Relationship between the changes of plasma levels of leptin and obesity in patients with insulinoma / 中华消化杂志

Objective To analyze the relationship between the changes of fasting plasma level of leptin and obesity in patients with insulinoma before operation.Methods From January 2003 to May 2008,40 patients with insulinoma diagnosed at Peking Union Medical College Hospital were selected.Preoperative fasting plasma samples of them were collected.From January 2003 to May 2008,the plasma samples of 28 volunteers matched with age,gender and body weight matched with the patients were collected as the controls.All the subjects were divided into overweight-obesity group and normal weight group according to their body mass index (BMI).Plasma levels of leptin of all the subjects were measured by enzyme linked immunosorbent assay (ELISA).The Mann-Whitney U test and the correlation coefficient test were used for statistical analysis.Results The plasma leptin level of patients with insulinoma was 0.35 ng/mL (0.25 ng/mL to 1.13 ng/mL),which was higher than that of the control group (0.29 ng/mL,0.25 ng/mL to 1.15 ng/mL),and the difference was statistically significant (U =324.50,P =0.003).In the normal-weight group,the plasma leptin level of the patients with insulinoma was 0.35 ng/mL (0.27 ng/mL to 0.62 ng/mL),which was higher than that of the control group (0.28 ng/mL,0.25 ng/mL to 0.37 ng/mL),and the difference was statistically significant (U =28.000,P =0.001).While in the overweight-obesity group,the plasma leptin levels of the patients with insulinoma and the controls were 0.35 ng/mL (0.25 ng/mL to 1.13 ng/mL) and 0.34 ng/mL (0.26 ng/mL to 1.15 ng/mL),respectively,and the difference was not statistically significant (U =153.500,P =0.525).Plasma leptin levels in both the patients with insulinoma and the controls,were correlated with BMI (r =0.355,P =0.025;r =0.571,P =0.001,respectively).Conclusion Preoperative fasting plasma level of leptin increase in patients with insulinoma which is correlated with BMI.

Expression of microtubule-associated protein 2 correlates with better prognosis of pancreatic neuroendocrine tumors / 中国肿瘤临床

Objective: To determine whether microtubule-associated protein 2 (MAP2) and microtubule-associated protein 1B (MAP1B) could be prognostic biomarkers for patients with pancreatic neuroendocrine tumors (PNETs). Methods:With immunohisto-chemical staining, the expressions of MAP2 and MAP1B were examined in 193 and 120 primary tumors and peritumoral tissues, re-spectively. Then, the relationship between the expression of each protein and clinicopathological characteristics, including prognosis was analyzed. Results:MAP2 and MAP1B were expressed in 88 of 193 (45.6%) and 77 of 120 (64.2%) tumors, respectively. The expres-sion of MAP2 was significantly associated with the favorable overall survival of patients with PNETs (P=0.012). Moreover, MAP2 expres-sion was associated with the improved overall survival in a subset of patients with stageⅡand stageⅢtumors (P=0.017). The MAP1B expression did not correlate with other clinicopathological features and prognosis. Conclusion:MAP2 could be a novel, independent prognostcbiomarker for PNETs.

Basic and translational research progress of gastrointestinal neuroendocrine neoplasmas / 中华胃肠外科杂志

Gastrointestinal neuroendocrine tumors are a group of highly heterogeneous tumors. Their incidences have increased in the Western countries as well as in Asia for years. In recent years, predominant progression has been made in the basic and translational studies on gastrointestinal neuroendocrine tumors. Gastric neuroendocrine neoplasmas are classified as four types: type I( occurs on the basis of autoimmune atrophic gastritis, type II( clinically manifests as multiple endocrine tumor type I( and Zollinger-Ellison syndrome, type III( is sporadic neuroendocrine neoplasmas, and type IIII( is neuroendocrine carcinoma. According to the location of primary tumor, intestinal neuroendocrine neoplasmas are classified as small intestine neuroendocrine neoplasmas and colorectal neuroendocrine neoplasmas. The latest finding shows that familial type I( gastric neuroendocrine neoplasmas exists homozygous missense mutation (c.2107C>T) of ATP4A gene. A number of researches focus on small intestine neuroendocrine neoplasmas recently. The chromosome instability, whole genome low methylation and abnormal expression of microRNA can be found in small intestine neuroendocrine neoplasmas. Part of them presents heterozygous mutations and loss of heterozygosity of CDKN1B gene. A recent study showed the heterozygous mutations of IPMK gene (c.990-993del) in familial small intestinal neuroendocrine neoplasmas. PROX1 and Annexin A1 may be involved in the malignant progression of rectal neuroendocrine neoplasmas via the Wnt pathway. The molecular mechanism of gastrointestinal neuroendocrine carcinoma is significantly different from gastrointestinal neuroendocrine tumors. The expression of mTOR, thymidylate synthase and PD-L1 protein, and gene mutation of BRAF V600E and KRAS have been exclusively found in gastrointestinal neuroendocrine carcinoma. The expression of thymidylate synthase, p27, p16, Gα15, PROX1 and Annexin A1 in gastrointestinal neuroendocrine neoplasmas is associated with the prognosis of these patients. Neurokinin A is a specific peripheral blood tumor biomarker for the prognosis and response to the treatment of patients with small intestinal neuroendocrine neoplasmas. INSL5 can be used as a unique biomarker for rectal neuroendocrine neoplasmas.

Expression of neuronal intermediate filament protein (NF-66) and relationship with benign and malignancy of insulinomas / 中华胰腺病杂志

ObjectiveTo investigate whether neuronal intermediate filament protein(NF-66) could be used as a molecular marker for the determination of malignancy of insulinoma.MethodsThe expression of NF-66 protein was detected in insulinoma and pana - cancerous tissues and 3 insulinoma cell lines by immunohistochemistry staining. The relationship between the expression of NF-66 protein and the clinicopathological characteristics,survival was analyzed by univariate and multivariate statistical analysis.ResultsExpression of NF-66 was found in 102(77％ ) out of 132 insulinomas and none of 98 paired control (P =4.86 × 10-31 ).NF-66 was highly expressed in 3 insulinoma cell lines.The expression of NF-66 was found in 96 (81％) out of 118 benign tumors (P =0.003),while out of 14 malignant insulinomas,6(43％ ) were found to express NF-66 ( P =0.003 ).The expression of NF-66 was significantly associated with tumor size (3 cm as the cut-off point),distant metastasis (38％ vs 81％,P =0.013) and distant plus lymph node metastasis (46％ vs 81％,P =0.009),respectively.The expression of NF-66 was not correlated with age,gender,recurrence and overall survival.ConclusionsDown-regulation of NF-66 was significantly associated with tumor malignancy,suggesting that NF-66 could be a potentially novel molecular bionarker to distinguish malignancy from benign insulinoma.

Occurrence of CpG island methylation phenotype and expression of p27 in insulinoma / 中华胰腺病杂志

ObjectiveTo study the expression of p27 and its relationship with CpG island methylation phenotype (CIMP) in insulinoma.MethodsExpression of p27 was tested in 27 insulinoma tissues and 11 paired control tissues by immunohistochemistry staining.CpG island methylation of p16,MLH1,RAR-β,MGMT,THBS1 (CIMP) was detected in 27 insulinoma tissues and 11 paired cantrol tissues by methylation specific PCR (MSP).The data of p27 and CIMP expression were correlated with the clinicopathological characteristics.ResultsThe positive expression rate of p27 in insulinoma tissues was significantly lower than that in paired control tissues (48％ vs 91％,P =0.008).High rate of CIMP occurrence in insulinoma tissues was 33％ (9/27),while it was 18％ (2/11) in paired control tissues,and difference between the two groups was not statistically significant ( P =0.350 ).The methylation of MGMT was reversely associated with p16 methylation ( P =0.004).p27 expression in insulinoma tissues was reversely associated high rate of CIMP occurrence but it was not statistically significant ( P =0.420).Neither the expression of p27 nor the occurrence of CIMP was associated with the clinicopathological features.ConclusionsDown-regulation of p27 and high rate of CIMP occurred in insulinomas,suggesting that the inactivation of p27 and epigenetic alterations of several genes might contribute to the carcinogenesis of insulinoma.

Expression of ghrelin and its receptor GHS-R 1A in pancreatic endocrine tumors and the plasma levels of ghrelin and leptin / 中华胰腺病杂志

Objective To study the plasma and intratumoral levels of ghrelin, leptin and their relationship and clinical significance in patients with pancreatic endocrine tumor.Methods Preoperative plasma levels of ghrelin and leptin were detected by ELISA in 11 patients with pancreatic endocrine tumors and 28 normal controls.Expressions of ghrelin and its receptor GHS-R 1A were tested in 11 tumors and 27 paired control tissues by immunohistochemistry staining, and they were correlated with the clinicopathological characteristics.Results The plasma levels of ghrelin was ( 16.0 ± 5.0) pg/ml, which was significantly lower than that in normal controls [ (21.0 ± 2.0) pg/ml, P = 0.047 ].The plasma levels of leptin was (0.34 ±0.03 ) ng/ml, which was not significantly different with that in normal controls [ 0.38 ± 0.04) ng/ml ].There was positive association between plasma levels of leptin and ghrelin (P =0.015 ), but was not associated with clinicopathological parameters.The plasma levels of leptin in control group was positively associated with BMI (P = 0.002), but they were not associated in patients with tumor.The expression rate of ghrelin in tumor tissue was significantly lower than that in control group (64% vs 100%, P = 0.004 ).But the expression rate of GHS-R I A was not significantly different between the two groups.The expression of ghrelin and GHS-R1A in tumor was not significantly associated with clinicopathological parameters.Conclusions The ghrelin and its receptor GHS-R 1A were extensively expressed in pancreatic endocrine tumors, and the serum levels of ghrelin and leptin was changed.

Expression and clinical implications of hMSH2 gene in sporadic insnlinomns / 中华胰腺病杂志

Objective To investigate the role of hMSH2 in the pathogenesis of sporadic insulinomas and to determine whether the expression of hMSH2 could be used to differentiate benign sporadic insulinomas from malignant ones. Methods Fifty-five sporadic insulinomas (40 benign and 15 malignant tumors) resected from 50 patients were obtained. Expression of hMSH2 was detected by immunohistochemistry staining. DNA was obtained from micradissected tissue. Loss of heterozygnsity (LOH) of hMSH2 gene was detected by PCR-LOH. 6 microsatellite markers were selected on 3 chromosomes, and microsatellite instability (MSI) status of tumor tissue were detected by PCR. The findings were analyzed in relation to the clinicopathological characteristics. Results Down-regulation of hMSH2 expression was found in 13% of 55 sporadic insulinomas. LOH of the hMSH2 gene was not present in 55 insulinomas. High frequency MSI (MSI-H, MSI occurred in at least 2 out of 6 sites) was present in 36% (20/55) of all the insulinomas. Down-regulation of hMSH2 expression was found in 33% of the 15 malignant tumors, while it was 5% in benign tumors (P < 0. 05). Conclusions Down-regulation of mismatch repair gene hMSH2 may be correlated with the degree of tumor malignancy. The expression of hMSH2 could be used as a potential marker for distinguishing benign insulinoma from malignant ones.

DNA demethylation of ARHI and cell apoptosis in pancreatic cancer / 中华胰腺病杂志

H1 gene inactivation.Demethylation agent inhibits human pancreatic cancer cell line growth in association with ARH1 re-expression and reduced p-stat3 expression.