Shih-Pei Huang

Interleukin-6 Increases Vascular Endothelial Growth Factor and Angiogenesis in Gastric Carcinoma

Interleukin-6 (IL-6) is a proinflammatory cytokine associated with the disease status of gastric carcinoma (GC). Vascular endothelial growth factor (VEGF) is a potent tumor angiogenic factor in GC. In this study, we attempted to clarify whether IL-6 can regulate VEGF and angiogenesis in GC. GC samples from 54 surgical specimens were subjected to immunohistochemical examination of IL-6, VEGF, and tumor microvessels, and results showed that IL-6 was positively correlated with VEGF expression and tumor vasculature. We determined VEGF expression in four GC cell lines by ELISA, revealing that GC cells can produce significant amount of VEGF with increasing dose and duration of IL-6 stimulation. Next, a luciferase reporter gene assay was employed to determine the signaling pathway driving the VEGF promoter by IL-6, which showed that the JAK/STAT pathway is involved in the stimulation of VEGF gene expression. The effects of IL-6 on angiogenesis in vitro and in vivo were evaluated by HUVEC studies and the Matrigel plug assay, respectively. Results showed that IL-6 effectively promoted HUVEC proliferation and tube formation in vitro and Matrigel plug vascularization in vivo, primarily by inducing VEGF in GC. This study provides evidence that the multifunctional cytokine, IL-6, may induce VEGF expression which increases angiogenesis in gastric carcinogenesis.

Tumor Necrosis Factor–α and Interleukin-10 Promoter Polymorphisms in Epstein-Barr Virus–Associated Gastric Carcinoma

To investigate whether genetic differences in cytokine promoter polymorphisms effect various outcomes after exposure to Epstein-Barr virus (EBV) infection, 30 patients with EBV-positive gastric carcinoma (GC), 120 patients with EBV-negative GC, and 220 control subjects were enrolled. Promoter polymorphisms of tumor necrosis factor (TNF)-alpha at positions -238 and -308 and of interleukin (IL)-10 at position -1082 were determined. The frequency of the high-producer allele (-308A) in the TNF-alpha gene was significantly higher among EBV-positive GC patients compared with control subjects (23.3% vs. 12.0%, P<.05), whereas the frequency of the high-producer allele (-1082G) in the IL-10 gene was significantly higher among EBV-negative GC patients compared with control subjects (6.3% vs. 3.0%, P<.05). These data support the notion that genetic factors may modify the outcomes of infectious diseases through different TNF-alpha- or IL-10-producing capabilities.

Prevalence and clinical characteristics of Barrett's esophagus in a Chinese general population.

Background The prevalence of Barrett esophagus (BE) remains elusive in the general populations. Goals The purpose of this study was to identify the prevalence and clinical characteristics of BE in a Chinese general population. Study Between June 2003 and December 2006, consecutive subjects were evaluated via upper gastrointestinal endoscopy during a routine health examination. Patients were evaluated for any abnormalities, including endoscopically suspected esophageal metaplasia (ESEM) and erosive esophagitis (EE). Biopsies were attained from patients with ESEM to confirm a diagnosis of BE. The demographic data and endoscopic findings were retrospectively analyzed. Results Of the 19,812 endoscopies performed, 56 patients (0.28%) were diagnosed with ESEM and 3129 patients (15.7%) with EE. Twelve of the 56 patients diagnosed with ESEM (0.06% of the total number of patients who underwent endoscopy) were confirmed to have BE after histologic analysis of the biopsies. Patients with BE were older than patients without BE (61.6 vs. 51.7 y), and only one of the 12 patients diagnosed with BE (8.3%) reported typical gastroesophageal reflux symptoms. A majority of the BE patients were categorized as short-segment BE (91.7%) and concomitant EE was found in 4 (33.3%). Smoking, alcohol, and metabolic disorders seemed to be associated with the presence of BE and EE. Conclusions The prevalence of BE in a Chinese general population was lower than that in other reported studies, particularly in comparison with the studies originating from Western countries. Patients with advanced age and metabolic disorders are risk factors for developing BE.

Comparative analysis between psychological and endoscopic profiles in patients with gastroesophageal reflux disease: A prospective study based on screening endoscopy

Background:  Associations between psychological and endoscopic profiles are not clearly validated among the heterogeneous patients with gastroesophageal reflux disease (GERD). The purpose of the present paper was therefore to identify any associations by means of cross‐sectional study.

Serum Interleukin-6 Level but not Genotype Predicts Survival after Resection in Stages II and III Gastric Carcinoma

Purpose: It has been suggested that interleukin-6 (IL-6) is a prognostic indicator for survival in patients with gastric carcinoma, but this has not been proved using survival analysis. In Asians, the −634G allele is associated with increased IL-6 production. The objective of this study was to evaluate the association between serum IL-6 levels, −634G/C polymorphism, and overall survival after resection for gastric carcinoma. Experimental Design: A total of 155 consecutive patients with gastric carcinoma were evaluated. Serum IL-6 levels were analyzed using an enzyme-linked immunoabsorbent assay. Genotype was determined by PCR and restriction fragment length polymorphism. Serum levels and survival were correlated with genotype and clinicopathologic factors. Results: Age and stage, but not −634G/C genotype, were associated with serum IL-6 levels. The median survival for patients with stage II or stage III gastric carcinoma was 1,418 days in patients with low (≤13 pg/mL) versus 618 days in patients with high (>13 pg/mL) serum IL-6 levels (P = 0.038). Results of a multivariate analysis showed that serum IL-6 level of >13 pg/mL was a significant predictor of poor survival (hazard ratio, 1.77; 95% confidence interval, 1.07-2.92; P = 0.026). Conclusions: Serum IL-6 level of >13 pg/mL correlates with tumor progression and is an independent predictor of poor survival after resection. In patients with stage II and III gastric carcinoma, serum IL-6 level is more effective than stage as a prognostic indicator. By measuring IL-6, these patients can be divided into two groups with significant differences in survival. The −634G/C polymorphism is not associated with serum IL-6 level or survival.

Correlation of histologic subtypes and replication error phenotype with comparative genomic hybridization in gastric cancer

To characterize phenotypic and genotypic changes in gastric cancer (GC), DNA copy number aberrations (CNAs) were assessed in 53 tumors using comparative genomic hybridization (CGH) and correlated with clinicopathologic characteristics and status of TP53 and replication error (RER). The number of CNAs per tumor was 6.8 (gain 5.3, loss 1.5), and the number of changes was significantly higher in tumors with advanced stage, TP53 mutation, and without RER than in those with early stage (7.7 vs. 3.0), no TP53 mutations (12.4 vs. 4.8) or RER phenotype (8.2 vs. 2.6). Frequent abnormalities included gains on chromosomal arms 8q (43%), 6q (26%), 11q (26%), 13q (24%), 7p (23%), 17q (23%), and 20q (23%), and losses on chromosomal arms 16q (26%), 19p (23%), 5q (19%), 3p (15%), 4q(15%), and 1p (15%). Advanced GC demonstrated a higher prevalence of gains of 8q (51% vs. 10%, P < 0.05) and loss of 16q (33% vs. 0%, P < 0.05) than early GC. Gains on 8q (64% vs. 20%, P < 0.05), 17q (39% vs. 4%, P < 0.05) and losses on 3p (25% vs. 4%, P = 0.05) and 5q (32% vs. 4%, P < 0.05) were higher in intestinal GC than in diffuse GC. On the other hand, gains on 13q were more common in the diffuse type (40% vs. 11%, P < 0.05). As compared with noncardia cancer, cardia cancer showed more gains on 7p (58% vs. 12%, P < 0.05) and 20q (58% vs. 12%, P < 0.05) and more losses on 4q (50% vs. 5%, P < 0.05). The finding of histology‐related aberrations and the combination of CGH and molecular data thus provide additional evidence suggesting genetic heterogeneity of GC.

A prospective study of the frequency and the topographical distribution of colon neoplasia in asymptomatic average-risk Chinese adults as determined by colonoscopic screening

BACKGROUND The goal of this study was to determine the frequency of colorectal neoplasia in an asymptomatic Taiwanese population and the topographic distribution of lesions relative to age and gender. METHODS Colonoscopy was performed in 1846 consecutive asymptomatic adults undergoing a health evaluation in 2003. Neoplastic lesions were considered advanced if they exceeded 10 mm in size, had a villous component, or contained moderately or severely dysplastic tissue or invasive cancer. Lesions at and proximal to the splenic flexure were considered proximal in location; those distal to the splenic flexure were classified as distal in location. RESULTS Of 1741 (94.3%) patients (1041 men, 700 women; mean 52.5 years) enrolled, 1708 (98.1%) underwent total colonoscopy. Of these patients, 263 (15.4%) had colorectal neoplasia; 51 (3.0%) had advanced lesions. A total of 331 lesions were detected; 125 (37.8%) were proximal in location. Two thirds of patients with proximal advanced lesions (66.7%, 10/15) had no distal lesion. The proportion of patients with proximal or proximal plus distal lesions increased with age ( p = 0.027). CONCLUSIONS Colonoscopy is an effective primary screening modality for colorectal neoplasia in asymptomatic Chinese patients. Many lesions would be missed, especially in the elderly, if only sigmoidoscopy was used for initial screening.

Promoter polymorphisms of tumor necrosis factor-alpha are associated with risk of gastric mucosa-associated lymphoid tissue lymphoma.

Genes involved in regulating antimicrobial immunity and inflammation may modulate the risk of Helicobacter pylori–associated diseases. IL‐1 and TNF‐α are major cytokines detected in H. pylori–infected tissues. We aimed to determine the role of gene polymorphisms for these cytokines and their receptors in 2 distinct H. pylori–related gastric malignancies, adenocarcinoma (GAC) and maltoma. Genotyping for IL‐1β (–31 C/T, –511 C/T), TNF‐α (–238 G/A, –308 G/A, –857 C/T, –863 C/A, –1031 T/C), TNFR1 (–383 A/C) and TNFR2 (196 G/T) was undertaken for 70 patients with maltoma and 204 patients with noncardia GAC and compared to 210 unrelated healthy controls. Genotype frequencies showed no differences among patients with GAC or maltoma and controls for IL‐1β, TNFR1 or TNFR2. The TNF‐α –857 T variant was significantly underrepresented in maltoma compared to controls (6.4% vs. 14.3%, p = 0.018), conferring a 3‐fold decrease in risk (OR = 0.33, 95% CI 0.15–0.75). Comparison of allele frequencies between GAC and controls failed to show any statistical significance for TNF‐α polymorphisms. We concluded that TNF‐α –857 T itself or a neighboring gene may modify the risk of maltoma. The differences in genetic background as well as divergent clinicopathologic features between GAC and maltoma support the notion that fundamental mechanistic differences exist in these 2 well‐defined H. pylori–related malignancies.

Correlation between serum levels of interleukin-6 and vascular endothelial growth factor in gastric carcinoma

Background and Aim: Vascular endothelial growth factor (VEGF) and interleukin‐6 (IL‐6) are associated with the disease status of gastric carcinoma. However, their relationship remains unclear. This study aims to determine and correlate serum levels of VEGF and IL‐6 in gastric carcinoma.

Prediction of bleeding and stricture formation after corrosive ingestion by EUS concurrent with upper endoscopy

BACKGROUND Upper endoscopy provides information that can be used to predict complications and to facilitate clinical decisions for patients who have ingested corrosive substances. The role of EUS in corrosive injury has not been investigated. The aim of this study was to determine whether concurrent catheter-probe EUS provides additional information that predicts complications after corrosive injury. METHODS Eighteen patients were referred (from 1997 to 2003) for EGD and concurrent EUS within 24 hours after ingestion of a caustic agent. Two patients were excluded (1 pneumoperitoneum, 1 markedly swollen cricoarytenoid cartilage/epiglottis). The severity of injury in the different segments of the esophagus and stomach was graded (0, 1, 2a, 2b, 3a, 3b) by endoscopy and by EUS (0, M, SM, MP, SS). The development of complications during hospitalization and 3-month follow-up were recorded. OBSERVATIONS All 16 patients underwent EGD with EUS without complication. The frequency of early and late complications increased as the endoscopic and the EUS severity grades increased. The accuracy of prediction of bleeding or stricture was 100% when endoscopic grade 3a was used as a cutoff. For EUS, the highest accuracy was observed in the prediction of bleeding (75%) and stricture (100%) when EUS grade MP was used as a cutoff. CONCLUSIONS EUS can be performed safely within 24 hours of ingestive of corrosive substances. However, when used in conjunction with conventional endoscopic observation, it does not increase the accuracy for prediction of early or late complications. Standard endoscopy alone is sufficient for evaluation and prediction of bleeding and stricture complications after corrosive injury in the upper-GI tract.