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Abstract: The Shb adapter protein is a signaling intermediate that operates downstream of vascular endothelial growth factor receptor-2 (VEGFR-2) in endothelial cells. The Shb knockout mouse displays a dysfunctional microvasculature and impaired growth of subcutaneously implanted tumor cells. We decided to investigate tumor growth and angiogenesis in the absence of Shb in an inheritable tumor model, the RIP-Tag2 mouse, which produces insulinomas in a manner highly dependent on de novo angiogenesis. We observed a reduced tumor incidence and burden in both RIP-Tag2 Shb−/− and RIP-Tag2 Shb+/− mice. This correlated with a reduced microvascular density, measured as a percentage of insulinoma area positive for CD31 staining, and altered vascular morphology. However, treatment with a VEGF-A blocking antibody was without effect on the Shb mutant tumor volume whereas it significantly inhibited tumor volume in the wild-type mice, suggesting that in mice with reduced Shb expression tumor angiogenesis was primarily sustained by VEGF-A independent pathway(s). This notion was further substantiated by gene expression analysis of angiogenic markers showing reduced VEGF-A expression in Shb-deficient tumors. Considerable heterogeneity with respect to the gene expression profiles of other angiogenic markers and the signal-transduction characteristics was observed between different tumors, suggesting that multiple “rescue” pathways could be operating. The numbers of invasive tumors or metastases were unchanged in the Shb mutant. It is concluded that the Shb mutant background reduces tumor frequency by chronically suppressing VEGF-A dependent angiogenesis. However, VEGF-A independent angiogenesis supports a significant degree of tumor expansion in Shb-deficient mice, indicating heterogeneity in the mechanisms by which tumor expansion is promoted. Interference with Shb signaling may provide novel means for future cancer therapy. [Copyright &y& Elsevier]

Objectives: Pancreatic neuroendocrine tumors (PNET) are fairly uncommon. Recent data highlight the importance of EUS in diagnosis of PNET. With this background, we decided to review our experience from a tertiary cancer center with regard to the presentation and clinical features of PNET and the diagnostic utility of EUS-FNA in this scenario. Methods: We identified patients who underwent EUS at our institution between January 1st 2001 and December 31st 2009 for a suspected PNET. Data on clinical features, cross-sectional imaging findings, EUS findings, and cytology results were collected. Results: A total of 81 patients were referred for EUS-FNA for a suspected PNET. Mean age was 58.1 years. There were 41 (50.6%) males. PNET was found incidentally in 38 (46.9%) patients. Computed tomography scanning identified a pancreatic mass in 72 out of 79 (91.1%) cases. Mean diameter of the largest lesion seen on EUS was 27.5 mm (range: 6.9-80 mm). The most common site (34; 42%) was the head of the pancreas. EUS-FNA correctly confirmed a PNET in 73 out of 81 cases with diagnostic accuracy of 90.1%. Seven (8.6%) out of 81 patients had functional lesions, including three gastrinomas and four insulinomas. Liver metastases were found in 31 out of 81 (38.3%) cases. Of the 31 patients with liver metastasis, the mean diameter of lesions on EUS was 33.9 mm compared with 23.5 mm in patients without liver metastasis ( P = 0.005). Conclusion: EUS-FNA is a reliable modality for further characterization of suspected lesions and for establishing a tissue diagnosis. The occurrence of complications of EUS-FNA in this setting is low. Non-functional PNET are more frequently encountered than functional PNET. [ABSTRACT FROM AUTHOR]

Imaging techniques are in permanent evolution and so are their respective sensitivities. We present a case of a patient who had three abdominal CT scans over 10 years for the detection of pancreatic insulinomas. The first was made on an incremental CT and showed no lesion, the second on a single-slice helical CT which revealed a single centimetric tumor of the head of the pancreas, and the third on 64-slice CT which revealed 5 infracentimetric tumors. We do not know if all were present at the first scan but it is possible that these small tumors could have been missed on thick CT scan slices with overlap. The ideal imaging technique for the detection of endocrine pancreatic tumor is not known yet. The detection rates in the latest publications are 80% for CT scans and 70% for MRI, but there is a slight preference for CT scan because of its larger availability and higher resolution. [ABSTRACT FROM AUTHOR]

Abstract: Multiple Endocrine Neoplasia type 1 (MEN1) is an autosomal-dominant disorder characterised by the occurrence of tumours of the parathyroids, pancreas and anterior pituitary. The MEN1 gene, consists of 10 exons that encode a 610-amino acid protein referred to as Menin. Menin is predominantly a nuclear protein that has roles in transcriptional regulation, genome stability, cell division and proliferation. Germ-line mutations usually result in MEN1 or occasionally in an allelic variant referred to as Familial Isolated Hyperparathyroidism (FIHP). MEN1 tumours frequently have loss of heterozygosity (LOH) of the MEN1 locus, which is consistent with a tumour suppressor role of MEN1. Furthermore, somatic abnormalities of MEN1 have been reported in MEN1 and non-MEN1 endocrine tumours. To date, over 1300 mutations have been reported, and the majority (>70%) of these are predicted to lead to truncated forms of Menin. The mutations are scattered throughout the >9 kb genomic sequence of the MEN1 gene. Four, which consist of c.249_252delGTCT (deletion at codons 83–84), c.1546_1547insC (insertion at codon 516), c.1378C>T (Arg460Ter) and c.628_631delACAG (deletion at codons 210–211) have been reported to occur frequently in 4.5%, 2.7%, 2.6% and 2.5% of families, respectively. However, a comparison of the clinical features in patients and their families with the same mutations reveals an absence of phenotype–genotype correlations. The majority of MEN1 mutations are likely to disrupt the interactions of Menin with other proteins and thereby alter critical events in cell cycle regulation and proliferation. [ABSTRACT FROM AUTHOR]

Aim: The goal of this retrospective study was to analyze the strategy for the surgical management of insulinomas. Methods: From May 2000 to October 2006, the medical records of 52 patients with insulinomas were retrospectively studied. Results: All tumors were localized precisely by imaging techniques combined with intraoperative palpation. Forty-eight patients with benign lesions underwent surgical treatment: 41 patients open and 7 patients laparoscopic procedures. Four patients with malignant insulinomas underwent tumor resection; 3 of them underwent metastatic lesion and/or lymph node dissection. There were no discrepancies regarding operation time, blood loss, and complication rate between open enucleation and laparoscopic surgery. The mean hospital stay was 11.8 ± 3.4 days after laparoscopic surgery, shorter than the 17.0 ± 6.0 days after the open approach. Twenty-two complications occurred in 17 patients (32%) following resection. On follow-up, 86% of the patients were free from symptoms, and surgical cure was achieved in 95% of the patients with benign insulinomas. Conclusions: The choice of the surgical strategy for the treatment of pancreatic insulinomas depends on size and location of the tumor and the risk of malignancy. The optimal surgical procedure is key to prevent postoperative complications. The laparoscopic approach is safe and feasible for patients with benign tumors located in body or tail of the pancreas. Copyright © 2007 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Pancreatic insulinomas are rare tumours of the islet cells of the pancreas, which account for the majority of functional neuroendocrine tumours of the pancreas. There is often a typical history of recurrent hypoglycaemic collapse and dizzy spells. Insulinomas are usually solitary, and the vast majority are intra-pancreatic in location. They are characteristically small with approximately 66% being less than 2cm at presentation. Insulinomas continue to pose a diagnostic challenge to physicians, surgeons and radiologists alike. The role of imaging is to detect and provide precise anatomical localization and staging of tumours prior to surgery. Due to their small size at clinical presentation, they are notoriously difficult to localize radiologically, and specifically designed protocols are necessary to aid detection. In this review, we describe the current “state of the art” imaging protocols that may be used in the preoperative localization of insulinomas. [Copyright &y& Elsevier]