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Insulinoma is one of the pancreatic neuroendocrine tumors (PanNET) and is exceptionally rare in children. The tumor leads to severe hypoglycemia caused by excessive insulin release. We report a pediatric patient with malignant insulinoma who underwent liver transplantation (LT) due to liver metastases of the insulinoma. A 13-year-old girl presented with symptoms of hypoglycemia due to hyperinsulinism. On computed tomography (CT), a polycystic lesion in the head of the pancreas and enlarged lymph nodes were revealed. A modified Whipple's operation was performed, and histological examination confirmed PanNET. CT also showed an enlarged liver with numerous metastases. Allogeneic LT was carried out successfully. Positron emission tomography-CT using 68Ga-DOTA-labeled somatostatin analogs (SSAs) at the age of 22 years confirmed complete metabolic remission. The patient currently remains under immunosuppressive and anti-proliferative treatment. Multiple surgical interventions, LT combined with SSAs, and immunosuppressive medication proved effective in this case of metastatic malignant insulinoma. [ABSTRACT FROM AUTHOR]

PURPOSE: Biallelic germline pathogenic variants of the base excision repair (BER) pathway gene MUTYH predispose to colorectal cancer (CRC) and other cancers. The possible association of heterozygous variants with broader cancer susceptibility remains uncertain. This study investigated the prevalence and consequences of pathogenic MUTYH variants and MUTYH loss of heterozygosity (LOH) in a large pan-cancer analysis. MATERIALS AND METHODS: Data from 354,366 solid tumor biopsies that were sequenced as part of routine clinical care were analyzed using a validated algorithm to distinguish germline from somatic MUTYH variants. RESULTS: Biallelic germline pathogenic MUTYH variants were identified in 119 tissue biopsies. Most were CRCs and showed increased tumor mutational burden (TMB) and a mutational signature consistent with defective BER (COSMIC Signature SBS18). Germline heterozygous pathogenic variants were identified in 5,991 biopsies and their prevalence was modestly elevated in some cancer types. About 12% of these cancers (738 samples: including adrenal gland cancers, pancreatic islet cell tumors, nonglioma CNS tumors, GI stromal tumors, and thyroid cancers) showed somatic LOH for MUTYH , higher rates of chromosome 1p loss (where MUTYH is located), elevated genomic LOH, and higher COSMIC SBS18 signature scores, consistent with BER deficiency. CONCLUSION: This analysis of MUTYH alterations in a large set of solid cancers suggests that in addition to the established role of biallelic pathogenic MUTYH variants in cancer predisposition, a broader range of cancers may possibly arise in MUTYH heterozygotes via a mechanism involving somatic LOH at the MUTYH locus and defective BER. However, the effect is modest and requires confirmation in additional studies before being clinically actionable. Pan-Cancer Interrogation of MUTYH Variants Reveals Rare Biallelic Inactivation and Defective Base Excision Repair. [ABSTRACT FROM AUTHOR]

Simple Summary: The survival and disease recurrence for pancreatic neuroendocrine tumors differs greatly. The aim of our retrospective study was to investigate prognostic factors influencing recurrence and survival of 413 patients. For outcome evaluation the cohort was split in three groups: those under surveillance, those who had surgery with the intention to cure, and those with unresectable disease. For small tumors (<2 cm) under surveillance only 1 of 59 required surgery. For those who had surgery 20% had recurrence within 5-years with tumor size, high Ki-67 index, and location in the pancreatic head as risk factors. Half of the patients with unresectable tumors survived longer than approximately 2 years with high age, high chromogranin A levels, and increased markers of tumor proliferation being linked to survival. In conclusion, the current results add valuable knowledge in terms of predicting outcomes for individuals with pancreatic neuroendocrine neoplasms. Introduction: The prognosis and impact of different prognostic factors in pancreatic neuroendocrine neoplasms (pNEN) remain controversial. Aim: To investigate prognostic factors for recurrence-free survival and disease-specific survival in patients with pNEN, divided into three groups: patients undergoing surveillance (tumor size < 2 cm, group 1), patients followed after curative-intended surgery (group 2), and patients with unresectable disease or residual tumors after resection (group 3). Method: A single-center retrospective study including consecutive patients over a 20-year period. Multivariate Cox regression analyses were performed to identify risk factors. Results: 413 patients were included, with a mean (SD) age of 62 ± 14 years. In group 1 (n = 51), median (IQR) follow-up was 29 (21–34) months, and tumor size was 1.0 (0.8–1.4) cm. One progressed and had a tumor resection. In group 2 (n = 165), follow-up 59 (31–102) months, median tumor size 2 (1.2–3.4) cm, median Ki-67 index 5 (3–10)%, the 5-year recurrence rate was 21%. Tumor size (p < 0.001), Ki-67 index (p = 0.02), and location in the pancreatic head (p < 0.001) were independent risk factors. In group 3 (n = 197), follow-up 19 (6–46) months, median tumor size 4.2 (2.6–7.0) cm, Ki-67 index 17 (9–64)%, the median disease-specific survival was 22 (6–75) months—99 in NET G1; 54 in NET G2; 14 in NET G3; and 6 months in neuroendocrine carcinomas (NEC). Age (p = 0.029), plasma chromogranin A (p = 0.014), and proliferation, expressed by grade (p = 0.001) and Ki-67 index (p < 0.001), were risk factors. Conclusion: Growth in pNET < 2 cm requiring surgery was observed in 1/51. Tumor size, Ki-67 index, and location in the head were prognostic factors for disease recurrence, while age, plasma chromogranin A, and proliferation predicted mortality in patients with unresectable disease or residual tumors after resection. [ABSTRACT FROM AUTHOR]

Simple Summary: We described post-operative complications, pancreatic sequelae, and post-surgical progression/relapse of pancreatic neuroendocrine neoplasms (PNENs) in 43 patients with multiple endocrine neoplasia type 1 (MEN1), who underwent major or minimal pancreatic surgeries. The performance of a more conservative intervention, compared to both pancreaticoduodenectomy (PD) and distal pancreatectomy (DP), was associated with the absence of post-surgical complications, but required further pancreas surgeries for tumor relapse in 40.0% of the operated cases. Our data showed that major pancreatic resections (PD and DP) were effective in both preventing tumoral progression and guaranteeing a long-term PNEN relapse-free survival time in most of N+ and/or M+ patients. Pancreatic neuroendocrine neoplasms (PNENs) affect over 80% of patients with multiple endocrine neoplasia type 1 (MEN1). Surgery is usually the therapy of choice, but the real immediate and long-term therapeutic benefit of a partial extensive pancreatic resection remains controversial. We analyzed, in 43 PNEN MEN1 patients who underwent 19 pancreaticoduodenectomies (PD), 19 distal pancreatectomies (DP), and 5 minimal pancreatectomies, the prevalence of surgery-derived early complications and post-operative pancreatic sequelae, and the PNEN relapse-free survival time after surgery, comparing major (PD+DP) and minimal pancreatic surgeries. No post-operative mortality was observed. Metastatic cancers were found in 12 cases, prevalently from duodenal gastrinoma. Long-term cure of endocrine syndromes, by the 38 major pancreatic resections, was obtained in 78.9% of gastrinomas and 92.9% of insulinomas. In only one patient, hepatic metastases, due to gastrinoma, progressed to death. Out of the 38 major surgeries, only one patient was reoperated for the growth of a new PNEN in the remnant pancreas. No functioning PNEN persistence was reported in the five minimal pancreatic surgeries, PNEN relapse occurred in 60% of patients, and 40% of cases needed further pancreatic resection for tumor recurrence. No significant difference in PNEN relapse-free survival time after surgery was found between major and minimal pancreatic surgeries. [ABSTRACT FROM AUTHOR]

Background: Insulinoma in women during pregnancy and postpartum is very rare; approximately 65% of cases are diagnosed early in pregnancy and ~ 35% immediately after delivery, few being found in middle or late pregnancy, likely due to increased insulin resistance seen after early-stage pregnancy. We successfully treated a case of insulinoma in which severe hypoglycemic coma immediately after delivery occasioned detailed investigation and diagnosis. Case presentation: Our patient experienced hypoglycemic coma in the 3rd month of pregnancy (initially considered due to her hyperemesis gravidarum) that improved spontaneously during the gestational period. No abnormalities of plasma glucose or body weight were found in regular checkups during her pregnancy; however, recurrence of hypoglycemic coma after delivery led us to suspect insulinoma. While contrast enhanced computer tomography and endoscopic ultrasonography (EUS) initially failed to detect a tumor in the pancreas, selective arterial calcium stimulation test revealed an insulin-secreting tumor localized in the pancreatic body. She then underwent spleen-preserving distal pancreatectomy; a 10-mm tumor positive for chromogranin A, synaptophysin and insulin was identified. Conclusions: Although pregnancy can mask insulinoma-associated symptoms and make diagnosis challenging, hypoglycemic episodes during early pregnancy, which were observed in this case, are suggestive of insulinoma. Importantly, in this case, accurate preoperative localization of the tumor enabled prompt curative surgery after delivery. Thus, clinical vigilance for the occurrence of insulinoma and its localization is appropriate for pregnant women suffering severe hypoglycemia. [ABSTRACT FROM AUTHOR]

This study aims to analyze the effect of mangosteen peel on increasing the number of pancreatic islets in Langerhans endocrine cells and decreasing TNF-α in male white rats induced by streptozotocin. The research conducted was laboratory experimental in nature. The research design used is a Randomized Post Test Only Control Group Design. The samples were 24 male white rats of the Wistar strain. Rats were grouped into six groups: negative control group (KN), positive control STZ (K1), positive control metformin synthetic drug therapy (K2), mangosteen rind extract therapy dose of 200 mg/kgbb (K3), a dose of 400 mg/kgbb (K4), a dose of 600 mg/kgbb (K5). Administration of therapy for 14 days orally. Pancreatic organs were examined by HE and IHC staining. Pancreatic histopathological observation and TNF-α expression were carried out microscopically. Statistical analysis using the Kolmogorov-Smirnov, ANOVA test, and Pearson's correlation. The results of the effect of mangosteen peel extract can increase the proliferation of endocrine cells in the islets of Langerhans, at a dose of 600 mg/kg BW/day. While the decrease in TNF-α expression was shown by all doses of mangosteen peel extract and appeared to be significantly different when compared to the K1 group, namely the STZ-induced group without any therapy. Pearson's correlation results show that there is an inverse relationship between the number of endocrine cells and TNF-α expression. The conclusion is that administration of mangosteen peel extract can increase the number of pancreatic islets of Langerhans endocrine cells and decrease Tumor Necrosis Factor Alpha in streptozotocin-induced male white rats. Suggestions need to do research on anti-inflammatory cytokines that occur in endocrine cells of the islets of Langerhans due to streptozotocin-induced mangosteen peel extract in rats so that there is a balance with pro-inflammatory cytokines. [ABSTRACT FROM AUTHOR]

Simple Summary: In endocrinology, endoscopic ultrasound is a useful and reliable diagnostic technique in the assessment of multiple endocrine neoplasia type 1, localizing insulinomas, and identifying aldosterone-producing adenomas. In endocrinology, endoscopic ultrasound (EUS) may be used to image the adrenals, the endocrine pancreas, and other organs where endocrine neoplasms may occur. During the recent decades, EUS has been established predominantly to assess multiple endocrine neoplasia type 1, to localize insulinomas, and to identify aldosterone-producing adenomas. EUS in endocrinology requires special skills and individual experience in order to provide reliable diagnostic information. [ABSTRACT FROM AUTHOR]

Aim: To investigate the protective effect of α-lipoic acid on sodium arsenite (NaAsO2) induced INS-1 cells injury and its mechanism. Methods: The cell viability was measured by CCK-8 assay. The autophagosomes was observed under transmission electron microscopy. The autophagosomes in cells transfected with green fluorescent protein microtubule-associated protein light chain 3 (GFP-LC3) plasmids were observed under a laser scanning con-focal microscope. The expression of LC3-II, P62, PI3K, and mTOR proteins in INS-1 cells treated with a combination of chloroquine (CQ, autophagy inhibitor) and NaAsO2 were detected by Western blot assay. The expression of LC3-II, P62, PI3K, and mTOR proteins were detected in INS-1 cells treated with a combination of rapamycin (autophagy inducer, mTOR inhibitor) and α-LA. Results: The cytotoxicity induced by NaAsO2 was reversed by α-LA, and the viability of NaAsO2-treated INS-1 cells increased. α-LA pretreatment decreased the autophagosome accumulation induced by NaAsO2. α-LA also reduced the fluorescence spot aggregation of GFP-LC3 in INS-1 cells exposed to NaAsO2 as observed under a laser scanning con-focal microscope. α-LA inhibited NaAsO2 induced autophagy by up-regulating PI3K and mTOR and down-regulating LC3-II and P62. CQ inhibited NaAsO2 induced autophagy by up-regulating PI3K, mTOR, P62 and down-regulating LC3-II. α-LA inhibited rapamycin-induced autophagy by up-regulating PI3K, mTOR and P62 and down-regulating LC3-II. The results showed that NaAsO2 could induce autophagy activation in INS-1 cells. The α-LA may inhibit autophagy activation by regulating the PI3K/mTOR pathway. Conclusion: The data indicated that α-LA might inhibit the NaAsO2-induced autophagic death of INS-1 cells by regulating the PI3K/mTOR pathway. [ABSTRACT FROM AUTHOR]

Background: Insulinoma is an uncommon insulin-secreting neuroendocrine tumor that presents with severe recurrent hypoglycemia. Although cases of extrapancreatic insulinomas have been reported, the majority of insulinomas occur in the pancreas. The number of reported cases of ectopic insulinomas with follow-up assessments is limited and they do not report disease recurrence. The current report presents the first documented case of recurrent extrapancreatic insulinoma with 8 years of follow-up, provides relevant literature review, and proposes surveillance and treatment strategies. Case presentation: We describe an insulinoma localized in the duodenal wall of a 36-year-old female who presented in 2013 with weight gain and Whipple's triad and was successfully managed with duodenotomy and enucleation. She presented again in 2017 with recurrent Whipple's triad and was found to have metastatic disease localized exclusively to peripancreatic lymph nodes. Primary pancreatic insulinoma was not evident and her hypoglycemia resolved following lymph node dissection. Eight years after initial presentation continuous glucose monitoring (CGM) showed a trend for euglycemia, and PET-CT Gallium 68 DOTATATE scan evaluation indicated absence of recurrent disease. Conclusion: Insulinomas are rare clinical entities and extrapancreatic insulinomas are particularly uncommon. Follow-up evaluation and treatment strategies for ectopic insulinoma recurrence presents a significant clinical challenge as the condition has hitherto remained undescribed in the literature. Available evidence in the literature indicates that lymph node metastases of intrapancreatic insulinomas likely do not change prognosis. Given the absence of long-term data informing the management and monitoring of patients with extrapancreatic insulinoma, we suggest patient education for hypoglycemic symptoms, monitoring for hypoglycemia with CGM, annual imaging, and a discussion with patients regarding treatment with octreotide or alternative somatostatin receptor analog therapies. [ABSTRACT FROM AUTHOR]

Pancreatic neuroendocrine neoplasms (PanNENs) are rare and clinically challenging entities. At the molecular level, PanNENs' genetic profile is well characterized, but there is limited knowledge regarding the contribution of the newly identified genes to tumor initiation and progression. Genetically engineered mouse models (GEMMs) are the most versatile tool for studying the plethora of genetic variations influencing PanNENs' etiopathogenesis and behavior over time. In this review, we present the state of the art of the most relevant PanNEN GEMMs available and correlate their findings with the human neoplasms' counterparts. We discuss the historic GEMMs as the most used and with higher translational utility models. GEMMs with Men1 and glucagon receptor gene germline alterations stand out as the most faithful models in recapitulating human disease; RIP-Tag models are unique models of early-onset, highly vascularized, invasive carcinomas. We also include a section of the most recent GEMMs that evaluate pathways related to cell cycle and apoptosis, Pi3k/Akt/mTOR, and Atrx/Daxx. For the latter, their tumorigenic effect is heterogeneous. In particular, for Atrx/Daxx, we will require more in-depth studies to evaluate their contribution; even though they are prevalent genetic events in PanNENs, they have low/inexistent tumorigenic capacity per se in GEMMs. Researchers planning to use GEMMs can find a road map of the main clinical features in this review, presented as a guide that summarizes the chief milestones achieved. We identify pitfalls to overcome, concerning the novel designs and standardization of results, so that future models can replicate human disease more closely. [ABSTRACT FROM AUTHOR]

BACKGROUND: The differences between sporadic and multiple endocrine neoplasia type 1 (MEN-1)–associated insulinoma are not well described. Herein, we compared demographics, neoplasm characteristics, presentation, and survival in patients with sporadic vs MEN-1 insulinomas including benign and malignant disease. STUDY DESIGN: A retrospective study identified insulinoma patients. MEN-1 was defined based on genetic testing or clinically in patients with 2 or more primary MEN-1 tumor types. RESULTS: A total of 311 patients were identified: 84% benign and 16% malignant. The incidence of malignancy was similar (18% vs 16%, MEN-1 vs sporadic, p = 0.76). Within malignant patients, the median (interquartile range) age was 33 (25,44) years in MEN-1 vs 54 (41, 70) years in sporadic insulinoma (p = 0.04). There was no difference in sex or tumor size between MEN-1 and sporadic malignant insulinoma (p > 0.05). Of the 260 patients with benign insulinoma, 7% had MEN-1 syndrome. MEN-1 patients presented with insulinoma at a younger age: median (interquartile range) age was 38 (24, 49) years vs 52 (43, 65) years (p < 0.01). Resection of benign insulinoma was performed in 78% of the MEN-1 and 94% of the sporadic group (p = 0.03). Resected benign tumors were larger in the MEN-1 group: 2.0 (1.65, 2.45) cm vs 1.5 (1.2, 2.0) cm, respectively (p = 0.03). Concurrent insulinomas were more common in MEN-1 (17% vs 2%; p < 0.01). CONCLUSIONS: MEN-1 patients present with insulinoma at younger age and have larger benign pancreatic lesions at the time of resection compared with sporadic neoplasms. Younger patients and those with multifocal pancreatic neuroendocrine tumor in the setting of endogenous hyperinsulinism should be evaluated for MEN-1. [ABSTRACT FROM AUTHOR]

Pancreatic neuroendocrine tumors (PNETs) or islet cell tumors are neuroendocrine neoplasms that arise from cells of the endocrine and nervous system within the pancreas. Patients with PNET sometimes do not show any symptoms, known as nonfunctioning (NF) sporadic PNET. It is still debatable regarding the best approach in the NF for small PNET. Currently, the surgical approach is considered the best; however, it is a highly invasive procedure, and it has a potentially high risk of complications as it requires a skilled and experienced operator. Herewith, we reported a 48-year-old female with incidentaloma of nonfunctioning PNET (NF-PNET) whose tumor has been successfully treated with endoscopic ultrasound guided radiofrequency ablation (EUSRA). There was no adverse event observed during and after the EUS procedure, and even 1 week after the procedure. One year later, abdominal magnetic resonance imaging (MRI) examination was carried out and size of the tumor was significantly getting smaller where it could hardly be seen anymore. After 2 years of follow-up, the latest abdominal MRI study showed no solid part of the tumor could be seen anymore. In conclusion, EUSRA can be an alternative option for incidentaloma of NF-PNET management. [ABSTRACT FROM AUTHOR]

Background: Pancreatic neuroendocrine tumors (pNET) are rare diseases and surgical treatment is promising. In this study, we retrospectively analyzed the patients who underwent surgical treatment for pancreatic neuroendocrine tumor in our hospital in the last 11 years; We aimed to present our findings to the literature. Materials and Methods: The files of the patients who applied for pNET between January 2011 and March 2022 were retrospectively analyzed. Patients with multiple data deficiencies, who did not undergo surgery, and who were younger than 18 years of age were excluded from the study. The patients were evaluated in terms of age, gender, type of operation, tumor size, type and histological features, hospital stay, recurrent disease and survival. Results: Of the 33 patients included in the study, 13 were female and 20 were male, and the median age was 56 (18-86). There were 8 patients with functional tumors, one was somatostatinoma and the others were insulinomas. Enucleation in 7 of the patients; Pancreatectomy was performed in 26 of them. There were three patients whose main lesion was adenocarcinoma and serous cystadenoma, who underwent resection and whose specimen pathology had incidental pNET. We had 23, 7 and 3 patients with grade 1,2 and 3 tumors, respectively. The median value of tumor diameter was 24 (3-80) mm. The median value for hospital stay was 7 (2-50) days. The median value of follow-up was 24 (1-71) months; disease-free survival was 14 (1-71) months. Conclusions: pNETs are a rare disease that can be detected incidentally and should be carefully managed. Studies with larger series are needed to reach a consensus on the surgical and conservative treatment of pNET. [ABSTRACT FROM AUTHOR]

Background: ACTH-independent macronodular hyperplasia (AIMAH) is an uncommon disorder characterized by massive enlargement of both adrenal glands and hypersecretion of cortisol. Concomitant AIMAH and multiple endocrine neoplasia type1 (MEN1) is rare to our knowledge. Case presentation: Herein, we describe a 32 year old woman with long history of prolactinoma and secondary ammonhrea presented with not-severe manifestation of hypoglycemia due to concomitant presence of insulinoma with AIMAH leading to 12 years delay of MEN1 diagnosis. Laboratory tests showed severe hypoglycemia associated with hyper insulinemia (non-fasting blood sugar = 43 mg/dl, insulin = 80.6 μIU /ml, C-peptide = 9.3 ng/ml) hyperparathyroidism (calcium = 10.3 mg/dl, phosphor = 3.1 mg/dl, PTH = 280 pg/ml) and chemical evidence of an ACTH-independent hypercortisolism (serum cortisol value of 3.5, after 1 mg dexamethasone suppression test serum ACTH value of 17 pg/ml, and high urinary cortisol level). Abdominal CT scan demonstrated two enhancing well-defined masses 27*20 mm and 37*30 mm in the tail and body of the pancreas, respectively, and a 36*15 mm mass in left adrenal gland (seven Hounsfield units). Dynamic pituitary MRI revealed a partial empty sella. The physical examination of the patient was unremarkable. Distal pancreatectomy and a left adrenalectomy were performed. After the surgery, we observed clinical and biochemical remission of hyper insulinemia and gradual decrease in urinary cortisol. The histological features of the removed left adrenal gland were consistent with AIMAH. Histological examination of the pancreatic lesions revealed well differentiated neuroendocrine tumors. Genetic abnormalities in the MEN1, heterozygote for pathogenic variant chr11; 645,773,330-64577333AGAC, c.249-252delGTCT, p. (11e85Serfs Ter33) in exon 2 were found. It was recommended the patient undergoes parathyroidectomy as soon as possible. Conclusion: Given the history and presentation of our case, we recommend that the clinicians consider the possibility of autonomous cortisol production in MEN1 patients who do not show severe symptoms of hypoglycemia in the presence of insulinoma. [ABSTRACT FROM AUTHOR]

Simple Summary: Adult-onset familial insulinomatosis is a rare disorder with recurrent, severe hypoglycemia caused by multiple insulin-secreting pancreatic tumors. The etiology was unclear until the genetic variant p.Ser64Phe in the MAFA protein, a key coordinator of insulin secretion in pancreatic cells, was defined as the cause in two families. Based on the cases of two sisters with insulinomatosis, we aimed to identify further disease causes. The sequencing of the complete coding regions of the patients' genomes revealed a second genetic MAFA variant, p.Thr57Arg, as the cause of familial insulinomatosis, linking genetic, clinical, and biochemical analyses from the patients' family to the pre-described cell culture data. Thus, we confirm a defect in a crucial regulatory region of the MAFA protein as an important cause of a specific hereditary syndrome, which is characterized by insulinomatosis and/or mild hyperglycemia. This study extends the pathophysiological and diagnostic disease concept and verifies the inheritance pattern of familial insulinomatosis. Adult-onset familial insulinomatosis is a rare disorder with recurrent, severe hypoglycemia caused by multiple insulin-secreting pancreatic tumors. The etiology was unclear until the variant p.Ser64Phe in the transcription factor MAFA, a key coordinator of β-cell insulin secretion, was defined as the cause in two families. We here describe detailed genetic, clinical, and family analyses of two sisters with insulinomatosis, aiming to identify further disease causes. Using exome sequencing, we detected a novel, heterozygous missense variant, p.Thr57Arg, in MAFA's highly conserved transactivation domain. The impact of the affected region is so crucial that in vitro expression studies replacing Thr57 have already been performed, demonstrating a phosphorylation defect with the impairment of transactivation activity and degradation. However, prior to our study, the link to human disease was missing. Furthermore, mild hyperglycemia was observed in six additional, heterozygote family members, indicating that not only insulinomatosis but also MODY-like symptoms co-segregate with p.Thr57Arg. The pre-described MAFA variant, p.Ser64Phe, is located in the same domain, impairs the same phosphorylation cascade, and results in the same symptoms. We confirm MAFA phosphorylation defects are important causes of a characteristic syndrome, thus complementing the pathophysiological and diagnostic disease concept. Additionally, we verify the high penetrance and autosomal dominant inheritance pattern. [ABSTRACT FROM AUTHOR]

Background: Multiple endocrine neoplasia type 1 (MEN 1) syndrome is a rare, complex genetic disorder characterized by increased predisposition to tumorigenesis in multiple endocrine and non-endocrine tissues. Diagnosis and management of MEN 1 syndrome is challenging due to its vast heterogeneity in clinical presentation. Case presentation: A 23-year-old female, previously diagnosed with Polycystic Ovarian Syndrome (PCOS) and pituitary microprolactinoma presented with drowsiness,confusion and profuse sweating developing over a period of one day. It was preceded by fluctuating, hallucinatory behavior for two weeks duration. There was recent increase in appetite with significant weight gain. There was no fever, seizures or symptoms suggestive of meningism. Her Body mass index(BMI) was 32 kg/m2.She had signs of hyperandrogenism. Multiple cutaneous collagenomas were noted on anterior chest and abdominal wall. Her Glasgow Coma Scale was 9/15. Pupils were sluggishly reactive to light. Tendon reflexes were exaggerated with up going planter reflexes. Moderate hepatomegaly was present. Rest of the clinical examination was normal. Laboratory evaluation confirmed endogenous hyperinsulinaemic hypoglycaemia suggestive of an insulinoma. Hypercalcemia with elevated parathyroid hormone level suggested a parathyroid adenoma. Presence of insulinoma, primary hyperparathyroidism and pituitary microadenoma, in 3rd decade of life with characteristic cutaneous tumours was suggestive of a clinical diagnosis of MEN 1 syndrome. Recurrent, severe hypoglycaemia complicated with hypoglycaemic encephalopathy refractory to continuous, parenteral glucose supplementation and optimal pharmacotherapy complicated the clinical course. Insulinoma was localized with selective arterial calcium stimulation test. Distal pancreatectomy and four gland parathyroidectomy was performed leading to resolution of symptoms. Conclusions: Renal calculi or characteristic cutaneous lesions might be the only forewarning clinical manifestations of an undiagnosed MEN 1 syndrome impending a life-threatening presentation. Comprehensive management of MEN 1 syndrome requires multi-disciplinary approach with advanced imaging modalities, advanced surgical procedures and long-term follow up due to its heterogeneous presentation and the varying severity depending on the disease phenotype. [ABSTRACT FROM AUTHOR]

Background: MEN1 mutations can inactivate or disrupt menin function and are leading to multiple endocrine neoplasia type 1, a rare heritable tumor syndrome. Case presentation: We report on a MEN1 family with a novel heterozygous germline mutation, c.674delG; p.Gly225Aspfs*56 in exon 4 of the MEN1 gene. Diagnosis and clinical phenotyping of MEN1 was established by laboratory tests, ultrasound, biopsy, MRI imaging and endosonography. The clinical course of the disease was followed in the index patient and her family members for eight years. The mutation was associated with distinct clinical phenotypes in the index patient and three family members harboring p.Gly225Aspfs*56. Family members affected showed primary hyperparathyroidism but variable patterns of associated endocrine tumors, adrenal cortical adenomas, prolactinoma, multifocal pancreatic neuroendocrine tumors, insulinoma and nonsecretory neuroendocrine tumors of the pancreas. The mutation c.674delG; p.Gly225Aspfs*56 leads to a frameshift from codon 225 with early truncation of the menin protein. In silico analysis predicts loss of multiple protein-menin interactions in p.Gly225Aspfs*56, potentially rendering menin insufficient to control cell division and replication. However, no aggressive neuroendocrine tumors were observed in the follow-up of this family. Conclusions: We report a novel heterozygous MEN1 frameshift mutation, potentially causing (at least partial) inactivation of menin tumor suppression potential but lacking a genotype–phenotype correlation. Our study highlights the importance of personalized care with appropriate testing and counseling in MEN1 families. [ABSTRACT FROM AUTHOR]

Objective Insulinomas are rare in the post-bariatric surgery setting. The differential diagnosis for hypoglycemia is broad, requiring laboratory testing to verify endogenous hyperinsulinemic hypoglycemia. Selective arterial calcium stimulation testing (SACST) can help localize abnormal insulin production. We describe a patient with histologically confirmed insulinoma after bariatric surgery diagnosed with the aid of SACST. Methods We present a 67 year old woman with a history of Roux-en-Y bypass surgery who presented with endogenous hyperinsulinemic hypoglycemia. Initially, no pancreatic lesion was identified radiologically. We pursued SACST to localize the source of insulin production. Results The SACST successfully localized the source of hyperfunctioning islet cells to the pancreatic tail with absolute insulin values in a range consistent with insulinoma. Additional radiologic studies showed a small tumor in the pancreatic tail. Pathology showed a well-differentiated neuroendocrine tumor, compatible with insulinoma. Conclusion This case study illustrates the usefulness of SACST for the diagnosis and localization of insulinoma. [ABSTRACT FROM AUTHOR]

Cancer-associated fibroblasts (CAFs), a stromal cell population with cell-of-origin, phenotypic and functional heterogeneity, are the most essential components of the tumor microenvironment (TME). Through multiple pathways, activated CAFs can promote tumor growth, angiogenesis, invasion and metastasis, along with extracellular matrix (ECM) remodeling and even chemoresistance. Numerous previous studies have confirmed the critical role of the interaction between CAFs and tumor cells in tumorigenesis and development. However, recently, the mutual effects of CAFs and the tumor immune microenvironment (TIME) have been identified as another key factor in promoting tumor progression. The TIME mainly consists of distinct immune cell populations in tumor islets and is highly associated with the antitumor immunological state in the TME. CAFs interact with tumor-infiltrating immune cells as well as other immune components within the TIME via the secretion of various cytokines, growth factors, chemokines, exosomes and other effector molecules, consequently shaping an immunosuppressive TME that enables cancer cells to evade surveillance of the immune system. In-depth studies of CAFs and immune microenvironment interactions, particularly the complicated mechanisms connecting CAFs with immune cells, might provide novel strategies for subsequent targeted immunotherapies. Herein, we shed light on recent advances regarding the direct and indirect crosstalk between CAFs and infiltrating immune cells and further summarize the possible immunoinhibitory mechanisms induced by CAFs in the TME. In addition, we present current related CAF-targeting immunotherapies and briefly describe some future perspectives on CAF research in the end. [ABSTRACT FROM AUTHOR]

Background: Because management is very different, it is important to differentiate between small focal insulinomas and diffuse pancreatic dysplasia (nesidioblastosis) in patients with confirmed endogenous hyperinsulinaemic hypoglycaemia (EHH). Most insulinomas highly express glucagon‐like peptide‐1 receptors enabling positron emission tomography–computed tomography imaging with its radiolabelled analogue; 68Ga‐DOTA‐Exendin‐4 (Exendin). Aim: To determine: (i) the utility of Exendin in EHH patients in a clinical setting; and (ii) whether the degree of Exendin uptake differentiates non‐insulinoma pancreatogenous hypoglycaemia syndrome (NIPHS) from post‐gastric bypass hypoglycaemia (PGBH). Methods: This retrospective study reviewed the clinical, biochemistry and prior imaging findings in confirmed EHH patients referred for Exendin. Accuracy of Exendin was based on surgical findings and treatment outcomes. Finally, average Exendin uptake (SUVmax) of five PGBH studies was compared with the SUVmax of a key NIPHS case report. Results: Twenty of 25 consecutive patients had confirmed EHH. Exendin located insulinomas in eight of nine patients enabling successful surgical excision with rapid and durable cure. Exendin correctly identified diffuse nesidioblastosis in two of three cases requiring partial pancreatectomy for hypoglycaemia control. All three relapsed within 1.7 years with one needing completion pancreatectomy. Establishing the cause in the remainder relied on other investigations, clinical correlation and response to empirical treatment. Finally, Exendin SUVmax could not distinguish between NIPHS and PGBH. Conclusion: In EHH patients, Exendin accurately identifies the site of insulinoma and thereby differentiates it from nesidioblastosis but negative findings should not be ignored. Exendin is unlikely to differentiate between normal pancreatic uptake, NIPHS and PGBH. [ABSTRACT FROM AUTHOR]

Type 1 diabetes (T1D) is an autoimmune and inflammatory disease with excessive loss of pancreatic islet β -cells. Accumulating evidence indicated that endoplasmic reticulum (ER) stress played a critical role in β -cells loss, leading to T1D. Therefore, promoting the survival of pancreatic β cells would be beneficial for patients with T1D. Puerarin is a natural isoflavone that has been demonstrated to be able to decrease blood glucose in patients with T1D. However, it remains unknown whether puerarin improves ER stress to prevent β -cells from apoptosis. Here, we sought to investigate the role of puerarin in ER stress-associated apoptosis and explore its underlying mechanism in the mouse insulinoma cell line (MIN6). Flow cytometry and cell counting kit-8 (CCK8) experiments showed that puerarin caused a significant increase in the viability of MIN6 cells injured by H2O2. Furthermore, the protein kinase R-like ER kinase (PERK) signal pathway, a critical branch of ER stress response, was found to be involved in this process. Puerarin inhibited the phosphorylation of PERK, subsequently suppressed the phosphorylation of eukaryotic initiation factor 2 α (eIF2 α) , then decreased the activating transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP) expression, ultimately attenuating ER stress to prevent MIN6 cells from apoptosis. In addition, puerarin inhibited the activation of Janus kinase 2 (JAK2)/signal transducer and activators of transcription 3 (STAT3), which suppressed the PERK signal cascade with decreased ATF4 and CHOP levels. Taken together, our results firstly demonstrated that puerarin could prevent MIN6 cells from apoptosis at least in part by inhibiting the PERK-eIF2 α -ATF4-CHOP axis under ER stress conditions, which might be mediated by inactivation of the JAK2/STAT3 signal pathway. Therefore, investigating the mechanism underlying the effects of puerarin might highlight the potential roles of puerarin developing into an antidiabetic drug. [ABSTRACT FROM AUTHOR]

A case study is presented of a 55-year-old male who was brought to the emergency department via EMS due to confusion, non- sensical speech, diaphoresis, and a serum glucose level. In order to confirm a hyperfunctioning pancre- atic tumor, a fasting blood glucose measurement was taken, after the dextrose infusion was turned off, his blood glucose decreased, and the findings were consistent with an insulinoma.

Insulinoma is a rare neuroendocrine tumor originating from hypersecreting beta-cells of islets of Langerhans in the pancreas. We report a case of 72-year-old male, with chronic alcohol abuse, presenting with atypical features like refractory recurrent secondary generalized seizures and behavioral disturbances with increased irritability, initially mistreated as alcohol withdrawal. Detailed history, particularly the relationship of the symptoms with food intake, made us think of other causes of seizures. Fasting biochemical investigations and localizing studies helped clinch the diagnosis. The tumor was localized with the help of endoscopic ultrasonography and whole-body Ga68-DOTANOC PET-CT. The patient was treated conservatively with diazoxide and is doing well on follow-up. The present case report emphasizes the importance of detailed clinical history, more so in atypically presenting cases of refractory seizures. Insulinoma can be medically managed despite surgery being the gold standard curative treatment. [ABSTRACT FROM AUTHOR]

Introduction: Pancreatic islet-cell tumors (PICT) often present with atypical signal-characteristics and are often missed on preoperative imaging. The aim of this study is to provide a multiparametric PICT characterization and investigate factors impeding PICT detection. Material and methods: This is a detailed MRI analysis of a prospective, monocenter study, including 49 consecutive patients (37 female, 12 male; median age 50) with symptoms due to endogenous hyperinsulinemic hypoglycemia (EHH) and mostly negative prior-imaging. All patients received a 3-T MRI and a 68Ga-DOTA-exendin-4-PET/CT. Pooled accuracy, sensitivity, specificity and inter-reader agreement were calculated. Reference-standard was histopathology and 68Ga-DOTA-Exendin-4-PET/CT in one patient who refused surgery. For PICT analyses, 34 patients with 49 PICTs (48 histologically proven; one 68Ga-DOTA-exendin-4-PET/CT positive) were assessed. Dynamic contrast-enhanced (DCE) Magnetic Resonance Images (MRI) with Golden-Angle-Radial-Sparse-Parallel (GRASP) reconstruction, enabling imaging at high spatial and temporal resolution, was used to assess enhancement-patterns of PICTs. Tumor-to-background (T2B) ratio for each sequence and the employed quantitative threshold for conspicuity of PICTs were analyzed in regard to prediction of true-positive PICTs. Results: Evaluation of 49 patients revealed a pooled lesion-based accuracy, sensitivity and specificity of 70.3%, 72.9% and 62.5%, respectively. Mean PICT size was 12.9±5.3mm for detected, 9.0±2.9mm for undetected PICTs (p-value 0.0112). In-phase T1w detected the most PICT (67.3%). Depending on the sequence, PICTs were isointense and poorly visible in 29–68%. Only 2/41(4.9%) PICTs showed typical signal-characteristics across T1w, T2w, DWI and ceT1w combined. 66.6% of PICTs enhanced simultaneously to the parenchyma, 17.8% early and 15.6% late. Predictor screening analysis showed number of sequences detecting a PICT, lesion size and in-phase T1w T2B ratio had the highest contribution for detecting a true-positive PICT. Conclusion: The majority of PICTs enhance simultaneously to surrounding parenchyma, present with atypical signal-characteristics and thus are poorly visible. In non-enhancing PICTs, radiologists should search for small lesions most likely conspicuous on unenhanced T1w or DWI. [ABSTRACT FROM AUTHOR]

• Tyrosine kinase inhibitors Recent interest in the use of tyrosine kinase inhibitors such as toceranib phosphate (Palladia TM) has emerged, based on the efficacy of sutanib, another tyrosine kinase inhibitor, in clinical trials of humans with pancreatic neuroendocrine tumours. 20 Tumour size and Ki67 index (a proliferation marker depicting the mitotic rate of the tumour on histopathology) have also been identified as prognostic markers in canine insulinoma. Veterinary Ireland Journal I Volume 11 Number 3 172 Approach to canine insulinoma Myles McKenna MVB MVetSci MVetMed DACVIM (SAIM) DECVIM-CA MRCVS, assistant professor in small animal internal medicine at University College Dublin, presents an overview of canine insulinoma Insulinoma is defined as an insulin-secreting tumour of pancreatic beta-cells, and is the most common endocrine tumour of the pancreas in dogs. Streptozocin for treatment of pancreatic islet cell tumors in dogs: 17 cases (1989-1999). [Extracted from the article]

The article focuses on neuroendocrine tumors (NET) are a rare and heterogeneous group of neoplasms with variable biological behavior. Topics include the frequently metastasize to the liver, requiring active, multimodality treatment, the liver transplantation (LT) has emerged as a potential curative treatment due to relatively slow growth and indolent behavior of the metastases, and the selected patients with metastatic NET disease as an indication for LT treated in our center.

Aims: To evaluate the diagnostic relevance of autoantibodies against zinc transporter 8 (ZnT8) in schoolchildren from the general population as well as in people with autoimmune diabetes. Methods: A total of 137 schoolchildren positive for at least one of the three major diabetes‐associated autoantibodies, without diabetes heredity or preselection on HLA typing, from the Karlsburg Type 1 Diabetes Risk Study, as well as 102 people at type 1 diabetes onset, 88 people with latent autoimmune diabetes in adults and 119 people with type 2 diabetes, were analysed for different ZnT8 autoantibody variants. Results: Zinc transporter 8 autoantibody positivity was found in 18% of autoantibody‐positive schoolchildren, with a noticeable association with other autoantibodies associated with type 1 diabetes and disease progression. Furthermore, ZnT8 autoantibody positivity was associated with diabetes progression in schoolchildren positive for autoantibodies against insulinoma‐associated antigen‐2 (IA‐2) and, importantly, in seven IA‐2 autoantibody‐negative schoolchildren. Additionally, ZnT8 autoantibodies were found in 56% of people with type 1 diabetes, predominantly directed against all three ZnT8 variants and comparable to schoolchildren with multiple autoantibodies. In contrast, ZnT8 autoantibodies were detected in 10% of people with latent autoimmune diabetes in adults, none of them with reactivity to all three isoforms. Conclusion: Zinc transporter 8 autoantibodies are useful markers for prediction of type 1 diabetes in a general population, further stratifying the risk of progression in autoantibody‐positive children. ZnT8 autoantibodies are also important markers in adult‐onset diabetes, with a completely different reaction pattern in type 1 diabetes in comparison to latent autoimmune diabetes in adults, and may therefore help to differentiate between the two forms. [ABSTRACT FROM AUTHOR]

We also reviewed the published literatures and summarized the clinical characteristics, diagnostic methods, treatment strategies and patient prognosis of multiple myeloma with involvement of the pancreas. A plain abdominal computed tomography (CT) scan showed dilatation of the upper segment of the common bile duct (CBD) and the intrahepatic bile duct. Surgical procedures other than distal pancreatectomy for isolated pancreatic tail involvement are not commonly performed due to the common systemic nature of the disease.5 ERCP can be used to treat obstructive jaundice via a biliary stent placement and has been increasingly used in patients with secondary pancreatic plasmacytoma in recent years. [Extracted from the article]

We present the case of an 83-year-old woman with recurrent episodes of delirium occurring overnight, associated with hypoglycaemia. Other causes for delirium were excluded. Laboratory findings were in keeping with endogenous insulin production. Computerised tomography imaging revealed a small mass in the pancreas supporting a presumed diagnosis of an insulinoma. Given the patient's frailty and cognitive impairment, a conservative management approach was taken. Diazoxide was commenced with resolution of episodes of delirium. This case highlights hypoglycaemia, and insulinoma, as a rare, but treatable cause of delirium. It demonstrates the importance of blood sugar screening in delirium. It emphasises the holistic modifications to management, which must be taken to ensure patient-centred care when caring for an older adult living with frailty, who may have cognitive impairment. [ABSTRACT FROM AUTHOR]

Background: Neuroendocrine tumors (NETs) are rare tumors harboring overexpression of somatostatin receptors (SSTRs) on their cell membrane. Because some organs, such as the spleen, adrenal glands and liver, physiologically express SSTR, it might be challenging to distinguish some pancreatic NETs located in the pancreatic tail from the accessory spleen next to the splenic hilum. In this manuscript, we report a case with hypoglycemia attack and 2 different masses displayed by Gallium 68-tetraazacyclododecane tetraacetic acid-octreotate (68Ga-DOTATATE) positron emission tomography/computed tomography (PET/CT). Case presentation: A 63-year-old woman presented to the hospital with confusion and profuse sweating. Biochemical diagnosis of insulinoma was established. 68Ga-DOTATATE PET/CT revealed two masses with increased tracer uptake located adjacent to the splenic hilum and inferior pole of the spleen which were initially reported as two separate accessory spleens. Then, 99mTc-labelled heat-denaturated red blood cell (99mTc-HDRBC) scintigraphy-single-photon emission computed tomography (SPECT)/CT was performed to distinguish a NET in the pancreatic tail from accessory spleen at the splenic hilum. Enhanced tracer uptake remained in the inferior pole of spleen, but not in the splenic hilum. The lesions were suggestive of insulinoma in the pancreatic tail and an accessory spleen adjacent to the inferior pole of the spleen. Conclusion: Approximately 10% of the population have an accessory spleen which can show similar imaging characteristics with pancreatic NETs, especially if located in the pancreatic tail. In our presented case, 99mTc-HDRBC scintigraphy-SPECT/CT is a useful nuclear medicine method to differentiate a NET in the pancreatic tail from accessory spleen at the splenic hilum which may avoid unnecessary surgeries in the presence of enhanced tracer uptake or vice versa. [ABSTRACT FROM AUTHOR]

Solid Pseudopapillary Neoplasms of the pancreas are rare pancreatic tumors with low-grade malignant potential, typically affecting young females. In this review, we discuss the surgical anatomy; the imaging characteristics, and image reporting essentials for proper surgical planning along with the atypical features which should caution the physician regarding the risk of malignancy. We also discuss the common surgical procedures and organ preservation surgeries along with a comprehensive review of the literature. • Solid Pseudopapillary Neoplasms of the pancreas are rare pancreatic tumors with low grade malignant potential, typically affecting young females. • Small SPNs (< 3cm in diameter) usually appear as completely solid tumors with sharp margins and gradually enhancing, well encapsulated masses in the pancreas and may demonstrate varying amounts of hemorrhage. • Large lesions have mixed solid – cystic components showing early weak enhancement with gradual increase in enhancement in the hepatic venous phase. • Atypical features including extracapsular, as well as parenchymal invasion, simulation of islet cell tumors, calcifications, ductal obstruction, and metastasis are suspicious for malignant degradation. • The tumor is considered unresectable in the event that it invades or encases the aorta, encases >180 degree of the SMA regardless of tumor location in the pancreas, abuts the celiac artery (when the tumor is located in the pancreatic head) or encases >180 degree of the celiac artery (when the tumor is located in the body/tail of the pancreas). [ABSTRACT FROM AUTHOR]

These findings provide valuable insights on the mechanisms of ESCC progression mediated by cell-cell interactions among cancer cells, TAMs and CAFs in the tumor microenvironment. I have studied "the significance of cell-cell interactions between tumor cells and stromal cells" in the tumor microenvironment. Subsequent investingations on NKX2.2-negative non-Ewing round cell sarcomas evolved into detailed characterization of CIC-rearranged sarcoma and "SMARCA4-deficient thoracic sarcoma", which helped in establishing these tumor concepts. [Extracted from the article]

A 37-year-old active duty male Air Force instructor pilot, with no prior medical history, was found unresponsive at his home after awakening with symptoms of altered mental status when the Emergency Medical Service (EMS) was called. The patient was found to be hypoglycemic with a glucose of 37 mg/dL. The patient recovered after administration of a dextrose bolus. Further investigation revealed that over the last several years, the patient exhibited symptoms of lightheadedness and tremors if fasted greater than 3 hours. Further clinical workup strongly suggested the presence of a neuroendocrine tumor. Initial imaging studies to include a multiphasic dedicated pancreatic computed tomography (CT) scan did not demonstrate a pancreatic lesion. However, the utilization of an innovative new nuclear medicine imaging modality, a 68Ga-Dotatate PET/CT, clearly demonstrated a 19 × 16 mm lesion of the distal pancreatic tail, which guided surgical resection. He underwent a robotic-assisted laparoscopic distal pancreatectomy, pathologically characterized as an insulinoma. The patient's symptoms immediately resolved with no recurrence over the next 6 months. The pilot was granted a waiver, returning him to his flying duties. The 68Ga-Dotatate PET/CT enabled the identification of an otherwise occult pancreatic neuroendocrine tumor ultimately leading to this patient's definitive cure and the salvage of this military asset's aviation career. [ABSTRACT FROM AUTHOR]

Aims: High‐expressed miR‐330‐3p in gestational diabetes mellitus (GDM) patients was reported. However, the role and mechanism of miR‐330‐3p in GDM are rarely reported. In this research, we aim to investigate the effects of miR‐330‐3p on GDM. Methods: MiR‐330‐3p expression in the GDM patients' blood was determined by q‐PCR. Blood glucose of blood samples was detected using blood glucose detection kits. Glucokinase (GCK) was confirmed to be a target gene of miR‐330‐3p by bioinformatics and luciferase analysis. Correlations between miR‐330‐3p with GCK and blood glucose were analyzed by Pearson correlation analysis. After INS‐1 cells were treated with glucose and transfected with mimic, inhibitor or siGCK, GCK expression was detected by western blot, and q‐PCR, enzyme‐linked immunosorbent assays, cell counting kit‐8 and Annexin‐V/propidium iodide were conducted to examine the expression of insulin, cell viability and apoptosis. Results: MiR‐330‐3p was high‐expressed in GDM patients' blood, while GCK was low‐expressed. The miR‐330‐3p expression level positively correlated with blood glucoseand and it was highly expressed in glucose‐treated INS‐1 cells (11 and 22 mmol/L), while miR‐330‐3p expression negatively correlated with GCK expression. GCK expression was inhibited by miR‐330‐3p mimic and enhanced by the miR‐330‐3p inhibitor. MiR‐330‐3p mimic inhibited INS‐1 cells' insulin expression, cell viability and induced apoptosis. Yet miR‐330‐3p inhibitor and siGCK exhibited opposite effects which miR‐330‐3p mimic and GCK played on INS‐1 cells. In addition, siGCK reversed the effect of miR‐330‐3p inhibitor on INS‐1 cells. Conclusion: Our findings proved that miR‐330‐3p targeting GCK lead to the dysfunction of INS‐1 cells in GDM, and could become a therapeutic target for GDM treatment. [ABSTRACT FROM AUTHOR]

Insulinomas are rare tumors of the islet cells of the pancreas and are the most common cause of endogenous hyperinsulinism. Although they usually present with symptoms of hypoglycemia, sometimes they can have vague symptoms. We present the case of a 62-year-old diabetic female who was diagnosed with a large insulinoma after being investigated for the 'cure' of her diabetes. We also review the literature regarding insulinomas in patients with diabetic. A 62-year-old, obese woman with type 2 diabetes mellitus was initially investigated for an unexplained normalization of her blood glucose levels after the cessation of antidiabetic medication due to an episode of severe hypoglycemia. She remained without antidiabetics for three months maintaining normoglycemia, and thereafter, she started experiencing frequent but less severe hypoglycemic episodes. She did not change her diet habits or level of activity and did not lose any weight. The patient underwent further investigation with a supervised 72 h fasting test, which resulted in the biochemical diagnosis of endogenous hyperinsulinism. Imaging studies revealed the presence of a large insulinoma in the head of the pancreas. Finally, the patient underwent a pylorus preserving Whipple procedure, which reversed the aforementioned 'normalization' of glucose levels and the underlying diabetes mellitus reappeared. Insulinomas are rare tumors causing hypoglycemia. Even more rarely are found in diabetic patients, making the diagnosis more challenging and probably delayed, as the symptoms are masked by the presence of diabetes, thereby leading to a more advanced disease diagnosis. [ABSTRACT FROM AUTHOR]

Objectives: This study aimed to determine whether Ki-67 index evaluated on cytologic material could reliably grade pancreatic neuroendocrine tumors (PanNETs).Methods: Cases with adequate cell block and available surgical specimens were included. Ki-67 index was calculated using "eyeballing," "hot spot," and "complete" counting methods.Results: The overall concordance rates between cytology and surgical specimens were 71%, 73%, and 59%, respectively, by using eyeballing, hot spot, and complete counting approaches. All grade 1 tumors were correctly graded on cytology, but in grade 2 tumors concordance rates were only 36%, 41%, and 9%, respectively. All grade 2 tumors were undergraded when cell blocks contained fewer than 1,000 cells, while concordance rate increased to 57%, 64%, and 14%, respectively, in cases with 1,000 cells or more.Conclusions: Grade 2 PanNETs can be significantly undergraded when Ki-67 index is evaluated on cell block material. In cases with 1,000 or more cells, the hot spot counting method has better correlation with surgical specimens. [ABSTRACT FROM AUTHOR]

Introduction: We previously demonstrated that insulin secreting cells (ISCs) accelerate healing of chronic wounds, and it is known that mesenchymal stem cells (MSCs) also accelerate wound healing. Here, we report that the combination of both cell types coencapsulated into a synthetic hydrogel dressing accelerates chronic wound healing 3 × faster than control and 2 × faster than each cell type delivered singly. Specifically, insulin released by ISCs activates the PI3/Akt pathway, which is vital to the function and survival of MSCs. MSCs in turn improve the viability and function of ISCs. Materials and Methods: MSCs and/or rat islet tumor RIN-m cells were encapsulated into polyethylene glycol diacrylate hydrogel sheets and applied to 1 cm2 full thickness excisional wounds on the dorsa of genetically diabetic male mice (BKS.Cg-m +/+Leprdb/J) in accordance with protocols approved by the Rutgers IACUC. Encapsulated cell viability was assessed using a LIVE/DEAD® Viability/Cytotoxicity Kit. Akt phosphorylation, insulin, VEGF, and TGF-β1 secretion were assessed by ELISA. Animals were sacrificed on postoperative days 14 and 28 and wound tissue was collected for histological and western blot analysis. Results: ISC:MSC combination groups had the highest levels of every secreted product and phosphorylated Akt, and closed wounds in 14 days, ISC-only or MSC-only groups closed wounds in 28 days, control groups closed wounds in 40 days. Further, ISC:MSC groups healed without intermediate scab or scar. Conclusions: Combining MSCs with ISCs results in a more robust healing response than singly delivered cells, warranting further investigation of coencapsulation for MSC therapies. [ABSTRACT FROM AUTHOR]

We report a case of a non-secretory neuroendocrine tumor which transformed into an insulin secreting tumor after treatment with Sunitinib. To our knowledge, this has only been described in three other cases worldwide. Previously reported case series find transformation of non-secretory neuroendocrine cancers into secretory lesions occurs in 3.4–6.8% of cases. Sunitinib is known to have the potential to lower blood glucose and induce epigenetic changes in cells of various types. We hypothesize that the mechanism for Sunitinib-induced transformation in cancer phenotype is through epigenetic changes in DNA expression within the tumor cells. [ABSTRACT FROM AUTHOR]

Glucagon-like peptide-1 receptor (GLP-1R) is a kind of G protein coupled receptor which regulates the insulin secretion and serves as potential target in the diagnosis of functional pancreas neuroendocrine tumor. The aim of this study was to evaluate the feasibility of GLP-1R targeted tracer [68Ga]Ga-NOTA-MAL-Cys39-exendin-4 in the detection of insulinoma. NOTA-MAL-Cys39-exendin-4 was synthesized and then radiolabeled with gallium-68 in iQS® Ga-68 Fluidic Labeling Module. The in vitro binding affinity and cell uptake studies were evaluated in INS-1 cells. The in vivo micro-PET/CT imaging and biodistribution studies were performed on INS-1 xenograft tumor models. [68Ga]Ga-NOTA-MAL-Cys39-exendin-4 can be efficiently radiolabelled with a yield of about 85% (non-decay corrected) and radiochemical purity of >95% with a favorable stability. The molar activity was at least 145.5 GBq/μmol. The affinity (IC50) for [68Ga]Ga-NOTA-MAL-Cys39-exendin-4 was 12.99 ± 0.81 nM. Micro-PET/CT images showed intense tumor uptake with good contrast to background. Biodistribution study showed the predominant uptake was in the kidney, followed by pancreas, and the liver and spleen just showed mild uptake in the blood-pool phase with rapid clearance. At 1 h post- injection, the tumor to blood, muscle and pancreas ratios were 30.64, 40.21 and 6.46, respectively. Blocking studies showed significantly decreased tumor uptake, which further confirmed binding affinity of [68Ga]Ga-NOTA-MAL-Cys39-exendin-4 to GLP-1R. [68Ga]Ga-NOTA-MAL-Cys39-exendin-4 was easily synthesized with high yield, favorable biodistribution and high affinity to islet tumor cell, making the tracer may have great potential in the detection of GLP-1R positive tumor such as an insulinoma. [ABSTRACT FROM AUTHOR]

Major challenges of dealing elder patients with diabetes mellitus (DM) are the individualization of consideration in persons with various comorbid types of conditions. In spite of the fact that microvascular and macrovascular problems associated with DM are well documented, there is only a few numbers of reports viewing different conditions, for example, cognitive dysfunction. Cognitive dysfunction is of specific significance due to its effect on self-care and quality of life. All in all, the etiology of cognitive dysfunction in the maturing populace is probably going to be the grouping of ischemic and degenerative pathology. It is likewise trusted that Hyperglycemia is engaged with the system of DM-related cognitive dysfunction. At present, it isn't certain in the case of enhancing glycemic control or utilizing therapeutic agents can enhance the risk of cognitive decay. Amylin was later characterized as an amyloidogenic peptide, confined from a beta cell tumor and called islet amyloid polypeptide (IAPP), and after that, amylin. Conversely, we investigate the beneficial role and hypothesizing the mechanism of amylin related expanding the level and activation of CGRP receptor to enhance the cognition declination amid diabetic dementia. • Amylin is a pancreatic hormone regulates glucose blood through decreasing feeding. • Amylin amyloids are harmful in the type 2 diabetes and likely Alzheimer disease. • Amylin activates CGRP to enhance the cognition declination amid diabetic dementia. [ABSTRACT FROM AUTHOR]

Objective: Green tea (Camellia sinensis) is one of the most consumed beverages in the world. C. sinensis consumption may prevent tumor and other diseases. Insulinomas are pancreatic islet cell tumors. In present study, the effects of the extract from C. sinensis were investigated in rat insulinoma INS-1 cells. Methods: C. sinensis leaves were collected in Rize, Turkey. The leaves were brewed in tap water for 20 and 40 minutes at 80°C. INS-1 cells were treated with different doses (1-5 mg/mL) of C. sinensis extract for 24 h. Cell viability, proliferation, death were examined. The malondialdehyde, glutathione and protein carbonyl levels were measured in INS-1 cells given C. sinensis extract. Results: The cell viability and the percentage of proliferating cell nuclear antigen immunopositive cells decreased, while the percentage of TUNEL positive cells increased in INS-1 cells treated with the extract from C. sinensis according to control group. While malondialdehyde and protein carbonyl levels in INS-1 cells treated with C. sinensis extract decreased, glutathione levels increased according to control group. Conclusion: The results indicate that the extracts from C. sinensis inhibited proliferation and caused apoptosis in INS-1 cell. C. sinensis may be natural agent for supporting the treatment of pancreatic tumors. [ABSTRACT FROM AUTHOR]

Abstract Ethnopharmacological relevance Mistletoe (Viscum album), an evergreen parasitic plant, has been widely used as an oriental phytomedicine to treat diabetes mellitus. However, it is unknown which mistletoe constituent exerts the beneficial effect against the disease. In this study, we examined the hypoglycemic activity of mistletoe and investigated whether the polypeptide viscothionin, purified from mistletoe, was responsible for the activity. Materials and methods Mistletoe extracts were prepared by heating mistletoe powder made of leaves and twigs in water for 3, 6, 9, and 12 h. Rat insulinoma RINm5F cells were used to test the cytotoxicity of the extracts and their effects on the secretion of insulin and its precursor, C-peptide. The inhibitory effects of a mistletoe extract on glucose absorption were measured using an α-glucosidase inhibition assay. To determine the component of mistletoe responsible for the observed effects, the mistletoe extract was precipitated with ethanol or hydrolyzed with a protease for further testing. A potential active constituent of mistletoe was isolated by chromatography and molecular weight cut-off fractionation, and its ability to induce insulin secretion was investigated. Results A 12-h heat-treated mistletoe extract, showing no cytotoxicity, significantly increased the secretion of insulin and C-peptide by RINm5F cells and enhanced the expression of glucose transporter type 4 (GLUT-4), insulin receptor substrate 1 (IRS-1), and protein kinase B (also known as AKT) in differentiated C2C12 cells. The extract also inhibited α-glucosidase activity. After ethanol precipitation, the extract showed much stronger effects on insulin- and C-peptide-secreting activities of cells, whereas the enzyme-hydrolyzed extract was less effective than the original extract, suggesting that the effect was mediated by a proteinaceous constituent of mistletoe. Subsequent analysis showed that viscothionin, a heat-stable 6-kDa polypeptide isolated from mistletoe, increased the level of insulin secretion by more than 20-fold compared to that induced by the extract. Conclusions Our study indicates that the hypoglycemic effect of mistletoe is mediated by its insulinotropic action and α-glucosidase inhibitory activity, and the effect is due to viscothionin, one of the major bioactive constituents of mistletoe. Graphical abstract fx1 [ABSTRACT FROM AUTHOR]

The article focuses on the treatment of rare mesenchymal tumor. Topics discussed include autosomal dominant von Hippel-Lindau (VHL) syndrome, whole genome sequencing (WGS) done before and after treatment with pazopanib, and identification of mitogen-activated protein kinase (MAPK) alterations and prediction of biologic behavior more similar to metastatic renal cell carcinoma (mRCC).

Aims/Hypothesis: Evidence of the role of cytomegalovirus (CMV) infection in the pathogenesis of type 1 diabetes (T1D) has remained inconclusive. Our aim was to elucidate the possible role of CMV infection in the initiation of islet autoimmunity and in the progression to clinical T1D among children with human leukocyte antigen (HLA)‐conferred T1D risk. Methods: A total of 1402 children from the prospective Type 1 Diabetes Prediction and Prevention (DIPP) study were analyzed for CMV‐specific IgG antibodies during early childhood. All the children carried HLA‐DQ genotypes associated with increased risk for T1D. The effect of CMV infection on the appearance of T1D‐associated autoantibodies (insulin autoantibodies [IAA], glutamic acid decarboxylase [GADA], and insulinoma antigen‐2 [IA‐2A], n = 356) and on the progression rate to clinical T1D (n = 233) were analyzed with Kaplan‐Meier survival analysis and Log‐rank test. Results: Early childhood CMV infection was inversely associated with the development of T1D during childhood. Cumulative progression to T1D was decreased in subjects with an early CMV infection (P = 0.035). In further analyses, the effect of early CMV infection on the initiation of islet autoimmunity and progression to clinical T1D were examined separately. Interestingly, early CMV infection did not affect the appearance of T1D‐associated autoantibodies but a decelerating effect was observed on the progression rate from islet autoimmunity to clinical T1D (P = 0.015). Conclusion: Our results suggest that an early childhood CMV infection may decelerate the progression from islet autoimmunity to clinical T1D among at‐risk children and may thus protect these children from progressing to T1D during childhood. [ABSTRACT FROM AUTHOR]

Background: Radiofrequency ablation (RFA) has been increasingly employed in experimental and clinical settings for the management of pancreatic lesions. This study aimed to assess the safety and efficacy of endoscopic ultrasound (EUS)-guided RFA for benign solid pancreatic tumors.Methods: In a single-center, prospective study, 10 patients with benign solid pancreatic tumors underwent EUS-RFA. After the RFA electrode had been inserted into the pancreatic mass, the radiofrequency generator was activated to deliver 50 W of ablation power.Results: Among the 10 patients, 16 sessions of EUS-RFA were successfully performed. Diagnoses included nonfunctioning neuroendocrine tumor (n = 7), solid pseudopapillary neoplasm (n = 2), and insulinoma (n = 1); the median largest diameter of the tumors was 20 mm (range 8 - 28 mm). During follow-up (median 13 months), radiologic complete response was achieved in seven patients. Two adverse events (12.4 %; 1 moderate and 1 mild) occurred.Conclusions: EUS-RFA may be a safe and potentially effective treatment option in selected patients with benign solid pancreatic tumors. Multiple sessions may be required if there is a remnant tumor, and adverse events must be carefully monitored. [ABSTRACT FROM AUTHOR]