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Insulinomas are functioning pancreatic neuroendocrine tumors (NETs). They secrete insulin, and hence, present with hypoglycemia. We report a case of insulinoma in a 16-year-old girl presenting as seizures. She was initially managed at a private clinic and later commenced on carbamazepine when convulsion persisted. Convulsions were generalized, associated with dizziness and altered sensorium, often preceded by hunger and physical exertion, but relieved by the intake of carbonated drinks and fruit juice. She was referred to the neurology clinic when seizures persisted, despite the use of anticonvulsant. She was later referred to the endocrine clinic on suspicion of insulinoma when her random blood glucose (BG) was found to be low during an episode of convulsion. She was moderately obese but other examination findings were normal. She had a 72-hour prolonged fast, which was terminated when hypoglycemia (BG = 2.2 mmol/L) ensued after 12 hours, with elevated serum insulin and C-peptide. Abdominal magnetic resonance imaging scan showed a pancreatic tumor suggestive of insulinoma. She subsequently had distal pancreatectomy performed with complete resolution of symptoms. Unusual presentation of insulinoma may delay diagnosis, resulting in wastage of resources with increased morbidities and mortality. [ABSTRACT FROM AUTHOR]

Introduction: Oxaliplatin-based regimens have shown promising antitumor activity in digestive neuroendocrine tumors (NETs); however, the available data are limited. Our aim was to assess the efficacy of FOLFOX (association of 5-fluorouracil with oxaliplatin) in a large series of patients with advanced digestive NETs. Methods: All patients with advanced digestive well-differentiated NETs treated with at least 3 cycles of FOLFOX between January 2004 and December 2018 in 12 centers from the French Group of Endocrine Tumors were included. Tumor response rate according to Response Evaluation Criteria in Solid Tumors version 1.1 criteria, progression free survival (PFS), and overall survival, as well as prognostic factors, were analyzed retrospectively. Results: One hundred fifty-five patients were included. Primary tumor locations were pancreas (n = 89), small intestine (n = 40), unknown with no evidence for lung primary (n = 13), stomach (n = 7), and rectum (n = 6). Median Ki-67 was 10%, and 65% of the tumors were grade 2. The partial response rate was 30% for pancreatic NETs, 12.5% for small intestine NETs, 38.5% for unknown primary NETs, 14% for gastric NETs, and 17% for rectal NETs. Significant prognostic factors for poor PFS after FOLFOX were progressive disease at the beginning of treatment (hazard ratio [HR] = 1.83, p = 0.007), hepatic involvement superior to 50% (HR = 2.67, p = 0.0001), and rectal primary tumor location (HR = 2.6, p = 0.0036). Among pancreatic NETs, insulinomas had a better median PFS (22 months) than other pancreatic NETs (9 months, p = 0.026) and showed a high rate (8/9) of serum glucose normalization. Conclusions: FOLFOX shows a promising antitumor activity in advanced digestive NETs. Rapid symptomatic response is observed in metastatic insulinomas. [ABSTRACT FROM AUTHOR]

Pancreatic neuroendocrine neoplasms (PNENs) represent 10% of all pancreatic tumors by prevalence. Their incidence has reportedly increased over recent decades in parallel with that of pancreatic adenocarcinoma. PNENs are relatively rare, and of the few institutions that have published potential risk factors, findings have been heterogeneous. Our objective was to investigate the association between potential risk and protective factors for the occurrence of sporadic PNENs across a European population from several institutions. A multinational European case-control study was conducted to examine the association of selected environmental, family and medical exposure factors using a standardized questionnaire in face-to-face interviews. A ratio of 1:3 cases to controls were sex and age matched at each study site. Adjusted univariate and multivariate logistic regression analysis were performed for statistically significant factors. The following results were obtained: In 201 cases and 603 controls, non-recent onset diabetes (OR 2.09, CI 1.27-3.46) was associated with an increased occurrence of PNENs. The prevalence of non-recent onset diabetes was higher both in cases with metastatic disease (TNM stage III-IV) or advanced grade (G3) at the time of diagnosis. The use of metformin in combination with insulin was also associated with a more aggressive phenotype. Drinking coffee was more frequent in cases with localized disease at diagnosis. Our study concluded that non-recent onset diabetes was associated with an increased occurrence of PNENs and the combination of metformin and insulin was consistent with a more aggressive PNEN phenotype. In contrast to previous studies, smoking, alcohol and first-degree family history of cancer were not associated with PNEN occurrence. [ABSTRACT FROM AUTHOR]

About 90% of insulinomas are benign and 5%–15% are malignant. Benign insulinomas express the glucagon-like peptide-1 receptor (GLP-1R) and low levels of somatostatin receptors (SSTR), while malignant insulinomas over-express SSTR or GLP-1R in low levels. A kit for the preparation of Lys 27 ( 99m Tc-EDDA/HYNIC)-Exendin(9-39)/ 99m Tc-EDDA/HYNIC-Tyr 3 Octreotide was formulated to detect 100% of insulinomas. The formulation showed radiochemical purity of 97 ± 1%, high stability in human serum, and GLP-1R and SSTR affinity. The biodistribution and imaging studies demonstrated properties suitable for its use as a target-specific agent for the simultaneous molecular imaging of GRP-1R- and/or SSTR-positive tumors. [ABSTRACT FROM AUTHOR]

Pancreatic neuroendocrine neoplasms (PNENs) constitute a rare tumour entity, and prognosis and treatment options depend on tumour-mediating hallmarks such as angiogenesis, proliferation rate and resistance to apoptosis. The molecular pathways that determine the malignant phenotype are still insufficiently understood and this has limited the use of effective combination therapies in the past. In this study, we aimed to characterise the effect of the oncogenic transcription factor Cut homeobox 1 (CUX1) on proliferation, resistance to apoptosis and angiogenesis in murine and human PNENs. The expression and function of CUX1 were analysed using knockdown and overexpression strategies in Ins-1 and Bon-1 cells, xenograft models and a genetically engineered mouse model of insulinoma (RIP1Tag2). Regulation of angiogenesis was assessed using RNA profiling and functional tube-formation assays in HMEC-1 cells. Finally, CUX1 expression was assessed in a tissue microarray of 59 human insulinomas and correlated with clinicopathological data. CUX1 expression was upregulated during tumour progression in a time- and stage-dependent manner in the RIP1Tag2 model, and associated with pro-invasive and metastatic features of human insulinomas. Endogenous and recombinant CUX1 expression increased tumour cell proliferation, tumour growth, resistance to apoptosis, and angiogenesis in vitro and in vivo. Mechanistically, the pro-angiogenic effect of CUX1wasmediated via upregulation of effectors such as HIF1a and MMP9. CUX1 mediates an invasive pro-angiogenic phenotype and is associated with malignant behaviour in human insulinomas. [ABSTRACT FROM AUTHOR]

Highlights: [•] Comparison of protein profiles of human pancreatic islets and insulinomas. [•] We identified proteins never described neither in human insulinomas nor in islets. [•] MAGE2 and Dermcidin could represent potential biomarkers for human insulinomas. [•] Caldesmon a protein involved in granule secretion, was increased in human islets. [•] The differences are related to their phenotype: normal or tumoural endocrine cells. [Copyright &y& Elsevier]

The gene expression profile of 10 primary canine insulinomas was compared with that of their accompanying metastases using microarray analysis and quantitative real time-PCR. Analysis of microarray data revealed 84 genes that were differentially expressed between primary insulinomas and their metastases, along with 243 genes differentially expressed between a low-metastatic and a high-metastatic subset of primary insulinomas. The genes differently expressed between primary insulinomas and their metastases clustered together in nine signalling pathways. Comparing the low-metastatic to the high-metastatic subset of primary insulinomas, 26 pathways appeared to be significantly influenced. The acinar enzymes pancreatic lipase (PNLIP) and chymotrypsinogen B1 (CTRB1) were amongst the most down-regulated genes in the malignant group of primary insulinomas and in metastases. Immunofluorescence demonstrated co-localisation of insulin and PNLIP in tumour cells. Different subsets of canine insulinomas can be identified on the basis of their gene expression profile. Canine insulinomas appear to contain amphicrine cells, which exhibit both endocrine and exocrine cell features. [ABSTRACT FROM AUTHOR]

Purpose: Assessing information on tumor progression in the RIP1-Tag2 mouse in vivo is a great challenge because the tumors form spontaneously throughout the pancreas and are difficult to detect with current imaging modalities. In this study, we focused on non-invasive magnetic resonance imaging, providing information on tumor growth. Procedures: Tissue relaxation times were measured over time and were compared between tumors and healthy pancreatic tissue. The effects of age and body temperature on these relaxation times, possibly influencing image contrast and therefore detection capabilities, were evaluated. Results: Tumors appeared hyperintense in T2-weighted images when they exceeded 0.8 mm in diameter, and both relaxation times showed significantly higher values in tumors than in the healthy pancreas. Conclusion: Visualization and monitoring of these small tumors in vivo is feasible, even under adverse conditions of permanent gut movement. In the mouse model studied, the relaxation times of tumors differed significantly from healthy pancreatic tissue. [ABSTRACT FROM AUTHOR]

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]

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]

Pancreatic endocrine tumours are rare tumours, and arise from the types of pancreatic cells that produce hormones. These tumours may or may not secrete hormones themselves and may or may not be cancerous (malignant). Functioning tumours secrete a particular hormones which may cause various syndromes. The present article reviews the latest reports on the pancreatic endocrine tumours. [ABSTRACT FROM AUTHOR]