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Palazzo E.,Service de Rhumatologie | Palazzo C.,Service de Reeducation Fonctionnelle | Palazzo M.,Service de Gastroenterologie Pancreatologie
Joint Bone Spine | Year: 2014

The term "IgG4-related disease" encompasses several disorders described many years ago under various designations depending on the organ or system involved (e.g., Mikulicz syndrome, Riedel's thyroiditis, and retroperitoneal fibrosis). The clinical presentation varies widely, as one or more organs may be affected, usually in the same region of the body and either synchronously or metachronously. The main targets are the pancreas, bile ducts, salivary glands, lachrymal glands, mediastinal lymph nodes, and retroperitoneum. IgG4-related disease is rare, with an estimated incidence of 0.2 to 1/100000 in Japan and no available incidence data in occidental countries. Men older than 50 years are predominantly affected. Serum IgG4 levels are often greater than 1.35. g/L. Enlargement of the involved organs, which may be pseudotumoral, is due to a combination of infiltration by T cells and IgG4-expressing plasma cells, storiform fibrosis, and obliterative thrombophlebitis. Glucocorticoid therapy is effective but may be followed by relapses requiring the use of immunomodulating agents such as azathioprine, methotrexate and, more recently, rituximab. IgG4-related disease is not an autoimmune condition related to IgG4 autoantibodies, and neither does it involve immune complexes. Specific joint involvement has been reported in a very small number of patients. © 2013 Société française de rhumatologie. Source

De Mestier L.,Service de Gastroenterologie Pancreatologie | Neuzillet C.,Service de Gastroenterologie Pancreatologie | Hentic O.,Service de Gastroenterologie Pancreatologie | Kianmanesh R.,University Paris Diderot | And 2 more authors.
Case Reports in Gastroenterology | Year: 2012

Peritoneal carcinomatosis is a well-known factor of poor prognosis in patients with digestive adenocarcinomas. Peritoneal dissemination may also occur in midgut well-differentiated neuroendocrine tumors, but its influence on survival is ill-defined. We report here the history of a 64-year-old woman who had a neuroendocrine tumor of the cecum with multiple synchronous metastases in the liver and diffuse peritoneal carcinomatosis. She underwent surgical resection of the primary tumor and cytoreduction of liver metastases, and received subsequently chemotherapy and somatostatin analogs. In spite of the widespread extension of the disease, she survived for 13 years and died from a carcinoid heart disease. We discuss the natural history and prognostic factors in patients with midgut well-differentiated neuroendocrine tumors, with a focus on the impact of the peritoneal carcinomatosis. Copyright © 2012 S. Karger AG, Basel. Source

Sipos B.,University of Tubingen | Sperveslage J.,University of Tubingen | Anlauf M.,Institute of Pathology | Hoffmeister M.,University of Tubingen | And 10 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2015

Context: Glucagon cell adenomatosis (GCA) was recently recognized as a multifocal hyperplastic and neoplastic disease of the glucagon cells unrelated to multiple endocrine neoplasia type 1 and von-Hippel-Lindau disease. Objective: The study focused on the molecular analysis of the glucagon receptor (GCGR) gene in GCA and a description of the clinicopathological features of GCA with and without GCGR mutations. Design: Pancreatic tissues from patients showing multiple glucagon cell tumors were morphologically characterized and macro- or microdissected. All exons of the GCGR gene were analyzed for mutations by Sanger and next-generation sequencing. Genotyping for all detected GCGR variants was performed in 2560 healthy individuals. Patients: Six patients with GCA, and the parents of one patient were included in the study. Main Outcome Measures: The main outcome measures were the correlations between the patients' GCGR mutation status and the respective clinicopathological data. Results: GCGR germline mutations were found in three of six patients. Patient 1 harbored a homozygous stop mutation. This patient's parents showed an identical but heterozygous GCGR mutation. Patient 2 had two different heterozygous point mutations leading each to premature stop codons. Patient 3 exhibited two homozygous missense mutations. No GCGR mutations were identified in the three other patients and in a large cohort of healthy subjects. The patients harboring GCGR mutations exhibited a greater number of tumors and larger tumors than patients with wild-type GCGR. One of the patients with wild-type GCGR showed lymph node micrometastases. Conclusions: GCA with GCGR germline mutations seems to follow an autosomal-recessive trait. By interrupting the GCGR signaling pathways GCGR mutations probably cause GCA via glucagon cell hyperplasia. GCA also occurs in patients without GCGR mutations, but seems to be associated with fewer and smaller tumors. Copyright © 2015 by the Endocrine Society. Source

Deschamps L.,Service dAnatomie Pathologique | Bacha D.,Service dAnatomie Pathologique | Rebours V.,Service de Gastroenterologie Pancreatologie | Rebours V.,University Paris Diderot | And 10 more authors.
Neuroendocrinology | Year: 2012

Background/Aim: The hypoxia-inducible factor pathway regulates the expression of a diverse group of molecules such as CA9 and CXCR4. Our aim was to investigate the expression of these markers in a series of patients with an ileal neuroendocrine tumour (IET) at various stages of tumorigenesis. Methods: The immunohistochemical expression of CA9 and CXCR4 was examined in 51 patients with a resected IET. A 'hypoxic score' was calculated, integrating the expression of both CA9 and CXCR4 (hypoxic score 0: absence of expression of both molecules; hypoxic score 1: expression of CXCR4 and/or CA9). Results were compared to histoprognostic factors (including tumour size, stage and grade, WHO and TNM classifications, presence of vascular or perineural invasion, presence of a fibrotic stroma and microvascular density) and to survival. Results: All tumours were well differentiated. 69% of tumours were less than 25 mm. 46% of tumours largely infiltrated the intestinal wall (≥T3, subserosa and serosa) and 90% were classified as N1 and/or 63% as M1. 57% of tumours were of grade G1, 43% of grade G2. Grade G2 (p = 0.004) and larger tumour infiltration (≥T4; p = 0.03) correlated with lower survival. Hypoxic score 1 correlated with a greater tumour size (p = 0.034), larger tumour infiltration (T3 or T4; p = 0.001), grade G2 (p = 0.046), presence of lymph node metastasis (p = 0.0066) and with lower survival of patients (p = 0.03). Conclusion: The hypoxia-inducible factors CA9 and CXCR4 were found associated to the malignant progression of neuroendocrine tumours of the ileum. Their expression may reflect higher tumour aggressivity. Copyright © 2011 S. Karger AG, Basel. Source

Speisky D.,Service dAnatomie Pathologique | Duces A.,University of Paris Descartes | Bieche I.,University of Paris Descartes | Rebours V.,Service de Gastroenterologie Pancreatologie | And 21 more authors.
Clinical Cancer Research | Year: 2012

Purpose: Von Hippel-Lindau (VHL) disease is an inherited syndrome caused by germline mutations in the VHL tumor suppressor gene, predisposing to a variety of neoplasms including pancreatic neuroendocrine tumors (PanNET). In VHL disease, PanNET probably progress according to a specific pathway of carcinogenesis. Our aim was to characterize by molecular quantitative analysis a panel of molecules implicated in the VHL pathway and in tumor progression in the PanNET of patients with VHL. Experimental Design: The expression of 52 genes was studied by quantitative reverse transcriptase PCR in 18 patients with VHL operated on for PanNET and compared with 16 non-VHL PanNET. The VHL and non-VHL tumors were matched according to their size and cell proliferation. For some genes, we looked for differences in the protein expression in VHL PanNET (n = 31), microadenomas (n = 22), and non-VHL PanNET (n = 16), included in tissue microarray blocks. Results: Nineteen (36%) genes were significantly upregulated and three (6%) downregulated in VHL PanNET. The upregulated genes were related to (i) hypoxia-inducible factor (HIF) molecules (CA9, HIF2A, and GLUT1), (ii) angiogenesis (CDH5, VEGFR1, EDNRA, ANGPT2, CD34, VEGFR2, VEGFA, and ANGPT1), (iii) the processes of epithelial-mesenchymal transition (VIM) and/or metastasis (LAMA4 and CXCR4), (iv) growth factors and receptors (PDGFB, IRS1, and ERBB1), or (v) cell cycle (CCND1 and CDKN2A). The downregulated genes were related to (i)EMT (OCLN) and (ii) signaling pathways (RPS6KB1 andGADD45B). Conclusion: This study shows that the progression of PanNET in patients with VHL tumors follows a specific pathway and supports that targeting molecules specifically involved may be of therapeutic importance. ©2012 AACR. Source

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