlated with a higher ISSWM score (p = 0.0003) in symptomatic patients. Patients with a higher MC density showed shorter median OS (56.5 months vs. nonreached, p = 0.0004), even in multivariate analysis after controlling for other predictive variables, such as age, ISSWM score, and CXCR4 mutational status. In conclusion, MC density can be accurately measured in WM patients using a specific digital tool on well‐outlined hematopoietic tissue surfaces. High MC density is associated with aggressive features and a poor clinical outcome, emphasizing the need for further investigation of the involvement of MCs in the pathophysiology of WM.

Published
2022
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4. AhR/IL-22 pathway as new target for the treatment of post-infectious irritable bowel syndrome symptoms

Author

Maëva Meynier, Elodie Baudu, Nathalie Rolhion, Manon Defaye, Marjolène Straube, Valentine Daugey, Morgane Modoux, Ivan Wawrzyniak, Frédéric Delbac, Romain Villéger, Mathieu Méleine, Esther Borras Nogues, Catherine Godfraind, Nicolas Barnich, Denis Ardid, Philippe Poirier, Harry Sokol, Jean-Marc Chatel, Philippe Langella, Valérie Livrelli, Mathilde Bonnet, and Frédéric Antonio Carvalho

Subjects
post-infectious ibs, colonic-associated microbiota, citrobacter rodentium, tryptophan, ahr, il-22, lactococcus lactis, well-being disorders, Diseases of the digestive system. Gastroenterology, RC799-869
Abstract

Alterations in brain/gut/microbiota axis are linked to Irritable Bowel Syndrome (IBS) physiopathology. Upon gastrointestinal infection, chronic abdominal pain and anxio-depressive comorbidities may persist despite pathogen clearance leading to Post-Infectious IBS (PI-IBS). This study assesses the influence of tryptophan metabolism, and particularly the microbiota-induced AhR expression, on intestinal homeostasis disturbance following gastroenteritis resolution, and evaluates the efficacy of IL-22 cytokine vectorization on PI-IBS symptoms. The Citrobacter rodentium infection model in C57BL6/J mice was used to mimic Enterobacteria gastroenteritis. Intestinal homeostasis was evaluated as low-grade inflammation, permeability, mucosa-associated microbiota composition, and colonic sensitivity. Cognitive performances and emotional state of animals were assessed using several tests. Tryptophan metabolism was analyzed by targeted metabolomics. AhR activity was evaluated using a luciferase reporter assay method. One Lactococcus lactis strain carrying an eukaryotic expression plasmid for murine IL-22 (L. lactisIL−22) was used to induce IL-22 production in mouse colonic mucosa. C. rodentium-infected mice exhibited persistent colonic hypersensitivity and cognitive impairments and anxiety-like behaviors after pathogen clearance. These post-infectious disorders were associated with low-grade inflammation, increased intestinal permeability, decrease of Lactobacillaceae abundance associated with the colonic layer, and increase of short-chain fatty acids (SCFAs). During post-infection period, the indole pathway and AhR activity were decreased due to a reduction of tryptophol production. Treatment with L. lactisIL−22 restored gut permeability and normalized colonic sensitivity, restored cognitive performances and decreased anxiety-like behaviors. Data from the video-tracking system suggested an upgrade of welfare for mice receiving the L.lactisIL−22 strain. Our findings revealed that AhR/IL-22 signaling pathway is altered in a preclinical PI-IBS model. IL-22 delivering alleviate PI-IBS symptoms as colonic hypersensitivity, cognitive impairments, and anxiety-like behaviors by acting on intestinal mucosa integrity. Thus, therapeutic strategies targeting this pathway could be developed to treat IBS patients suffering from chronic abdominal pain and associated well-being disorders.

Published
2022
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5. Epigenetic master regulators HDAC1 and HDAC5 control pathobiont Enterobacteria colonization in ileal mucosa of Crohn’s disease patients

Author

Mélissa Chervy, Adeline Sivignon, Flavie Dambrine, Anthony Buisson, Pierre Sauvanet, Catherine Godfraind, Matthieu Allez, Lionel Le Bourhis, The Remind Group, Nicolas Barnich, and Jérémy Denizot

Subjects
Histone deacetylases, Adherent-InvasiveE. coli, Crohn’s disease, histone acetylation, High-fat diet, Diseases of the digestive system. Gastroenterology, RC799-869
Abstract

Adherent-invasive Escherichia coli (AIEC), which abnormally colonize the ileal mucosa of Crohn’s disease (CD) patients, are known to contribute to the etiopathogenesis of CD. Molecular mechanisms favoring AIEC ileal colonization have not been completely characterized yet. The aim of this study was to investigate whether epigenetic regulators histone deacetylases (HDAC) expression in intestinal epithelial cells of CD patients regulate Enterobacteria and AIEC encroachment to intestinal mucosa. HDAC were inhibited in vitro and in CEABAC10 mice to decipher their involvement in the entry of AIEC within host cells. CD ileal samples from the REMIND cohort were used to study the relationship between HDAC expression level and Enterobacteria/AIEC colonization in patients. Mice were fed a westernized diet and orally challenged with AIEC to determine the impact of diet on HDAC expression. Global level of acetylated histone H3 is higher in patients colonized by AIEC bacteria compared to patients non-colonized by Enterobacteria and HDAC inhibition-mediated H3 hyperacetylation promotes the entry of AIEC bacteria within intestinal epithelial cells. HDAC1 and HDAC5 are central and antagonistic in the regulation of AIEC entry within host cells in vitro, in mouse models and in ileal mucosa of CD patients. In mice fed a western-type diet, AIEC infection decreases HDAC1 expression, inducing H3 hyperacetylation to favor their own colonization. CD patients under a western diet are more prone to be colonized by AIEC bacteria as such a diet affects intestinal homeostasis, enables AIEC access to intestinal mucosa where they then manipulate host-epigenome to their advantage.Abbreviations AIEC Adherent-Invasive Escherichia coli; BSA Bovine serum albumin; CD Crohn’s disease; CEABAC10 Carcinoembryonic antigen bacterial artificial chromosome 10; CEACAM Carcinoembryonic antigen-related cell adhesion molecule; FBS Fetal bovine serum; IBD Inflammatory Bowel Disease; HAT Histone acetyltransferase; HDAC Histone deacetylase; kDa KiloDalton; SAHA Suberoylanilide Hydroxamic Acid; Scr Scramble

Published
2022
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7. Correlation between DNA Methylation and Cell Proliferation Identifies New Candidate Predictive Markers in Meningioma

Author

Sébastien Hergalant, Chloé Saurel, Marion Divoux, Fabien Rech, Celso Pouget, Catherine Godfraind, Pierre Rouyer, Stéphanie Lacomme, Shyue-Fang Battaglia-Hsu, and Guillaume Gauchotte

Subjects
genome-wide DNA methylation, meningioma, methylome, proliferation signature, biomarkers, survival, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Meningiomas are the most common primary tumors of the central nervous system. Based on the 2021 WHO classification, they are classified into three grades reflecting recurrence risk and aggressiveness. However, the WHO’s histopathological criteria defining these grades are somewhat subjective. Together with reliable immunohistochemical proliferation indices, other molecular markers such as those studied with genome-wide epigenetics promise to revamp the current prognostic classification. In this study, 48 meningiomas of various grades were randomly included and explored for DNA methylation with the Infinium MethylationEPIC microarray over 850k CpG sites. We conducted differential and correlative analyses on grade and several proliferation indices and markers, such as mitotic index and Ki-67 or MCM6 immunohistochemistry. We also set up Cox proportional hazard models for extensive associations between CpG methylation and survival. We identified loci highly correlated with cell growth and a targeted methylation signature of regulatory regions persistently associated with proliferation, grade, and survival. Candidate genes under the control of these regions include SMC4, ESRRG, PAX6, DOK7, VAV2, OTX1, and PCDHA-PCDHB-PCDHG, i.e., the protocadherin gene clusters. This study highlights the crucial role played by epigenetic mechanisms in shaping dysregulated cellular proliferation and provides potential biomarkers bearing prognostic and therapeutic value for the clinical management of meningioma.

Published
2022
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8. DNA alteration‐based classification of uveal melanoma gives better prognostic stratification than immune infiltration, which has a neutral effect in high‐risk group

Author

Deepti Narasimhaiah, Catherine Legrand, Diane Damotte, Romain Remark, Marco Munda, Patrick De Potter, Pierre G. Coulie, Miikka Vikkula, and Catherine Godfraind

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background In uveal melanomas, immune infiltration is a marker of poor prognosis. This work intended to decipher the biological characteristics of intra‐tumor immune population, compare it to other established biomarkers and to patients' outcome. Methods Primary, untreated, and mainly large uveal melanomas with retinal detachment were analyzed using: transcriptomic profiling (n = 15), RT‐qPCR (n = 36), immunohistochemistry (n = 89), Multiplex Ligation‐dependent Probe Amplification (MLPA) for copy number alterations (CNA) analysis (n = 89), array‐CGH (n = 17), and survival statistics (n = 86). Results Gene expression analysis divided uveal melanomas into two groups, according to the IFNγ/STAT1‐IRF1 pathway activation. Tumors with IFNγ‐signature had poorer prognosis and showed increased infiltration of CD8+ T lymphocytes and macrophages. Cox multivariate analyses of immune cell infiltration with MLPA data delineated better prognostic value for three prognostic groups (three‐tier stratification) than two (two‐tier stratification). CNA‐based model comprising monosomy 3, 8q amplification, and LZTS1and NBL1 deletions emerged as the best predictor for disease‐free survival. It outperformed immune cell infiltration in receiver operating characteristic curves. The model that combined CNA and immune infiltration defined risk‐groups according to the number of DNA alterations. Immune cell infiltration was increased in the high‐risk group (73.7%), where it did not correlate with patient survival, while it was associated with poorer outcome in the intermediate risk‐group. Conclusions High degree of immune cell infiltration occurs in a subset of uveal melanomas, is interferon‐gamma‐related, and associated with poor survival. It allows for two‐tier stratification, which is prognostically less efficient than a three‐tier one. The best prognostic stratification is by CNA model with three risk‐groups where immune cell infiltration impacts only some subgroups.

Published
2019
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9. Colibactin-Producing Escherichia coli Induce the Formation of Invasive Carcinomas in a Chronic Inflammation-Associated Mouse Model

Author

Laurène Salesse, Cécily Lucas, My Hanh Thi Hoang, Pierre Sauvanet, Alexandra Rezard, Philip Rosenstiel, Christelle Damon-Soubeyrand, Nicolas Barnich, Catherine Godfraind, Guillaume Dalmasso, and Hang Thi Thu Nguyen

Subjects
colorectal cancer, microbiota, colibactin-producing E. coli, autophagy, toxin, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Background: Escherichia coli producing the genotoxin colibactin (CoPEC or colibactin-producing E. coli) abnormally colonize the colonic mucosa of colorectal cancer (CRC) patients. We previously showed that deficiency of autophagy in intestinal epithelial cells (IECs) enhances CoPEC-induced colorectal carcinogenesis in ApcMin/+ mice. Here, we tested if CoPEC trigger tumorigenesis in a mouse model lacking genetic susceptibility or the use of carcinogen. Methods: Mice with autophagy deficiency in IECs (Atg16l1∆IEC) or wild-type mice (Atg16l1flox/flox) were infected with the CoPEC 11G5 strain or the mutant 11G5∆clbQ incapable of producing colibactin and subjected to 12 cycles of DSS treatment to induce chronic colitis. Mouse colons were used for histological assessment, immunohistochemical and immunoblot analyses for DNA damage marker. Results: 11G5 or 11G5∆clbQ infection increased clinical and histological inflammation scores, and these were further enhanced by IEC-specific autophagy deficiency. 11G5 infection, but not 11G5∆clbQ infection, triggered the formation of invasive carcinomas, and this was further increased by autophagy deficiency. The increase in invasive carcinomas was correlated with enhanced DNA damage and independent of inflammation. Conclusions: CoPEC induce colorectal carcinogenesis in a CRC mouse model lacking genetic susceptibility and carcinogen. This work highlights the role of (i) CoPEC as a driver of CRC development, and (ii) autophagy in inhibiting the carcinogenic properties of CoPEC.

Published
2021
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10. The Implementation of DNA Methylation Profiling into a Multistep Diagnostic Process in Pediatric Neuropathology: A 2-Year Real-World Experience by the French Neuropathology Network

Author

Melanie Pages, Emmanuelle Uro-Coste, Carole Colin, David Meyronet, Guillaume Gauchotte, Claude-Alain Maurage, Audrey Rousseau, Catherine Godfraind, Karima Mokhtari, Karen Silva, Dominique Figarella-Branger, Pascale Varlet, and on behalf of the RENOCLIP-LOC Network

Subjects
DNA methylation, pediatric CNS tumors, tumor classification, copy-number variation, integrated diagnosis, molecular pathology, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

DNA methylation profiling has recently emerged as a powerful tool to help establish diagnosis in neuro-oncology. Here we present our national diagnostic strategy as the French neuropathology network (RENOCLIP-LOC) and our current approach of integrating DNA methylation profiling into our multistep diagnostic process for challenging pediatric CNS tumors. The tumors with diagnostic uncertainty were prospectively selected for DNA methylation after two rounds of review by neuropathology experts. We first integrated the classifier score into the histopathological findings. Subsequent analyses using t-SNE (t-Distributed Stochastic Neighbor Embedding) representation were performed. An additional step consisted of analyzing copy-number variation data (CNV). Finally, we combined all data to establish diagnoses and evaluated the impact of DNA methylation profiling on diagnostic and grading changes that would affect patient management. Over two years, 62 pediatric tumors were profiled. (1) Integrating the classifier score to the histopathological findings impacted the diagnosis in 33 cases (53%). (2) t-SNE analysis provided arguments for diagnosis in 26/35 cases with calibrated scores

Published
2021
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11. New Antibody-Free Mass Spectrometry-Based Quantification Reveals That C9ORF72 Long Protein Isoform Is Reduced in the Frontal Cortex of Hexanucleotide-Repeat Expansion Carriers

Author

Arthur Viodé, Clémence Fournier, Agnès Camuzat, François Fenaille, NeuroCEB Brain Bank, Morwena Latouche, Fanny Elahi, Isabelle Le Ber, Christophe Junot, Foudil Lamari, Vincent Anquetil, François Becher, Franck Letournel, Anne Vital, Françoise Chapon, Catherine Godfraind, Claude-Alain Maurage, Vincent Deramecourt, David Meyronnet, Nathalie Streichenberger, André Maues de Paula, Valérie Rigau, Fanny Vandenbos-Burel, Charles Duyckaerts, Danielle Seilhean, Véronique Sazdovitch, Serge Milin, Dan Christian Chiforeanu, Annie Laquerrière, and Béatrice Lannes

Subjects
frontotemporal dementia (FTD), frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS), C9ORF72, TDP-43, TDP43, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Frontotemporal dementia (FTD) is a fatal neurodegenerative disease characterized by behavioral and language disorders. The main genetic cause of FTD is an intronic hexanucleotide repeat expansion (G4C2)n in the C9ORF72 gene. A loss of function of the C9ORF72 protein associated with the allele-specific reduction of C9ORF72 expression is postulated to contribute to the disease pathogenesis. To better understand the contribution of the loss of function to the disease mechanism, we need to determine precisely the level of reduction in C9ORF72 long and short isoforms in brain tissue from patients with C9ORF72 mutations. In this study, we developed a sensitive and robust mass spectrometry (MS) method for quantifying C9ORF72 isoform levels in human brain tissue without requiring antibody or affinity reagent. An optimized workflow based on surfactant-aided protein extraction and pellet digestion was established for optimal recovery of the two isoforms in brain samples. Signature peptides, common or specific to the isoforms, were targeted in brain extracts by multiplex MS through the parallel reaction monitoring mode on a Quadrupole–Orbitrap high resolution mass spectrometer. The assay was successfully validated and subsequently applied to frontal cortex brain samples from a cohort of FTD patients with C9ORF72 mutations and neurologically normal controls without mutations. We showed that the C9ORF72 short isoform in the frontal cortices is below detection threshold in all tested individuals and the C9ORF72 long isoform is significantly decreased in C9ORF72 mutation carriers.

Published
2018
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12. Extensive Spinal Cord Injury following Staphylococcus aureus Septicemia and Meningitis

Author

Nicolas De Schryver, Guy Cosnard, Vincent van Pesch, Catherine Godfraind, and Philippe Hantson

Subjects
Bacterial meningitis, Septicemia, Spinal cord injury, Vasculitis, Neurology. Diseases of the nervous system, RC346-429
Abstract

Bacterial meningitis is rarely complicated by spinal cord involvement in adults. We report a case of Staphylococcus aureus septicemia complicated by meningitis and extensive spinal cord injury, leading to ascending brain stem necrosis and death. This complication was investigated by magnetic resonance imaging which demonstrated intramedullary hyperintensity on T2-weighted images and by multimodality evoked potentials. Postmortem microscopic examination confirmed that the extensive spinal cord injury was of ischemic origin, caused by diffuse leptomeningitis and endarteritis.

Published
2011
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13. MicroRNA and target protein patterns reveal physiopathological features of glioma subtypes.

Author

Elodie Lages, Audrey Guttin, Michèle El Atifi, Claire Ramus, Hélène Ipas, Isabelle Dupré, Delphine Rolland, Caroline Salon, Catherine Godfraind, Florence deFraipont, Mehdi Dhobb, Laurent Pelletier, Didier Wion, Emmanuel Gay, François Berger, and Jean-Paul Issartel

Subjects
Medicine, Science
Abstract

Gliomas such as oligodendrogliomas (ODG) and glioblastomas (GBM) are brain tumours with different clinical outcomes. Histology-based classification of these tumour types is often difficult. Therefore the first aim of this study was to gain microRNA data that can be used as reliable signatures of oligodendrogliomas and glioblastomas. We investigated the levels of 282 microRNAs using membrane-array hybridisation and real-time PCR in ODG, GBM and control brain tissues. In comparison to these control tissues, 26 deregulated microRNAs were identified in tumours and the tissue levels of seven microRNAs (miR-21, miR-128, miR-132, miR-134, miR-155, miR-210 and miR-409-5p) appropriately discriminated oligodendrogliomas from glioblastomas. Genomic, epigenomic and host gene expression studies were conducted to investigate the mechanisms involved in these deregulations. Another aim of this study was to better understand glioma physiopathology looking for targets of deregulated microRNAs. We discovered that some targets of these microRNAs such as STAT3, PTBP1 or SIRT1 are differentially expressed in gliomas consistent with deregulation of microRNA expression. Moreover, MDH1, the target of several deregulated microRNAs, is repressed in glioblastomas, making an intramitochondrial-NAD reduction mediated by the mitochondrial aspartate-malate shuttle unlikely. Understanding the connections between microRNAs and bioenergetic pathways in gliomas may lead to identification of novel therapeutic targets.

Published
2011
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14. Spatially-resolved metabolomic identifies colibactin-specific principles of reprogrammed lipid metabolism to promote cancer progression

Author

Nilmara de Oliveira Alves, Olivier Boulard, Amaury Vaysse, Guillaume Dalmasso, Darja Nikitina, Richard Ruez, Thierry Pedron, Emma Bergstein, Pierre Sauvanet, Diane Letourneur, Catherine Godfraind, Imène Najjar, Emmanuel Lemichez, Juan Lucio Iovanna, Denis Mestivier, Nicolas Barnich, Philippe Sansonetti, Christophe Malabat, Marc Monot, Sean Kennedy, Amel Mettouchi, Richard Bonnet, Iradj Sobhani, and Mathias Chamaillard

Abstract

The cellular heterogeneity within a variety of solid tumors is influenced by several type of tumor-associated bacteria through yet poorly understood mechanisms. Unbiased genomic analysis revealed that right-sided colorectal tumors with poorer prognosis are preferentially populated with species related toEscherichia coli, including strains that are producing colibactin. By applying metabolomic profilingin situ, the presence of colibactin-producingEscherichia coli(CoPEC) was identified to establish a high-glycerophospholipid microenvironment within right-sided colorectal tumors that are bearing mutations in either APC or KRAS. Using spatial approaches, we revealed that bacterial microniches are poorly infiltrated with CD8+T cells. The aforementioned alterations in lipid metabolism negatively correlated with immunomodulatory and neurotrophic factors among which the human regenerating family member 3 alpha gene (REG3A). Accordingly, the loss of its ortholog enhances growth at the proximal colon of tumors with a microenvironment that impedes immune surveillance and shares similarities to human right-sided colorectal tumors. This work clarifies how the presence of colibactin-producing bacteria may locally establish tumor heterogeneity for lipid metabolism to promote cancer progression and provide unique insights both for therapeutic intervention and enabling basic research into the mechanisms of microbiota-host interaction.STATEMENT OF SIGNIFICANCEApplyingin situmetabolic imaging to patients’ tumors revealed that the accumulation of colibactin-producing bacteria that locally creates a potential vulnerability to cancer treatments through lipid metabolic reprogramming of tumor cells.

Published
2023

15. Rosette-forming glioneuronal tumours are midline, FGFR1-mutated tumours

Author

Romain Appay, Franck Bielle, Philipp Sievers, Doriane Barets, Frédéric Fina, Jean Boutonnat, Clovis Adam, Guillaume Gauchotte, Catherine Godfraind, Benoît Lhermitte, Claude‐Alain Maurage, David Meyronet, Karima Mokhtari, Audrey Rousseau, Arnault Tauziède‐Espariat, Marie‐Claire Tortel, Emmanuelle Uro‐Coste, Fanny Burel‐Vandenbos, Guillaume Chotard, Florian Pesce, Pascale Varlet, Carole Colin, Dominique Figarella‐Branger, Institut de neurophysiopathologie (INP), and Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Histology, Brain Neoplasms, Class I Phosphatidylinositol 3-Kinases, [SDV]Life Sciences [q-bio], [SDV.CAN]Life Sciences [q-bio]/Cancer, Glioma, Neoplasms, Neuroepithelial, Pathology and Forensic Medicine, Central Nervous System Neoplasms, Class Ia Phosphatidylinositol 3-Kinase, Neurology, Physiology (medical), Humans, Neurology (clinical), Receptor, Fibroblast Growth Factor, Type 1
Abstract

Rosette-forming glioneuronal tumour (RGNT) is a rare central nervous system (CNS) World Health Organization (WHO) grade 1 brain neoplasm. According to the WHO 2021, essential diagnostic criteria are a 'biphasic histomorphology with neurocytic and a glial component, and uniform neurocytes forming rosettes and/or perivascular pseudorosettes associated with synaptophysin expression' and/or DNA methylation profile of RGNT whereas 'FGFR1 mutation with co-occurring PIK3CA and/or NF1 mutation' are desirable criteria.We report a series of 46 cases fulfilling the essential pathological diagnostic criteria for RGNT. FGFR1 and PIK3CA hotspot mutations were searched for by multiplexed digital PCR in all cases, whereas DNA methylation profiling and/or PIK3R1 and NF1 alterations were analysed in a subset of cases.Three groups were observed. The first one included 21 intracranial midline tumours demonstrating FGFR1 mutation associated with PIK3CA or PIK3R1 (n = 19) or NF1 (n = 1) or PIK3CA and NF1 (n = 1) mutation. By DNA methylation profiling, eight cases were classified as RGNT (they demonstrated FGFR1 and PIK3CA or PIK3R1 mutations). Group 2 comprised 11 cases associated with one single FGFR1 mutation. Group 3 included six cases classified as low-grade glioma (LGG) other than RGNT (one-sixth showed FGFR1 mutation and one a FGFR1 and NF1 mutation) and eight cases without FGFR1 mutation. Groups 2 and 3 were enriched in lateral and spinal cases.We suggest adding FGFR1 mutation and intracranial midline location as essential diagnostic criteria. When DNA methylation profiling is not available, a RGNT diagnosis remains certain in cases demonstrating characteristic pathological features and FGFR1 mutation associated with either PIK3CA or PIK3R1 mutation.

Published
2022

16. A polyphenotypic malignant paediatric brain tumour presenting a MN1‐PATZ1 fusion, no epigenetic similarities with CNS High‐Grade Neuroepithelial Tumour with MN1 Alteration (CNS HGNET‐MN1) and related to PATZ1 ‐fused sarcomas

Author

Christian Thomas, Claude-Alain Maurage, G. Duhil de Benaze, Gaëlle Pierron, Martin Hasselblatt, Dominique Figarella-Branger, S. Croze, Stéphanie Reynaud, Florence Pedeutour, V. Gregoire, N. Chivoret, M. Honavar, Catherine Godfraind, and F. Burel‐Vandenbos

Subjects
Neuroepithelial cell, Histology, Text mining, Neurology, business.industry, Physiology (medical), DNA methylation, Cancer research, Medicine, Neurology (clinical), Epigenetics, business, Pathology and Forensic Medicine
Published
2020

18. PATZ1 fusions define a novel molecularly distinct neuroepithelial tumor entity with a broad histological spectrum

Author

Elli Papaemmanuil, Bastiaan B. J. Tops, Torben Stamm Mikkelsen, Fanny Vandenbos, Christof M. Kramm, Nancy Bouvier, Katharina Filipski, Nagma Dalvi, Kristian W. Pajtler, Andrea Wittmann, Christine Haberler, Till Milde, Olaf Witt, Hildegard Dohmen, Martin Sill, George Jour, Matija Snuderl, Allison M. Martin, Torsten Pietsch, Antonis Kattamis, Nicholas G. Gottardo, Emmanuelle Uro-Coste, Philipp Sievers, Andreas von Deimling, Frank Alvaro, Simone Schmid, Damian Stichel, Jonas Ecker, Marcel Kool, Johannes Gojo, Lidija Kitanovski, Michal Zapotocky, Michael Delorenzo, Catherine Godfraind, Florian Selt, Alexander C Sommerkamp, Adam S. Levy, Pieter Wesseling, Evelina Miele, Lenka Krskova, Pengbo Beck, Matthias A. Karajannis, David Scheie, Jordan R. Hansford, Natalie Jäger, Karam T. Alhalabi, Andrey Korshunov, Felix Sahm, Mariëtte E.G. Kranendonk, David T.W. Jones, David Sumerauer, Chris Jones, Katja von Hoff, Heike Peterziel, Stefan M. Pfister, Dominik Sturm, Martin G. McCabe, Ina Oehme, Maria Filippidou, Claude Alain Maurage, Ingrid Øra, Till Acker, Pathology, CCA - Cancer biology and immunology, and CCA - Imaging and biomarkers

Subjects
Male, Pathology, medicine.medical_specialty, Oncogene Proteins, Fusion, PATZ1, Kruppel-Like Transcription Factors, Brain tumor, Neuroepithelial, Biology, Malignancy, Pathology and Forensic Medicine, Fusion gene, Cellular and Molecular Neuroscience, Biomarkers, Tumor, medicine, Humans, Oncogene Fusion, Copy-number variation, ddc:610, Child, Kruppel-Like Transcription Factors/genetics, Brain Neoplasms/genetics, Pediatric, Neoplasms, Neuroepithelial/genetics, Repressor Proteins/genetics, Original Paper, Manchester Cancer Research Centre, MN1, Brain Neoplasms, ResearchInstitutes_Networks_Beacons/mcrc, GATA2, Neurooncology, medicine.disease, Neoplasms, Neuroepithelial, Repressor Proteins, Neuroepithelial cell, EWSR1, Child, Preschool, Oncogene Proteins, Fusion/genetics, Female, Neurology (clinical), Biomarkers, Tumor/genetics, Chromosome 22, Gene fusion
Abstract

Large-scale molecular profiling studies in recent years have shown that central nervous system (CNS) tumors display a much greater heterogeneity in terms of molecularly distinct entities, cellular origins and genetic drivers than anticipated from histological assessment. DNA methylation profiling has emerged as a useful tool for robust tumor classification, providing new insights into these heterogeneous molecular classes. This is particularly true for rare CNS tumors with a broad morphological spectrum, which are not possible to assign as separate entities based on histological similarity alone. Here, we describe a molecularly distinct subset of predominantly pediatric CNS neoplasms (n = 60) that harbor PATZ1 fusions. The original histological diagnoses of these tumors covered a wide spectrum of tumor types and malignancy grades. While the single most common diagnosis was glioblastoma (GBM), clinical data of the PATZ1-fused tumors showed a better prognosis than typical GBM, despite frequent relapses. RNA sequencing revealed recurrent MN1:PATZ1 or EWSR1:PATZ1 fusions related to (often extensive) copy number variations on chromosome 22, where PATZ1 and the two fusion partners are located. These fusions have individually been reported in a number of glial/glioneuronal tumors, as well as extracranial sarcomas. We show here that they are more common than previously acknowledged, and together define a biologically distinct CNS tumor type with high expression of neural development markers such as PAX2, GATA2 and IGF2. Drug screening performed on the MN1:PATZ1 fusion-bearing KS-1 brain tumor cell line revealed preliminary candidates for further study. In summary, PATZ1 fusions define a molecular class of histologically polyphenotypic neuroepithelial tumors, which show an intermediate prognosis under current treatment regimens.

Published
2021

19. Answer to August 2021 Photo Quiz

Author

Nicolas Saroul, Elisa Creuzet, Maxime Moniot, Catherine Godfraind, Laurent Gilain, Céline Nourrisson, Philippe Poirier, Claudel Catinot Noubam Tchatat, Laura Montrieul, Laboratoire de Parasitologie et Mycologie [CHU Clermont-Ferrand], CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Infection Inflammation et Interaction Hôtes Pathogènes [CHU Clermont-Ferrand] (3IHP ), Direction de la recherche clinique et de l’innovation [CHU Clermont-Ferrand] (DRCI), Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte (M2iSH), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Recherche en Nutrition Humaine d'Auvergne (CRNH d'Auvergne)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Clermont Auvergne (UCA), Service d'Anatomie Pathologique [CHU Clermont-Ferrand], Service de Chirurgie Maxillo-Faciale et Chirurgie Plastique [CHU Clermont-Ferrand], CHU Estaing [Clermont-Ferrand], Laboratoire Microorganismes : Génome et Environnement (LMGE), and Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne (UCA)

Subjects
Microbiology (medical), 0303 health sciences, medicine.medical_specialty, 030306 microbiology, business.industry, Photo Quiz, Scedosporium, 03 medical and health sciences, 0302 clinical medicine, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Medicine, Medical physics, 030223 otorhinolaryngology, business, ComputingMilieux_MISCELLANEOUS
Abstract

International audience

Published
2021

20. Photo Quiz: A Bag of Marbles in the Nose

Author

Catherine Godfraind, Laurent Gilain, Céline Nourrisson, Laura Montrieul, Maxime Moniot, Nicolas Saroul, Elisa Creuzet, Philippe Poirier, Claudel Catinot Noubam Tchatat, Laboratoire de Parasitologie et Mycologie [CHU Clermont-Ferrand], CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Infection Inflammation et Interaction Hôtes Pathogènes [CHU Clermont-Ferrand] (3IHP ), Direction de la recherche clinique et de l’innovation [CHU Clermont-Ferrand] (DRCI), Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte (M2iSH), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Recherche en Nutrition Humaine d'Auvergne (CRNH d'Auvergne)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Clermont Auvergne (UCA), Service d'Anatomie Pathologique [CHU Clermont-Ferrand], Service de Chirurgie Maxillo-Faciale et Chirurgie Plastique [CHU Clermont-Ferrand], CHU Estaing [Clermont-Ferrand], Laboratoire Microorganismes : Génome et Environnement (LMGE), Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne (UCA), and Molé, Christine

Subjects
Microbiology (medical), 0303 health sciences, 030306 microbiology, media_common.quotation_subject, Photo Quiz, Art, Anatomy, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, medicine, 030212 general & internal medicine, [SDV.MP] Life Sciences [q-bio]/Microbiology and Parasitology, Nose, ComputingMilieux_MISCELLANEOUS, media_common
Abstract

International audience

Published
2021

22. Phase 1 trial of ralimetinib (LY2228820) with radiotherapy plus concomitant temozolomide in the treatment of newly diagnosed glioblastoma

Author

R. Bellini, Julian Biau, Ioana Molnar, Catherine Godfraind, D. Stefan, Emmanuel Chautard, Fabrice Kwiatkowski, Xavier Durando, M. Boone, B. Chauffert, Emilie Thivat, Damien Richard, C. Bourgne, Pierre Verrelle, Lucie Karayan-Tapon, S. Levesque, COLO, Mouniati, Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Unité de génétique médicale et oncogénétique [CHU Amiens Picardie], CHU Amiens-Picardie, CHirurgie, IMagerie et REgénération tissulaire de l’extrémité céphalique - Caractérisation morphologique et fonctionnelle - UR UPJV 7516 (CHIMERE), Université de Picardie Jules Verne (UPJV), Role of intra-Clonal Heterogeneity and Leukemic environment in ThErapy Resistance of chronic leukemias (CHELTER), Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Neuro-Dol (Neuro-Dol), Centre d'Investigation Clinique [CHU Clermont-Ferrand] (CIC 1405), Institut National de la Santé et de la Recherche Médicale (INSERM)-Direction de la recherche clinique et de l’innovation [CHU Clermont-Ferrand] (DRCI), CHU Clermont-Ferrand-CHU Clermont-Ferrand, Institut Curie [Paris], CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand, Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte (M2iSH), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Recherche en Nutrition Humaine d'Auvergne (CRNH d'Auvergne)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Clermont Auvergne (UCA), Institut National du Cancer (INCA) France foundation ARC, UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), Laboratoire de neurosciences expérimentales et cliniques (LNEC), and Université de Poitiers-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
[SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, medicine.medical_specialty, Nausea, Pyridines, medicine.medical_treatment, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Phases of clinical research, [SDV.CAN]Life Sciences [q-bio]/Cancer, Gastroenterology, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, Temozolomide, Medicine, Humans, Radiology, Nuclear Medicine and imaging, Antineoplastic Agents, Alkylating, Ralimetinib, Chemotherapy, Radiotherapy, business.industry, Brain Neoplasms, Imidazoles, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Hematology, Chemoradiotherapy, Rash, 3. Good health, Radiation therapy, Dacarbazine, Oncology, 030220 oncology & carcinogenesis, Concomitant, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Leukocytes, Mononuclear, Phase I clinical trial, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, medicine.symptom, business, Glioblastoma, medicine.drug
Abstract

International audience; Background and purpose: This phase 1 trial aimed to determine the maximum tolerated dose (MTD; primary objective) of a p38-MAPK inhibitor, ralimetinib, with radiotherapy (RT) and chemotherapy (TMZ), in the treatment of newly diagnosed glioblastoma (GBM) patients.Materials and methods: The study was designed as an open-label dose-escalation study driven by a Tite-CRM design and followed by an expansion cohort. Ralimetinib was administered orally every 12 h, 7 days a week, for 2 cycles of 2 weeks at a dose of 100, 200 or 300 mg/12 h. Patients received ralimetinib added to standard concurrent RT (60 Gy in 30 fractions) with TMZ (75 mg/m2/day) and 6 cycles of adjuvant TMZ (150–200 mg/m2 on days 1–5 every 28 days).Results: The MTD of ralimetinib was 100 mg/12 h with chemoradiotherapy. The three patients treated at 200 mg/12 h presented a dose-limiting toxicity: one patient had a grade 3 face edema, and two patients had a grade 3 rash and grade 3 hepatic cytolysis (66%). Of the 18 enrolled patients, 15 received the MTD of ralimetinib. At the MTD, the grade ≥ 3 adverse events during concomitant chemoradiotherapy were hepatic cytolysis (2/15 patients), dermatitis/rash (1/15), lymphopenia (1/15) and nausea/vomiting (1/15). No interaction of TMZ and ralimetinib when administrated concomitantly has been observed. Inhibition of pMAPKAP-K2 (−54%) was observed in peripheral blood mononuclear cells.Conclusion:This phase 1 trial is the first trial to study the combination of a p38-MAPK inhibitor, ralimetinib, with radiotherapy (RT) and chemotherapy (TMZ), in the treatment of newly diagnosed glioblastoma (GBM) patients. The MTD of ralimetinib was 100 mg/12 h. The most frequent dose-limiting toxicities were hepatic cytolysis and rash.

Published
2021

23. Fecal dysbiosis associated with colonic hypersensitivity and behavioral alterations in chronically Blastocystis-infected rats

Author

Céline Nourrisson, Denis Ardid, Elodie Baudu, Ivan Wawrzyniak, Nicolas Barnich, Amandine Lashermes, Agathe Gelot, Julie Barbier, Virginie Bonnin, Frédéric Delbac, Manon Defaye, Maeva Meynier, Mathieu Meleine, Catherine Godfraind, Benoit Chassaing, Mathilde Bonnet, Philippe Poirier, Frederic A. Carvalho, Laboratoire Microorganismes : Génome et Environnement (LMGE), Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), Neuro-Dol (Neuro-Dol), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Laboratoire de Parasitologie et Mycologie [CHU Clermont-Ferrand], CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte (M2iSH), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre de Recherche en Nutrition Humaine d'Auvergne (CRNH d'Auvergne)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Georgia State University, University System of Georgia (USG), Mucosal microbiota in chronic inflammatory diseases [Paris], Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Université Paris Cité (UPCité), Service d'Anatomie Pathologique [CHU Clermont-Ferrand], This work was supported by co-financing from the Region Auvergne-Rhône-Alpes and FEDER in 2015 ('Thématiques émergentes'). Manon Defaye and Elodie Baudu received grants from the Auvergne-Rhône-Alpes Region. This work was supported by the « Ministère de la Recherche et de la Technologie », Inserm and University Clermont Auvergne [UMR1107, UMR1071], INRA [USC-2018], CNRS [UMR6023]., Region Auvergne-Rhone-Alpes European Union (EU) Region Auvergne-Rhone-AlpesRegion Bourgogne-Franche-ComteRegion Hauts-de-FranceRegion Nouvelle-Aquitaine Ministere de la Recherche et de la Technologie Institut National de la Sante et de la Recherche Medicale (Inserm) University Clermont Auvergne UMR1107UMR1071INRA USC-2018Centre National de la Recherche Scientifique (CNRS)UMR6023, Bodescot, Myriam, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Université de Paris (UP), Service d'Anatomopathologie [Clermont-Ferrand], CHU Clermont-Ferrand, and Interactions microbiote/mucus dans les maladies inflammatoires chroniques = Mucosal microbiota in chronic inflammatory diseases

Subjects
0301 basic medicine, Elevated plus maze, Intestinal parasite, lcsh:Medicine, Blastocystis Infections, Gut flora, medicine.disease_cause, Microbiology, Article, 03 medical and health sciences, Colonic Diseases, Feces, 0302 clinical medicine, medicine, Animals, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, Risk factor, Rats, Wistar, lcsh:Science, Irritable bowel syndrome, Blastocystis, Multidisciplinary, biology, Behavior, Animal, business.industry, Microbiota, lcsh:R, Gastroenterology, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, biology.organism_classification, medicine.disease, Fatty Acids, Volatile, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, 3. Good health, Rats, Disease Models, Animal, 030104 developmental biology, ROC Curve, Area Under Curve, Immunology, Dysbiosis, 030211 gastroenterology & hepatology, lcsh:Q, Serine Proteases, business, [SDV.MP.PAR] Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology
Abstract

Background: Infectious gastroenteritis is a risk factor for the development of post-infectious Irritable Bowel Syndrome (PI-IBS). Recent clinical studies reported a higher prevalence of the intestinal parasite Blastocystis in IBS patients. Using a rat model, we investigated the possible association between Blastocystis infection, colonic hypersensitivity (CHS), behavioral disturbances and gut microbiota changes. Methods: Rats were orally infected with Blastocystis subtype 4 (ST4) cysts, isolated from human stool samples. Colonic sensitivity was assessed by colorectal distension and animal behavior with an automatic behavior recognition system (PhenoTyper), the Elevated Plus Maze test and the Forced Swimming tests. Feces were collected at different time points after infection to study microbiota composition by 16 S rRNA amplicon sequencing and for short-chain fatty acid (SFCA) analysis. Results: Blastocystis-infected animals had non-inflammatory CHS with increased serine protease activity. Infection was also associated with anxiety- and depressive-like behaviors. Analysis of fecal microbiota composition showed an increase in bacterial richness associated with altered microbiota composition. These changes included an increase in the relative abundance of Oscillospira and a decrease in Clostridium, which seem to be associated with lower levels of SCFAs in the feces from infected rats. Conclusions: Our findings suggest that experimental infection of rats with Blastocystis mimics IBS symptoms with the establishment of CHS related to microbiota and metabolic shifts.

Published
2020

24. Primary Cutaneous CD4+ Small/Medium T-Cell Lymphoproliferative Disorders: A Clinical, Pathologic, and Molecular Study of 60 Cases Presenting With a Single Lesion: A Multicenter Study of the French Cutaneous Lymphoma Study Group

Author

B. Vergier, Bruno Pereira, Michel D'Incan, Saskia Ingen-Housz-Oro, Marie-Hélène Delfau, Laura Pelletier, F. Franck, Marie Beylot-Barry, Nicolas Ortonne, Catherine Godfraind, and Fanny Beltzung

Subjects
Adult, CD4-Positive T-Lymphocytes, Male, Pathology, medicine.medical_specialty, Skin Neoplasms, Remission, Spontaneous, Lymphoproliferative disorders, Cutaneous lymphoma, Pathology and Forensic Medicine, 030207 dermatology & venereal diseases, 03 medical and health sciences, 0302 clinical medicine, Dermis, Biopsy, medicine, Biomarkers, Tumor, Humans, Aged, Retrospective Studies, Aged, 80 and over, medicine.diagnostic_test, business.industry, Lineage markers, Sequence Analysis, DNA, Hyperplasia, Middle Aged, medicine.disease, Immunohistochemistry, 3. Good health, Lymphoma, Lymphoma, T-Cell, Cutaneous, medicine.anatomical_structure, Phenotype, 030220 oncology & carcinogenesis, Localized disease, Mutation, Surgery, Female, France, Anatomy, business, Follow-Up Studies
Abstract

Primary cutaneous CD4 small/medium T-cell lymphoproliferative disorder (PCSMLPD) is a recently recognized entity in the 2017 World Health Organization (WHO) classification. It belongs to the T-follicular helper (TFH) lymphoproliferations. The clinical, pathologic, and molecular features of this localized disease are underresearched. We conducted a retrospective multicentric study of 60 patients with a PCSMLPD that presented as a single cutaneous lesion. Clinical, pathologic, and targeted molecular analyses were performed. PCSMLPD presented mostly as a nodule (45%), located on the head and neck area (50%) in adults (mean age: 59 y [43.3 to 75.2]). All patients had an indolent disease course, either at initial staging or during follow-up (mean: 16.6 mo [1.3 to 31.9]). Spontaneous regression was reported in 31.9% of cases. The infiltrates were most often nodular and/or diffuse, expanding in the whole dermis (78%, Pattern 1), rather than subepidermal band-like in the superficial dermis (22%, Pattern 2). Epidermotropism, folliculotropism, and capillary hyperplasia were common. The expression of TFH lineage markers was more extensive in lesions with Pattern 2, but a substantial B-cell infiltrate was seen in both types of lesions. A clonal rearrangement of the TCR genes was identified in 68% of cases. One sample of the 13 tested revealed a mutation in the DNMT3A gene among the 9 genes studied (TET2, DNMT3A, IDH2, RHOA, SETD2, PLCG1, STAT3, STAT5B, and CD28). PCSMLPD follows a benign clinical course and can spontaneously regress after biopsy. Although PCSMLPD expresses TFH lineage markers, mutations usually found in angioimmunoblastic T-cell lymphomas are uncommon.

Published
2020

25. Autophagy of Intestinal Epithelial Cells Inhibits Colorectal Carcinogenesis Induced by Colibactin-Producing Escherichia coli in Apc Mice

Author

Laurène Salesse, Mathilde Bonnet, Catherine Godfraind, Denis Pezet, Cécily Lucas, Nicolas Barnich, Anaïs Larabi, Hang Thi Thu Nguyen, My Hanh Thi Hoang, Pierre Sauvanet, Guillaume Dalmasso, Johan Gagnière, Philip Rosenstiel, Richard Bonnet, Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte (M2iSH), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre de Recherche en Nutrition Humaine d'Auvergne (CRNH d'Auvergne)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Laboratoire de Neuropathologie, Université Catholique de Louvain = Catholic University of Louvain (UCL)-Clinique Saint-Luc, CHU Clermont-Ferrand, Department of Digestive Surgery, University Medical Hospital, Institute of Clinical Molecular Biology, Kiel University, CCSD, Accord Elsevier, and ANR-16-IDEX-0001,CAP 20-25,CAP 20-25(2016)

Subjects
0301 basic medicine, Carcinogenesis, Colon, DNA repair, DNA damage, Adenomatous Polyposis Coli Protein, ATG5, Autophagy-Related Proteins, Mice, Transgenic, Biology, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Mice, 03 medical and health sciences, 0302 clinical medicine, Autophagy, Escherichia coli, Animals, Humans, Intestinal Mucosa, RNA, Small Interfering, ATG16L1, ComputingMilieux_MISCELLANEOUS, Cell Proliferation, Hepatology, Gastroenterology, Epithelial Cells, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, HCT116 Cells, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, 3. Good health, Gene Expression Regulation, Neoplastic, Reverse transcription polymerase chain reaction, Disease Models, Animal, 030104 developmental biology, Real-time polymerase chain reaction, Gene Knockdown Techniques, Polyketides, Colonic Neoplasms, Host-Pathogen Interactions, Cancer research, 030211 gastroenterology & hepatology, Tumor necrosis factor alpha, [SDV.MP.BAC] Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Peptides, HeLa Cells
Abstract

Background & Aims Colibactin-producing Escherichia coli (CoPEC) colonize the colonic mucosa of a higher proportion of patients with vs without colorectal cancer (CRC) and promote colorectal carcinogenesis in susceptible mouse models of CRC. Autophagy degrades cytoplasmic contents, including intracellular pathogens, via lysosomes and regulates intestinal homeostasis. We investigated whether inhibiting autophagy affects colorectal carcinogenesis in susceptible mice infected with CoPEC. Methods Human intestinal epithelial cells (IECs) (HCT-116) were infected with a strain of CoPEC (11G5 strain) isolated from a patient or a mutant strain that does not produce colibactin (11G5ΔclbQ). Levels of ATG5, ATG16L1, and SQSTM1 (also called p62) were knocked down in HCT-116 cells using small interfering RNAs. ApcMin/+ mice and ApcMin/+ mice with IEC-specific disruption of Atg16l1 (ApcMin/+/Atg16l1ΔIEC) were infected with 11G5 or 11G5ΔclbQ. Colonic tissues were collected from mice and analyzed for tumor size and number and by immunohistochemical staining, immunoblot, and quantitative reverse transcription polymerase chain reaction for markers of autophagy, DNA damage, cell proliferation, and inflammation. We analyzed levels of messenger RNAs (mRNAs) encoding proteins involved in autophagy in colonic mucosal tissues from patients with sporadic CRC colonized with vs without CoPEC by quantitative reverse-transcription polymerase chain reaction. Results Patient colonic mucosa with CoPEC colonization had higher levels of mRNAs encoding proteins involved in autophagy than colonic mucosa without these bacteria. Infection of cultured IECs with 11G5 induced autophagy and DNA damage repair, whereas infection with 11G5ΔclbQ did not. Knockdown of ATG5 in HCT-116 cells increased numbers of intracellular 11G5, secretion of interleukin (IL) 6 and IL8, and markers of DNA double-strand breaks but reduced markers of DNA repair, indicating that autophagy is required for bacteria-induced DNA damage repair. Knockdown of ATG5 in HCT-116 cells increased 11G5-induced senescence, promoting proliferation of uninfected cells. Under uninfected condition, ApcMin/+/Atg16l1ΔIEC mice developed fewer and smaller colon tumors than ApcMin/+ mice. However, after infection with 11G5, ApcMin/+/Atg16l1ΔIEC mice developed more and larger tumors, with a significant increase in mean histologic score, than infected ApcMin/+ mice. Increased levels of Il6, Tnf, and Cxcl1 mRNAs, decreased level of Il10 mRNA, and increased markers of DNA double-strand breaks and proliferation were observed in the colonic mucosa of 11G5-infected ApcMin/+/Atg16l1ΔIEC mice vs 11G5-infected ApcMin/+ mice. Conclusion Infection of IECs and susceptible mice with CoPEC promotes autophagy, which is required to prevent colorectal tumorigenesis. Loss of ATG16L1 from IECs increases markers of inflammation, DNA damage, and cell proliferation and increases colorectal tumorigenesis in 11G5-infected ApcMin/+ mice. These findings indicate the importance of autophagy in response to CoPEC infection, and strategies to induce autophagy might be developed for patients with CRC and CoPEC colonization.

Published
2020

26. Machine Learning for Better Prognostic Stratification and Driver Gene Identification Using Somatic Copy Number Variations in Anaplastic Oligodendroglioma

Author

Luc Bauchet, Denys Fontaine, D. Larrieu‐Ciron, M. Andraud, H. Aubriot‐Lorton, Fabien Forest, G. Runavot, Shai Rosenberg, I. Carpiuc, François Labrousse, Christine Desenclos, Annie Laquerrière, Georges Noël, Olivier Chinot, Catherine Godfraind, Patrick Beauchesne, Jean-Yves Delattre, Caroline Dehais, T. Cruel, Danchristian Chiforeanu, F. Dhermain, Dominique Cazals-Hatem, Claude Gaultier, W. Lahiani, Marie-Laure Tanguy, C. Dehais, S. Elouadhani‐Hamdi, Pomone Richard, François Ghiringhelli, Olivier Langlois, Ca. Maurage, Dominique Figarella-Branger, Ahmed Idbaih, Carole Ramirez, Philippe Menei, François Ducray, Benoit Lhermitte, Nabila Elarouci, M. Campone, F. Vandenbos‐Burel, Mj. Motso‐Fotso, C. Blechet, Nicolas Desse, Sandrine Eimer, Valérie Rigau, Agusti Alentorn, Anne Jouvet, Damien Ricard, Mc. Tortel, T. Khallil, Clovis Adam, Hugues Loiseau, L. Bekaert, Henri Sevestre, Chiara Villa, M. Fesneau, Isabelle Quintin-Roue, Antoine Petit, Philippe Colin, Elodie Vauleon, S. Lopez, S. Gaillard, Guillaume Gauchotte, Antoine F. Carpentier, Phong Dam-Hieu, Md. Diebold, Yannick Marie, Thierry Faillot, Serge Milin, Aurélien de Reyniès, Emmanuelle Lechapt-Zalcman, Fabrice Parker, E. Cohen‐Moyal, Delphine Loussouarn, Emmanuelle Uro-Coste, Em. Gueye, Audrey Rousseau, F. Ducray, M‐I Mihai, Aurelie Kamoun, Karima Mokhtari, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), (le programme) Cartes d'identité des tumeurs (CIT), Ligue Nationales Contre le Cancer (LNCC), Biologie des Interactions Neurones / Glie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de neurophysiopathologie (INP), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Anatomie Pathologique-Neuropathologique [AP-HM Hôpital La Timone], Hôpital de la Timone [CHU - APHM] (TIMONE), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
Male, 0301 basic medicine, Cancer Research, DNA Copy Number Variations, Survival, Somatic cell, [SDV]Life Sciences [q-bio], Oligodendroglioma, Machine learning, computer.software_genre, medicine.disease_cause, Cohort Studies, Loss of heterozygosity, 03 medical and health sciences, microRNA, medicine, Humans, Neuro‐Oncology, Copy-number variation, Gene, Pathological, business.industry, Genomics, Glioma, Middle Aged, Prognosis, Precision medicine, 3. Good health, 030104 developmental biology, Oncology, Female, Artificial intelligence, Carcinogenesis, business, computer
Abstract

Background 1p/19q-codeleted anaplastic gliomas have variable clinical behavior. We have recently shown that the common 9p21.3 allelic loss is an independent prognostic factor in this tumor type. The aim of this study is to identify less frequent genomic copy number variations (CNVs) with clinical importance that may shed light on molecular oncogenesis of this tumor type. Materials and Methods A cohort of 197 patients with anaplastic oligodendroglioma was collected as part of the French POLA network. Clinical, pathological, and molecular information was recorded. CNV analysis was performed using single-nucleotide polymorphism arrays. Computational biology and feature selection based on the random forests method were used to identify CNV events associated with overall survival and other clinical-pathological variables. Results Recurrent chromosomal events were identified in chromosomes 4, 9, and 11. Forty-six focal amplification events and 22 focal deletion events were identified. Twenty-four focal CNV areas were associated with survival, and five of them were significantly associated with survival after multivariable analysis. Nine out of 24 CNV events were validated using an external cohort of The Cancer Genome Atlas. Five of the validated events contain a cancer-related gene or microRNA: CDKN2A deletion, SS18L1 amplification, RHOA/MIR191 copy-neutral loss of heterozygosity, FGFR3 amplification, and ARNT amplification. The CNV profile contributes to better survival prediction compared with clinical-based risk assessment. Conclusion Several recurrent CNV events, detected in anaplastic oligodendroglioma, enable better survival prediction. More importantly, they help in identifying potential genes for understanding oncogenesis and for personalized therapy. Implications for Practice Genomic analysis of 197 anaplastic oligodendroglioma tumors reveals recurrent somatic copy number variation areas that may help in understanding oncogenesis and target identification for precision medicine. A machine learning multivariable model built using this genomic information enables better survival prediction.

Published
2018

27. 580 WESTERN DIET AND DEFECTIVE AUTOPHAGY CAUSE DISRUPTED INTESTINAL HOMEOSTASIS, GUT DYSBIOSIS, INCREASED HOST SUSCEPTIBILITY TO AIEC INFECTION AND INTESTINAL INFLAMMATION

Author

Guillaume Dalmasso, Julien Delmas, Hang T. Nguyen, Laurène Salesse, My Hanh Thi Hoang, Pierre Sauvanet, Catherine Godfraind, and Nicolas Barnich

Subjects
Intestinal homeostasis, Hepatology, Host (biology), Intestinal inflammation, Autophagy, Western diet, Gastroenterology, Gut dysbiosis, Biology, Microbiology
Published
2021

28. 47 INFECTION WITH COLIBACTIN-PRODUCING ESCHERICHIA COLI TRIGGERS THE APPEARANCE OF ADENOMATOUS LESIONS IN A NOVEL MOUSE MODEL OF COLORECTAL CARCINOGENESIS

Author

Pierre Sauvanet, Alexandra Rezard, My Hanh Thi Hoang, Cécily Lucas, Guillaume Dalmasso, Nicolas Barnich, Hang T. Nguyen, Catherine Godfraind, Philip Rosenstiel, and Laurène Salesse

Subjects
Hepatology, Colibactin, Gastroenterology, medicine, Cancer research, Colorectal carcinogenesis, Biology, medicine.disease_cause, Escherichia coli
Published
2021

29. IMPACTS OF ADDITIVE FOOD E171 (TITANIUM DIOXIDE) ON THE GUT MICROBIOTA AND COLORECTAL CARCINOGENESIS IN APCMIN/+ MURINE MODEL

Author

Sandrine Brugiroux, Thomas Sauvaitre, Gwenaelle Roche, Célia Ledieu, Caroline Chevarin, Catherine Godfraind, Christophe Massard, Komla Oscar Awitor, Nicolas Barnich, Mathilde Bonnet, Delphine Boucher, Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte (M2iSH), Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre de Recherche en Nutrition Humaine d'Auvergne (CRNH d'Auvergne), Institut Universitaire de Technologie - Clermont-Ferrand (IUT Clermont-Ferrand), Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), OUERTANI, jeannette, Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte - Clermont Auvergne (M2iSH), Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA)-Centre de Recherche en Nutrition Humaine d'Auvergne (CRNH d'Auvergne), IUT de Clermont-Ferrand (IUT de Clermont-Ferrand), Université Clermont Auvergne (UCA), and Massard, Christophe

Subjects
[SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, [SDV.MP.BAC] Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, ComputingMilieux_MISCELLANEOUS
Abstract

International audience; Background and aim: Contaminant molecules could play a key role in the initiation and/or promotion of colorectal cancer (CRC) which is the second leading cause of cancer worldwide. Among the different pollutants, titanium dioxide (TiO2) is a white natural metal oxide which is particularly monitored. It is one of the most widely used engineered nanomaterials in daily consumer products, including food. Long-term inhalation studies with TiO2 nanoparticles (NPs) in rats reported development of lung tumors leading to classify this compound as a possible carcinogen for humans by International Agency for Research on Cancer. The food additive TiO2, referred to as E171 in the European Union, is commonly used as a whitening and brightening agent in sugar confectionary, sauces, ice creams and pastries. The gastro-intestinal tract may be an important absorption route for TiO2 NPs and additive E171 could be involved in the CRC etiology. Thus, this project aimed to assess the impact of chronic exposure of food additive E171 in CRC development using APCmin/+ mouse model which spontaneously develop intestinal tumors. Because intestinal microbiota play a role in colorectal carcinogenesis, carcinogenic properties of TiO2 will be evaluated in association with microbiota dysbiosis.Methods: Additive E171 composition was characterized by X-ray diffraction (XRD) and thermogravimetric analysis (TGA). APCmin/+ mice were chronically exposed (twice per week) to E171 (1 and 10 mg/kg of body weight (BW)) or vehicle (water) for 28 days via intragastric gavage. Micro-inflammation was assessed by the quantification of fecal lipocalin-2 (LCN-2) marker. At the end of the experimental protocol, macroscopic and histologic examinations of colon were performed and colonic mucosa-associated microbiota was analyzed by quantitative PCR.Results: As shown by the TGA analysis, the E171 compound is purely mineral and the size of NPs administrated to mice in this study did not exceed 28 nm (XRD analysis). No significant body weight loss was observed between mice groups suggesting no toxicity in our experimental conditions. However macroscopic and histological observations showed a more advanced tumor development in mice receiving the additive E171 (at a dose of 10 mg/kg of BW) compared to control animals. At the end of the experiment, high level of fecal LCN-2 concentration correlated with increase of tumoral volume. Mice with adenocarcinoma within this group also exhibit an increase of Bacteroides and Akkermansia as well as a higher prevalence of Escherichia coli and a decrease of Bifidobacterium.Conclusion: Additive E171 promotes colonic tumorigenesis and induces change in gut microbiota composition. Underlying carcinogenic mechanisms focusing on microbiota dysbiosis implication are in progress. This study supports the carcinogenic properties of TiO2 in the context of colorectal cancer.

Published
2019

30. Association Between Microscopic Lesions at Ileal Resection Margin and Recurrence After Surgery in Patients With Crohn’s Disease

Author

Alexandra Traverse-Glehen, Nassim Hammoudi, Olivier Corcos, Philippe Marteau, Julien Loreau, Mariane Maillet, Martine Leconte, Jonathan Catry, Yves Francois, Najim Chafai, Xavier Dray, Marjolaine Ngollo, Philippe Seksik, Pierre Cattan, Benjamin Pariente, Nicolas Munoz-Bongrand, Peggy Falgon, Stéphane Nancey, Nathan Beaupel, Isabelle Nion-Larmurier, Andrée Nisard, Christophe Attencourt, Emmanuel Tiret, Ulrika Chaput, Denis Chatelain, Marion Chauvenet, Dominique Cazals-Hatem, Eddy Cotte, Laurent Beaugerie, Madeleine Bezault, Mircea Chirica, Gilles Boschetti, Sarah Boyer, Loic Brot, Julien Kirchgesner, Hugo Bottois, Anne Dubois, Magali Svrcek, Yoram Bouhnik, Jean-Marc Gornet, Rachid Kaci, Brice Gergaud, Carmen Stefanescu, Helene Corte, Claire Auzolle, Jean-Louis Dupas, Juliette Joubert Zakeyh, Leila Chedouba, Amine Rahili, Elodie Quévrain, Charles Sabbagh, Lionel Le Bourhis, Maria Nachury, Anne Bourrier, Nathalie Guedj, Florence Renaud, Helena Hadjisavvas, Charlotte Gardair, Gilles Bommelaer, Céline Grand, Xavier Treton, Xavier Jouven, Anthony Buisson, Jérémie H. Lefevre, Paul Hofmann, Stéphanie Patouraux, Jérôme Filippi, Xavier Hébuterne, Driffa Moussata, Clotilde Baudry, Nelson Lourenco, Marion Goutte, Harry Sokol, Victor Chardiny, My-Linh Tran-Minh, Bernard Flourié, Pierre Desreumaux, Catherine Godfraind, Coralie Sommeville, Mathurin Fumery, Nicolas Barnich, Joëlle Bonnet, Anne-Laure Charlois, Dilek Coban, Leon Magiorri, Yves Panis, Matthieu Allez, Jean-François Fléjou, Franck Brazier, M. Ferron, Ecotaxie, microenvironnement et développement lymphocytaire (EMily (UMR_S_1160 / U1160)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'hépato-gastro-entérologie, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Diderot - Paris 7 (UPD7), Département de Pathologie [Hôpital Beaujon], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Laboratoire de pathologie [AP-HP Hôpital Saint-Louis], Hopital Saint-Louis, Assistance Publique – Hôpitaux de Paris (AP-HP), Autophagie infections immunité – Autophagy Infection Immunity, Centre International de Recherche en Infectiologie - UMR (CIRI), Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Service d'Hépato-gastroentérologie, Hôpital Huriez-Université de Lille, Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte - Clermont Auvergne (M2iSH), Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA)-Centre de Recherche en Nutrition Humaine d'Auvergne (CRNH d'Auvergne), Service de Gastroentérologie [Hôpital Beaujon], Hôpital Beaujon, Service d'Hépato Gastroenterologie [CHU Amiens-Picardie], CHU Amiens-Picardie, Laboratoire des biomolécules (LBM UMR 7203), Université Pierre et Marie Curie - Paris 6 (UPMC)-Département de Chimie - ENS Paris, École normale supérieure - Paris (ENS Paris)-École normale supérieure - Paris (ENS Paris)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Pathologie [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Saint-Antoine [APHP], Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Autophagie infection et immunité - Autophagy Infection Immunity (APY), Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte (M2iSH), Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Recherche en Nutrition Humaine d'Auvergne (CRNH d'Auvergne)-Institut National de la Recherche Agronomique (INRA), Hôpital Beaujon [AP-HP], Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Chimie - ENS Paris, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre de Recherche en Nutrition Humaine d'Auvergne (CRNH d'Auvergne), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7), Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), 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, medicine.medical_specialty, Cryptitis, Ileum, REMIND Trial, 03 medical and health sciences, 0302 clinical medicine, Crohn Disease, Recurrence, Interquartile range, medicine, Humans, Prospective Studies, Colectomy, Digestive System Surgical Procedures, Outcome, Crohn's disease, Hepatology, medicine.diagnostic_test, business.industry, Prognostic Factor, IBD Surgery, Anastomosis, Surgical, Gastroenterology, Margins of Excision, Histology, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Odds ratio, Middle Aged, medicine.disease, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, 3. Good health, Endoscopy, Surgery, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Female, 030211 gastroenterology & hepatology, Complication, business
Abstract

International audience; Background and AimsDifferent types of histologic lesions at the ileal margin, detected by histology, have been associated with increased rates of recurrence after ileocaecal surgery in patients with Crohn’s disease (CD). We aimed to characterize histologic features of the ileal margin and to evaluate their association with disease recurrence.MethodsWe collected histologic data from 211 patients with ileal or ileocolonic CD who underwent ileocolonic resections at hospitals in France from September 2010 through December 2016. Ileal margins were analyzed. Early endoscopic recurrence was defined by a Rutgeerts score of i2 or more, 6 months after surgery. We also collected data from 10 adults with healthy ileum who underwent ileocecal resection for colonic tumors (controls). Clinical relapse was defined by CD-related symptoms confirmed by imaging, endoscopy, therapy intensification, CD-related complication, or subsequent surgery.ResultsSix months after surgery, 49% of patients had endoscopic recurrence; 5 years after surgery, 57% of patients had clinical relapse. Ileal margins were macroscopically affected in 20.9% of patients. CD transmural lesions at the margin (defined by mucosal ulceration or cryptitis, submucosal fibrosis and lymphoplasmacytic infiltrate of the subserosa) were observed in 13.6% of patients. Endoscopic recurrence was observed in 75% of patients with CD transmural lesions vs 46% of patients without (P =.005). In multivariate analysis, CD transmural lesions at the margin were independently associated with early endoscopic recurrence (OR, 3.83; 95% CI, 1.47-11.05; P =.008) and clinical recurrence (OR 2.04; 95% CI, 1.09-3.99; P =.026).ConclusionIn patients with CD, transmural lesions at the ileal margin were associated with an increased risk of post-operative recurrence. Histologic features of the ileal margin should be included in making decisions about post-operative therapy.

Published
2019

31. DNA alteration-based classification of uveal melanoma gives better prognostic stratification than immune infiltration, which has a neutral effect in high-risk group

Author

Diane Damotte, Romain Remark, Pierre Coulie, Patrick De Potter, Miikka Vikkula, Marco Munda, Deepti Narasimhaiah, Catherine Legrand, Catherine Godfraind, UCL - SSS/DDUV - Institut de Duve, UCL - SSS/DDUV/GECE - Génétique cellulaire, UCL - SSS/DDUV/GEHU - Génétique, UCL - SSS/IONS - Institute of NeuroScience, UCL - SSS/IONS/NEUR - Clinical Neuroscience, UCL - SSH/LIDAM/ISBA - Institut de Statistique, Biostatistique et Sciences Actuarielles, and UCL - (SLuc) Service d'ophtalmologie

Subjects
0301 basic medicine, Oncology, Male, Uveal Neoplasms, Cancer Research, Monosomy, medicine.medical_specialty, Population, Gene Expression, lcsh:RC254-282, Disease-Free Survival, 03 medical and health sciences, 0302 clinical medicine, Immune system, Internal medicine, Medicine, Humans, Radiology, Nuclear Medicine and imaging, Multiplex ligation-dependent probe amplification, education, Melanoma, Original Research, Cancer Biology, education.field_of_study, business.industry, medicine.disease, Prognosis, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, 030104 developmental biology, 030220 oncology & carcinogenesis, Immunohistochemistry, Female, business, Infiltration (medical), CD8
Abstract

Background In uveal melanomas, immune infiltration is a marker of poor prognosis. This work intended to decipher the biological characteristics of intra‐tumor immune population, compare it to other established biomarkers and to patients' outcome. Methods Primary, untreated, and mainly large uveal melanomas with retinal detachment were analyzed using: transcriptomic profiling (n = 15), RT‐qPCR (n = 36), immunohistochemistry (n = 89), Multiplex Ligation‐dependent Probe Amplification (MLPA) for copy number alterations (CNA) analysis (n = 89), array‐CGH (n = 17), and survival statistics (n = 86). Results Gene expression analysis divided uveal melanomas into two groups, according to the IFNγ/STAT1‐IRF1 pathway activation. Tumors with IFNγ‐signature had poorer prognosis and showed increased infiltration of CD8+ T lymphocytes and macrophages. Cox multivariate analyses of immune cell infiltration with MLPA data delineated better prognostic value for three prognostic groups (three‐tier stratification) than two (two‐tier stratification). CNA‐based model comprising monosomy 3, 8q amplification, and LZTS1and NBL1 deletions emerged as the best predictor for disease‐free survival. It outperformed immune cell infiltration in receiver operating characteristic curves. The model that combined CNA and immune infiltration defined risk‐groups according to the number of DNA alterations. Immune cell infiltration was increased in the high‐risk group (73.7%), where it did not correlate with patient survival, while it was associated with poorer outcome in the intermediate risk‐group. Conclusions High degree of immune cell infiltration occurs in a subset of uveal melanomas, is interferon‐gamma‐related, and associated with poor survival. It allows for two‐tier stratification, which is prognostically less efficient than a three‐tier one. The best prognostic stratification is by CNA model with three risk‐groups where immune cell infiltration impacts only some subgroups.

Published
2019

32. Individual Comparison of Cholesterol Metabolism in Normal and Tumour Areas in Radical Prostatectomy Specimens from Patients with Prostate Cancer: Results of the CHOMECAP Study

Author

Jean-Marc A. Lobaccaro, Claudio Caccia, Olivier Celhay, Laura Bousset, Amalia Trousson, Cyrille de Joussineau, Jean-Louis Kemeny, Christelle Damon-Soubeyrant, Laurent Guy, Laurent Morel, Angélique De Haze, Silvère Baron, Valerio Leoni, Bruno Pereira, Laura Sabourin, Catherine Godfraind, Celhay, O, Bousset, L, Guy, L, Kemeny, J, Leoni, V, Caccia, C, Trousson, A, Damon-Soubeyrant, C, De Haze, A, Sabourin, L, Godfraind, C, de Joussineau, C, Pereira, B, Morel, L, Lobaccaro, J, Baron, S, 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), Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), Cancer Resistance Exploring and Targeting (CREaT), Université d'Auvergne - Clermont-Ferrand I (UdA), Laboratory of Clinical Pathology and Medical Genetics, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', University of Groningen [Groningen], CHU Clermont-Ferrand, service de Biostatistiques, DRCI, 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), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])

Subjects
Apolipoprotein E, Male, [SDV]Life Sciences [q-bio], 030232 urology & nephrology, Prostate cancer, chemistry.chemical_compound, 0302 clinical medicine, Prostate, Gene Regulatory Networks, Ester, Acetyl-CoA C-Acetyltransferase, Principal Component Analysis, Esters, Oxysterols, Middle Aged, Scavenger Receptors, Class B, 3. Good health, Gene Expression Regulation, Neoplastic, Sterols, medicine.anatomical_structure, Cholesterol, Oncology, 030220 oncology & carcinogenesis, Immunohistochemistry, lipids (amino acids, peptides, and proteins), Sterol Regulatory Element Binding Protein 2, medicine.medical_specialty, Urology, [SDV.CAN]Life Sciences [q-bio]/Cancer, Deregulation, 03 medical and health sciences, Apolipoproteins E, Oxysterol, Internal medicine, medicine, Humans, Radiology, Nuclear Medicine and imaging, Aged, Prostatectomy, [SDV.EE.SANT]Life Sciences [q-bio]/Ecology, environment/Health, business.industry, Gene Expression Profiling, Prostatic Neoplasms, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease, Sterol, SCARB1, Endocrinology, chemistry, Surgery, business, Lipoprotein
Abstract

International audience; BACKGROUND: Deregulation of cholesterol metabolism represents a hallmark of prostate cancer (PCa) and promotes its development. OBJECTIVE: To compare cholesterol metabolism on individual paired normal and tumour prostate tissues obtained from patients with PCa. DESIGN, SETTING, AND PARTICIPANTS: Between 2008 and 2012, normal and tumour paired tissue samples were collected from radical prostatectomy specimens from a cohort of 69 patients treated for localised PCa. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Tumour and normal tissues were subjected to gene analysis, sterol measurement, and immunohistochemistry. The Wilcoxon paired test and Spearman test were applied for comparison and correlation analyses, respectively. Principal component analysis was also carried out to investigate relationships between quantitative variables. RESULTS AND LIMITATIONS: Overall, cholesterol concentrations were not significantly different between tissue pairs. However, tumour samples were significantly associated with downregulated de novo cholesterol synthesis, but exhibited 54.7% overexpression of SCARB1 that could increase high-density lipoprotein uptake in PCa. Tumour tissues showed different trafficking of available cholesterol, with significantly lower ACAT1, and an altered efflux via APOE. Furthermore, cholesterol metabolism in tumour tissues was characterised by higher accumulation of 7alpha-hydroxycholesterol (OHC), 7betaOHC, and 7-ketosterol, and a lower level of 27OHC. CONCLUSIONS: Focusing on individually paired prostate tissues, our results highlighted several differences between normal and tumour samples linked to a metabolic shift in cholesterol flux. PCa samples exhibited a specific tissue signature characterised by higher SCARB1 expression, higher accumulation of OHC species, and clear downregulation of de novo cholesterol synthesis. PATIENT SUMMARY: Comparing normal and tumour tissues from the same prostates, our study identified a set of alterations in prostate cancer samples in terms of their use of cholesterol. These included higher cholesterol uptake, accumulation of oxidised cholesterol derivatives, and autonomous cellular production of cholesterol. Together, these data provide promising clinical targets to fight prostate cancer.

Published
2019

33. Somatic Activating PIK3CA Mutations Cause Venous Malformation

Author

Raphaël Helaers, Antonella Mendola, Laurence M. Boon, Miikka Vikkula, Catherine Godfraind, Nisha Limaye, Jaakko Kangas, Lauri Eklund, and Matthieu J. Schlögel

Subjects
Somatic cell, Class I Phosphatidylinositol 3-Kinases, Vascular Malformations, P110α, Transfection, Receptor tyrosine kinase, Veins, 03 medical and health sciences, Phosphatidylinositol 3-Kinases, 0302 clinical medicine, Gene Frequency, Report, Human Umbilical Vein Endothelial Cells, Genetics, Humans, Genetics(clinical), Receptor, Protein kinase B, neoplasms, Protein Kinase Inhibitors, Genetics (clinical), PI3K/AKT/mTOR pathway, Alleles, Genetic Association Studies, 030304 developmental biology, Phosphoinositide-3 Kinase Inhibitors, 0303 health sciences, biology, Neovascularization, Pathologic, High-Throughput Nucleotide Sequencing, Phenotype, Molecular biology, Receptor, TIE-2, 3. Good health, Endothelial stem cell, Thiazoles, Gene Expression Regulation, 030220 oncology & carcinogenesis, Mutation, biology.protein, Cancer research, Signal Transduction
Abstract

Somatic mutations in TEK, the gene encoding endothelial cell tyrosine kinase receptor TIE2, cause more than half of sporadically occurring unifocal venous malformations (VMs). Here, we report that somatic mutations in PIK3CA, the gene encoding the catalytic p110α subunit of PI3K, cause 54% (27 out of 50) of VMs with no detected TEK mutation. The hotspot mutations c.1624G>A, c.1633G>A, and c.3140A>G (p.Glu542Lys, p.Glu545Lys, and p.His1047Arg), frequent in PIK3CA-associated cancers, overgrowth syndromes, and lymphatic malformation (LM), account for >92% of individuals who carry mutations. Like VM-causative mutations in TEK, the PIK3CA mutations cause chronic activation of AKT, dysregulation of certain important angiogenic factors, and abnormal endothelial cell morphology when expressed in human umbilical vein endothelial cells (HUVECs). The p110α-specific inhibitor BYL719 restores all abnormal phenotypes tested, in PIK3CA- as well as TEK-mutant HUVECs, demonstrating that they operate via the same pathogenic pathways. Nevertheless, significant genotype-phenotype correlations in lesion localization and histology are observed between individuals with mutations in PIK3CA versus TEK, pointing to gene-specific effects.

Published
2015
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34. 1152 AUTOPHAGY INHIBITS COLORECTAL CARCINOGENESIS INDUCED BY COLIBACTIN-PRODUCING ESCHERICHIA COLI

Author

Denis Pezet, Anaïs Larabi, Hang Thi Thu Nguyen, Nicolas Barnich, Catherine Godfraind, Cécily Lucas, My Hanh Thi Hoang, Philip Rosenstiel, Johan Gagnière, Guillaume Dalmasso, Pierre Sauvanet, Richard Bonnet, Laurène Salesse, and Mathilde Bonnet

Subjects
Hepatology, Chemistry, Colibactin, Autophagy, Gastroenterology, medicine, Cancer research, Colorectal carcinogenesis, medicine.disease_cause, Escherichia coli
Published
2020

35. Prognostic value of a combination of innovative factors (gut microbiota, sarcopenia, obesity, metabolic syndrome) to predict surgical/oncologic outcomes following surgery for sporadic colorectal cancer: a prospective cohort study protocol (METABIOTE)

Author

Karine Poirot, Bruno Pereira, Lucie Cassagnes, Denis Pezet, Mathilde Bonnet, Caroline Chevarin, Pierre Sauvanet, Benoit Chassaing, Frédéric Robin, Catherine Godfraind, Johan Gagnière, Nicolas Barnich, Julie Veziant, CHU Clermont-Ferrand, Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte (M2iSH), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre de Recherche en Nutrition Humaine d'Auvergne (CRNH d'Auvergne)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Service de Chirurgie Digestive et Hépatobiliaire [CHU Clermont-Ferrand], CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, 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], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Georgia State University, University System of Georgia (USG), Télécom ParisTech, Laboratoire de Neuropathologie, Université Catholique de Louvain = Catholic University of Louvain (UCL)-Clinique Saint-Luc, Department of Digestive Surgery, University Medical Hospital, Unité de biostatistiques, ANR-16-IDEX-0001,CAP 20-25,CAP 20-25(2016), Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte - Clermont Auvergne (M2iSH), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA)-Centre de Recherche en Nutrition Humaine d'Auvergne (CRNH d'Auvergne)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), 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), OUERTANI, jeannette, and CAP 20-25 - - CAP 20-252016 - ANR-16-IDEX-0001 - IDEX - VALID

Subjects
obesity, medicine.medical_specialty, postoperative outcomes, Colorectal cancer, colorectal cancer, Gut flora, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, metabolic syndrome, sarcopenia, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Informed consent, medicine, Humans, Prospective Studies, Prospective cohort study, ComputingMilieux_MISCELLANEOUS, gut microbiota, biology, business.industry, prognostic factors, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, General Medicine, Length of Stay, medicine.disease, biology.organism_classification, Survival Analysis, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Obesity, Gastrointestinal Microbiome, 3. Good health, Surgery, Clinical trial, Treatment Outcome, pathogenicE, coli, Oncology, pathogenicE. coli, 030220 oncology & carcinogenesis, Sarcopenia, Body Composition, 030211 gastroenterology & hepatology, [SDV.MP.BAC] Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Metabolic syndrome, Colorectal Neoplasms, business
Abstract

IntroductionColorectal cancer (CRC) is still associated with poor prognosis, especially in patients with advanced disease. Development of new prognostic tools replacing or supplementing those routinely used is definitely needed, with the aim to optimise and personalise treatment strategies. Gut microbiota composition and body composition profile (obesity, sarcopenia and metabolic syndrome) have recently been reported separately as new relevant prognostic factors for postoperative surgical and oncologic outcomes following CRC surgery. However interactions that exist between these factors have been poorly studied. The purpose of this translational prospective cohort study (METABIOTE) is to investigate potential interactions between gut microbiota, body composition profile and postoperative outcomes and recurrence in patients undergoing surgery for non-metastatic sporadic CRC.Methods and analysisThis single-centre project aims to prospectively enrol 300 consecutive patients undergoing surgery for non-metastatic sporadic CRC at the University Hospital of Clermont-Ferrand, France for the identification of specific microbial signatures (from tumour, colonic mucosa and stools samples) associated with particular metabolic profiles that could impact postoperative morbidity and oncologic outcomes, using microbiological, molecular and imaging approaches. The primary outcome is the 5-year overall survival (OS). Other outcomes are 5-year CRC-related OS, 5-year disease-free survival, 30-day postoperative morbidity, 90-day postoperative mortality and length of hospital stay.Ethics and disseminationThis study protocol was reviewed and approved by an independent French regional review board (n°2018-A00352-53, ‘Comité de Protection des Personnes Ile de France VII’ on 4 July 2018, declared to the competent French authority (‘Agence Nationale de Sécurité du Médicament et des produits de santé’, France), and registered on the Clinical Trials web-based platform (NCT 03843905). Oral and written informed consent will be obtained from each included patient. Study results will be reported to the scientific community at conferences and in peer-reviewed scientific journals.Trial registration numberNCT03843905..

Published
2020

36. Clinicopathologic Features of CIC-NUTM1 Sarcomas, a New Molecular Variant of the Family of CIC-fused Sarcomas

Author

Gaëlle Pierron, François Le Loarer, Louise Galmiche-Rolland, Jean Michel Coindre, Franck Tirode, Sarah Watson, A. Michot, Daniel Pissaloux, Dominique Ranchère-Vince, Catherine Godfraind, Antoine Italiano, Laetitia Mayeur, Alexandre Vasiljevic, Karen Silva, 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), Immunité et cancer, Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Clermont-Ferrand, Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de pathologie [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Necker - Enfants Malades [AP-HP], Université Paris Descartes - Paris 5 (UPD5), Laboratory of Solid Tumors Genetics, Nice University Hospital, Service de chirurgie plastique et reconstructive, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Unité de Génétique Somatique, Institut Curie [Paris], Service de Pathologie, Hospices Civils de Lyon (HCL)-Hôpital neurologique et neurochirurgical Pierre Wertheimer [CHU - HCL], Hospices Civils de Lyon (HCL), Université de Lyon, Institut Bergonié [Bordeaux], UNICANCER, Centre de recherche de l'Institut Curie [Paris], INSERM U1218 ACTION, Université de Bordeaux (UB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Centre de Recherche en Cancérologie de Lyon (CRCL), Université Claude Bernard Lyon 1 (UCBL), 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), Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM), Imagerie Moléculaire et Stratégies Théranostiques - Clermont Auvergne (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Institut Curie, and Institut Bergonié - CRLCC Bordeaux

Subjects
Adult, Male, 0301 basic medicine, Pathology, medicine.medical_specialty, Adolescent, Recombinant Fusion Proteins, Soft Tissue Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Pathology and Forensic Medicine, Young Adult, 03 medical and health sciences, Exon, 0302 clinical medicine, DUX4, Humans, Medicine, Child, Lung, medicine.diagnostic_test, business.industry, Breakpoint, Nuclear Proteins, Soft tissue, Sarcoma, medicine.disease, Phenotype, Neoplasm Proteins, 3. Good health, Repressor Proteins, 030104 developmental biology, medicine.anatomical_structure, Child, Preschool, 030220 oncology & carcinogenesis, Female, Surgery, Anatomy, business, Fluorescence in situ hybridization
Abstract

International audience; CIC-fused sarcomas represent an emerging family of tumors, for long connected to the Ewing family group of tumors, but underlined by distinct CIC fusions with different partners. 3' Fusion partners include DUX4, FOXO4, and, as recently emphasized, NUTM1. In this study, we report the clinicopathologic and molecular features of a series of 6 CIC-NUTM1 sarcomas. Mean age at diagnosis was 6 years (2 to 27 y), and 4 patients were male individuals. Primary tumors were located in the central nervous system (n=3), paravertebral soft tissue and epidural spaces (n=1, each), and lung (n=1). Median overall survival was 17.5 months (7 to 37 mo), and all but one patient died of disease. All tumors displayed classic features of CIC-DUX4 sarcomas with round cell to epithelioid microscopic appearance. Most tumors expressed ETV4 and NUTM1 (n=5/6 and 6/6, respectively), whereas WT1cter was positive in only 2 cases. All tested tumors were positive for break-apart fluorescence in situ hybridization for CIC and NUTM1. Apart from CIC or NUTM1 genomic breakpoints, no other recurrent copy number alteration was seen on genomic profiles. Fusion transcripts were identified by RNA-sequencing on either formalin-fixed paraffin-embedded or frozen material. CIC and NUTM1 breakpoints were located between exons 16 and 20 and exons 2 and 5, respectively. Altogether, CIC-NUTM1 sarcomas represent a new molecular variant of CIC-fused sarcomas with a predilection for the central nervous system and younger pediatric population. Its phenotype may be confused with NUT carcinomas.

Published
2018

37. Radiotherapy plus temozolomide in elderly patients with glioblastoma: a 'real-life' report

Author

Anne Fogli, Toufic Khalil, P. Dalloz, Emmanuel Chautard, Bruno Pereira, Catherine Godfraind, Anne-Françoise Dillies, Julian Biau, Xavier Durando, Mélanie Müller-Barthélémy, Pierre Verrelle, E. De Schlichting, G. Dupic, Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), CHU Clermont-Ferrand, and École Centrale de Nantes (ECN)

Subjects
Oncology, Male, Stereotactic biopsy, medicine.medical_treatment, 0302 clinical medicine, Elderly, ComputingMilieux_MISCELLANEOUS, Aged, 80 and over, medicine.diagnostic_test, Brain Neoplasms, Standard treatment, Radiotherapy Dosage, Chemoradiotherapy, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Prognosis, 3. Good health, Dacarbazine, Survival Rate, 030220 oncology & carcinogenesis, Cohort, Female, Glioblatoma, medicine.drug, lcsh:Medical physics. Medical radiology. Nuclear medicine, medicine.medical_specialty, lcsh:R895-920, lcsh:RC254-282, Hypofractionated radiotherapy, 03 medical and health sciences, Internal medicine, medicine, Temozolomide, Humans, Radiology, Nuclear Medicine and imaging, Survival rate, Antineoplastic Agents, Alkylating, Aged, business.industry, Research, Radiation therapy, Radiotherapy, Intensity-Modulated, business, Glioblastoma, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Follow-Up Studies
Abstract

Background The optimization of the management for elderly glioblastoma patients is crucial given the demographics of aging in many countries. We report the outcomes for a “real-life” patient cohort (i.e. unselected) comprising consecutive glioblastoma patients aged 70 years or more, treated with different radiotherapy +/− temozolomide regimens. Methods From 2003 to 2016, 104 patients ≥ 70 years of age, consecutively treated by radiotherapy for glioblastoma, were included in this study. All patients were diagnosed with IDH-wild type glioblastoma according to pathological criteria. Results Our patient cohort comprised 51 female patients (49%) and 53 male. The median cohort age was 75 years (70–88), and the median Karnofsky performance status (KPS) was 70 (30–100). Five (5%) patients underwent macroscopic complete resection, 9 (9%) had partial resection, and 90 (86%), a stereotactic biopsy. The MGMT promoter was methylated in 33/73 cases (45%). Fifty-two (50%), 38 (36%), and 14 (14%) patients were categorized with RPA scores of III, IV, and I-II. Thirty-three (32%) patients received normofractionated radiotherapy (60 Gy, 30 sessions) with temozolomide (Stupp), 37 (35%) received hypofractionated radiotherapy (median dose 40 Gy, 15 sessions) with temozolomide (HFRT + TMZ), and 34 (33%) HFRT alone. Patients receiving only HFRT were significantly older, with lower KPSs. The median overall survival (OS; all patients) was 5.2 months. OS rates at 12, 18, and 24 months, were 19%, 12%, and 5%, respectively, with no statistical differences between patients receiving Stupp or HFRT + TMZ (P = 0.22). In contrast, patients receiving HFRT alone manifested a significantly shorter survival time (3.9 months vs. 5.9 months, P = 0.018). In multivariate analyses, the prognostic factors for OS were: i) the type of surgery (HR: 0.47 [0.26–0.86], P = 0.014), ii) RPA class (HR: 2.15 [1.17–3.95], P = 0.014), and iii) temozolomide use irrespective of radiotherapy schedule (HR: 0.54 [0.33–0.88], P

Published
2017

38. Natural course and prognosis of anaplastic gangliogliomas: a multicenter retrospective study of 43 cases from the French Brain Tumor Database

Author

Luc Bauchet, Eric Bord, Valérie Rigau, Johan Pallud, Bertrand Muckenstrum, Guillaume Gauchotte, Louis-Marie Terrier, Walid Farah, Patrick François, Isabelle Filipiak, Bertrand Debono, Phong Dam Hieu, Bernard Irthum, Audrey Rousseau, Pierre-Hugues Roche, Catherine Godfraind, Pierre-Jean Le Reste, Marie-Bernadette Delisle, Agnès Caille, Philippe Metellus, Stéphane Velut, Alain Czorny, Anne-Marie Bergemer-Fouquet, Philippe Menei, D. Liguoro, Michel Wager, Marie-Hélène Aubriot-Lorton, Emmanuel Mandonnet, Pascale Varlet, Jimmy Voirin, Serge Milin, Sonia Zouaoui, Kevin Janot, Ilyess Zemmoura, Hugues Loiseau, Jacques Guyotat, Marc Zanello, Philippe Cornu, Evelyne Emery, Aymeric Amelot, Vincent Lubrano, Guillaume Lot, Fabien Almairac, Dominique Figarella-Branger, Anne Vital, Emmanuelle Uro-Coste, Institut des Neurosciences de Montpellier (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre référent Sclérose Latérale Amyotrophique [CHRU Montpellier] (SLA CHRU Montpellier), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Université Paris Descartes - Faculté de Médecine (UPD5 Médecine), Université Paris Descartes - Paris 5 (UPD5), UNICANCER - Institut régional du Cancer Montpellier Val d'Aurelle (ICM), CRLCC Val d'Aurelle - Paul Lamarque, Physiologie de la reproduction et des comportements [Nouzilly] (PRC), Institut National de la Recherche Agronomique (INRA)-Institut Français du Cheval et de l'Equitation [Saumur] (IFCE)-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS), Centre d’Investigation Clinique [Tours] CIC 1415 (CIC ), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau-Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Biologie Valrose (IBV), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Service de Pathologie [CHU de Dijon], Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Service de neurochirurgie [Brest], Hôpital de la Cavale Blanche - CHRU Brest (CHU - BREST ), CIC Brest, Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital de la Cavale Blanche, Service de neurochirurgie [CHU Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), 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), Sérine protéases et physiopathologie de l'unité neurovasculaire, Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de neurochirurgie [CHU Dijon], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Laboratoire de Neuropathologie, Université Catholique de Louvain = Catholic University of Louvain (UCL)-Clinique Saint-Luc, Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Service de Neurochirurgie [CHU Clermont-Ferrand], CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, 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), Service de neurochirurgie, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Service Neurochirurgie [CHU Toulouse], Pôle Neurosciences [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Laboratoire Kastler Brossel (LKB (Lhomond)), Fédération de recherche du Département de physique de l'Ecole Normale Supérieure - ENS Paris (FRDPENS), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Service de neurochirurgie [CHU Angers], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Service de neurochirurgie [CHU Marseille], Université de la Méditerranée - Aix-Marseille 2-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Cibles moléculaires et thérapeutiques de la maladie d'Alzheimer (CIMoTHeMA), Université de Poitiers, Design and Application of Innovative Local Treatments in Glioblastoma (CRCINA-ÉQUIPE 17), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Laboratoire Mouvement Adaptation Cognition (MAC), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), Cellules souches leucémiques et thérapeuthiques, Université de Poitiers-Centre hospitalier universitaire de Poitiers (CHU Poitiers), Université Sorbonne Paris Cité (USPC), Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Anatomo-Cyto-Pathologie et de NeuroPathologie [Hôpital de la Timone - APHM] (ACPNP), Aix Marseille Université (AMU)- Hôpital de la Timone [CHU - APHM] (TIMONE), Archimedes Pharma®, Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université Montpellier 1 (UM1), UNICANCER - Institut régional du Cancer [Montpellier] (ICM), Centre National de la Recherche Scientifique (CNRS)-Université de Tours-Institut Français du Cheval et de l'Equitation [Saumur]-Institut National de la Recherche Agronomique (INRA), CIC 1415, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Francois Rabelais [Tours], Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de neurochirurgie [Rouen], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital de Rangueil, CHU Toulouse [Toulouse], Service de neurochirurgie [CHU de Dijon], Université Catholique de Louvain (UCL)-Clinique Saint-Luc, Service de Neurochirurgie [Clermont-Ferrand], CHU Clermont-Ferrand-Hôpital Gabriel Montpied, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Imagerie cérébrale et handicaps neurologiques, Institut des sciences du cerveau de Toulouse. (ISCT), Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Design and Application of Innovative Local Treatments in Glioblastoma (CRCINA - Département NOHMAD - Equipe 17), Centre de recherche de Cancérologie et d'Immunologie / Nantes - Angers (CRCINA), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Imagerie et cerveau, Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Recherche Agronomique (INRA)-Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau-Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), CHU Clermont-Ferrand-CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand, 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), Département de Neurochirurgie [CHU Toulouse], Université Pierre et Marie Curie - Paris 6 (UPMC)-Fédération de recherche du Département de physique de l'Ecole Normale Supérieure - ENS Paris (FRDPENS), Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), and Institut National de la Recherche Agronomique (INRA)-Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Adult, Male, Cancer Research, medicine.medical_specialty, Pathology, Adolescent, Databases, Factual, [SDV]Life Sciences [q-bio], Clinical Investigations, Brain tumor, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.MHEP.CHI]Life Sciences [q-bio]/Human health and pathology/Surgery, Ganglioglioma, cerebral malignancy, surgery, Young Adult, 03 medical and health sciences, 0302 clinical medicine, medicine, Humans, Progression-free survival, Pathological, Survival rate, ComputingMilieux_MISCELLANEOUS, Aged, Retrospective Studies, Intracranial pressure, Brain Neoplasms, business.industry, Retrospective cohort study, Middle Aged, medicine.disease, Combined Modality Therapy, 3. Good health, Survival Rate, Oncology, 030220 oncology & carcinogenesis, Anaplastic Ganglioglioma, Disease Progression, Female, Neurology (clinical), Radiology, prognosis, business, 030217 neurology & neurosurgery, anaplastic ganglioglioma, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Follow-Up Studies
Abstract

International audience; Background - Anaplastic gangliogliomas (GGGs) are rare tumors whose natural history is poorly documented. We aimed to define their clinical and imaging features and to identify prognostic factors. Methods - Consecutive cases of anaplastic GGGs in adults prospectively entered into the French Brain Tumor Database between March 2004 and April 2014 were screened. After diagnosis was confirmed by pathological review, clinical, imaging, therapeutic, and outcome data were collected retrospectively. Results - Forty-three patients with anaplastic GGG (median age, 49.4 y) from 18 centers were included. Presenting symptoms were neurological deficit (37.2%), epileptic seizure (37.2%), or increased intracranial pressure (25.6%). Typical imaging findings were unifocal location (94.7%), contrast enhancement (88.1%), central necrosis (43.2%), and mass effect (47.6%). Therapeutic strategy included surgical resection (95.3%), adjuvant radiochemotherapy (48.8%), or radiotherapy alone (27.9%). Median progression-free survival (PFS) and overall survival (OS) were 8.0 and 24.7 months, respectively. Three- and 5-year tumor recurrence rates were 69% and 100%, respectively. The 5-year survival rate was 24.9%. Considering unadjusted significant prognostic factors, tumor midline crossing and frontal location were associated with shorter OS. Temporal and parietal locations were associated with longer and shorter PFS, respectively. None of these factors remained statistically significant in multivariate analysis. Conclusions - We report a large series providing clinical, imaging, therapeutic, and prognostic features of adult patients treated for an intracerebral anaplastic GGG. Our results show that pathological diagnosis is difficult, that survivals are only slightly better than for glioblastomas, and that complete surgical resection followed with adjuvant chemoradiotherapy offers longer survival.

Published
2017

39. Detection of the alternative lengthening of telomeres pathway in malignant gliomas for improved molecular diagnosis

Author

Bruno Pereira, Marie-Véronique Demattei, Pierre Verrelle, Jean-Louis Kemeny, Anne Fogli, Julian Biau, Nathalie Grandin, Philippe Arnaud, Emmanuel Chautard, Laetitia Corset, Catherine Godfraind, Michel Charbonneau, Catherine Vaurs-Barrière, T. Khalil, Service de Biochimie et Génétique Moléculaire [CHU Clermont-Ferrand], CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand-CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand, Génétique, Reproduction et Développement (GReD ), 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), Génétique, immunothérapie, chimie et cancer (GICC), UMR 7292 CNRS [2012-2017] (GICC UMR 7292 CNRS), Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS), Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, Cancer Resistance Exploring and Targeting (CREaT), Université d'Auvergne - Clermont-Ferrand I (UdA), Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Laboratoire de pathologie, Laboratoire de Neuropathologie, Université Catholique de Louvain = Catholic University of Louvain (UCL)-Clinique Saint-Luc, Unité de Biostatistiques [CHU Clermont-Ferrand], Direction de la recherche clinique et de l’innovation [CHU Clermont-Ferrand] (DRCI), CHU Clermont-Ferrand-CHU Clermont-Ferrand, Service de Neurochirurgie [CHU Clermont-Ferrand], Image Guided Clinical Neurosciences and Connectomics (IGCNC), Génétique, Reproduction et Développement (GReD), Institut de Génétique Moléculaire de Montpellier (IGMM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Génétique, Reproduction et Développement - Clermont Auvergne (GReD), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Etude des Parasites Génétiques (LEPG), Université de Tours, Université de Tours-Centre National de la Recherche Scientifique (CNRS), Génétique, Reproduction et Développement - Clermont Auvergne (GReD ), Thérapie ciblée combinatoire en Onco-Hématologie (EA3846), Imagerie Moléculaire et Stratégies Théranostiques - Clermont Auvergne (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), service d’anatomopathologie, Centre Hospitalier Universitaire Gabriel Montpied, Laboratoire de Pathologie, Université Catholique de Louvain (UCL)-Clinique Saint-Luc, Délégation à la Recherche Clinique et à l’Innovation, Centre Hospitalier Universitaire de Clermont-Ferrand, Service de Neurochirurgie A [Clermont-Ferrand], CHU Clermont-Ferrand-Hôpital Gabriel Montpied, Nutrition, inflammation et dysfonctionnement de l'axe intestin-cerveau (ADEN), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Jean Perrin, CRLCC Jean Perrin, CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand-CHU Gabriel Montpied [Clermont-Ferrand], Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Clermont-Ferrand-CHU Gabriel Montpied [Clermont-Ferrand], 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), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Service de Biochimie Médicale et Biologie Moléculaire [CHU Clermont-Ferrand], Génétique, Reproduction et Développement - Clermont Auvergne ( GReD ), IFR79-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Clermont Auvergne ( UCA ) -Centre National de la Recherche Scientifique ( CNRS ), UMR 6239, Equipe Cellules usine, Ingénierie des protéines et Bio-informatique, Université Francois Rabelais [Tours]-Centre National de la Recherche Scientifique ( CNRS ), Génétique, Immunothérapie, Chimie et Cancer ( GICC ), Université de Tours-Centre National de la Recherche Scientifique ( CNRS ), Cancer Resistance Exploring and Targeting ( CREaT ), Université d'Auvergne - Clermont-Ferrand I ( UdA ), Imagerie Moléculaire et Stratégies Théranostiques - Clermont Auvergne ( IMoST ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Clermont Auvergne ( UCA ), Université Catholique de Louvain ( UCL ) -Clinique Saint-Luc, Biostat Unit, Image Guided Clinical Neurosciences and Connectomics ( IGCNC ), Institut de Génétique Moléculaire de Montpellier ( IGMM ), Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), and CHAUTARD, Emmanuel

Subjects
0301 basic medicine, Male, Cancer Research, Telomerase, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], medicine.disease_cause, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Cohort Studies, Exon, chemistry.chemical_compound, DNA Modification Methylases, ComputingMilieux_MISCELLANEOUS, Mutation, Brain Neoplasms, Brain, Methylation, Glioma, Middle Aged, Isocitrate Dehydrogenase, 3. Good health, Neurology, Oncology, [ SDV.NEU.NB ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Female, Adult, X-linked Nuclear Protein, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Extrachromosomal DNA, Cell Line, Tumor, medicine, Humans, ATRX, Tumor Suppressor Proteins, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Telomere Homeostasis, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Molecular biology, Telomere, 030104 developmental biology, DNA Repair Enzymes, chemistry, RNA, Neurology (clinical), Neoplasm Grading, DNA
Abstract

International audience; Human malignant gliomas exhibit acquisition of either one of two telomere maintenance mechanisms, resulting from either reactivation of telomerase expression or activation of an alternative lengthening of telomeres (ALT) mechanism. In the present study, we analyzed 63 human malignant gliomas for the presence of ALT-specific extrachromosomal circles of telomeric DNA (C-circles) and measured telomerase expression, telomeric DNA content (Telo/Alu method), and telomeric repeat-containing RNAs (TERRA) levels. We also assessed histomolecular markers routinely used in clinical practice. The presence of C-circles significantly correlated with IDH1/2 mutation, MGMT exon 1 methylation, low Ki-67 immunostaining, increased telomeric DNA content, absence of functional ATRX protein and level of HTERT gene expression. In multivariate analysis, we observed a trend to a correlation between elevated TERRA levels and increased survival. Interestingly, the C-circles assay allowed to detect ALT activation in glioblastomas exhibiting wild-type IDH1/2 and ATRX expression. These results suggest that, after the correlations uncovered here have been confirmed on larger numbers of tumors, telomeric markers might be useful in improving diagnosis. They also point out to the utility of using the specific, sensitive and quantitative C-circle and Telo/Alu assays that can work with as few as 30 ng of tumor DNA

Published
2017

40. Réseau de relecture des tumeurs pédiatriques du système nerveux central par le Groupe d’étude de neuropathologie oncologique pédiatrique (GENOP)

Author

Karen Silva, Claude-Alain Maurage, Marie-Bernadette Delisle, Catherine Godfraind, Anne-Isabelle-Bertozzi Salamon, Anne Jouvet, Catherine Miquel, Jean-Claude Gentet, Dominique Figarella-Branger, Alexandre Vasiljevic, David Meyronet, and Pascale Varlet

Subjects
Pathology and Forensic Medicine
Abstract

Resume Les tumeurs pediatriques du systeme nerveux central posent des problemes diagnostiques car les criteres histopronostiques de la classification OMS, definis pour les tumeurs de l’adulte, ne leur sont pas toujours adaptes. En raison de leur rarete, environ 400 cas par an en France repartis en plus de 50 types histopathologiques, leur diagnostic pose des problemes aux pathologistes dont le recrutement pediatrique est souvent quantitativement insuffisant pour en acquerir une experience optimale. Devant ces difficultes, un groupe d’etude de neuropathologie oncologique pediatrique a ete cree grâce a l’impulsion du comite « Tumeurs cerebrales » de la Societe francaise de lutte contre les cancers de l’enfant. Le reseau est a present soutenu par l’Institut national du cancer (INCa). Son objectif est la double lecture centralisee des tumeurs du systeme nerveux central de l’enfant afin d’en harmoniser le diagnostic pathologique au niveau national et ainsi de permettre une meilleure prise en charge therapeutique. La double lecture systematique des cas de diagnostic difficile a permis d’identifier les groupes de tumeurs qui posent le plus de probleme et de mettre en place un ensemble de techniques immunohistochimiques et moleculaires specialisees adaptees. Une meilleure distinction entre gliomes infiltrants et gliomes circonscrits a pu etre proposee ainsi qu’une meilleure identification des tumeurs glioneuronales. Elle a permis de preciser les types de tumeurs embryonnaires, en particulier les sous-types de medulloblastomes.

Published
2014

41. Contents Vol. 5, 2014

Author

Mathilde Huckert, Séraphin Nguefack, John F. Bateman, Renata Moldenhauer Minillo, Nara Sobreira, Vinciane Wouters, Corinne Stoetzel, Marie-Cécile Manière, Cedrik Tekendo-Ngongang, Virginie Laugel-Haushalter, Bee Chin Chen, Vincent Laugel, Kerry A. Miller, Rutger Meinsma, Kimberly F. Doheny, Cristina Has, Stefania Gimelli, Kurt N. Hetrick, Elisabeth Flori, Sophie Dahoun, Peter G. Farlie, David Valle, John B. Mulliken, Anne Dompmartin, Helen Mecili, Georgina Caruana, Martin Poot, Susan M. White, André B.P. van Kuilenburg, Laurence Myriam Boon, Decio Brunoni, Rowani Mohd Rawi, Agnès Bloch-Zupan, Ambroise Wonkam, Ilkka Kaitila, Raoul C.M. Hennekam, Druckerei Stückle, Judith Meijer, Megan F Welfare, Ana B. Alvarez Perez, Mustapha Amyere, Satz Mengensatzproduktion, Maria de Fátima de Faria Soares, John F. Bertram, Zornitza Stark, Odile Enjolras, Jean Muller, Ebtesam M. Abdalla, Miikka Vikkula, Tiong Yang Tan, Frédérique Sloan-Béna, Julie Jurgens, Catherine Godfraind, Pierre-Louis Docquier, Hua Ling, Ravi Savarirayan, Andrew A Heggie, Hélène Dollfus, and Trent Burgess

Subjects
Genetics, Genetics (clinical)
Published
2014

42. Common Somatic Alterations Identified in Maffucci Syndrome by Molecular Karyotyping

Author

Pierre-Louis Docquier, Anne Dompmartin, Odile Enjolras, Mustapha Amyere, Laurence M. Boon, Vinciane Wouters, Miikka Vikkula, Catherine Godfraind, John B. Mulliken, and Ilkka Kaitila

Subjects
Mutation, Pathology, medicine.medical_specialty, Somatic cell, Biology, medicine.disease, medicine.disease_cause, IDH2, Maffucci syndrome, Genetics, medicine, Enchondromatosis, Enchondroma, Original Article, Chondrosarcoma, Ollier disease, Genetics (clinical)
Abstract

Maffucci syndrome (MS) is a rare congenital disorder characterized by multiple central cartilaginous tumors (enchondromas) in association with cutaneous spindle cell hemangiomas. These patients have a high incidence of malignant transformation. No familial case is known and the etiopathogenic cause remains unknown. In enchondromatosis (Ollier disease, OD), which is comprised of enchondromas only, 4 mutations in the PTHR1 gene have been identified in 4 patients; 3 were somatic and 1 was germline. No PTHR1 mutations have been detected in MS, whereas somatic IDH1 and, more rarely, IDH2 mutations have been observed in 77% of patients with MS and 81% of patients with OD. These genetic alterations are shared with other tumors, including glioma, leukemia and carcinoma. To search for underlying somatic genomic causes, we screened MS tissues using Affymetrix SNP-chips. We looked for CNVs, LOH and uniparental isodisomy (UPID) by performing pairwise analyses between allelic intensities in tumoral DNA versus the corresponding blood-extracted DNA. While common chromosomal anomalies were absent in constitutional DNA, several shared CNVs were identified in MS-associated tumors. The most frequently encountered somatic alterations were localized in 2p22.3, 2q24.3 and 14q11.2, implicating these chromosomal rearrangements in the formation of enchondromas and spindle cell hemangiomas in MS. In one chondrosarcoma specimen, large amplifications and/or deletions were observed in chromosomes 3, 6, 9, 10, 12, 13, and 19. Some of these genetic changes have been reported in other chondrosarcomas suggesting an etiopathogenic role. No LOH/UPID was observed in any Maffucci tissue. Our findings identify frequent somatic chromosomal rearrangements on 2p22.3, 2q24.3 and 14q11.2, which may unmask mutations leading to the lesions pathognomonic of MS.

Published
2014

43. Su1976 – Impacts of Additive Food E171 (Titanium Dioxide) on the Gut Microbiota and Colorectal Carcinogenesis in ApcMIN/+ Murine Model

Author

Oscar Komla Awitor, Caroline Chevarin, Célia Ledieu, Delphine Boucher, Gwenaëlle Roche, Thomas Sauvaitre, Nicolas Barnich, Mathilde Bonnet, Sandrine Brugiroux, Christophe Massard, and Catherine Godfraind

Subjects
Hepatology, biology, Chemistry, Gastroenterology, Cancer, Context (language use), Akkermansia, Pharmacology, Gut flora, biology.organism_classification, medicine.disease, medicine, media_common.cataloged_instance, European union, Dysbiosis, Carcinogen, media_common, Bifidobacterium
Abstract

Background and aim: Contaminant molecules could play a key role in the initiation and/or promotion of colorectal cancer (CRC) which is the second leading cause of cancer worldwide. Among the different pollutants, titanium dioxide (TiO2) is a white natural metal oxide which is particularly monitored. It is one of the most widely used engineered nanomaterials in daily consumer products, including food. Long-term inhalation studies with TiO2 nanoparticles (NPs) in rats reported development of lung tumors leading to classify this compound as a possible carcinogen for humans by International Agency for Research on Cancer. The food additive TiO2, referred to as E171 in the European Union, is commonly used as a whitening and brightening agent in sugar confectionary, sauces, ice creams and pastries. The gastro-intestinal tract may be an important absorption route for TiO2 NPs and additive E171 could be involved in the CRC etiology. Thus, this project aimed to assess the impact of chronic exposure of food additive E171 in CRC development using APCmin/+ mouse model which spontaneously develop intestinal tumors. Because intestinal microbiota play a role in colorectal carcinogenesis, carcinogenic properties of TiO2 will be evaluated in association with microbiota dysbiosis. Methods: Additive E171 composition was characterized by X-ray diffraction (XRD) and thermogravimetric analysis (TGA). APCmin/+ mice were chronically exposed (twice per week) to E171 (1 and 10 mg/kg of body weight (BW)) or vehicle (water) for 28 days via intragastric gavage. Micro-inflammation was assessed by the quantification of fecal lipocalin-2 (LCN-2) marker. At the end of the experimental protocol, macroscopic and histologic examinations of colon were performed and colonic mucosa-associated microbiota was analyzed by quantitative PCR. Results: As shown by the TGA analysis, the E171 compound is purely mineral and the size of NPs administrated to mice in this study did not exceed 28 nm (XRD analysis). No significant body weight loss was observed between mice groups suggesting no toxicity in our experimental conditions. However macroscopic and histological observations showed a more advanced tumor development in mice receiving the additive E171 (at a dose of 10 mg/kg of BW) compared to control animals. At the end of the experiment, high level of fecal LCN-2 concentration correlated with increase of tumoral volume. Mice with adenocarcinoma within this group also exhibit an increase of Bacteroides and Akkermansia as well as a higher prevalence of Escherichia coli and a decrease of Bifidobacterium. Conclusion: Additive E171 promotes colonic tumorigenesis and induces change in gut microbiota composition. Underlying carcinogenic mechanisms focusing on microbiota dysbiosis implication are in progress. This study supports the carcinogenic properties of TiO2 in the context of colorectal cancer.

Published
2019

44. Supratentorial clear cell ependymomas with branching capillaries demonstrate characteristic clinicopathological features and pathological activation of nuclear factor-kappaB signaling

Author

Stephanie Theresa Jünger, Didier Scavarda, François Labrousse, Catherine Godfraind, Henri Sevestre, Philippe Metellus, Anne Jouvet, Carole Colin, Isabelle Quintin-Roue, Corinne Bouvier, Emeline Tabouret, Marie-Christine Machet, Felipe Andreiuolo, Emmanuèle Lechapt-Zalcman, Fabien Forest, André Maues De Paula, Anne Heitzmann, Torsten Pietsch, Serge Milin, Dominique Figarella-Branger, Service d'Anatomo-Cyto-Pathologie et de NeuroPathologie [Hôpital de la Timone - APHM] (ACPNP), Aix Marseille Université (AMU)- Hôpital de la Timone [CHU - APHM] (TIMONE), 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), Département de Pathologie [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Neuro-Oncologie [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), University of Bonn, Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), Centre Hospitalier Sainte Anne [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHRU Brest - Laboratoire d'Anatomo-Pathologie (CHU - AnaPath), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Service de pathologie [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), Centre Hospitalier Régional d'Orléans (CHRO), Centre hospitalier universitaire de Poitiers (CHU Poitiers), CHU Amiens-Picardie, CHU Clermont-Ferrand, Service d'Anatomie Pathologique [CHU Limoges], CHU Limoges, Service de neurochirurgie, Université de la Méditerranée - Aix-Marseille 2-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Pédiatrie et oncologie pédiatrique [Hôpital de la Timone - APHM], Universität Bonn = University of Bonn, Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de neurochirurgie [CHU Marseille], and figarella-branger, dominique

Subjects
Ependymoma, [SDV.MHEP.AHA] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Cancer Research, Pathology, medicine.medical_specialty, intracranial, clear cell ependymomas, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Viral Oncogene, RelA, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Chromosome 19, Chromosome instability, medicine, [SDV.MHEP.AHA]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Humans, NF kappa B, trisomy 19, Pathological, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Supratentorial Neoplasms, medicine.disease, 3. Good health, Oncology, 030220 oncology & carcinogenesis, DNA methylation, Basic and Translational Investigations, Clinicopathological features, Neurology (clinical), 030217 neurology & neurosurgery, Clear cell
Abstract

International audience; Clear cell ependymoma is one of the 4 main histological subtypes of ependymomas defined by the World Health Organization (WHO) classification of tumors of the CNS. DNA methylation profiling can distinguish 4 subgroups of intracranial ependymomas, including supratentorial (ST) ependymomas with Yes-associated protein 1 fusion (YAP1), ST ependymomas with fusion of v-rel avian reticuloendotheliosis viral oncogene homolog A (RELA), posterior fossa ependymomas with balanced genome, and posterior fossa ependymomas with chromosomal instability. In addition, trisomy 19 is a genomic hallmark of ependymomas with rich branching capillaries. However, the relation of histological and molecular subtypes is unclear.

Published
2016

45. Distinct disease-risk groups in pediatric supratentorial and posterior fossa ependymomas

Author

James Dalton, Thomas E. Merchant, Amar J. Gajjar, Karen Wright, David W. Ellison, Robert A. Sanford, F.A. Boop, Catherine Godfraind, Joanna M. Kaczmarska, Mehmet Kocak, UCL - (SLuc) Département de neuropsychiatrie et pathologies spéciales, and UCL - (SLuc) Service d'anatomie pathologique

Subjects
Male, Ependymoma, medicine.medical_specialty, Adolescent, Infratentorial Neoplasms, Biology, Article, Disease-Free Survival, Pathology and Forensic Medicine, Young Adult, Cellular and Molecular Neuroscience, Risk Factors, CDKN2A, medicine, Humans, Young adult, Child, Pathological, Therapeutic effect, Supratentorial Neoplasm, Infant, Supratentorial Neoplasms, Prognosis, medicine.disease, Surgery, Chromosomes, Human, Pair 1, Child, Preschool, Infratentorial Neoplasm, Cohort, Chromosomes, Human, Pair 6, Female, Neurology (clinical), Radiology, Chromosomes, Human, Pair 9
Abstract

No reliable classification is in clinical use for the therapeutic stratification of children with ependymoma, such that disease risk might be identified and patients treated to ensure a combination of maximal cure rates and minimal adverse therapeutic effects. This study has examined associations between clinicopathologic and cytogenetic variables and outcome in a trial cohort of children with ependymoma, with the aim of defining a practical scheme for stratifying this heterogeneous tumor. Intracranial ependymomas (n = 146) from children treated on the RT1 trial at St. Jude Children's Research Hospital were evaluated for the status of multiple pathological features. Interphase FISH (iFISH) defined the status of loci on chromosomes 1q (EXO1), 6q (LATS1) and 9, including 9p21 (CDKN2A). Data relating to these clinicopathological and cytogenetic variables were compared with survival data in order to model disease risk groups. Extent of surgical resection was a significant determinant of outcome in both supratentorial and infratentorial compartments. Tumor cell density and mitotic count were associated with outcome among children with posterior fossa ependymomas (n = 119). Among pathologic features, only brain invasion was associated with outcome in children with supratentorial ependymomas (n = 27). For posterior fossa tumors, gain of 1q was independently associated with outcome and in combination with clinicopathological variables defined both a two-tier and three-tier system of disease risk. Among children developing posterior fossa ependymomas treated with maximal surgical resection and conformal radiotherapy, key clinicopathological variables and chromosome 1q status can be used to define tiers of disease risk. In contrast, risk factors for pediatric supratentorial tumors are limited to sub-total resection and brain invasion.

Published
2012

46. IDH1mutation, a genetic alteration associated with adult gliomatosis cerebri

Author

Paul Desclée, Catherine Miquel, Elisabeth Verhamme, Deepti Narasimhaiah, Catherine Godfraind, and Guy Cosnard

Subjects
Pathology, medicine.medical_specialty, Lineage (genetic), IDH1, medicine.medical_treatment, Gliomatosis cerebri, General Medicine, Biology, medicine.disease, Phenotype, IDH2, Pathology and Forensic Medicine, Targeted therapy, Concomitant, Glioma, medicine, Neurology (clinical)
Abstract

Recently, mutations in IDH1 and IDH2 have been reported as an early and common genetic alteration in diffuse gliomas, being possibly followed by 1p/19q loss in oligodendrogliomas and TP53 mutations in astrocytomas. Lately, IDH1 mutations have also been identified in adult gliomatosis cerebri (GC). The aim of our study was to test the status of IDH1/2, p53 and of chromosomes 1 and 19 in a series of 12 adult and three pediatric GC. For all tumors, clinico-radiologic characteristics, histopathologic features, status of IDH1/2, p53 and of chromosomes 1 and 19 were evaluated. IDH1 mutations were detected only in GC of adult patients (5/12). They all corresponded to R132H. Additional 1p/19q losses were observed in two of them with histological features of oligodendroglial lineage. Other copy number alterations of chromosomes 1 and 19 were also noticed. The median overall survival in adults was 10.5 months in non-mutated GC and 43.5 months in mutated GC. IDH1 mutations were present in GC of adult patients, but not in those of children. There was a trend toward longer overall survival in mutated GC when compared to non-mutated ones. Concomitant 1p/19q loss was observed in IDH1-mutated GC with oligodendroglial phenotype. These observations contribute toward establishing a stronger link between GC and diffuse glioma. In addition, these results also emphasize the importance of testing for IDH1/2 mutations and 1p/19q deletions in GC to classify them better and to allow the development of targeted therapy.

Published
2011

47. Reconstructive surgery in the management of a patient with CLOVES syndrome

Author

Pascal Brouillard, Laurence M. Boon, Frank Hammer, Ali Modarressi, Philippe Clapuyt, Axel Feyaerts, Fanny Ballieux, Pierre-Louis Docquier, Miikka Vikkula, and Catherine Godfraind

Subjects
medicine.medical_specialty, Reconstructive surgery, ddc:617, business.industry, medicine, Surgery, medicine.disease, business, CLOVES syndrome
Published
2013

48. Classification and controversies in pathology of ependymomas

Author

Catherine Godfraind

Subjects
Ependymoma, medicine.medical_specialty, Pathology, Proliferative index, Brain Neoplasms, business.industry, Brain, General Medicine, medicine.disease, Diagnosis, Differential, Variable Expression, Pediatrics, Perinatology and Child Health, Humans, Medicine, Immunohistochemistry, Neurology (clinical), Neurosurgery, Tumour classification, business, Grading (tumors), Neoplasm Staging
Abstract

PURPOSE: Bailey and Cushing established ependymoma as a brain tumour entity in the first brain tumour classification (1926). Diagnosis of ependymomas is not subject to controversy as long as other tumours presenting ependymoma-like features have been ruled out. Grading conversely is a source of debate. Description of histological features establishing diagnosis and grading of ependymomas may help to better understand this controversy. METHODS: Literature has been reviewed using PubMed with the following key words: ependymoma, +/- prognosis, +/- biomaker, +/- grading, +/- immunohistochemistry, +/- proliferative index. RESULTS: Grading controversy arises from elusive WHO features and individual characteristics of ependymomas including tumour location, tumour pattern/variant and variable expression of biomarkers. CONCLUSION: There is a need for a grading scheme with a proven general ability to dissociate grades, and to predict individual clinical evolution. Only then will stratified and targeted therapeutics for ependymal tumours be possible.

Published
2009

49. Atteinte cérébrale au cours d’une maladie de Wegener

Author

Séverine Noirhomme, Catherine Godfraind, Max Lonneux, Michel Lambert, Chantal Lefebvre, François Jouret, and Cécile Grandin

Subjects
Physics, Tomography x ray computed, X ray computed, business.industry, Wegener granulomatosis, Gastroenterology, Internal Medicine, Nuclear medicine, business
Abstract

Introduction : La granulomatose de Wegener (GW) est une vascularite necrosante systemique associee a la presence d’auto-anticorps de type c-ANCA. L’atteinte du systeme nerveux central dans la GW est rare et correspond a une vascularite intraparenchymateuse, a la formation in situ de granulomes cerebromeninges ou a une extension par contiguite au depart de la sphere ORL. Observation : Nous rapportons ici le cas d’une GW nasosinusienne severe compliquee d’une extension intracrânienne pseudotumorale, confirmee par l’examen histologique. Conclusion : L’apport de la tomographie par emission de positons, dans notre observation, est un nouvel exemple de l’interet de cette imagerie fonctionnelle dans le bilan d’activite et d’extension, voire le suivi de la GW.

Published
2008

50. Schwannome intraventriculaire: à propos d'un cas

Author

M.-M. Ruchoux, Marc Lévêque, Catherine Godfraind, Claude Gilliard, and Thierry Gustin

Subjects
Text mining, business.industry, otorhinolaryngologic diseases, Medicine, Surgery, Neurology (clinical), Anatomy, Schwannoma, business, medicine.disease, Right lateral ventricle
Abstract

Ventricular schwannomas are very uncommon. We report such a tumor in the right lateral ventricle of a 16-year-old young man. The various etiopathogenic hypotheses are discussed.

Published
2007

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