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1. Middle ear adenomatous neuroendocrine tumours: single institution experience with five cases

Author

Frédéric Tankéré, Dominique Cazals-Hatem, Lauranne Alciato, Olivier Sterkers, Ghizlene Lahlou, Daniele Bernardeschi, Alexis Bozorg-Grayeli, Unité d’Otologie, implants auditifs et chirurgie de la base du crâne [CHU Pitié-Salpêtrière], Service d'Oto-Rhino-Laryngologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-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), Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Dijon, and Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)

Subjects
medicine.medical_specialty, mastoidectomy, medicine.medical_treatment, Mastoidectomy, [SDV.CAN]Life Sciences [q-bio]/Cancer, MEANT, 03 medical and health sciences, paraganglioma, 0302 clinical medicine, tympanoplasty, Paraganglioma, Temporal bone, middle ear adenoma, medicine, otorhinolaryngologic diseases, Carcinoid tumour, [SDV.MHEP.OS]Life Sciences [q-bio]/Human health and pathology/Sensory Organs, 030223 otorhinolaryngology, cholesteatoma, schwannoma, business.industry, Cholesteatoma, Tympanoplasty, medicine.disease, 3. Good health, Surgery, medicine.anatomical_structure, Otorhinolaryngology, 030220 oncology & carcinogenesis, Middle Ear Adenoma, Middle ear, facial nerve, temporal bone, business, carcinoid tumour
Abstract

International audience; Middle ear adenomatous neuroendocrine tumours are extremely rare causes of middle ear masses. Differential diagnosis is of primary importance to decide on the correct management since they require surgery whereas other lesions can be actively watched.CT and MRI show a non‐hypervascular lesion, differentiating it from paraganglioma. It is a mesotympanic lesion that usually encases the ossicles without bone erosion and it can invade the retrotympanum and Eustachian tube.Radical surgery is the treatment of choice. Since middle ear adenomatous neuroendocrine tumours adhere to adjacent structures and lack a tumour capsule, gross total resection is challenging.Late recurrences may be observed and complicated by the development of middle ear cholesteatoma, emphasising the importance of a long follow‐up.Recurrence can be associated with neural and intracranial invasion, lymph node or distant metastasis, highlighting the malignant potential of middle ear adenomatous neuroendocrine tumours.

Published
2021

2. CARMN-NOTCH2 fusion transcript drives high NOTCH2 expression in glomus tumors of the upper digestive tract

Author

Janick Selves, Jean-François Emile, Marie Laure Raffin-Sanson, Benoǐt Terris, Chiara Villa, Nicolas Girard, Jérôme Cros, Catherine Julie, Jean François Fléjou, Zofia Hélias-Rodzewicz, Jean Michel Coindre, Christine Lagorce-Pages, Anne Sophie de Lajarte-Thirouard, Nathalie Guedj, Florence Renaud, Dominique Cazals-Hatem, Simon Martin de Beauce, Cristi Marin, Henri Jean Garchon, Biomarqueurs et essais cliniques en Cancérologie et Onco-Hématologie (BECCOH), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay, Service de pathologie [CHU Ambroise Paré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Ambroise Paré [AP-HP], Hôpital Foch [Suresnes], CHU Pontchaillou [Rennes], Centre hospitalier [Valenciennes, Nord], Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Lille Neurosciences & Cognition - U 1172 (LilNCog (ex-JPARC)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Service d’Anatomie Pathologique [CHU Beaujon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Infection et inflammation (2I), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d’endocrinologie et nutrition [AP-HP Ambroise-Paré], Hôpital Ambroise Paré [AP-HP], Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Service de Pathologie [CHU Saint-Antoine], 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), Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil (UVSQ Santé), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Institut Bergonié [Bordeaux], UNICANCER, Validation et identification de nouvelles cibles en oncologie (VINCO), UNICANCER-UNICANCER-Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de pathologie [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Association Pour la Recherche et L'enseignement en Pathologie, AREP, The study was supported by grants from Association pour la Recherche et l'Enseignement en Pathologie (AREP). The authors would like to thank Nathalie Terrones, Dominique Pechaud, Véronique Toulza, and Tristan Robert for performing tissue arrays sections and immunohistochemistry., École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Lille Neurosciences & Cognition - U 1172 (LilNCog), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Saint-Antoine [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
Cancer Research, Pathology, medicine.medical_specialty, endocrine system, endocrine system diseases, translocation, Chromosomal translocation, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, digestive tract, Fusion gene, 03 medical and health sciences, CARMN, 0302 clinical medicine, NOTCH2, Biomarkers, Tumor, Genetics, medicine, Humans, Receptor, Notch2, Gene, Exome, Gastrointestinal Neoplasms, 030304 developmental biology, 0303 health sciences, Stomach, medicine.disease, Phenotype, Glomus tumor, MicroRNAs, medicine.anatomical_structure, Fusion transcript, glomus tumor, 030220 oncology & carcinogenesis, Gene Fusion
Abstract

International audience; Glomus tumors (GTs) are perivascular tumors mostly occurring in the distal extremities. Rare cases arise in the digestive tract and may be misdiagnosed with neuroendocrine or gastrointestinal stromal tumors. We aimed to specify the features of GT of the upper digestive tract. Clinical, histological, phenotypic, and molecular features of 16 digestive GTs were analyzed, of whom two underwent whole exome and RNA sequencing to search for gene alterations. RNA-sequencing disclosed a t(1:5)(p13;q32) translocation, which resulted in the fusion of CARMN and NOTCH2 in two GTs. The fusion gene encoded a protein sequence corresponding to the NOTCH2 intracellular domain that functions as transcription factor. These finding was supported by high expression of genes targeted by NOTCH. The CARMN-NOTCH2 translocation was detected in 14 out of 16 (88%) GTs of the upper digestive tract; but in only in two out of six cutaneous GTs (33%). Most digestive GT arose from the stomach (n = 13), and the others from duodenal (2) or oesophagous (1). Nuclear expression of NOTCH2 was detected in the 14 cases containing the fusion transcripts. The CARMN-NOTCH2 fusion transcript may contribute to activation of the NOTCH2 pathway in GT and drive tumor development. The high frequency of this translocation in GT of the upper digestive track suggest that detection of nuclear NOTCH2 expression may be useful diagnostic biomarker of these tumors.

Published
2021

3. High-grade gliomas in adolescents and young adults highlight histomolecular differences from their adult and pediatric counterparts

Author

Arnault Tauziède-Espariat, Karima Mokhtari, Steven Knafo, Emmanuel Mandonnet, Pascale Varlet, Fabrice Chrétien, Marc Polivka, Clovis Adam, Johan Pallud, Marie-Anne Debily, Albane Gareton, Dominique Figarella-Branger, Thierry Faillot, Raphaël Saffroy, Marc Sanson, Alexandre Roux, Stéphanie Puget, Mathilde Desplanques, Frédéric Dhermain, Jacques Grill, François Doz, Franck Bourdeaut, Aurélie Dauta, Myriam Edjlali-Goujon, Nathalie Boddaert, Mélanie Pagès, Dominique Cazals-Hatem, Georges Dorfmüller, Institut de neurophysiopathologie (INP), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Anatomie Pathologique-Neuropathologique [AP-HM Hôpital La Timone], and Hôpital de la Timone [CHU - APHM] (TIMONE)

Subjects
Oncology, Cancer Research, medicine.medical_specialty, [SDV]Life Sciences [q-bio], World health, whole exome sequencing, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Glioma, glioma, medicine, Young adult, 10. No inequality, Exome sequencing, business.industry, glioblastoma, Retrospective cohort study, medicine.disease, humanities, 3. Good health, Isocitrate dehydrogenase, 030220 oncology & carcinogenesis, Immunohistochemistry, DNA-methylation analysis, Neurology (clinical), Oligodendroglioma, business, 030217 neurology & neurosurgery, integrated diagnosis
Abstract

Background Considering that pediatric high-grade gliomas (HGGs) are biologically distinct from their adult counterparts, the objective of this study was to define the landscape of HGGs in adolescents and young adults (AYAs). Methods We performed a multicentric retrospective study of 112 AYAs from adult and pediatric Ile-de-France neurosurgical units, treated between 1998 and 2013 to analyze their clinicoradiological and histomolecular profiles. The inclusion criteria were age between 15 and 25 years, histopathological HGG diagnosis, available clinical data, and preoperative and follow-up MRI. MRI and tumoral samples were centrally reviewed. Immunohistochemistry and complementary molecular techniques such as targeted/next-generation sequencing, whole exome sequencing, and DNA-methylation analyses were performed to achieve an integrated diagnosis according to the 2016 World Health Organization (WHO) classification. Results Based on 80 documented AYA patients, HGGs constitute heterogeneous clinicopathological and molecular groups, with a predominant representation of pediatric subtypes (histone H3-mutants, 40%) but also adult subtypes (isocitrate dehydrogenase [IDH] mutants, 28%) characterized by the rarity of oligodendrogliomas, IDH mutants, and 1p/19q codeletion and the relative high frequency of “rare adult IDH mutations” (20%). H3G34-mutants (14%) represent the most specific subgroup in AYAs. In the H3K27-mutant subgroup, non-brainstem diffuse midline gliomas are more frequent (66.7%) than diffuse intrinsic pontine gliomas (23.8%), contrary to what is observed in children. We found that WHO grade has no prognostic value, but molecular subgrouping has major prognostic importance. Conclusions HGGs in AYAs could benefit from a specific classification, driven by molecular subtyping rather than age group. Collaborative efforts are needed from pediatric and adult neuro-oncology teams to improve the management of HGGs in AYAs.

Published
2020

4. Adipocytes orchestrate the formation of tertiary lymphoid organs in the creeping fat of Crohn's disease affected mesentery

Author

Kevin Guedj, Dominique Cazals-Hatem, Yves Panis, Antonino Nicoletti, Léon Maggiori, Giuseppina Caligiuri, Yoram Bouhnik, Yael Abitbol, Olivier Corcos, Marion Morvan, Laboratoire de Recherche Vasculaire Translationnelle (LVTS (UMR_S_1148 / U1148)), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Université Sorbonne Paris Nord

Subjects
0301 basic medicine, Pathology, medicine.medical_specialty, Chemokine, Stromal cell, [SDV]Life Sciences [q-bio], Immunology, High endothelial venules, Abdominal Fat, Organ culture, Cohort Studies, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Immune system, Crohn Disease, Adipocyte, medicine, Adipocytes, Immunology and Allergy, Humans, Mesentery, Lymphocytes, Prospective Studies, Cells, Cultured, 030203 arthritis & rheumatology, biology, Gene Expression Profiling, Immunohistochemistry, 3. Good health, Intestines, 030104 developmental biology, Lymphatic system, medicine.anatomical_structure, Tertiary Lymphoid Structures, chemistry, biology.protein, Larva Migrans, Chemokines
Abstract

The formation of tertiary lymphoid organs (TLOs) is orchestrated by the stromal cells of tissues chronically submitted to inflammatory stimuli, in order to uphold specific adaptive immune responses. We have recently shown that the smooth muscle cells of the arterial wall orchestrate the formation of the TLOs associated with atherosclerosis in response to the local release of TNF-α. Observational studies have recently documented the presence of structures resembling TLOs the creeping fat that develops in the mesentery of patients with Crohn's disease (CD), an inflammatory condition combining a complex and as yet not elucidated infectious and autoimmune responses. We have performed a comprehensive analysis of the TLO structures in order to decipher the mechanism leading to their formation in the mesentery of CD patients, and assessed the effect of infectious and/or inflammatory inducers on the potential TLO-organizer functions of adipocytes. Quantitative analysis showed that both T and B memory cells, as well as plasma cells, are enriched in the CD-affected mesentery, as compared with tissue from control subjects. Immunohistochemistry revealed that these cells are concentrated within the creeping fat of CD patients, in the vicinity of transmural lesions; that T and B cells are compartmentalized in clearly distinct areas; that they are supplied by post-capillary high endothelial venules and drained by lymphatic vessels indicating that these nodules are fully mature TLOs. Organ culture showed that mesenteric tissue samples from CD patients contained greater amounts of adipocyte-derived chemokines and the use of the conditioned medium from these cultures in functional assays was able to actively recruit T and B lymphocytes. Finally, the production of chemokines involved in TLO formation by 3T3-L1 adipocytes was directly elicited by a combination of TNF-α and LPS in vitro. We therefore propose a mechanism in which mesenteric adipocyte, through their production of key chemokines in response to inflammatory/bacterial stimuli, may orchestrate the formation of functional TLOs developing in CD-affected mesentery.

Published
2019

5. Low specificity of washout to diagnose hepatocellular carcinoma in nodules showing arterial hyperenhancement in patients with Budd-Chiari syndrome

Author

Morgane Van Wettere, Pierre-Emmanuel Rautou, Valérie Vilgrain, Onorina Bruno, Dominique Valla, Maxime Ronot, Dominique Cazals-Hatem, Aurélie Plessier, Audrey Payancé, Yvonne Purcell, Université Paris Diderot - Paris 7 (UPD7), Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)

Subjects
0301 basic medicine, Adult, Male, medicine.medical_specialty, Cirrhosis, Carcinoma, Hepatocellular, Adolescent, [SDV]Life Sciences [q-bio], Budd-Chiari Syndrome, Lesion, 03 medical and health sciences, Young Adult, 0302 clinical medicine, medicine, Humans, 10. No inequality, Aged, Retrospective Studies, Hepatology, business.industry, Liver Neoplasms, Washout, Nodule (medicine), Retrospective cohort study, Middle Aged, medicine.disease, Magnetic Resonance Imaging, 3. Good health, 030104 developmental biology, Liver, Hepatocellular carcinoma, Budd–Chiari syndrome, 030211 gastroenterology & hepatology, Female, Radiology, alpha-Fetoproteins, medicine.symptom, Liver cancer, business
Abstract

It remains unclear whether the classic imaging criteria for the non-invasive diagnosis of hepatocellular carcinoma (HCC) can be applied to chronic vascular liver diseases, such as Budd-Chiari syndrome (BCS). Herein, we aimed to evaluate the diagnostic value of washout for the discrimination between benign and malignant lesions in patients with BCS.This retrospective study included all patients admitted to our institution with a diagnosis of BCS and focal lesions on MRI from 2000 to 2016. MRI images were reviewed by 2 radiologists blinded to the nature of the lesions. Patient and lesion characteristics were recorded, with a focus on washout on portal venous and/or delayed phases. Lesions were compared using Chi-square, Fisher's, Student's t or Mann-Whitney U tests.A total of 49 patients (mean age 35 ± 12 years; 34 women [69%] and 15 men [31%]) with 241 benign lesions and 12 HCC lesions were analyzed. Patients with HCC were significantly older (mean age 44 ± 16 vs. 33 ± 9 years, p = 0.005), with higher alpha-fetoprotein (AFP) levels (median 16 vs. 3 ng/ml, p = 0.007). Washout was depicted in 9/12 (75%) HCC, and 69/241 (29%) benign lesions (p0.001). A total of 52/143 (36%) lesions ≥1 cm with arterial hyperenhancement showed washout (9 HCC and 43 benign lesions). In this subgroup, the specificity of washout for the diagnosis of HCC was 67%. Adding T1-w hypointensity raised the specificity to 100%. A serum AFP15 ng/ml was associated with 95% specificity.Washout was observed in close to one-third of benign lesions, leading to an unacceptably low specificity for the diagnosis of HCC. The non-invasive diagnostic criteria proposed for cirrhotic patients cannot be extrapolated to patients with BCS.Washout on MRI is depicted in a significant proportion of benign nodules in patients with Budd-Chiari syndrome (BCS), limiting its value for the differentiation between benign and malignant lesions. Criteria proposed for the non-invasive diagnosis of hepatocellular carcinoma in patients with cirrhosis cannot be extrapolated to patients with BCS. Additional imaging findings and patient characteristics, including alpha-fetoprotein serum level, can help determine the probability of a nodule being HCC in patients with BCS.

Published
2019

6. 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

7. Prevalence of Yersinia Species in the Ileum of Crohn's Disease Patients and Controls

Author

Guillaume Le Baut, Claire O'Brien, Paul Pavli, Maryline Roy, Philippe Seksik, Xavier Tréton, Stéphane Nancey, Nicolas Barnich, Madeleine Bezault, Claire Auzolle, Dominique Cazals-Hatem, Jérome Viala, Matthieu Allez, The REMIND GROUP, Jean-Pierre Hugot, Anne Dumay, Cibles et médicaments de l'infection, de l'immunité et du cancer (IICiMed), Université de Nantes - UFR des Sciences Pharmaceutiques et Biologiques, Université de Nantes (UN)-Université de Nantes (UN), Australian National University (ANU), CRI UMR 1149, Lab Excellence Inflamex, Université Paris Diderot - Paris 7 (UPD7), Service de Gastroentérologie et nutrition [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Saint-Antoine [APHP], Centre de recherche biomédicale Bichat-Beaujon (CRB3), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'hépato-gastroentérologie, Hospices Civils de Lyon (HCL), 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), INSERM, U1160, Département de Gastroentérologie, Hôpital Saint-Louis, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Diderot - Paris 7 (UPD7), Origine, structure et évolution de la biodiversité, Centre National de la Recherche Scientifique (CNRS), Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Cibles et Médicaments des Infections et de l'Immunité (IICiMed), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), 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), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Origine, structure et évolution de la biodiversité (OSEB), Muséum national d'Histoire naturelle (MNHN)-Centre National de la Recherche Scientifique (CNRS), Investissements d'Avenir programme, Sorbonne Paris Cite, Laboratoire d'excellence INFLAMEX ANR-11-IDEX-0005-02, Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), 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), and 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)

Subjects
0301 basic medicine, Microbiology (medical), système immunitaire, Immunology, lcsh:QR1-502, Ileum, Biology, Gut flora, Yersinia, Microbiology, Inflammatory bowel disease, lcsh:Microbiology, yersinia, 03 medical and health sciences, 0302 clinical medicine, NOD2, Immunologie, medicine, mucosal immune system, ATG16L1, innate immunity, Crohn's disease, gut microbiota, ileal mucosa, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, maladie de crohn, medicine.disease, biology.organism_classification, molecular test, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, 3. Good health, ileon, 030104 developmental biology, Infectious Diseases, medicine.anatomical_structure, microflore digestive, IRGM, 030211 gastroenterology & hepatology
Abstract

International audience; Yersinia are common contaminants of food products, but their prevalence in the human gut is poorly documented. Yersinia have been implicated in Crohn's Disease (CD, an inflammatory bowel disease) however their role in CD is controversial. We performed highly sensitive PCR assays of specific sequences for the gyrB gene of Y. aldovae, Y. bercovieri, Y. enterocolitica, Y. intermedia, Y. mollaretii and the inv gene of Y. pseudotuberculosis. We analyzed a total of 470 ileal samples taken from 338 participants (262 CD patients and 76 controls) belonging to three independent cohorts. All patients and controls were phenotyped and genotyped for the main CD susceptibility variants: NOD2, ATG16L1, and IRGM. Yersinia were found in 7.7% of ileal samples (respectively 7.9 and 7.6% in controls and CD patients) corresponding to 10% of participants (respectively 11.8 and 9.5% in controls and CD patients). Y. enterocolitica, Y. pseudotuberculosis and Y. intermedia were the most frequently identified species. The bacteria were more frequent in resected specimens, lymph nodes and Peyer's patches. Yersinia were no more likely to be detected in CD tissues than tissues from inflammatory and non-inflammatory controls. CD patients treated with immunosuppressants were less likely to be Yersinia carriers. In conclusion, this work shows that Yersinia species are frequently found at low levels in the human ileum in health and disease. The role of Yersinia species in this ecosystem should now be explored.

Published
2018

8. Topological Modelling of Deep Ulcerations in Patients with Ulcerative Colitis

Author

Gilles Wainrib, Eric Ogier-Denis, Ian Morilla, Hatem Zaag, Xavier Treton, Mathieu Uzzan, Dominique Cazals-Hatem, Service d'Anatomo-Pathologie, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Diderot - Paris 7 (UPD7)-Hôpital Beaujon, Laboratoire Analyse, Géométrie et Applications (LAGA), Université Paris 8 Vincennes-Saint-Denis (UP8)-Université Paris 13 (UP13)-Institut Galilée-Université Sorbonne Paris Cité (USPC)-Centre National de la Recherche Scientifique (CNRS), Faculté de Médecine Xavier Bichat, Service de gastro-entérologie et assistance nutritive, Hôpital Beaujon-Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris 8 Vincennes-Saint-Denis (UP8)-Centre National de la Recherche Scientifique (CNRS)-Institut Galilée-Université Paris 13 (UP13), Hôpital Beaujon [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)

Subjects
0301 basic medicine, business.industry, Inference, medicine.disease, Topology, Inflammatory bowel disease, Ulcerative colitis, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], digestive system diseases, 3. Good health, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, 030220 oncology & carcinogenesis, Cohort, Medicine, [MATH.MATH-AP]Mathematics [math]/Analysis of PDEs [math.AP], In patient, business, ComputingMilieux_MISCELLANEOUS
Abstract

Aims: Steadily the clinicians of our team in inflammatory bowel disease encounter ulcerative colitis patients that develop deep ulcers during their treatment. Currently, these practitioners are only equipped with their grade of expertise in inflammatory domains to decide what new therapy maybe use in such cases. Encouraged by the limited knowledge of this frequent pathology, we seek to determine the molecular conditions underlying the recurrent formation of deep ulcerations in certain group of patients. Method: The goal of this strategy is to expose differences between groups of patients based on similarities computed by random walk graph kernels and performing functional inference on those differences. Results: We apply the methodology to a cohort of eleven miRNA microarrays of ulcerative colitis patients. Our results showed how the group of ulcerative colitis patients with presence of deep ulcers is topologically more similar (0.35) than ulcerative colitis patients (0.18) to control. Such topological constraint drove functional inference to complete the information that clinicians need. Conclusions: Our analyses reveal highly interpretable in the guidance of practitioners to eventually correct initial therapies of ulcerative colitis patients that develop deep ulcers. The methodology can provide them with useful molecular hypotheses necessaries prior to make any decision on the newest course of the treatment.

Published
2017

9. Integrative Network-based Analysis of Colonic Detoxification Gene Expression in Ulcerative Colitis According to Smoking Status

Author

Yannick Ladeiro, Yong-Ping Ding, Ian Morilla, Assiya Marah, Xavier Treton, Dominique Cazals-Hatem, Gilles Wainrib, Fanny Daniel, Philippe Seksik, Eric Ogier-Denis, Yoram Bouhnik, Hatem Zaag, Jean-Pierre Hugot, Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Physiopathologie de la réactivite bronchique et vasculaire, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de gastro-entérologie et assistance nutritive, Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Laboratoire Analyse, Géométrie et Applications (LAGA), Université Paris 8 Vincennes-Saint-Denis (UP8)-Centre National de la Recherche Scientifique (CNRS)-Institut Galilée-Université Paris 13 (UP13), Service d'Anatomo-Pathologie, Université Pierre et Marie Curie - Paris 6 (UPMC), Institut de Recherche pour le Développement, UR 178 Fundamentals & Domains of Disease Emergence (IRD UR178), Faculté de Médecine Xavier Bichat, Hôpital Beaujon-Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Université Paris 8 Vincennes-Saint-Denis (UP8)-Université Paris 13 (UP13)-Institut Galilée-Université Sorbonne Paris Cité (USPC)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Université Paris 8 Vincennes-Saint-Denis (UP8)-Université Paris 13 (UP13)-Institut Galilée-Centre National de la Recherche Scientifique (CNRS)

Subjects
Adult, Male, 0301 basic medicine, Colon, Gene Expression, Disease, Real-Time Polymerase Chain Reaction, Inflammatory bowel disease, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Gene interaction, Detoxification, Gene expression, Humans, Medicine, ComputingMilieux_MISCELLANEOUS, Principal Component Analysis, business.industry, Smoking, Gastroenterology, General Medicine, Middle Aged, medicine.disease, Ulcerative colitis, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], 3. Good health, 030104 developmental biology, Real-time polymerase chain reaction, Case-Control Studies, Inactivation, Metabolic, Immunology, Colitis, Ulcerative, Female, 030211 gastroenterology & hepatology, business, Homeostasis
Abstract

Backgrounds and Aims: The effect of cigarette smoking [CS] is ambivalent since smoking improves ulcerative colitis [UC] while it worsens Crohn’s disease [CD]. Although this clinical relationship between inflammatory bowel disease [IBD] and tobacco is well established, only a few experimental works have investigated the effect of smoking on the colonic barrier homeostasis focusing on xenobiotic detoxification genes. Methods: A comprehensive and integrated comparative analysis of the global xenobiotic detoxification capacity of the normal colonic mucosa of healthy smokers [ n = 8] and non-smokers [ n = 9] versus the non-affected colonic mucosa of UC patients [ n = 19] was performed by quantitative real-time polymerase chain reaction [qRT PCR]. The detoxification gene expression profile was analysed in CD patients [ n = 18], in smoking UC patients [ n = 5], and in biopsies from non-smoking UC patients cultured or not with cigarette smoke extract [ n = 8]. Results: Of the 244 detoxification genes investigated, 65 were dysregulated in UC patients in comparison with healthy controls or CD patients. The expression of ≥ 45/65 genes was inversed by CS in biopsies of smoking UC patients in remission and in colonic explants of UC patients exposed to cigarette smoke extract. We devised a network-based data analysis approach for differentially assessing changes in genetic interactions, allowing identification of unexpected regulatory detoxification genes that may play a major role in the beneficial effect of smoking on UC. Conclusions: Non-inflamed colonic mucosa in UC is characterised by a specifically altered detoxification gene network, which is partially restored by tobacco. These mucosal signatures could be useful for developing new therapeutic strategies and biomarkers of drug response in UC.

Published
2016

10. Increased Proliferation of the Ileal Epithelium as a Remote Effect of Ulcerative Colitis

Author

Eric Ogier-Denis, Dominique Cazals-Hatem, Fanny Daniel, Frédérick Barreau, Eric Pedruzzi, Nicolas Montcuquet, Shirin Sedghi, Xavier Treton, Jean-Pierre Hugot, Ian Morilla, Emilie Rannou, Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Institut de Recherche en Santé Digestive (IRSD ), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Radioprotection et de Sûreté Nucléaire (IRSN), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Association Francois Aupetit, AFAInstitut National de la Santé et de la Recherche Médicale, InsermCentre National de la Recherche Scientifique, CNRS

Subjects
0301 basic medicine, Pathology, medicine.medical_specialty, MAP Kinase Signaling System, [SDV]Life Sciences [q-bio], Inflammation, Biology, Inflammatory bowel disease, Mice, 03 medical and health sciences, 0302 clinical medicine, Immune system, Ileum, medicine, Animals, Humans, Immunology and Allergy, Intestinal Mucosa, Colitis, Wnt Signaling Pathway, beta Catenin, Cell Proliferation, Gastroenterology, Wnt signaling pathway, medicine.disease, Ulcerative colitis, Small intestine, 3. Good health, Mice, Inbred C57BL, Interleukin 10, 030104 developmental biology, medicine.anatomical_structure, Trinitrobenzenesulfonic Acid, Case-Control Studies, 030220 oncology & carcinogenesis, Immunology, Colitis, Ulcerative, medicine.symptom
Abstract

Background Aside from cases of backwash ileitis, the ileal mucosa of patients with ulcerative colitis (UC), an idiotypic inflammatory bowel disease, has received little attention despite the fact that colitis is known to trigger alterations in morphology and/or functions of the small intestine remotely. Methods The ileal mucosa was studied in patients with UC and in a spontaneous model of colitis (Il10/Nox1 dKO mice) mimicking the histological and clinical features of UC and was also studied in acute and chronic murine models of chemically induced colitis. Proliferation and apoptosis were assessed using morphological and immunohistological methods and Western blot analysis. Peyer's patch immune cell subsets were analyzed. Cytokines levels were quantified using quantitative PCR and Luminex xMAP technology. Total RNA from isolated ileal crypts was used for whole genome transcriptome analysis. Results The most striking features were an increased ileal crypt length associated with an enhanced cell proliferation of the transit-amplifying cells along with activation of the Wnt/β-catenin and MAPkinase pathways. These changes did not result from intestinal inflammation as assessed by histology and/or pro-inflammatory cytokine expression levels. The increased proliferation rate was dependent on the duration but not on the severity of colitis and was observed in different mouse models of colitis, including the Il10/Nox1 dKO model and 2,4,6-trinitrobenzenesulfonic acid-treated mice. Interestingly, the ileal mucosa of patients with UC also displayed longer crypts and enhanced cell proliferation compared with control patients. Conclusions These data show that despite the absence of inflammation in the small intestine, alterations in the ileal mucosa homeostasis are present in UC. Copyright © 2016 Crohn's and Colitis Foundation of America, Inc.

Published
2016

11. Effect of appendicectomy on colonic inflammation and neoplasia in experimental ulcerative colitis

Author

Eric Ogier-Denis, Léon Maggiori, Xavier Treton, Karim Boudjema, Yves Panis, Yann Harnoy, Yoram Bouhnik, Dominique Cazals-Hatem, Laurent Sulpice, Nathalie Gault, Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), LabEx Inflamex, Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Pontchaillou [Rennes], Hôpital Beaujon, AP HP, Departement de Gastroenterologie et d'assistance Nutritive, Université Paris Diderot - Paris 7 (UPD7), Foie, métabolismes et cancer, Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service de Chirurgie Hépatobiliaire et Digestive [Rennes] = Hepatobiliary and Digestive Surgery [Rennes], Association Francois Aupetit, Societe Francaise de Chirurgie Digestive, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Hôpital Beaujon, Service de Chirurgie Hépatobiliaire et Digestive, and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes]

Subjects
Adult, Male, medicine.medical_specialty, appendicitis, Colorectal cancer, medicine.medical_treatment, [SDV.CAN]Life Sciences [q-bio]/Cancer, Gastroenterology, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Laparotomy, Medicine, Animals, Appendectomy, Humans, Colitis, Colectomy, business.industry, Rectal Neoplasms, colorectal-cancer, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Middle Aged, suppression, medicine.disease, Ulcerative colitis, Appendix, Appendicitis, 3. Good health, Interleukin-10, Mice, Inbred C57BL, medicine.anatomical_structure, Dysplasia, 030220 oncology & carcinogenesis, Chronic Disease, Colonic Neoplasms, 030211 gastroenterology & hepatology, Surgery, Colitis, Ulcerative, Female, protects, business, bowel-disease
Abstract

International audience; BackgroundUlcerative colitis (UC) promotes cancer, and can be ameliorated by early appendicectomy for appendicitis. The aim of the study was to explore the effect of appendicectomy on colitis and colonic neoplasia in an animal model of colitis and a cohort of patients with UC. MethodsFive-week old IL10/Nox1(DKO) mice with nascent colitis and 8-week-old IL10/Nox1(DKO) mice with established colitis underwent appendicectomy (for experimental appendicitis or no appendicitis) or sham laparotomy. The severity and extent of colitis was assessed by histopathological examination, and a clinical disease activity score was given. From a cohort of consecutive patients with UC who underwent colectomy, the prevalence of appendicectomy and pathological findings were collected from two institutional databases. ResultsAppendicectomy for appendicitis ameliorated experimental colitis in the mice; the effect was more pronounced in the 5-week-old animals. Appendicectomy in the no-appendicitis group was associated with an increased rate of colonic high-grade dysplasia (HGD) or cancer compared with rates in sham and appendicitis groups (13 of 20 versus 0 of 20 and 0 of 20 respectively; P < 0001). Fifteen of 232 patients who underwent colectomy for UC had previously had an appendicectomy, and nine of these had colonic cancer or HGD. Thirty (138 per cent) of 217 patients with the appendix insitu had colonic neoplastic lesions. Multivariable analysis showed that previous appendicectomy was associated with colorectal neoplasia (odds ratio 1688, 95 per cent c.i. 332 to 11269). ConclusionAppendicectomy for experimental appendicitis ameliorated colitis. The risk of colorectal neoplasia appeared to increase following appendicectomy without induced appendicitis in a mouse model of colitis, and in patients with UC who had undergone appendicectomy. Surgical relevance Appendicectomy for appendicitis protects against UC. In this murine model of colitis, appendicectomy for experimental appendicitis protected against colitis, but appendicectomy without appendicitis promoted colorectal carcinogenesis. In patients with ulcerative colitis who underwent colectomy, absence of the appendix (proof of previous appendicectomy) in the resection specimen was independently associated with colorectal neoplasia. Although patients with UC and a history of appendicectomy represent a small subset, they may need closer monitoring for colorectal neoplasia. Appendicectomy reduces inflammation, increases risk for cancer

Published
2016

12. Small Bowel Adenocarcinomas Complicating Crohn's Disease Are Associated With Dysplasia: A Pathological and Molecular Study

Author

Pascale Cervera, Jean-François Rahier, Severine Vermeire, Gottfried Novacek, Dominique Cazals-Hatem, Sandro Ardizzone, Monique Delos, Guillaume Cadiot, Laurent Beaugerie, Paolo Fociani, Olivier Lascols, Nizar El-Murr, Sylvie Dumont, Jean-François Fléjou, Magali Svrcek, Fritz Wrba, Yoram Bouhnik, Florence Le Pessot, Marie-Danièle Diebold, Franck Carbonnel, Aurelie Scriva, Gaël Piton, Karel Geboes, Antoinette Lemoine, Emmanuelle Leteurtre, Jacques Cosnes, Guillaume Savoye, Jean-Frederic Colombel, Service de gastro-entérologie, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Université Pierre et Marie Curie - Paris 6 (UPMC), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Microenvironnement et Physiopathologie de la Differenciation, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Hépato-Gastroentérologie [CHU Rouen], Hôpital Charles Nicolle [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Service d'Hépato-gastroentérologie, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Pole des maladies de l'appareil digestif, gastroentérologie et assistance nutritive, Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'Anatomo-Pathologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université de Reims Champagne-Ardenne (URCA), Laboratoire d'Anatomopathologie, Centre hospitalier Universitaire, UCL Mont Godinne, Hépatogastroentérologie, CHU de Bicêtre, Service de Gastroentérologie et nutrition [CHU Saint-Antoine], 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), Service d'anatomie et cytologie pathologiques [CHU Saint-Antoine], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Hôpital Charles Nicolle [Rouen]-Université de Rouen Normandie (UNIROUEN), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Hôpital Jean Minjoz, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Saint-Antoine [APHP], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Saint-Antoine [APHP], Centre de Recherche Saint-Antoine (CR Saint-Antoine), Hepato Gastroenterology, Hospital and University of Rouen, Service d'Hépato-Gastroentérologie [Rouen], Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Hôpital Charles Nicolle [Rouen]-CHU Rouen, Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer (JPArc - U837 Inserm), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université Lille 2 - Faculté de Médecine, AP-HP Hôpital Beaujon, and Hôpital Beaujon-Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)

Subjects
Adult, Male, Pathology, medicine.medical_specialty, Colorectal cancer, Fibromuscular dysplasia, Adenocarcinoma, Gastroenterology, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Crohn Disease, Risk Factors, Internal medicine, Intestine, Small, medicine, Fibromuscular Dysplasia, Humans, Immunology and Allergy, Survival rate, neoplasms, Inflammation, Crohn's disease, business.industry, [CHIM.ORGA]Chemical Sciences/Organic chemistry, Cancer, Middle Aged, Prognosis, medicine.disease, Ulcerative colitis, digestive system diseases, 3. Good health, Survival Rate, Dysplasia, 030220 oncology & carcinogenesis, Female, 030211 gastroenterology & hepatology, Colorectal Neoplasms, business, Follow-Up Studies
Abstract

International audience; BACKGROUND:: Crohn's disease (CD) is associated with an increased risk of small bowel adenocarcinoma (SBA). However, there are no guidelines for the screening and early diagnosis of SBA. Colorectal cancer associated with chronic colitis arises from dysplasia. High-risk patients benefit from surveillance colonoscopies aimed to detect dysplasia. The dysplasia-carcinoma sequence remains poorly documented in CD-associated SBA. Moreover, molecular data about SBA complicating CD and associated dysplasia are very limited. We therefore assessed dysplasia and several key molecular markers of carcinogenesis in SBA and dysplasia developed in patients with CD. METHODS:: Forty-five SBA complicating CD and 4 specimens with dysplasia without SBA were screened. In SBA, we looked for dysplasia and determined their pathological characteristics (type, grade, distribution). We also stained for mismatch repair proteins (MLH1, MSH2, MSH6, PMS2), p53, β-catenin, and p16 and looked for KRAS, BRAF and PIK3CA mutations. RESULTS:: All neoplastic lesions, except 1 lesion, were found in inflamed mucosal areas. Dysplasia was found in 20 of 41 patients with SBA (49%). Dysplasia was flat or raised, low grade or high grade, and adjacent or distant to concomitant SBA. Molecular markers of SBA carcinogenesis complicating CD were similar to those observed in chronic colitis-related colorectal cancer (KRAS, BRAF, p53, MSI), although differences were observed for β-catenin and p16. No PIK3CA mutations were observed. CONCLUSIONS:: These results suggest that there is an inflammation-dysplasia-adenocarcinoma sequence in at least half of CD-related SBA, similar to what is observed in chronic colitis-related colorectal cancer and may have implications for the prevention and treatment of this cancer.

Published
2014

13. The sensing of poorly deformable red blood cells by the human spleen can be mimicked in vitro

Author

Narla Mohandas, François Paye, Innocent Safeukui, François Lacoste, Sylvie Perrot, Guillaume Deplaine, Béatrice Aussilhou, Pierre Buffet, Dominique Cazals Hatem, Dominique Mazier, Alain Sauvanet, Fakhri Jeddi, Marc Thellier, Micheline Guillotte, Peter H. David, Sylvestre Biligui, Valentine Brousse, Geneviève Milon, Odile Mercereau-Puijalon, Safi Dokmak, Corinne Guitton, Immunologie moléculaire des parasites, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC), Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Hôpital Beaujon [AP-HP], CHU Saint-Antoine [AP-HP], Immunophysiologie et Parasitisme Intracellulaire, Institut Pasteur [Paris] (IP), New York Blood Center, This work was supported by the 'Fonds dédié Combattre les maladies parasitaires,' Sanofi Aventis-Ministère de l'Enseignement Supérieur et de la Recherche-Institut Pasteur, the Centre National de la Recherche Scientifique, and the Institut Pasteur. G.D. was supported by the Délégation Générale à l'Armement (fellowship 05 60 00 032). F.L. was supported by Fondation Inckerman-Fondation de France and the Région Ile de France. I.S. was funded by a fellowship from the Région Ile de France. V.B. was supported by Fondation pour la Recherche Médicale. Research of the IMP Unit at Institut Pasteur is partly supported by the BioMalPar European Network of Excellence from the Priority 1 'Life Sciences, Genomics and Biotechnology for Health' in the 6th Framework Programme and by the Project: Mechanisms of erythrocytic Infection & Anemia in Malaria PI Kasturi Haldar, and the National Institutes of Health (Award Number 5P01HL078826-06). N.M. acknowledges the 'Fonds dédié Combattre les maladies parasitaires,' Sanofi Aventis-Ministère de l'Enseignement Supérieur et de la Recherche-Institut Pasteur, which made possible his sabbatical stay at Institut Pasteur., European Project: 26843,BIOMALPAR, and Institut Pasteur [Paris]

Subjects
Pathology, MESH: Erythrocyte Deformability, Erythrocytes, MESH: Spleen, Cell Separation, 030204 cardiovascular system & hematology, Biochemistry, Hereditary spherocytosis, 0302 clinical medicine, hemic and lymphatic diseases, MESH: Microcirculation, Erythrocyte deformability, 0303 health sciences, education.field_of_study, MESH: Erythrocytes, hemic and immune systems, Hematology, MESH: Hematologic Diseases, MESH: Spherocytosis, Hereditary, Microspheres, Hemolysis, 3. Good health, Cell biology, medicine.anatomical_structure, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Splenic Red Pulp, circulatory and respiratory physiology, medicine.medical_specialty, Immunology, Population, Spherocytosis, MESH: Microspheres, Spleen, Spherocytosis, Hereditary, Biology, Models, Biological, MESH: Cell Separation, Microcirculation, 03 medical and health sciences, Red Cells, Iron, and Erythropoiesis, Erythrocyte Deformability, medicine, Humans, education, 030304 developmental biology, MESH: Humans, MESH: Models, Biological, Cell Biology, medicine.disease, Hematologic Diseases
Abstract

Retention of poorly deformable red blood cells (RBCs) by the human spleen has been recognized as a critical determinant of pathogenesis in hereditary spherocytosis, malaria, and other RBC disorders. Using an ex vivo perfusion system, we had previously shown that retention of Plasmodium falciparum–infected RBCs (Pf-RBCs) occur in the splenic red pulp, upstream from the sinus wall. To experimentally replicate the mechanical sensing of RBCs by the splenic microcirculation, we designed a sorting device where a mixture of 5- to 25-μm-diameter microbeads mimics the geometry of narrow and short interendothelial splenic slits. Heated RBCs, Pf-RBCs, and RBCs from patients with hereditary spherocytosis were retained in the microbead layer, without hemolysis. The retention rates of Pf-RBCs were similar in microbeads and in isolated perfused human spleens. These in vitro results directly confirm the importance of the mechanical sensing of RBCs by the human spleen. In addition, rigid and deformable RBC subpopulations could be separated and characterized at the molecular level, and the device was used to deplete a stored RBC population from its subpopulation of rigid RBCs. This experimental approach may contribute to a better understanding of the role of the spleen in the pathogenesis of inherited and acquired RBC disorders.

Published
2011

14. L’entérite radique chronique : corrélations anatomo-cliniques à partir d’une cohorte monocentrique de 41 patients opérés

Author

Didier, Jérôme, Université Paris Descartes - Faculté de Médecine (UPD5 Médecine), Université Paris Descartes - Paris 5 (UPD5), and Dominique Cazals-Hatem

Subjects
Grêle, MESH: Intestine, Small, Corrélations, Ischémique, Phénotype, MESH: Radiation Injuries, Chronic radiation enteritis, Entérite radique chronique, MESH: Phenotype, Anatomoclinique, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, MESH: Enteritis
Abstract

Introduction: the aim of our study was 1/characterizing histological lesions of chronical radiation enteritis (CRE), 2/correlating them with clinical presentation 3/isolating a phenotype associated with a pejorative evolution. Methods: the retrospective study dealt with all patients treated for CRE which required an intestinal resection in our hospital between 2006 and 2017. The histological data where correlated with the initial clinical data and the recurrent clinical symptoms observed during the follow-up (the median follow-up was 32 months [4;180] after resection). Results: 41 patients were included. Among them, there were 39 (95%) women and 2 men. The intestinal resection, brought 60 [10;220] cm of diseased small bowel. The histological findings showed an amyotrophy, villous atrophy, ulcerations observed among 66, 63 and 34% of the panel respectively. The intestinal wall arteries were obliterated among 24 (59%) patients, significantly associated with villous atrophy, ulcerations and an amyotrophy, defining a CRE of ischemic phenotype. CRE with ischemic phenotype was found among patients lately treated by surgery after a radiotherapy (between 13 years ± 2,3 vs 2,6 years ± 0,6, p=0.0002). During the follow-up, a recurrence of occlusive syndrome and the necessity of new intervention was observed among 10 (25%) and 4 (10%) patients respectively. The recurrence was the same whatever could be the histological phenotype. Conclusion: the intestinal wall arteries diffusely obliterated are observed in 59% of CRE and are associated with an ischemic histological phenotype. However, they are not correlated with postoperative recurrence of CRE symptoms.; Introduction : l’objectif de notre étude était 1/ de caractériser les lésions histologiques de l’entérite radique chronique (ERC) 2/ de les corréler à la présentation clinique 3/ d’isoler un phénotype lésionnel associé à une évolution péjorative. Matériel et méthode : il s’agissait d’une étude rétrospective incluant tous les patients suivis pour une ERC ayant nécessité une résection intestinale dans notre centre entre 2006 et 2017. Les données histologiques ont été corrélées aux données cliniques initiales et à la récidive de symptômes cliniques observée au cours du suivi (32 mois en médiane [4 ; 180] après la résection). Résultats : 41 patients opérés ont été sélectionnés. Il s’agissait de 39 (95%) femmes et 2 hommes. La résection iléale emportait 60 [10 ; 220] cm d’iléon pathologique. En histologie, une amyotrophie, une atrophie villositaire et des ulcérations étaient observées chez 66, 63 et 34% des patients. Les artères de la paroi intestinale étaient oblitérées chez 24 (59%) patients, associées significativement à de l’atrophie villositaire, des ulcérations et à une amyotrophie, définissant une ERC de phénotype ischémique. Celle-ci était retrouvée chez les patients opérés tardivement après la radiothérapie (délai de 13 ans ± 2,3 vs 2,6 ans ± 0,6 ; p=0,0002). Au cours du suivi, une récidive du syndrome subocclusif et la nécessité d’une réintervention étaient observées chez 10 (25%) et 4 (10%) patients et ce, quel que soit le phénotype histologique. Conclusion : les lésions artérielles oblitérantes s’observent dans 59% des ERC et sont associées à un phénotype histologique ischémique mais ne sont pas corrélées à la récidive post-opératoire des symptômes de l’ERC.

Published
2018

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