Long-Term Safety of Delayed Surgery After Upfront Endoscopic Resection for Early Gastric Cancer: A Propensity Matched Study.

BACKGROUND: When non-curative resection is confirmed after endoscopic resection (ER) of early gastric cancer (EGC), delayed surgery is recommended because it provides favorable survival outcomes. Long-term outcome after surgery of EGC with or without previous ER has not been evaluated. OBJECTIVE: The aim of this study was to compare the long-term oncologic safety between primary surgery and delayed surgery after ER. METHODS: Patients who had undergone curative surgery (R0) for EGC were included and were divided into primary and delayed surgery groups. Primary surgery was defined as gastrectomy without ER for EGC, whereas delayed surgery was defined as additional curative gastrectomy due to non-curative resection after ER; an average delay of 21.5 days (range 1-195) was observed. Propensity score matching was performed. The primary outcome was overall survival (OS) and the secondary outcomes were cancer-specific survival (CSS) and disease-free survival (DFS). RESULTS: After propensity score matching, 1439 patients were included, of whom 1042 (72.4%) were in the primary surgery group and 397 (27.6%) were in the delayed surgery group. The OS (hazard ratio [HR] 0.87, 95% confidence interval [CI] 0.59-1.27; p = 0.459), CSS (HR 0.47, 95% CI 0.15-1.47; p = 0.196), and DFS (HR 0.54, 95% CI 0.15-1.90; p = 0.334) were not different. CONCLUSIONS: The long-term outcomes of delayed surgery after non-curative ER for EGC were non-inferior to primary surgery. Therefore, an attempt for ER of EGC that satisfies the absolute and expanded indication seems justified for preventing gastrectomy. In case of non-curative resection after ER, additional delayed surgery should be performed.

ß-cell serotonin production is associated with female sex, old age, and diabetes-free condition.

Serotonin is known to be present in pancreatic ß-cells and to play several physiological roles, including insulin secretion, ß-cell proliferation, and paracrine inhibition of α-cells. However, the serotonin production of different cell lines and islets has not been compared based on age, sex, and diabetes related conditions. Here, we directly compared the serotonin concentrations in ßTC and MIN6 cell lines, as well as in islets from mice using ultra-performance liquid chromatography tandem mass spectrometry. The average serotonin concentration was 5-10 ng/mg protein in the islets of male and non-pregnant female mice. The serotonin level was higher in females than males at 8 weeks, although there was no difference at 1 year. Furthermore, we observed serotonin by immunofluorescence staining in the pancreatic tissues of mice and human. Serotonin was detected by immunofluorescence staining in a portion of ß-cells from islets of old female mice, but not of male or young female mice. A similar pattern was observed in human pancreas as well. In humans, serotonin production in ß-cells was associated with a diabetes-free condition. Thus, serotonin production in ß-cells was associated with old age, female sex, and diabetes-free condition.

Clinical characteristics of the responders to dipeptidyl peptidase-4 inhibitors in Korean subjects with type 2 diabetes.

We investigated characteristics associated with the efficacy of dipeptidyl peptidase-4 inhibitors (DPP4i) in Korean patients with type 2 diabetes. We reviewed medical records of 477 patients who had taken sitagliptin or vildagliptin longer than 40 weeks. Response to DPP4i was evaluated with HbA1c change after therapy (ΔHbA1c). The Student's t-test between good responders (GR: ΔHbA1c > 1.0%) and poor responders (PR: ΔHbA1c < 0.5%), a correlation analysis among clinical parameters, and a linear multivariate regression analysis were performed. The mean age was 60 yr, duration of diabetes 11 yr and HbA1c was 8.1%. Baseline fasting plasma glucose (FPG), HbA1c, C-peptide, and creatinine were significantly higher in the GR compared to the PR. Duration of diabetes, FPG, HbA1c, C-peptide and creatinine were significantly correlated with ΔHbA1c. In the multivariate analysis, age (r(2) = 0.006), duration of diabetes (r(2) = 0.019), HbA1c (r(2) = 0.296), and creatinine levels (r(2) = 0.024) were independent predictors for the response to DPP4i. Body mass index and insulin resistance were not associated with the response to DPP4i. In conclusion, better response to DPP4i would be expected in Korean patients with type 2 diabetes who have higher baseline HbA1c and creatinine levels with shorter duration of diabetes.

Serotonin Regulates Adult ß-Cell Mass by Stimulating Perinatal ß-Cell Proliferation.

A sufficient ß-cell mass is crucial for preventing diabetes, and perinatal ß-cell proliferation is important in determining the adult ß-cell mass. However, it is not yet known how perinatal ß-cell proliferation is regulated. Here, we report that serotonin regulates ß-cell proliferation through serotonin receptor 2B (HTR2B) in an autocrine/paracrine manner during the perinatal period. In ß-cell-specific Tph1 knockout (Tph1 ßKO) mice, perinatal ß-cell proliferation was reduced along with the loss of serotonin production in ß-cells. Adult Tph1 ßKO mice exhibited glucose intolerance with decreased ß-cell mass. Disruption of Htr2b in ß-cells also resulted in decreased perinatal ß-cell proliferation and glucose intolerance in adulthood. Growth hormone (GH) was found to induce serotonin production in ß-cells through activation of STAT5 during the perinatal period. Thus, our results indicate that GH-GH receptor-STAT5-serotonin-HTR2B signaling plays a critical role in determining the ß-cell mass by regulating perinatal ß-cell proliferation, and defects in this pathway affect metabolic phenotypes in adults.

Oral Glucose Tolerance Testing Allows Better Prediction of Diabetes in Women with a History of Gestational Diabetes Mellitus.

BACKGROUND: We aimed to identify the postpartum metabolic factors that were associated with the development of diabetes in women with a history of gestational diabetes mellitus (GDM). In addition, we examined the role of the oral glucose tolerance test (OGTT) in the prediction of future diabetes. METHODS: We conducted a prospective study of 179 subjects who previously had GDM but did not have diabetes at 2 months postpartum. The initial postpartum examination including a 75-g OGTT and the frequently sampled intravenous glucose tolerance test (FSIVGTT) was performed 12 months after delivery, and annual follow-up visits were made thereafter. RESULTS: The insulinogenic index (IGI30) obtained from the OGTT was significantly correlated with the acute insulin response to glucose (AIRg) obtained from the FSIVGTT. The disposition indices obtained from the OGTT and FSIVGTT were also significantly correlated. Women who progressed to diabetes had a lower insulin secretory capacity including IGI30, AIRg, and disposition indices obtained from the FSIVGTT and OGTT compared with those who did not. However, the insulin sensitivity indices obtained from the OGTT and FSIVGTT did not differ between the two groups. Multivariate logistic regression analysis showed that the 2-hour glucose and disposition index obtained from the FSIVGTT were significant postpartum metabolic risk factors for the development of diabetes. CONCLUSION: We identified a crucial role of ß-cell dysfunction in the development of diabetes in Korean women with previous GDM. The 2-hour glucose result from the OGTT is an independent predictor of future diabetes. Therefore, the OGTT is crucial for better prediction of future diabetes in Korean women with previous GDM.

Generation of a highly efficient and tissue-specific tryptophan hydroxylase 1 knockout mouse model.

Recent studies on tissue-autonomous serotonin (5-hydroxytryptamine [5-HT]) function have identified new roles for 5-HT in peripheral organs. Most of these studies were performed by crossing mice carrying the Tph1tm1Kry allele with tissue specific Cre mice. In the present study, we found that 5-HT production was not completely abolished in Tph1tm1Kry KO mice. The residual 5-HT production in Tph1tm1Kry KO mice is attributed to the expression of a truncated form of TPH1 containing the catalytic domain. Hence, in an effort to obtain mice with a Tph1 null phenotype, we generated mice harboring a new Tph1 floxed allele, Tph1tm1c, targeting exons 5 and 6 which encode the catalytic domain of TPH1. By crossing the new Tph1 floxed mice with villin-Cre or insulin-Cre mice, we observed near-complete ablation of 5-HT production in the intestine and ß cells. In conclusion, this improved Tph1 floxed mouse model will serve as useful and accurate tool for analyzing peripheral 5-HT system.

Efficacy and safety of the addition of a dipeptidyl peptidase-4 inhibitor to insulin therapy in patients with type 2 diabetes: A systematic review and meta-analysis.

AIMS: To compare the efficacy and safety of the addition of a dipeptidyl peptidase-4 (DPP-4) inhibitor or a placebo in patients with type 2 diabetes inadequately controlled with insulin. METHODS: We searched randomised controlled trials (RCTs) from MEDLINE, EMBASE, LILACS, the Cochrane Central Register of Controlled Trials and the ClinicalTrials.gov online registry. Studies of at least 12week treatment duration were eligible if they were RCTs in patients with type 2 diabetes comparing addition of a DPP-4 inhibitor to insulin therapy (INS/DPP4i) with addition of a placebo to insulin therapy (INS/PCB) and contained information on the change in glycated haemoglobin (HbA1c) from baseline. RESULTS: Of 3105 potentially relevant published articles and 206 registered trials, 9 studies were included for meta-analysis. Compared to INS/PCB, INS/DPP4i exhibited a greater reduction in HbA1c (weighted mean difference [WMD] -0.58%; 95% CI -0.70, -0.46) and fasting plasma glucose (WMD -0.59mmol/L; 95% CI -0.79, -0.40) with less daily insulin doses (WMD -1.86IU; 95% CI -3.27, -0.45) and with no difference in weight gain (WMD -0.04kg; 95% CI -0.25, 0.16). The risk of hypoglycaemia was similar between INS/DPP-4i and INS/PCB (the RR in favour of INS/PCB was 0.94; 95% CI 0.84, 1.05). CONCLUSIONS: Compared to placebo, DPP-4 inhibitors exhibit a better glycaemic control without further increasing the risk of weight gain and hypoglycaemia in patients with type 2 diabetes inadequately controlled with insulin.

Expression mechanism of tryptophan hydroxylase 1 in mouse islets during pregnancy.

Serotonin signaling plays key roles in augmentation of pancreatic ß-cell function during pregnancy. Increased expression of tryptophan hydroxylase 1 (Tph1), a rate-limiting enzyme for serotonin synthesis by lactogenic hormones, is involved in this phenomenon. To investigate its mechanisms, we here performed 5'-RACE and identified ß-cell-specific transcription initiation sites for Tph1. Prolactin enhanced the expression of mRNA containing these exons; however, reporter gene plasmids containing the proximal 5'-flanking region of these exons did not show prolactin responsiveness in MIN6 cells. Prolactin-induced Tph1 expression was inhibited by a Jak2 inhibitor and was partially inhibited by an MEK1/2 or PI3K inhibitor. Therefore, we analyzed interferon γ-activated sequences (GAS) and found GAS-A about 9-kbp upstream of the transcription start site. The reporter gene plasmid containing the GAS-A region linked to a heterologous promoter showed increased promoter activity by prolactin, which was inhibited by the forced expression of a dominant-negative mutant form of Stat5A and a Jak2 inhibitor. Chromatin immunoprecipitation analysis showed that prolactin treatment augmented Stat5 binding to the GAS-A region in MIN6 cells, as well as in isolated mouse islets, and that Stat5 recognized the GAS-A region in pregnant mouse islets. In addition, the transactivation activity of Stat5 was enhanced by prolactin through the Erk and PI3K pathways in MIN6 cells. Finally, serotonin expression was attenuated in islets of ß-cell-specific Stat5-deficient mice compared with that of control littermates during pregnancy. Our findings suggest that prolactin-induced Tph1 expression is mediated by the activation of Jak2/Stat5, Erk, and PI3K pathways in ß cells.

Transformation of nonfunctioning pancreatic neuroendocrine carcinoma cells into insulin producing cells after treatment with sunitinib.

We report a rare case of severe hypoglycemia after sunitinib treatment for pancreatic neuroendocrine carcinoma. We describe the initial clinical presentation, laboratory results, pathologic findings, and managment in a patient with a nonfunctioning pancreatic neuroendocrine carcinoma with liver metastases who developed life threatening hypoglycemia after 2 months of sunitinib therapy. A 46-year-old woman presented to the emergency department with loss of consciousness from hypoglycemia. Serum C-peptide and insulin levels at fasting state revealed that the hypoglycemia resulted from endogenous hyperinsulinemia. She had been diagnosed with nonfunctioning pancreatic neuroendocrine carcinoma based on a biopsy of metastatic cervical lymph node and was being treated with sunitinib, a small molecule tyrosine kinase inhibitor. Immunohistochemical stain of the metastatic liver mass demonstrated that the initially nonfunctioning neuroendocrine carcinoma cells had changed into insulin-producing cells after sunitinib therapy. Transarterial chemoembolization of the liver masses and systemic chemotherapy with streptozotocin/adriamycin relieved the hypoglycemia. A nonfunctioning pancreatic neuroendocrine carcinoma was transformed into an insulin-producing tumor after treatment with sunitinib, causing endogenous hyperinsulinemia and severe hypoglycemia.