Gastroenteropancreatic neuroendocrine neoplam (GEP-NEN) is a rare group of tumors with its incidence rising significantly in recent decades. Because of the late presentation of the disease and limitations in conventional biomarkers, about 50% of GEP-NEN patients manifests advanced disease when diagnosed. Therefore, it is vital to identify circulating biomarkers which can not only be used for early diagnosis but also accurately evaluating the biological behavior of GEP-NEN. This review summarizes the advances of circulating biomarkers in diagnosing and evaluating efficacy of treatment in GEP-NEN. Well-known circulating biomarkers include chromogranin A (CgA), pancreastatin (PST), chromogranin B (CgB), neuron-specific enolase (NSE) and pancreatic peptide(PP). Novel biomarkers including circulating tumor cell(CTC), microRNA and NETest are promising biomarkers with potential clinical benefit, but further researches are needed before their clinical applications.
Biomarkers, Tumor ; blood ; Chromogranin A ; blood ; Chromogranin B ; blood ; chemistry ; Gastrointestinal Neoplasms ; blood ; chemistry ; diagnosis ; genetics ; Humans ; MicroRNAs ; blood ; Neoplastic Cells, Circulating ; Neuroendocrine Tumors ; blood ; chemistry ; diagnosis ; genetics ; Pancreatic Neoplasms ; blood ; chemistry ; diagnosis ; genetics ; Pancreatic Polypeptide ; blood ; Phosphopyruvate Hydratase ; blood

BACKGROUND AND OBJECTIVES: Type 1 Diabetes Mellitus (T1DM) is an autoimmune disorder resulting out of T cell mediated destruction of pancreatic beta cells. Immunomodulatory properties of mesenchymal stem cells may help to regenerate beta cells and/or prevent further destruction of remnant, unaffected beta cells in diabetes. We have assessed the ability of umbilical cord derived MSCs (UCMSCs) to differentiate into functional islet cells in vitro. METHODS AND RESULTS: We have isolated UCMSCs and allowed sequential exposure of various inducing agents and growth factors. We characterized these cells for confirmation of the presence of islet cell markers and their functionality. The spindle shaped undifferentiated UCMSCs, change their morphology to become triangular in shape. These cells then come together to form the islet like structures which then grow in size and mature over time. These cells express pancreatic and duodenal homeobox -1 (PDX-1), neurogenin 3 (Ngn-3), glucose transporter 2 (Glut 2) and other pancreatic cell markers like glucagon, somatostatin and pancreatic polypeptide and lose expression of MSC markers like CD73 and CD105. They were functionally active as demonstrated by release of physiological insulin and C-peptide in response to elevated glucose concentrations. CONCLUSIONS: Pancreatic islet like cells with desired functionality can thus be obtained in reasonable numbers from undifferentiated UCMSCs in vitro. This could help in establishing a "very definitive source" of islet like cells for cell therapy. UCMSCs could thus be a game changer in treatment of diabetes.
C-Peptide ; Cell- and Tissue-Based Therapy* ; Diabetes Mellitus, Type 1 ; Genes, Homeobox ; Glucagon ; Glucose ; Glucose Transport Proteins, Facilitative ; Insulin* ; Insulin-Secreting Cells ; Intercellular Signaling Peptides and Proteins ; Islets of Langerhans ; Mesenchymal Stromal Cells* ; Pancreatic Polypeptide ; Somatostatin ; Stem Cells ; Umbilical Cord*

Prostate stem cell antigen (PSCA) is a glycosylphosphatidylinositol-anchored cell surface antigen with an organ-dependent expression pattern in cancers; e.g., up-regulated in prostate cancer and down-regulated in gastric cancer. Previously it was reported that PSCA is not expressed in the normal pancreas but aberrantly expressed in pancreatic cancer. In this present study, we identified PSCA expression in islets of the pancreas by immunohistochemistry, which was co-localized with four islet-cell markers: insulin, glucagon, somatostatin and pancreatic polypeptide. In our investigation of the transcription start site of PSCA, we found a non-coding splicing variant of PSCA as well as authentic PSCA transcripts in mRNA samples from a normal pancreas. Both the transcripts were also identified in several pancreatic cancer cell lines. We previously reported that PSCA expression is correlated to the methylation status of the enhancer region in gastric and gallbladder cancer cell lines but not in pancreatic cancer cell lines, suggesting that PSCA expression is regulated in a diff erent mode in pancreatic cancer from that in gastric and gallbladder cancers.
Antigens, Surface ; Cell Line ; Gallbladder Neoplasms ; Glucagon ; Immunohistochemistry ; Insulin ; Islets of Langerhans ; Methylation ; Pancreas ; Pancreatic Neoplasms ; Pancreatic Polypeptide ; Prostate ; Prostatic Neoplasms ; RNA, Messenger ; Somatostatin ; Stem Cells ; Stomach Neoplasms ; Transcription Initiation Site

The prevalence of obesity has been rapidly increasing worldwide over the last several decades and has become a major health problem in developed countries. The brain, especially the hypothalamus, plays a key role in the control of food intake by sensing metabolic signals from peripheral organs and modulating feeding behaviors. To accomplish these important roles, the hypothalamus communicates with other brain areas such as the brainstem and reward-related limbic pathways. The adipocyte-derived hormone leptin and pancreatic beta-cell-derived insulin inform adiposity to the hypothalamus. Gut hormones such as cholecystokinin, peptide YY, pancreatic polypeptide, glucagon-like peptide 1, and oxyntomodulin transfer satiety signals to the brain and ghrelin relays hunger signals. The endocannabinoid system and nutrients are also involved in the physiological regulation of food intake. In this article, we briefly review physiological mechanisms of appetite regulation.
Adiposity ; Appetite ; Appetite Regulation ; Brain ; Brain Stem ; Cholecystokinin ; Developed Countries ; Eating ; Endocannabinoids ; Feeding Behavior ; Ghrelin ; Glucagon-Like Peptide 1 ; Hunger ; Hypothalamus ; Insulin ; Leptin ; Obesity ; Oxyntomodulin ; Pancreatic Polypeptide ; Peptide YY ; Prevalence

We report a case of giant pancreatic pseudocyst after acute pancreatitis, successfully treated with saikokeishitokabushi. A 71-year-old man had been undergoing treatment in our hospital for cerebral infarction and diabetes. He was complicated with acute pancreatitis. He received conservative treatment, showing a tendency toward symptomatic improvement, although abdominal pain and anorexia subsequently developed. A giant pancreatic pseudocyst was identified on abdominal computed tomography. Therefore, we administered saikokeishitokabushi without changing the other oral medication. Many of his symptoms disappeared, and cyst reduction was noted. saikokeishitokabushi is generally prescribed for epigastric pain or anorexia after febrile illness. In this case, it is thought that saikokeishitokabushi exhibited an action leading to cyst reduction.
Acute pancreatitis ; Large ; Treated with ; Reduction (chemical) ; Pancreatic polypeptide, avian

Neuropeptide Y (NPY) receptors are present in cardiac membranes. However, its physiological roles in the heart are not clear. The aim of this study was to define the direct effects of pancreatic polypeptide (PP) on atrial dynamics and atrial natriuretic peptide (ANP) release in perfused beating atria. Pancreatic polypeptides, a NPY Y4 receptor agonist, decreased atrial contractility but was not dose-dependent. The ANP release was stimulated by PP in a dose-dependent manner. GR 23118, a NPY Y4 receptor agonist, also increased the ANP release and the potency was greater than PP. In contrast, peptide YY (3-36) (PYY), an NPY Y2 receptor agonist, suppressed the release of ANP with positive inotropy. NPY, an agonist for Y1, 2, 5 receptor, did not cause any significant changes. The pretreatment of NPY (18-36), an antagonist for NPY Y3 receptor, markedly attenuated the stimulation of ANP release by PP but did not affect the suppression of ANP release by PYY. BIIE0246, an antagonist for NPY Y2 receptor, attenuated the suppression of ANP release by PYY. The responsiveness of atrial contractility to PP or PYY was not affected by either of the antagonists. These results suggest that NPY Y4 and Y2 receptor differently regulate the release of atrial ANP.
Animals ; Arginine/analogs & derivatives/pharmacology ; Atrial Natriuretic Factor/*metabolism ; Benzazepines/pharmacology ; Gene Expression Regulation ; Pancreatic Polypeptide/pharmacology ; Peptide YY/pharmacology ; Rats ; Rats, Sprague-Dawley ; Receptors, Neuropeptide Y/agonists/antagonists & inhibitors/*metabolism

The density of intestinal endocrine cells, in Balb/c mice with colon 26 (CT-26) carcinoma cells, were examined immunohistochemically at 28 days after implantation. After CT-26 cell administration there was a significant decrease in most of the intestinal endocrine cells (p < 0.01) compared with the control group. The significant quantitative changes in the intestinal endocrine cell density might contribute to the development of the gastrointestinal symptoms commonly encountered in cancer patients.
Animals ; Enteroendocrine Cells/metabolism/*pathology ; Female ; Gastrointestinal Tract/pathology ; Glucagon/metabolism ; Mice ; Mice, Inbred BALB C ; Neoplasm Transplantation ; Neoplasms, Experimental/metabolism/*pathology ; Pancreatic Polypeptide/metabolism ; Serotonin/metabolism ; Sincalide/metabolism ; Somatostatin/metabolism

A 65-year-old man was referred to our hospital in April 2003 with a pancreas tumor detected by a thorough medical checkup. Computed tomography (CT) showed swelling of the pancreatic body and tail, and magnetic resonance cholangiopancreatography (MRCP) showed only the main pancreatic duct in the head of the pancreas. Diagnosing autoimmune pancreatitis, we observed the patient without medication. However, one year later CT showed stenosis of the splenic artery and portal vein accompanied by development of collateral circulation around the pancreas. He had no symptoms, and CT showed no changes in the pancreatic swelling.;;He was admitted to our hospital on January 6, 2005, presenting with a history of jaundice which first appeared on January 1, 2005, and increased collateral circulation around the pancreas with pancreatic swelling were seen on CT. We started prednisolone therapy at 40 mg/day for exacerbation of autoimmune pancreatitis. Serum bilirubin levels improved from 11.9 mg/dl to 2.5 mg/dl, and pancreatic swelling also improved four weeks after starting therapy.;;We present a rare case of autoimmune pancreatitis that developed marked collateral circulations.
X-Ray Computed Tomography ; Pancreatitis ; Collateral Circulation ; Pancreatic polypeptide, avian ; Swelling

The distributions and frequencies of some endocrine cells in the gastrointestinal (GI) tract of ddY mice were studied with immunohistochemical method using 7 types of antisera against bovine chromogranin (BCG), serotonin, gastrin, cholecystokinin (CCK)-8, somatostatin, glucagon and human pancreatic polypeptide (HPP). All of 7 types of immunoreactive (IR) cells were identified. Most of IR cells in the intestinal portion were generally spherical or spindle in shape (open typed cell) while cells showing round in shape (close typed cell) were found in the intestinal gland and stomach regions occasionally. Their relative frequencies were varied according to each portion of GI tract. BCG-IR cells were demonstrated throughout whole GI tract except for the cecum and they were most predominant in the fundus and pylorus. Serotonin-IR cells were detected throughout whole GI tract and they were most predominant cell types in this species of mice. Gastrin-IR cells were restricted to the pylorus and CCK-8-IR cells were demonstrated in the pylorus, duodenum and jejunum with numerous frequencies in the pylorus. Somatostatin-IR cells were detected throughout whole GI tract except for the cecum and rectum and they showed more numerous frequencies in the stomach regions. In addition, glucagon-IR cells were restricted to the fundus, duodenum and jejunum with rare frequencies, and HPP-IR cells were restricted to the rectum only with rare frequency. In conclusion, some strain-dependent unique distributional patterns of gastrointestinal endocrine cells were found in GI tract of ddY mice.
Animals ; Biological Markers/analysis ; Cholecystokinin/analysis ; Chromogranins/analysis ; Enteroendocrine Cells/*cytology/immunology ; Female ; Gastrins/analysis ; Glucagon/analysis ; Immunoenzyme Techniques ; Mice ; Pancreatic Polypeptide/analysis ; Protein Precursors/analysis ; Serotonin/analysis

PURPOSE: This study was designed to delineate the anatomical details of the pancreatic head for a ventral or dorsal segmental pancreatic resection along the embryological fusion plane, and to determine the feasibility of both procedures. METHODS: The resected pancreaticoduodenectomy specimens were analyzed (n=8), with the pancreatic and distal common bile ducts visualized by pancreatography (n=8). Immunohistochemical staining, with pancreatic polypeptide (PP), was performed in serially sliced specimens (n=3). The immunohistochemical and H&E staining were performed to evaluate the composition of the anatomical structures of the two differentially stained pancreas. RESULTS: What was presumed to be the embryological fusion plane was discovered between two differentially stained segments. This started just above the anterior inferior pancreaticoduodenal artery, directed to the posterior superior part of the pancreatic head and ended at the anterior surface of the distal common bile duct. The duct of Wirsung and the distal common bile duct were included in the posterior segment of the pancreas (ventral pancreas). There were two types of pancreatic duct arrangement, with the differences between the two types being; (1) the distance between the fusion point of the ventral and dorsal pancreatic ducts and the papilla of Vater, and (2) the stream of the Santorini duct. The branches of the pancreatic ducts were scattered over the entire pancreatic head region in multiple-directions. CONCLUSION: The fusion plane of the ventral and dorsal pancreas seems to initiate just above the anterior inferior pancreaticoduodenal artery, in a posterior-superior direction along the anterior surface of the distal common bile duct. A ventral pancreatectomy seems an impractical procedure with regard to the postoperative morbidity and operative difficulty, while a dorsal pancreatectomy seems to be more practical and feasible in its clinical aspects.
Arteries ; Common Bile Duct ; Head* ; Pancreas ; Pancreatectomy ; Pancreatic Ducts ; Pancreatic Polypeptide ; Pancreaticoduodenectomy ; Rivers