Perioperative Hypotensive Crisis in an Adolescent with a Pancreatic VIPoma and MEN1-Gene Variant.

BACKGROUND: Vasoactive intestinal peptide-secreting tumours (VIPomas) lead to high-volume secretory diarrhoea with hypokalaemia, as well as hyperglycaemia and hypercalcaemia. Diagnosis is often delayed. CASE DESCRIPTION: We present a 13-year-old girl with a distal pancreatic VIPoma diagnosed on her second hospital presentation who became severely hypotensive on anaesthetic induction prior to tumour removal, likely due to the vasodilatory effect of supraphysiological VIP levels. Prior to the second surgical attempt, an octreotide infusion was started preoperatively to suppress systemic VIP levels and counter the potential for VIP-induced hypotension upon tumour manipulation, and the tumour was successfully resected. Hyperparathyroidism and history of GI tumour resection were subsequently identified in the father, and the two members were found to have a heterozygous variant of uncertain significance in the multiple endocrine neoplasia type 1 (MEN1) gene. However, as this family meets the diagnostic criteria for MEN1 clinically, ongoing surveillance for MEN1 tumours and genetic counseling for at-risk family members are required despite the non-pathogenic genetic result. CONCLUSION: This case highlights the importance of screening for a VIPoma in patients with high-volume secretory diarrhoea and preventing cardiovascular complications with perioperative VIP suppression. Furthermore, careful interpretation of genetic results within the clinical context is required.

Prevalence of Vibrio cholerae O1 serogroup in Assam, India: A hospital-based study.

BACKGROUND & OBJECTIVES: Although cholera remains to be an important public health problem, studies on reliable population-based estimates of laboratory confirmed cholera in endemic areas are limited worldwide. The aim of this hospital-based study was to evaluate the prevalence of Vibrio cholerae serogroup in Assam, India, during 2003-2013. METHODS: Stool samples/rectal swabs were collected from acute watery diarrhoea (AWD) cases during 2003-2013 and processed by standard microbiological procedures. Antibiotic sensitivity test was done following the Clinical and Laboratory Standards Institute guidelines. Year-wise epidemiological trend of cholera was analyzed. RESULTS: Cholera contributed to 3.93 per cent of AWD cases. In Assam, cholera was found to be more prevalent in the rural areas (6.7%) followed by the tea gardens (5.06%), urban slum (1.9%) and urban areas (1.4%). Highest proportion of cholera (13.7%) was observed in 0-10 yr age group. Of them, 11.5 per cent belonged to 0-5 yr age group. V. cholerae O1 El Tor serotype Ogawa was the predominant isolate. Multiple drug-resistant isolates of V. cholerae O1 Ogawa were reported in the study. INTERPRETATION & CONCLUSIONS: Emergence of resistance amongst V. cholerae towards many antibiotics is a matter of concern. Hence, continuous surveillance for diarrhoeal disorders is necessary to control the future outbreaks of cholera in this region.

VIPoma with multiple endocrine neoplasia type 1 identified as an atypical gene mutation.

A 47-year-old man presented with persistent diarrhoea and hypokalaemia. CT revealed 4 pancreatic tumours that appeared to be VIPomas, because the patient had an elevated plasma vasoactive intestinal polypeptide level. MRI showed a low-intensity area in the pituitary suggestive of a pituitary tumour, and a parathyroid tumour was detected by ultrasonography and 99Tc-MIBI scintigraphy. Given these results, the patient was diagnosed with multiple endocrine neoplasia type 1 (MEN1) and scheduled for surgery. MEN1 is an autosomal dominant disorder associated with MEN1 mutations. Genetic testing indicated that the patient had a MEN1 gene mutation; his 2 sons had the same mutations. Most MEN1 tumours are benign, but some pancreatic and thymic tumours could become malignant. Without treatment, such tumours would result in earlier mortality. Despite its rarity, we should perform genetic testing for family members of patients with MEN1 to identify mutation carriers and improve the patients' prognosis.

MSH2 and CXCR4 involvement in malignant VIPoma.

BACKGROUND: Vasoactive intestinal polypeptide secreting tumors(VIPomas) are rare endocrine tumors of the pancreas with an estimated incidence of 0.1 per million per year. The molecular mechanisms that mediate development of VIPomas are poorly investigated and require definition. METHODS: A genome- and gene expression analysis of specimens of a primary pancreatic VIPoma with hepatic metastases was performed. The primary tumor, the metastases, the corresponding healthy tissue of the liver, and the pancreas were compared with each other using oligonucleotide microarrays and loss of heterozygosity (LOH). RESULTS: The results revealed multiple LOH events and several differentially expressed genes. Our finding of LOH and downregulation was conspicuous in the microarray analysis for the mismatch repair gene MSH2 in the primary pancreatic VIPoma tumor, the hepatic metastasis but not in the corresponding healthy tissue. Further a strong overexpression of the chemokine CXCR4 was detected in the hepatic metastases compared to its pancreatic primary. With a review of the literature we describe the molecular insights of metastatic development in VIPoma. CONCLUSION: In VIPoma, defects in the mismatch repair system especially in MSH2 may contribute to carcinogenesis, and increased CXCR4 may be associated with liver metastasis.

[Hereditary tumours of the endocrine pancreas]. / Az endokrin pancreas öröklódó daganatai.

The pathogenesis, diagnosis and therapy of tumours originating from the endocrine pancreas represent one of the most exciting challenges of contemporary medicine. Some of these tumours appear as part of four hereditary syndromes (multiple endocrine neoplasia type 1 (MEN1), von Hippel-Lindau disease (VHL), neurofibromatosis type 1 and tuberous sclerosis) that are all inherited as autosomal dominant traits and result from mutations of tumour suppressor genes. Considering its clinical relevance, MEN1 appears to be the most important among these four syndromes. Tumours of the endocrine pancreas develop in 30-80% of patients carrying mutations of the MEN1 gene. Gastrinomas are the most frequent functioning tumours in MEN1 patients, followed by insulinomas, whereas other tumors e.g. glucagonoma, VIP-oma, GRF-oma and somatostatinoma occur very rarely. Tumours of the endocrine pancreas are infrequent in patients suffering from VHL, neurofibromatosis and tuberous sclerosis. In this review article, the authors present a synopsis of tumours of the endocrine pancreas related to these hereditary syndromes underlining the clinical characteristics, diagnostical and therapeutical possibilities.

BRAF gene mutations are rare events in gastroenteropancreatic neuroendocrine tumors.

The BRAF gene, one of the human isoforms of RAF, is activated by ras, leading to cooperative effects in cells responsive to growth factor signals. We studied the frequency of BRAF and k-ras-2 mutations in primary neuroendocrine gastroenteropancreatic (GEP) tumors. Mutation analysis of the BRAF and k-ras-2 genes was performed in 40 primary neuroendocrine tumors of the GEP system. The expression of extracellular signaling-related kinase (ERK) 1/2, an important downstream point of convergence in the ras-RAF-mitogen-activated protein-ERK pathway was analyzed immunohistochemically. We detected one 1796 T-->A BRAF mutation that led to a substitution of valine by glutamic acid at position 599 (V599E) in 40 primary neuroendocrine GEP tumors (3%). We failed to detect specific mutation of the k-ras-2 gene. We identified constitutively activated ERK in almost all neuroendocrine tumor tissues tested irrespective of BRAF mutation or localization or functional activity. These results suggest that BRAF mutations do not have a role in tumorigenesis of neuroendocrine tumors. Nevertheless, activation of the RAF/mitogen-activated protein kinase pathway might have a causative role in the development of neuroendocrine tumors, independent of BRAF or k-ras-2 mutation.

Putative tumor suppressor loci at 6q22 and 6q23-q24 are involved in the malignant progression of sporadic endocrine pancreatic tumors.

Our previous comparative genomic hybridization study on sporadic endocrine pancreatic tumors (EPTs) revealed frequent losses on chromosomes 11q, 3p, and 6q. The aim of this study was to evaluate the importance of 6q losses in the oncogenesis of sporadic EPTs and to narrow down the smallest regions of allelic deletion. A multimodal approach combining polymerase chain reaction-based allelotyping, double-target fluorescence in situ hybridization, and comparative genomic hybridization was used in a collection of 109 sporadic EPTs from 93 patients. Nine polymorphic microsatellite markers (6q13 to 6q25-q27) were investigated, demonstrating a loss of heterozygosity (LOH) in 62.2% of the patients. A LOH was significantly more common in tumors >2 cm in diameter than below this threshold as well as in malignant than in benign tumors. We were able to narrow down the smallest regions of allelic deletion at 6q22.1 (D6S262) and 6q23-q24 (D6S310-UTRN) with LOH-frequencies of 50.0% and 41.2 to 56.3%, respectively. Several promising tumor suppressor candidates are located in these regions. Additional fluorescence in situ hybridization analysis on 46 EPTs using three locus-specific probes (6q21, 6q22, and 6q27) as well as a centromere 6-specific probe revealed complete loss of chromosome 6 especially in metastatic disease. We conclude that the two hot spots found on 6q may harbor putative tumor suppressor genes involved not only in the oncogenesis but maybe also in the malignant and metastatic progression of sporadic EPTs.

Mutations of the DPC4/Smad4 gene in neuroendocrine pancreatic tumors.

Tumors of the endocrine pancreas are extremely rare, and molecular mechanisms leading to their development are not well understood. A candidate tumor suppressor gene, DPC4, located at 18q21, has recently been shown to be inactivated in half of pancreatic adenocarcinoma xenografts. The close anatomical relationship of the exocrine and endocrine pancreas prompted us to determine the role of DPC4 in the tumorigenesis of 25 pancreatic islet cell tumors (11 insulinomas, nine non-functioning endocrine carcinomas, three gastrinomas, two vipomas). A mutation screening of the highly conserved COOH-terminal domain of DPC4 (exons 8-11) was performed by single-strand conformational variant (SSCP) analysis and a PCR-based deletion assay. Five of nine (55%) non-functioning endocrine pancreatic carcinomas revealed either point mutations, small intragenic deletions or homozygous deletion of DPC4 sequences compared to none of the insulinomas, gastrinomas or vipomas. These results suggest that DPC4 is an important target gene promoting tumorigenesis of non-functioning neuroendocrine pancreatic carcinomas.

MEN1 gene mutations in 12 MEN1 families and their associated tumors.

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant inherited tumor syndrome characterized by the development of multiple endocrine tumors. The gene responsible for the disease, termed MEN1 gene. has recently been isolated and germline mutations have been described in affected MEN1 individuals. Twelve unrelated (German MEN1 families and their associated tumors (5 parathyroid tumors, 1 vipoma, 1 gastrinoma, 1 insulinoma) were characterized for MEN1 gene mutations by single-strand conformational variant (SSCV) analysis and DNA sequence analysis as well as for loss of heterozygosity on chromosome 11q13. We identified nine different heterozygous germline mutations (6 frameshift, 2 missense, 1 nonsense), eight of them were novel. Four of five informative MEN1-associated tumors revealed deletion of the second MEN1 allele, supporting the concept of a tumor suppressor gene. Furthermore. SSCV analysis proved an effective and sensitive method for the detection of menin mutations providing a reliable genetic screening approach supporting genetic counseling and clinical management of MEN1 family members.

Multiple-hormone gene expression in ganglioneuroblastoma with watery diarrhea, hypokalemia, and achlorhydria syndrome.

BACKGROUND: It has been reported that vasoactive intestinal peptide (VIP)-producing tumors accompanied by watery diarrhea, hypokalemia, and achlorhydria (WDHA) syndrome often produce multiple hormones biochemically and immunohistochemically. METHODS: The authors examined the distribution of several peptides--VIP, peptide histidine methionine (PHM), neuropeptide Y (NPY), methionine-enkephalin (M-EK), somatostatin (SS), substance-P (Sub-P), corticotropin-releasing hormone, and tyrosine hydroxylase--with immunohistochemical studies and an in situ hybridization method in three ganglioneuroblastomas with WDHA syndrome. All patients had an extremely elevated plasma level of VIP. RESULTS: Peptides examined immunohistochemically in the tumor were all detectable in ganglionic cells and some neurites. The coexistence of those peptides was observed with serial section staining. The presence of messenger RNA of VIP/PHM-27, NPY, and SS was detectable in the cytoplasm of the tumor cells with the in situ hybridization. CONCLUSIONS: It was shown that multiple genes of peptides are expressed simultaneously and translated to proteins in those tumors.