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Objectives: To develop and validate radiomics models utilizing endoscopic ultrasonography (EUS) images to distinguish insulinomas from non-functional pancreatic neuroendocrine tumors (NF-PNETs)., Methods: A total of 106 patients, comprising 61 with insulinomas and 45 with NF-PNETs, were included in this study. The patients were randomly assigned to either the training or test cohort. Radiomics features were extracted from both the intratumoral and peritumoral regions, respectively. Six machine learning algorithms were utilized to train intratumoral prediction models, using only the nonzero coefficient features. The researchers identified the most effective intratumoral radiomics model and subsequently employed it to develop peritumoral and combined radiomics models. Finally, a predictive nomogram for insulinomas was constructed and assessed., Results: A total of 107 radiomics features were extracted based on EUS, and only features with nonzero coefficients were retained. Among the six intratumoral radiomics models, the light gradient boosting machine (LightGBM) model demonstrated superior performance. Furthermore, a peritumoral radiomics model was established and evaluated. The combined model, integrating both the intratumoral and peritumoral radiomics features, exhibited a comparable performance in the training cohort (AUC=0.876) and achieved the highest accuracy in predicting outcomes in the test cohorts (AUC=0.835). The Delong test, calibration curves, and decision curve analysis (DCA) were employed to validate these findings. Insulinomas exhibited a significantly smaller diameter compared to NF-PNETs. Finally, the nomogram, incorporating diameter and radiomics signature, was constructed and assessed, which owned superior performance in both the training (AUC=0.929) and test (AUC=0.913) cohorts., Conclusion: A novel and impactful radiomics model and nomogram were developed and validated for the accurate differentiation of NF-PNETs and insulinomas utilizing EUS images., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as potential conflicts of interest., (Copyright © 2024 Mo, Huang, Wang, Zhao, Wu, Jiang and Qin.)

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., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)

Background/objectives: Insulinomas are rare, functioning pancreatic neuroendocrine neoplasms (pNEN), whose gold standard therapy is surgical resection. Endoscopic ultrasound-guided radiofrequency ablation (EUS-RFA) is a recent technique that has emerged as a minimally invasive therapeutic option for patients with pancreatic lesions not eligible for surgery. In this study, we aimed to describe a series of patients with unresectable pancreatic insulinoma treated with EUS-RFA., Methods: This is a single-center, retrospective study including all consecutive patients with functioning pancreatic insulinoma undergoing EUS-RFA for surgical unfitness or surgery refusal, between March 2017 and September 2021. Technical success (i.e., complete mass ablation), adverse event rate and severity, clinical and radiologic outcomes (i.e., symptom remission with a normal concentration of blood glucose, and the presence of intralesional necrosis), and post-procedural follow-up were assessed., Results: A total of 10 patients (mean age: 67.1 ± 10.1years; F:M 7:3) were included. The mean size of insulinoma was 11.9 ± 3.3 mm. Technical success and clinical remission were achieved in 100% of patients. Only one (10%) patient was successfully treated with two RFA sessions. Two procedure-related early adverse events occurred, including two (20%) cases of mild abdominal pain. No major complications were observed. The complete radiologic response within 3 months after EUS-RFA was observed in all patients (100%). After a median follow-up of 19.5 (range12-59) months, symptom remission and persistent euglycemia were assessed in all the patients., Conclusions: Data from this case series suggest that EUS-RFA is a feasible and safe therapeutic approach for pancreatic insulinomas in patients unwilling or unable to undergo surgery with medium-term efficacy., Competing Interests: Declaration of competing interest Ivo Boskoski is a consultant for Apollo Endosurgery, Cook Medical, BostonScientific, and Nitinotes. Guido Costamagna is a consultant for Cook Medical, Boston Scientific, and Olympus. All the other authors have nothing to declare., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

PET imaging of the glucagon-like peptide-1 receptor (GLP-1R) using radiolabeled exendin is a promising imaging method to detect insulinomas. However, high renal accumulation of radiolabeled exendin could hamper the detection of small insulinomas in proximity to the kidneys and limit its use as a radiotherapeutic agent. Here, we report two new exendin analogues for GLP-1R imaging and therapy, designed to reduce renal retention by incorporating a cleavable methionine-isoleucine (Met-Ile) linker. We examined the renal retention and insulinoma targeting properties of these new exendin analogues in a nude mouse model bearing subcutaneous GLP-1R-expressing insulinomas. NOTA or DOTA was conjugated via a methionine-isoleucine linker to the C-terminus of exendin-4 (NOTA-MI-exendin-4 or DOTA-MI-exendin-4). NOTA- and DOTA-exendin-4 without the linker were used as references. The affinity for GLP-1R was determined in a competitive binding assay using GLP-1R transfected cells. Biodistribution of [ 68 Ga]Ga-NOTA-exendin-4, [ 68 Ga]Ga-NOTA-MI-exendin-4, [ 177 Lu]Lu-DOTA-exendin-4, and [ 177 Lu]Lu-DOTA-MI-exendin-4 was determined in INS-1 tumor-bearing BALB/c nude mice, and PET/CT was acquired to visualize renal retention and tumor targeting. For all tracers, dosimetric calculations were performed to determine the kidney self-dose. The affinity for GLP-1R was in the low nanomolar range (<11 nM) for all peptides. In vivo biodistribution revealed a significantly lower kidney uptake of [ 68 Ga]Ga-NOTA-MI-exendin-4 at 4 h post-injection (p.i.) (34.2 ± 4.2 %IA/g), compared with [ 68 Ga]Ga-NOTA-exendin-4 (128 ± 10 %IA/g). Accumulation of [ 68 Ga]Ga-NOTA-MI-exendin-4 in the tumor was 25.0 ± 8.0 %IA/g 4 h p.i., which was similar to that of [ 68 Ga]Ga-NOTA-exendin-4 (24.9 ± 9.3 %IA/g). This resulted in an improved tumor-to-kidney ratio from 0.2 ± 0.0 to 0.8 ± 0.3. PET/CT confirmed the findings in the biodistribution studies. The kidney uptake of [ 177 Lu]Lu-DOTA-MI-exendin-4 was 39.4 ± 6.3 %IA/g at 24 h p.i. and 13.0 ± 2.5 %IA/g at 72 h p.i., which were significantly lower than those for [ 177 Lu]Lu-DOTA-exendin-4 (99.3 ± 9.2 %IA/g 24 h p.i. and 45.8 ± 3.9 %IA/g 72 h p.i.). The uptake in the tumor was 7.8 ± 1.5 and 11.3 ± 2.0 %IA/g 24 h p.i. for [ 177 Lu]Lu-DOTA-MI-exendin-4 and [ 177 Lu]Lu-DOTA-exendin-4, respectively, resulting in improved tumor-to-kidney ratios for [ 177 Lu]Lu-DOTA-MI-exendin-4. The new exendin analogues with a Met-Ile linker showed 2-3-fold reduced renal retention and improved tumor-to-kidney ratios compared with their reference without the Met-Ile linker. Future studies should demonstrate whether [ 68 Ga]Ga-NOTA-MI-exendin-4 results in improved detection of small insulinomas in close proximity to the kidneys with PET/CT. [ 177 Lu]Lu-DOTA-MI-exendin-4 might open a window of opportunity for exendin-based radionuclide therapy.

The most common pancreatic tumour in dogs is the insulinoma. Canine insulinomas are considered to be malignant in more than 95% of the cases because they almost always tend to metastasise. The diagnosis of an insulinoma requires the demonstration of the simultaneous occurrence of hypoglycaemia and blood insulin levels that are within or above the high end of the reference interval. The staging of canine insulinomas is preferably conducted by contrast-enhanced computed tomography. In general, surgical treatment is the most effective because of it results in long survival times, but many dogs also require medical treatment at some point. The prognosis of canine insulinomas is guarded as clinical hypoglycaemia almost always returns due to metastasis or tumour regrowth. This review aims to provide a summary and update the current recommendations in the veterinary literature for the diagnosis, treatment and prognostication of canine insulinomas.

Background: Radiofrequency ablation (RFA) has been used to treat various abdominal tumors including pancreatic tumors. Multiple approaches such as laparoscopic, open, and percutaneous have been used for pancreatic tissue ablation. More recently, endoscopic ultrasound (EUS)-guided RFA has emerged as a new technique for pancreatic tissue ablation. The role of EUS-RFA in management of pancreatic lesions is still not well-established. In this study, our aim is to assess efficacy and safety of EUS-RFA for management of pancreatic lesions., Methods: MEDLINE, Scopus, and Cochrane Library databases were searched to identify studies reporting EUS-RFA of pancreatic lesions with outcomes of interest. Studies with <5 patients were excluded. Clinical success was defined as symptom resolution, decrease in tumor size, and/or evidence of necrosis on radiologic imaging. Efficacy was assessed by the pooled clinical response rate whereas safety was assessed by the pooled adverse events rate. Heterogeneity was assessed using I 2 . Pooled estimates and the 95% CI were calculated using random-effect model., Results: Ten studies (5 retrospective and 5 prospective) involving 115 patients with 125 pancreatic lesions were included. 152 EUS-RFA procedures were performed. The lesions comprised of 37.6% non-functional neuroendocrine tumors (NFNETs), 15.4% were insulinomas, 26.5% were pancreatic cystic neoplasms (PCNs), and 19.7% were pancreatic adenocarcinomas. The majority were present in the pancreatic head (40.2%), 38.3% in the body, 11.2% in the tail, and 10.3% in the uncinate process. Pooled overall clinical response rate was 88.9% (95% CI: 82.4-93.7, I 2 =38.1%). Pooled overall adverse events rate was 6.7% (95% CI: 3.4-11.7, I 2 =34.0%). The most common complication was acute pancreatitis (3.3%) followed by pancreatic duct stenosis, peripancreatic fluid collection, and ascites (2.8%) each. Only one case of perforation was reported with pooled rate of (2.1%)., Discussion: This study demonstrates that EUS-RFA is an effective treatment modality for pancreatic lesions, especially functional neuroendocrine tumors such as insulinomas., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tgh.amegroups.com/article/view/10.21037/tgh-20-84/coif). The authors have no conflicts of interest to declare., (2022 Translational Gastroenterology and Hepatology. All rights reserved.)

Background: Endoscopic ultrasound (EUS)-guided radiofrequency ablation (RFA) has recently been proposed as a local treatment for functional pancreatic neuroendocrine neoplasms in patients unfit for surgery, in order to obtain clinical syndrome regression. Data on the safety and long-term effectiveness of this approach are scarce, and EUS-RFA procedures are not standardized., Case Summary: The present case series reports 3 elderly patients with a pancreatic insulinoma and comorbidities, locally treated by EUS-guided RFA with clinical success in terms of hypoglycemic symptoms. RFA procedures were performed during deep sedation, under EUS control with a 19 G needle, an electrode 5-mm in size at a power of 30 W and multiple RFA applications during the same session in order to treat the whole area of the lesions. Immediate relief of symptoms was evident in 2 patients after the first EUS-RFA, while in the third patient a second endoscopic treatment was needed. All 3 patients are symptom-free without need of medications after 24 mo of follow-up with imaging follow-up showing no disease recurrence. A single adverse event of intraprocedural bleeding occurred, which was successfully treated endoscopically., Conclusion: EUS-RFA represents an effective and safe alternative to surgery for the treatment of insulinomas in elderly patients at high surgical risk. However, larger multicenter studies with longer follow-up are needed in order to better assess its safety and clinical success., Competing Interests: Conflict-of-interest statement: The authors have note conflicts of interest to declare., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

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., (© 2021 S. Karger AG, Basel.)

Aims: To compare survival in dogs with recurrent or metastatic insulinomas that were treated with palliative therapy, alone or in combination with toceranib phosphate and to assess tolerability of the combined therapy in dogs., Materials and Methods: Dogs diagnosed with insulinoma were retrospectively identified in the records of the Veterinary Teaching Hospital Complutense (Madrid, Spain). Diagnosis of insulinoma was based on clinical signs of hypoglycaemia, concentrations in serum of glucose <3.3 mmol/L and insulin >10 μIU/mL and presence of a pancreatic mass on diagnostic imaging. Dogs were treated surgically or medically, according to clinical stage established by imaging techniques, and monitored with blood and urine analyses monthly and abdominal ultrasonography every 3 months until death. Dogs that presented with metastatic disease at diagnosis or with recurrent hypoglycaemia after surgery were treated, according to the owner's decision, with one of two treatment protocols: palliative therapy alone (control group, n=7: diet, prednisone, famotidine or omeprazole, ±octreotide) or palliative therapy in combination with toceranib (treatment group, n=5; median dose of toceranib 2.52 mg/kg). Overall survival time (OST) and adverse events were compared between the two treatment groups., Results: The OST was longer in the treatment group (median 399, min 125, max 476 days) compared to the control group (median 67, min 23, max 387 days; p=0.042). Dogs in the treatment group had a higher incidence of grade 1-2 gastrointestinal toxicity (diarrhoea) than dogs in the control group (p=0.010). In all cases, gastrointestinal toxicity was solved by temporarily discontinuing toceranib., Conclusions and Clinical Relevance: The use of toceranib combined with palliative treatment in dogs with suspect metastatic or recurrent insulinomas increased survival time and was adequate tolerated.

Rationale and Objectives: To prospectively compare the image quality (IQ) and lesion detection performance of reduced field-of-view (rFOV) and full FOV (fFOV) diffusion-weighted imaging (DWI) sequences in detecting insulinomas., Materials and Methods: From October 2017 to September 2018, 67 patients with suspected insulinomas were prospectively enrolled and underwent imaging with both types of DWI sequences. The slice thickness (4 mm) and slice gaps (1 mm) were the same for the two DWI sequences, and the TR/TE was 2235/56 ms for the rFOV sequence and 1892/63 ms for the fFOV sequence. Three radiologists independently assessed the imaging quality (IQ) subjectively with a 5-point scale and objectively with signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) measurements. The IQ scores, CNR, SNR, lesion detection rates, and ADC values were compared. Receiver operating characteristic curves were generated, and the area under the curve (AUC) was used to compare the diagnostic performance., Results: Fifty patients were tumor positive, with 65 tumors (size: 1.31 ± 0.77 cm, range: 0.6-5.8 cm). The IQ score, SNR, and CNR were significantly higher for rFOV DWI than for fFOV DWI (IQ: 3.64 ± 0.487 vs 3.310 ± 0.577, SNR: 22.520 ± 8.690 vs 10.284 ± 3.321, CNR: 3.454 ± 2.642 vs 1.327 ± 2.801, and all p < 0.05). For lesions less than 1.5 cm (n = 55), the lesion detection rates of the rFOV were statistically improved compared to those of the fFOV (90.7% vs. 75.9%, p = 0.039). The sensitivity of lesion detection was significantly improved with the rFOV-DWI sequences compared to that with the fFOV-DWI sequences (0.924 vs. 0.773, p = 0.013). The ADC values of the two DWI sequences were consistent for insulinomas and normal parenchyma., Conclusion: Considering the improvements in overall IQ and lesion detection and the consistency of ADC measurements, we suggest that rFOV DWI is a reliable auxiliary alternative to fFOV DWI for clinical practice in the detection of pancreatic insulinomas., (Copyright © 2020. Published by Elsevier Inc.)

Purpose: The present study aimed to assess the accuracies of arterial stimulation with simultaneous venous sampling (ASVS) in preoperative localization of insulinomas. Materials and Methods: A cohort consisting of 6 males and 14 females (median age, 48.5y; range, 28-62y) with pathologically proven insulinomas were included in this study. Selective angiographies were performed with the superior mesenteric artery (SMA), gastroduodenal artery (GDA), proximal splenic artery, and midsplenic artery in all individuals. Then ASVS procedures were followed after angiographies for these arteries. Clinical characteristics of the patient and the tumor number, location, and size were recorded. The accuracy of preoperative localization of insulinomas was tested. Results: A total of 22 tumors were identified by histopathological diagnosis. The mean size of the tumor was 1.40±0.60cm. Five tumors were in the head/neck region and 17 in the body/tail region. ASVS accurately localized 17/20 (85%) cases with only biochemical data and 19/20 (95%) cases with biochemical data and angiography images. Variant pancreatic arterial anatomy was revealed in 2 false cases with inferior pancreatic artery replaced by the superior mesenteric artery. Conclusion: ASVS was highly accurate in localizing insulinomas and should be performed in most of the patients with suspected insulinomas before the operation., (© 2018 Shanghai Journal of Interventional Medicine Press. Production and hosting by Elsevier B.V. on behalf of KeAi.)

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., (© 2017 Society for Endocrinology.)

Introduction: The aim of this study was to analyze prognostic factors for survival and recurrence in patients with resected pancreatic neuroendocrine tumors (PNT)., Methods: Medical records of 95 patients with resected PNT were retrospectively reviewed. The variables studied were: age, sex, form of presentation (sporadic/familial tumors), functionality, type of tumor, localization, type of surgery, tumor size, multifocal tumors and recurrent rate. The new WHO classification (2010) was used., Results: There were 45 men and 50 women. Mean age was 46.8 years. Regarding the mode of presentation, it was sporadic in 66 patients (69.8%) and 29 cases were familial neuroendocrine tumors (30.2%) in association with MEN 1 syndrome. The 59% of patients suffered from non-functional tumors and 41% were functional: 20 insulinoma, 16 gastrinoma, and 3 glucagonoma. Distal pancreatectomy was the most common surgical procedure, followed by tumor enucleation in 19 patients. According to the WHO classification, 59 patients had a PNT G1, 24 PNT G2 and 12 with a poorly-differentiated carcinoma, respectively. The 5-year survival in well-differentiated tumors was 100%, regardless of the functionality. Sporadic PNT are more commonly unifocal (P<0.001), associating liver metastasis. Survival and recurrence rates after a mean follow-up of 85.3 months were 65.8 and 24%, respectively., Conclusions: In our experience, WHO classification was an independent prognostic factor in PNT survival., (Copyright © 2016 AEC. Publicado por Elsevier España, S.L.U. All rights reserved.)

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., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Aim: Most studies have considered gastroenteropancreatic neuroendocrine tumors (GEP-NETs) as a homogenous group of samples or distinguish only gastrointestinal from pancreatic endocrine tumors. This article investigates if DNA methylation patterns could distinguish subtypes of GEP-NETs., Materials & Methods: The DNA methylation level of 807 cancer-related genes was investigated in insulinomas, gastrinomas, non-functioning pancreatic endocrine tumors and small intestine endocrine tumors., Results: DNA methylation patterns were found to be tumor type specific for each of the pancreatic tumor subtypes and identified two distinct methylation-based groups in small intestine endocrine tumors. Differences of DNA methylation levels were validated by pyrosequencing for 20 candidate genes and correlated with differences at the transcriptional level for four candidate genes., Conclusion: The heterogeneity of DNA methylation patterns in the different subtypes of gastroenteropancreatic neuroendocrine tumors suggests different underlying pathways and, therefore, these tumors should be considered as distinct entities in molecular and clinical studies.

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 CUX1 was mediated via upregulation of effectors such as HIF1α and MMP9. CUX1 mediates an invasive pro-angiogenic phenotype and is associated with malignant behaviour in human insulinomas., (© 2014 Society for Endocrinology.)

In view of the great demand for human beta-cells for physiological and medical studies, we generated cell lines derived from human insulinomas which secrete insulin, C-peptide and express neuroendocrine and islet markers. In this study, we set out to characterize their proteomes, comparing them to those of primary beta-cells using DIGE followed by MS. The results were validated by Western blotting. An average of 1800 spots was detected with less than 1% exhibiting differential abundance. Proteins more abundant in human islets, such as Caldesmon, are involved in the regulation of cell contractility, adhesion dependent signaling, and cytoskeletal organization. In contrast, almost all proteins more abundant in insulinoma cells, such as MAGE2, were first described here and could be related to cell survival and resistance to chemotherapy. Our proteomic data provides, for the first time, a molecular snapshot of the orchestrated changes in expression of proteins involved in key processes which could be correlated with the altered phenotype of human beta-cells. Collectively our observations prompt research towards the establishment of bioengineered human beta-cells providing a new and needed source of cultured human beta-cells for beta-cell research, along with the development of new therapeutic strategies for detection, characterization and treatment of insulinomas., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

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., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Aims/hypothesis: Protein gene product 9.5 (PGP 9.5) is a marker for neuroendocrine cells but has not been used for pancreatic islet cells and pancreatic endocrine tumors (PETs). Antibodies for PGP 9.5 are now commercially available for immunocytochemical study, with which immunostaining may be able to differentiate between benign and malignant PETs., Results: All 4 kinds of normal islet cells were positively immunostained for PGP 9.5-moderately positive for β-cells and strongly positive for δ-cells, whereas ganglion cells were immunostained more strongly than islet cells. Nine of 12 insulinomas were moderately to strongly positive for PGP 9.5. Two glucagonomas, 3 of 6 pancreatic polypeptidomas (PPomas), 3 of 9 gastrinomas, and 2 of 4 non-functioning PETs were negative for PGP 9.5., Materials and Methods: Thirty-four PETs were immunocytochemically stained for PGP 9.5 using a rabbit polyclonal antibody together with immunostaining for 4 pancreatic hormones, chromogranin A (CgA), and gastrin. PETs consisted of 12 insulinomas, 2 glucagonomas, 1 somatostatinoma (SRIFoma), 6 PPomas, 9 gastrinomas, and 4 non-functioning PETs., Conclusion/interpretation: PGP 9.5 immunostaining was universally positive for 4 kinds of islet cells and was moderately to strongly positive for 9 of 12 (75%) insulinomas. All 22 non-β-cell PETs were negative or weakly positive for PGP 9.5, and thus negative or weakly positive PGP 9.5 immunostaining may be used as a marker for potential malignancy and poor prognosis for non-β-cell PETs.

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.