• anesthesia management
• difficult airway
• fiberoptic intubation
• glucagonoma
• necrolytic migratory erythema

• MEN1
• dietary habits
• multiple endocrine neoplasia type 1 (MEN1)
• neuroendocrine tumors
• nutrition
• pancreatic neuroendocrine tumors
• quality of life

• Humans
• Multiple Endocrine Neoplasia Type 1/complications
• Multiple Endocrine Neoplasia Type 1/therapy
• Nutritional Status

• Chromatin remodeling complexes
• Digestive system neoplasms
• Mismatch repair
• SWI/SNF

• Humans
• Digestive System Neoplasms/genetics
• Mutation
• Carcinogenesis
• Cell Transformation, Neoplastic
• Carcinogens
• Tumor Microenvironment

• 81802474 National Natural Science Foundation of China

• chronic diarrhea
• dotanoc pet-ct
• neuroendocrine tumor
• pancreatic net
• skeletal metastases

• GRK 2254, HEIST Deutsche Forschungsgemeinschaft (German Research Foundation)
• PREDICT-PACA, 70113834 Deutsche Krebshilfe (German Cancer Aid)
• TRANSCAN VI-PMTR-PanNET, ID 640 01KT1901B Bundesministerium für Bildung und Forschung (Federal Ministry of Education and Research)

• Cancer-specific survival
• Pancreatic neuroendocrine neoplasm
• Prediction model
• Risk factors
• Risk stratification

• Humans
• Neuroendocrine Tumors/diagnosis
• Pancreatic Neoplasms/diagnosis
• Nomograms
• Kaplan-Meier Estimate
• Risk Assessment

For at least 50 years, the prevailing view has been that the adenylate cyclase (AC)/cyclic AMP (cAMP)/protein kinase A pathway is the predominant signal mediating the hepatic glucose‐mobilizing actions of glucagon. A wealth of evidence, however, supports the alternative, that the operative signal most of the time is the phospholipase C (PLC)/inositol‐phosphate (IP3)/calcium/calmodulin pathway. The evidence can be summarized as follows: (1) The consensus threshold glucagon concentration for activating AC ex vivo is 100 pM, but the statistical hepatic portal plasma glucagon concentration range, measured by RIA, is between 28 and 60 pM; (2) Within that physiological concentration range, glucagon stimulates the PLC/IP3 pathway and robustly increases glucose output without affecting the AC/cAMP pathway; (3) Activation of a latent, amplified AC/cAMP pathway at concentrations below 60 pM is very unlikely; and (4) Activation of the PLC/IP3 pathway at physiological concentrations produces intracellular effects that are similar to those produced by activation of the AC/cAMP pathway at concentrations above 100 pM, including elevated intracellular calcium and altered activities and expressions of key enzymes involved in glycogenolysis, gluconeogenesis, and glycogen synthesis. Under metabolically stressful conditions, as in the early neonate or exercising adult, plasma glucagon concentrations often exceed 100 pM, recruiting the AC/cAMP pathway and enhancing the activation of PLC/IP3 pathway to boost glucose output, adaptively meeting the elevated systemic glucose demand. Whether the AC/cAMP pathway is consistently activated in starvation or diabetes is not clear. Because the importance of glucagon in the pathogenesis of diabetes is becoming increasingly evident, it is even more urgent now to resolve lingering uncertainties and definitively establish glucagon’s true mechanism of glycemia regulation in health and disease.

Vasoactive intestinal peptide (VIP) secreting tumour (VIPoma) is a rare functional neuroendocrine tumour that typically arises from pancreatic islet cells. These present as sporadic, solitary pancreatic neoplasias with an estimated incidence of one in ten million individuals per year. Only around 5% of VIPomas are associated with multiple endocrine neoplasia type I syndrome. Excessive VIP secretion produces a clinical syndrome characterized by refractory watery diarrhoea, hypokalemia and metabolic acidosis. These coupled with elevated plasma levels of VIP are diagnostic. The majority of VIPomas are malignant and have already metastasized at the time of diagnosis (60%). Metastases occur most frequently in the liver, or regional lymph nodes, lungs, kidneys and bones. Some reports of skin metastases have been documented. Complete surgical resection continues to be the only potentially curative treatment. However, when the neoplasia cannot be excised completely, surgical debulking may provide palliative benefit. Other palliative options have included recently the peptide receptor radionuclide therapy which has shown to be effective and well-tolerated. This article will review all aspects of pancreatic VIPomas highlighting aspects such as clinical presentation, diagnosis and management.

• VIPoma
• Octreotide
• Secretory diarrhoea
• Multiple endocrine neoplasia
• Vasoactive intestinal peptide
• Vermer-Morrison syndrome

• Adult
• Erythema
• Female
• Glucagonoma/complications
• Glucagonoma/diagnostic imaging
• Glucagonoma/radiotherapy
• Humans
• Necrolytic Migratory Erythema/diagnostic imaging
• Pancreatic Neoplasms/complications
• Pancreatic Neoplasms/diagnostic imaging
• Pancreatic Neoplasms/radiotherapy
• Positron Emission Tomography Computed Tomography
• Radioisotopes
• Receptors, Peptide

Pancreatic tumors are classified into endocrine and exocrine types, and the clinical manifestations in patients are nonspecific. Most patients, especially those with pancreatic ductal adenocarcinoma (PDAC), have lost the opportunity to receive for the best treatment at the time of diagnosis. Although chemotherapy and radiotherapy have shown good therapeutic results in other tumors, their therapeutic effects on pancreatic tumors are minimal. A multifunctional transcription factor, Yin-Yang 1 (YY1) regulates the transcription of a variety of important genes and plays a significant role in diverse tumors. Studies have shown that targeting YY1 can improve the survival time of patients with tumors. In this review, we focused on the mechanism by which YY1 affects the occurrence and development of pancreatic tumors. We found that a YY1 mutation is specific for insulinomas and has a role in driving the degree of malignancy. In addition, changes in the circadian network are a key causative factor of PDAC. YY1 promotes pancreatic clock progression and induces malignant changes, but YY1 seems to act as a tumor suppressor in PDAC and affects many biological behaviors, such as proliferation, migration, apoptosis and metastasis. Our review summarizes the progress in understanding the role of YY1 in pancreatic endocrine and exocrine tumors and provides a reasonable assessment of the potential for therapeutic targeting of YY1 in pancreatic tumors.

• Mutation
• Pancreatic ductal adenocarcinoma
• Pancreatic neuroendocrine tumor
• Tumor suppressor
• YY1

• Disease-Free Survival
• Female
• Humans
• Kaplan-Meier Estimate
• Male
• Middle Aged
• Neoplasm Recurrence, Local
• Neuroendocrine Tumors/diagnostic imaging
• Neuroendocrine Tumors/mortality
• Neuroendocrine Tumors/pathology
• Neuroendocrine Tumors/surgery
• Pancreatic Neoplasms/diagnostic imaging
• Pancreatic Neoplasms/mortality
• Pancreatic Neoplasms/pathology
• Pancreatic Neoplasms/surgery
• Retrospective Studies
• Tomography, X-Ray Computed

Pancreatic neuroendocrine tumors (pNETs) are a heterogeneous group of tumors with complicated treatment options that depend on pathological grading, clinical staging, and presence of symptoms related to hormonal secretion. With regard to diagnosis, remarkable advances have been made: Chromogranin A is recommended as a general marker for pNETs. But other new biomarker modalities, like circulating tumor cells, multiple transcript analysis, microRNA profile, and cytokines, should be clarified in future investigations before clinical application. Therefore, the currently available serum biomarkers are insufficient for diagnosis, but reasonably acceptable in evaluating the prognosis of and response to treatments during follow-up of pNETs. Surgical resection is still the only curative therapeutic option for localized pNETs. However, a debulking operation has also been proven to be effective for controlling the disease. As for drug therapy, steroids and somatostatin analogues are the first-line therapy for those with positive expression of somatostatin receptor, while everolimus and sunitinib represent important progress for the treatment of patients with advanced pNETs. Great progress has been achieved in the combination of systematic therapy with local control treatments. The optimal timing of local control intervention, planning of sequential therapies, and implementation of multidisciplinary care remain pending.

• Pancreatic neuroendocrine tumor
• Serum biomarkers
• Staging
• Grading
• Management
• Therapy

• Ablation Techniques/methods
• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/therapeutic use
• Biomarkers, Tumor/blood
• Chemotherapy, Adjuvant/methods
• Combined Modality Therapy
• Cytoreduction Surgical Procedures
• Disease-Free Survival
• Humans
• Lymph Node Excision
• Molecular Targeted Therapy/methods
• Neoplasm Grading
• Neoplasm Staging
• Neuroendocrine Tumors/blood
• Neuroendocrine Tumors/diagnosis
• Neuroendocrine Tumors/mortality
• Neuroendocrine Tumors/therapy
• Pancreas/pathology
• Pancreas/surgery
• Pancreatectomy/methods
• Pancreatic Neoplasms/blood
• Pancreatic Neoplasms/diagnosis
• Pancreatic Neoplasms/mortality
• Pancreatic Neoplasms/therapy
• Patient Care Team
• Prognosis
• Progression-Free Survival
• Somatostatin/analogs & derivatives
• Somatostatin/therapeutic use
• Treatment Outcome

• CUT-like homeobox 1
• matrix metalloprotease 9
• microRNA-744-5p
• pancreatic neuroendocrine tumor
• thrombospondin 2

• hyperinsulinaemia
• hypoglycaemia
• neuroendocrine tumour
• somatostatinoma

• biomarkers
• diagnosis
• gastroenteropancreatic tumors
• neuroendocrine tumors
• prognostic markers

• Biomarkers
• Chemotherapy resistance
• Nab paclitaxelin
• Pancreatic cancer
• Survival rate

Analogues of exendin-4 have been radiolabeled for imaging the glucagon-like peptide type 1 receptors (GLP-1R) which are overexpressed in insulinoma. The aim of this research was to synthesize an ¹⁸F–labeled silicon containing exendin-4 peptide (¹⁸F-2) and to evaluate its in vitro and in vivo behavior in CHL-GLP-1 receptor positive tumor-bearing mice.

¹⁸F–labeled silicon containing exendin-4 peptide (¹⁸F-2) was prepared via one-step nucleophilic substitution of a silane precursor with ¹⁸F–fluoride in the presence of acetic acid and K222. ¹⁸F-2 was then administered to tumor-bearing mice for PET imaging and ex vivo biodistribution experiments.

¹⁸F-2 was produced in a radiochemical yield (decay corrected) of 1.5% and a molar activity of max. 16 GBq/μmol. The GLP-1R positive tumors were clearly visualized by PET imaging. Biodistribution studies showed reduced uptake of ¹⁸F-2 in the kidneys compared to radiometal labeled exendin-4 derivatives. The radiotracer showed specific tumour uptake which remained steady over 2 h.

This exendin-4 analogue, ¹⁸F-2, is a potential probe for imaging GLP-1R positive tumors.

• 18F–Radiolabeling
• Exendin-4
• Glp-1R
• Insulinoma
• Pet
• Silicon

• Diagnostic Imaging/methods
• Elasticity Imaging Techniques
• Endoscopic Ultrasound-Guided Fine Needle Aspiration
• Endosonography
• Humans
• Magnetic Resonance Imaging
• Pancreatic Diseases/diagnostic imaging
• Pancreatic Neoplasms/diagnostic imaging
• Positron-Emission Tomography
• Precancerous Conditions/diagnostic imaging
• Sensitivity and Specificity
• Tomography, X-Ray Computed

• 10/4001/11 Department of Health
• 13/89/03 Department of Health
• PB-PG-0712-28114 Department of Health
• RG2014_01_PERERIA Pancreatic Cancer UK

• Adrenal ablation
• Cushing's syndrome
• Neuroendocrine tumor

• Cytology
• Cytopathology
• FNA
• Fine-needle aspiration
• Pancreas
• Pancreatic cytopathology

• Biomarkers, Tumor
• Cyst Fluid/cytology
• Cytodiagnosis
• Diagnosis, Differential
• Endoscopic Ultrasound-Guided Fine Needle Aspiration
• Humans
• Pancreas/cytology
• Pancreas/diagnostic imaging
• Pancreas/pathology
• Pancreatic Cyst/diagnostic imaging
• Pancreatic Cyst/pathology
• Pancreatic Neoplasms/diagnostic imaging
• Pancreatic Neoplasms/pathology
• Pancreatitis/diagnostic imaging
• Pancreatitis/pathology
• Predictive Value of Tests
• Reproducibility of Results
• Sensitivity and Specificity

• Pancreatic neuroendocrine tumors
• VIPoma
• gastrinoma
• glucagonoma
• insulinoma
• somatostatinoma

• Pancreatic and duodenal homeobox 1 (PDX1)
• RIP-TK
• RNA interference (RNAi)
• metformin
• pancreatic cancer

von Hippel-Lindau (VHL) disease is an autosomal dominantly inherited neoplastic syndrome that increases susceptibility to a variety of benign and malignant neoplasms. It has been well documented that, despite complete excision of initial neoplasms, VHL patients may develop further lesions, in some cases many years after the initial diagnosis. Therefore, the varied and complex clinical manifestations and radiological findings of VHL are of interest. The current study is the first to describe a case of VHL disease with lateral ventricular hemangioblastomas and subsequent pancreatic neuroendocrine tumor, bilateral renal cysts and renal cell carcinoma. The complete clinical course, radiological findings, including ultrasound, computed tomography and magnetic resonance imaging (MRI), and associated pathological findings are presented. Radiology is critical in the accurate diagnosis, treatment and follow-up of VHL. Continuous close and long-term follow-up with radiological examination, particularly MRI, must be conducted in patients with VHL disease. To the best of our knowledge, the current case is a rare phenomenon that has not yet been described in the English literature.

• central nervous system
• hemangioblastoma
• pancreatic neuroendocrine tumor
• renal cell carcinoma
• von Hippel-Lindau

Nonfunctional pancreatic neuroendocrine tumors (NF-pNETs) are increasingly being diagnosed but management, especially of small tumors, remains a clinical dilemma. Endoscopic ultrasound guided fine-needle aspiration (EUS-FNA) is now routinely used for diagnosis of pancreatic neuroendocrine tumors (pNETs) but has not been well studied as a tool for identifying aggressive disease.

A systematic search of the cytology database identified all patients at our center who underwent EUS-FNA from 1999 through 2011 and were diagnosed with NF-pNET.

A total of 50 patients were identified. Though patients with metastatic disease had a mean tumor size of 40 mm compared to 25 mm in patients without metastatic disease (P = 0.04), we also identified several patients with tumors <20 mm who presented with metastatic disease. Furthermore, we found no statistically significant difference in metastatic disease between tumors <20 mm and >20 mm (P = 0.13). Using receiver operating characteristic (ROC) analysis, we found that using a cutoff point of 20 mm only led to a sensitivity of 85% in screening for metastases, while lowering the cutoff point to 18 mm allowed for a sensitivity of 95%.

Currently, guidelines suggest that only patients with tumors greater than 20 mm undergo surgical resection, as tumors less than this size are thought to have low risk of metastases. Our analysis suggests that these recommendations could lead to undertreating patients with small tumors. Tumor size alone may be inadequate as a marker for aggressive NF-pNETs. Given this, other risk factors for aggressive pNETs should be studied to help identify the patients most likely to benefit from surgery.

• Animals
• Cell Line, Tumor
• Cell Proliferation
• Cloning, Molecular
• Humans
• Insulin/genetics
• Insulin/metabolism
• Insulin Secretion
• Insulin-Secreting Cells/metabolism
• Insulinoma/genetics
• Insulinoma/metabolism
• Pancreatic Neoplasms/genetics
• Pancreatic Neoplasms/metabolism
• Pancreatic Neoplasms/pathology
• Phosphorylation
• Protein Isoforms
• Protein Transport
• RNA Interference
• Rats
• Transcription, Genetic
• Transfection
• tau Proteins/genetics
• tau Proteins/metabolism

• MR/L016451/1 Medical Research Council
• G1100540 Medical Research Council
• G0900652 Medical Research Council
• G0400074 Medical Research Council
• G0502157 Medical Research Council

• Gynecologic neuroendocrine tumors
• Neuroendocrine tumors
• Ovarian cancer
• PNET
• Pancreatic cancer
• VIPoma

• YY1
• adenylyl cyclase
• cAMP
• exome sequencing
• insulinoma

Turner syndrome is a chromosomal abnormality in which the majority of patients have a 45XO karyotype, while a small number have a 45XO/47XXX karyotype. Congenital adrenal hyperplasia has been previously reported in patients with Turner syndrome. Although insulinomas are the most common type of functioning pancreatic neuroendocrine tumor and have been reported in patients with multiple endocrine neoplasias, the tumors have not been reported in patients with mosaic Turner syndrome. The present study reports the first case of an insulinoma in a patient with 45XO/47XXX mosaic Turner syndrome. The patient suffered from recurrent hypoglycemia, which was relieved following ingestion of glucose or food. A 5-h glucose tolerance test was performed and the levels of glucose, C-Peptide and insulin were detected. In addition, computed tomography (CT) and ultrasound scanning were performed to evaluate the possibility of an insulinoma. Pathological examination and karyotyping were performed on a surgical specimen and a whole blood sample, respectively. The patient was found to suffer from premature ovarian failure, and a physical examination was consistent with a diagnosis of Turner syndrome. An ultrasound scan demonstrated streak ovaries and the patient was found to have a 45XO/47XXX karyotype. Furthermore, a lesion was detected in the pancreas following CT scanning, which was identified as an insulinoma following surgical removal and histological examination. In conclusion, the present study reports the first case of an insulinoma in a patient with mosaic Turner syndrome. Since mosaic Turner syndrome and insulinoma are rare diseases, an association may exist that has not been previously identified.

• Turner syndrome
• insulinoma
• mosaic 45XO/47XXX
• premature ovary failure

• Ki67
• endoscopic ultrasonography
• endoscopic ultrasound-guided fine needle aspiration
• pancreatic neuroendocrine tumors

Necrolytic migratory erythma (NME) is an obligatory paraneoplastic syndrome. Here we describe a woman admitted to the dermatology ward with NME which was later found to be associated with glucagonoma, a slow-growing, rare pancreatic neuroendocrine tumor. Even more rarely, the tumor was located in the pancreas head, while most of such lesions are located in the distal pancreas. The diagnosis of this rare tumor requires an elevated serum glucagon level and imaging confirming a pancreatic tumor. After surgical removal of the tumor, the patient’s cutaneous and systemic features resolved. It is therefore imperative that clinicians recognize NME early in order to make an accurate diagnosis and to provide treatment for this rare tumor.

• allosteric
• blood glucose
• diabetes
• glycemic disorders
• hyperinsulinemia
• monoclonal antibody

• Animals
• Antibodies, Monoclonal/therapeutic use
• CHO Cells
• Cricetinae
• Cricetulus
• Humans
• Hyperglycemia/drug therapy
• Hypoglycemia/drug therapy
• Hypoglycemic Agents/therapeutic use
• Insulin/blood
• Insulin/metabolism
• Oncogene Protein v-akt/metabolism
• Phosphorylation
• Receptor, Insulin/immunology

Soluble N-ethylmaleimide sensitive factor attachment protein receptors (SNAREs) are crucial for exocytosis, trafficking, and neurite outgrowth, where vesicular SNAREs are directed toward their partner target SNAREs: synaptosomal-associated protein of 25 kDa and syntaxin. SNARE proteins are normally membrane bound, but can be cleaved and released by botulinum neurotoxins. We found that botulinum proteases types C and D can easily be transduced into endocrine cells using DNA-transfection reagents. Following administration of the C and D proteases into normally refractory Neuro2A neuroblastoma cells, the SNARE proteins were cleaved with high efficiency within hours. Remarkably, botulinum protease exposures led to cytotoxicity evidenced by spectrophotometric assays and propidium iodide penetration into the nuclei. Direct delivery of SNARE fragments into the neuroblastoma cells reduced viability similar to botulinum proteases' application. We observed synergistic cytotoxic effects of the botulinum proteases, which may be explained by the release and interaction of soluble SNARE fragments. We show for the first time that previously observed cytotoxicity of botulinum neurotoxins/C in neurons could be achieved in cells of neuroendocrine origin with implications for medical uses of botulinum preparations.

• SNARE
• botulinum
• cytotoxicity
• neuro2A
• syntaxin
• transfection reagents

• Antineoplastic Agents, Hormonal/therapeutic use
• Biomarkers, Tumor/metabolism
• Diagnosis, Differential
• Female
• Humans
• Incidence
• Insulinoma/diagnosis
• Insulinoma/mortality
• Male
• Mutation
• Neoplasm Staging
• Nesidioblastosis/diagnosis
• Nesidioblastosis/mortality
• Neuroendocrine Tumors/diagnosis
• Neuroendocrine Tumors/mortality
• Neuroendocrine Tumors/pathology
• Neuroendocrine Tumors/therapy
• Pancreatic Neoplasms/diagnosis
• Pancreatic Neoplasms/mortality
• Pancreatic Neoplasms/pathology
• Pancreatic Neoplasms/therapy
• Proto-Oncogene Proteins/metabolism
• United States/epidemiology
• Zollinger-Ellison Syndrome/diagnosis
• Zollinger-Ellison Syndrome/mortality

• Biopsy
• Diagnosis, Differential
• Diazoxide/adverse effects
• Diazoxide/therapeutic use
• Female
• Humans
• Insulinoma/drug therapy
• Pancreatic Neoplasms/diagnosis
• Pancreatic Neoplasms/drug therapy
• Thrombocytopenia/chemically induced
• Thrombocytopenia/diagnosis
• Tomography, X-Ray Computed
• Vasodilator Agents/adverse effects
• Vasodilator Agents/therapeutic use
• Young Adult

• glucagonoma
• neuroendocrine tumors
• necrolytic migratory erythema

• immunohistochemistry
• islet cell neoplasia
• nonhuman primate

• Adenoma, Islet Cell/complications
• Adenoma, Islet Cell/pathology
• Adenoma, Islet Cell/veterinary
• Animals
• Aotidae
• Male
• Monkey Diseases/pathology
• Pancreatic Neoplasms/complications
• Pancreatic Neoplasms/pathology
• Pancreatic Neoplasms/veterinary
• Pulmonary Embolism/etiology
• Pulmonary Embolism/pathology
• Pulmonary Embolism/veterinary

• Y99 AI999999 NIAID NIH HHS
• Z99 AI999999 Intramural NIH HHS

Precise cellular targeting of macromolecular cargos has important biotechnological and medical implications. Using a recently established ‘protein stapling’ method, we linked the proteolytic domain of botulinum neurotoxin type A (BoNT/A) to a selection of ligands to target neuroendocrine tumor cells. The botulinum proteolytic domain was chosen because of its well-known potency to block the release of neurotransmitters and hormones. Among nine tested stapled ligands, the epidermal growth factor was able to deliver the botulinum enzyme into pheochromocytoma PC12 and insulinoma Min6 cells; ciliary neurotrophic factor was effective on neuroblastoma SH-SY5Y and Neuro2A cells, whereas corticotropin-releasing hormone was active on pituitary AtT-20 cells and the two neuroblastoma cell lines. In neuronal cultures, the epidermal growth factor- and ciliary neurotrophic factor-directed botulinum enzyme targeted distinct subsets of neurons whereas the whole native neurotoxin targeted the cortical neurons indiscriminately. At nanomolar concentrations, the retargeted botulinum molecules were able to inhibit stimulated release of hormones from tested cell lines suggesting their application for treatments of neuroendocrine disorders.

• SNAP25
• botulinum
• growth factor
• neuroendocrine tumor
• neuropeptide
• targeting

• Clinical practice patterns
• Gastrointestinal cancers
• Health economics
• Neuroendocrine tumors
• Resource utilization

• Antineoplastic Agents/pharmacology
• Biomarkers, Tumor
• Disease Progression
• Hospitalization
• Humans
• Medical Oncology/standards
• Medical Oncology/trends
• Multivariate Analysis
• Neoplasm Metastasis
• Neuroendocrine Tumors/therapy
• Poisson Distribution
• Practice Patterns, Physicians'
• United States

• Adult
• Body Mass Index
• Female
• Humans
• Laparoscopy
• Male
• Middle Aged
• Neuroendocrine Tumors/genetics
• Neuroendocrine Tumors/surgery
• Pancreatectomy
• Pancreatic Fistula/etiology
• Pancreatic Neoplasms/genetics
• Pancreatic Neoplasms/surgery
• Pancreaticoduodenectomy
• Postoperative Complications
• Retrospective Studies
• Treatment Outcome

• Y99 CA999999 NCI NIH HHS
• Z99 CA999999 Intramural NIH HHS