Alain Calender

Cystic endocrine tumors of the pancreas: clinical, radiologic, and histopathologic features in 13 cases.

Cystic endocrine tumors of the pancreas are rare and raise difficult clinical problems. Our aims were to reevaluate the diagnostic and therapeutic strategy and to assess their histopathologic characteristics. Thirteen cystic endocrine tumors diagnosed in 10 patients were included. Clinical, radiologic, and pathologic data were reviewed. There were 6 male and 4 female patients (median age, 46 yrs). Six patients had evidence of multiple endocrine neoplasia type 1 (MEN1) disease. Four had a functional endocrine syndrome. Ten tumors were visible on imaging studies. The most suggestive radiologic features were the existence of a peripheral hypervascular rim (10 cases) and images of cyst into cyst (two cases). On gross and histologic examinations, two distinct types were present. Macrocystic tumors (six cases) were unilocular and limited by a thick wall containing nests of tumor cells. Microcystic tumors (seven cases) were characterized by the presence of multiple cystic spaces directly lined by tumor cells. Surgical resection was performed in all cases. Three patients had lymph node metastases at the time of diagnosis. One patient is dead with metastatic dissemination. The others are alive without recurrence or metastasis. The diagnosis of endocrine tumor must be considered for any pancreatic cyst discovered in a patient with a history of MEN1 syndrome or with clinical features suggestive of this syndrome. Cystic pancreatic endocrine tumors must be treated by surgical resection because of their possible malignant evolution.

MEN1 Missense Mutations Impair Sensitization to Apoptosis Induced by Wild-Type Menin in Endocrine Pancreatic Tumor Cells

BACKGROUND & AIMSnMissense mutations account for 30% of mutations identified in patients with the multiple endocrine neoplasia type 1 (MEN1) syndrome. They raise several issues: the distinction between pathogenic mutations and polymorphisms is sometimes difficult and the functional effects of missense mutations are unclear. We aimed to evaluate the functional consequences of missense MEN1 mutations in an appropriate endocrine cellular context.nnnMETHODSnFrom the INS-1 insulinoma cell line, we established clones conditionally over expressing wild-type (WT) menin or its A160T, H317Y, and A541T variants. We compared the consequences of WT or variant menin over expression on apoptotic response after gamma-irradiation and analyzed the interactions of these proteins with p53.nnnRESULTSnWT menin over expression sensitized INS-r3 cells to apoptosis through amplification of caspase-3 activation, increased p53 acetylation, and accelerated p21 activation; moreover, over expressed WT menin could be recovered in p53-containing complexes. For all 3 missense mutations tested, the functional effects observed with WT were impaired significantly and only low amounts of variant menin proteins were recovered in p53-containing complexes.nnnCONCLUSIONSnTaking advantage of a new endocrine cellular model, we show a loss of function for 2 missense disease-related menin mutants and for a controversial variant as well. Furthermore, our results suggest the existence of functional interactions between p53 and menin for the control of apoptosis, which may cast new light on the mechanisms of endocrine tumorigenesis.

Hereditary hemorrhagic telangiectasia: Evidence for regional founder effects of ACVRL1 mutations in French and Italian patients

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disease characterized by widespread arteriovenous malformations and caused by mutations in two major genes: ENG and ACVRL1. Two decades ago, a French epidemiological study pointed out that its prevalence was higher than previously thought and that its distribution varied greatly from one area to another, one of the highest concentrations of patients being found in the Haut-Jura mountains. Although germline mutations are usually family specific, some of them have been reported in unrelated patients, especially for ACVRL1. We performed haplotype analysis of 116 French and Italian patients carrying 13 ACVRL1 different mutations. For five of these mutations, we estimated the age of the most recent common ancestors (MRCAs) using the ESTIAGE program. Most mutations were related to both recurrent mutational events and founder effects with age estimates ranging from 100 to 550 years. The c.1112dupG mutation, which is likely to be responsible for the very high concentration of HHT patients found in the former epidemiological study, probably occurred in one inhabitant of the Haut-Jura Mountains more than three centuries ago. The p.Arg374Gln mutation occurred independently in at least two distinct geographical areas, including the area with the second highest prevalence in the epidemiological study and where the MRCA is rather recent (about 100 years ago). Partially shared haplotypes between French and Italian patients were found for three mutations. This suggests a common origin and a possible diffusion of these mutations from Italy to France.

Deregulation of anti-Mullerian hormone/BMP and transforming growth factor-β pathways in Leydig cell lesions developed in male heterozygous multiple endocrine neoplasia type 1 mutant mice

Multiple endocrine neoplasia type 1 (MEN1) results from the mutation of the predisposing gene, MEN1. Heterozygous Men1 mutant mice previously generated by several laboratories, including ours, mimic largely MEN1 pathology. Interestingly, our heterozygous Men1 mutant mice exhibit not only the endocrine tumours commonly seen in MEN1 patients, but also Leydig cell tumours (LCT) with high frequency, accompanied systematically by loss of the wild-type Men1 allele. As there exists a similarity of tumour phenotype between these mice and those mutated for the components of anti-Mullerian hormone (AMH)/bone morphogenic protein (BMP) pathway belonging to transforming growth factor-beta (TGF-beta) family, we investigated the expression and the activity of this pathway, known to have an important biological role in Leydig cells. Here, we report that the expression of AMH receptor type 2 is reduced in Men1 LCTs. Both immunostaining and western blot analyses also demonstrate a markedly decreased nuclear expression of Smad1, 3, 4 and 5 in the tumours. More interestingly, we show that the reconstituted menin expression in Men1-deficient Leydig cells derived from LCTs can significantly increase the transcriptional activity of a BMP pathway target promoter, XVent2. Furthermore, we found that the expression of p18, p27 and cyclin dependant kinase 4 (Cdk4), targets of TGF-beta pathways, is altered in the Leydig cell lesions. Our data provide the evidence of the deregulation of AMH/BMP and TGF-beta pathways in mouse Men1 LCTs, highlighting their involvement in tumorigenesis of Leydig cells due to Men1 inactivation.

High diagnostic and clinical impact of small-bowel capsule endoscopy in patients with hereditary hemorrhagic telangiectasia with overt digestive bleeding and/or severe anemia

BACKGROUNDnPatients with hereditary hemorrhagic telangiectasia (HHT) often present with recurrent anemia because of epistaxis or GI bleeding in relation to telangiectases mostly located in the stomach or small bowel. Capsule endoscopy is considered a major diagnostic tool for small-bowel diseases, but the impact of capsule endoscopy imaging on patient management in HHT is poorly understood.nnnOBJECTIVEnTo clarify the contribution of capsule endoscopy in selected patients with HHT.nnnDESIGNnProspective, descriptive study.nnnSETTINGnMulticenter, two university hospital tertiary-care centers, from January 2003 to June 2007.nnnPATIENTSnThis study involved 30 patients with HHT and severe anemia (hemoglobin <9 g/dL; normal: 11-15 g/dL) and minimal epistaxis or moderate anemia but overt GI bleeding.nnnINTERVENTIONnCapsule endoscopy investigation.nnnMAIN OUTCOME MEASUREMENTSnClinical characteristics and capsule endoscopy results and their clinical consequences.nnnRESULTSnCapsule endoscopy detected gastric and small-bowel telangiectases in 14 (46.7%) and 26 (86.7%) cases, respectively. Active bleeding was present in 36.7% of cases. Diffuse telangiectases were detected in 42.3% without correlation with age, sex, or type of HHT mutation. Further investigations were carried out as a consequence of the capsule endoscopy results in 67% of cases. Treatment, consisting mostly of endoscopic argon plasma coagulation, was scheduled in 46.7% of patients.nnnLIMITATIONSnOur population was essentially composed of patients with the ALK1 mutation.nnnCONCLUSIONnThis study shows that there is a high diagnostic yield for capsule endoscopy in selected patients with HHT. Capsule endoscopy makes possible precise mapping of lesions and has a considerable impact on the management of these selected patients by using a predefined algorithm: a limited number of accessible lesions is suitable for endoscopic treatment, whereas innumerable diffuse lesions require a medical approach. We suggest that capsule endoscopy could be a first-line, noninvasive, digestive tract examination in selected patients with HHT.

Metabolic expressivity of human genetic variants: NMR metabotyping of MEN1 pathogenic mutants

Functional consequences of mutations in predisposition genes for familial cancer syndromes remain often elusive, especially when the corresponding gene products play pleiotropic functions and interact with numerous partners. Understanding the consequences of these genetic alterations requires access to their functional effects at the phenotypic level. Nuclear magnetic resonance (NMR) has emerged as a promising functional genomics probe, through its ability to monitor the consequences of genetic variations at the biochemical level. Here, we determine by NMR the metabolic perturbations associated with different disease-related mutations in the MEN1 gene, responsible for the multiple endocrine neoplasia syndrome, type 1 (MEN1), an example of hereditary cancer. The MEN1 gene encodes the Menin protein. Based on a cellular model that allows exogenous overexpression of either the wild type (WT) Menin protein or disease-related variant forms, we evaluate the feasibility of using metabolic profiles to discriminate cells with WT versus variant Menin overexpression. High-resolution magic angle spinning (HRMAS) NMR of whole cells allows to determine the metabolic features associated with overexpression of WT Menin as compared to the one of six different missense variants observed in MEN1 patients. We then identify several statistically significant individual metabolites associated with the metabolic signature of pathogenic versus WT variants. Whether such a metabolic phenotyping approach using cell lines could be exploited as a functional test in a human genetic cancer syndrome is further discussed.