柴田 知行

Small-bowel bleeding comprises a majority of obscure gastrointestinal bleeding, but is caused by various kinds of diseases. For its diagnosis, history-taking and physical examination is requisite, leading to a suspicion of what diseases are involved. Next, cross-sectional imaging such as computed tomography should be done, followed by the latest enteroscopy, videocapsule endoscopy and deep enteroscopy according to the severity of hemorrhage and patient conditions. After comprehensive diagnosis, medical, enteroscopic, or surgical treatment should be selected.

Background and Aims Fusobacterium species are part of the gut microbiome in humans, but some species have been recognized as opportunistic pathogens implicated in inflammatory diseases including inflammatory bowel diseases. Here, we performed prevalence screening of Fusobacterium in ulcerative colitis (UC) in Japanese patients. Methods We examined Fusobacterium nucleatum (F. nucleatum) and whole Fusobacterium species (Panfusobacterium) by quantitative real-time PCR in 163 inflamed mucosae from 152 UC patients. Data were correlated with clinical subtypes of UC. Results In an initial prevalence screen, F. nucleatum and Pan-fusobacterium were detected in 6.3 % (4/64) and 53.1 % (34/64). For all 163 mucosae, the prevalence of Pan-fusobacterium was 54.6 % (89/163). Pan-fusobacterium status was concordant in inflamed and normal adjacent samples, and the matched cases during 1-year followup colonoscopy. The higher amount of Pan-fusobacterium was observed in chronic continuous type compared to one attack and relapse/remitting type (p = 0.039). The higher amount of Pan-fusobacterium was also associated with rather mild clinical course of disease, such as non-steroid dependency (p = 0.015), non-refractory phenotype (p = 0.013), and non-severe phenotype (p = 0.04). Based on the distribution of Pan-fusobacterium measurable cases, we identified 10 cases as having a high amount of Panfusobacterium (FB-high). The clinicopathological features of FB-high UC cases were also highlighted by chronic continuous type and mild phenotypes of disease. Conclusion Whole Fusobacterium species, but not F. nucleatum, are common in UC patients and have a role in persistence of colonic inflammation in UC. However, Fusobacterium infection is associated with rather mild clinical phenotypes of UC.

Accumulating data indicates that certain microRNAs (miRNAs or miRs) are differently expressed in samples of tumors and paired non-tumorous samples taken from the same patients with colorectal tumors. We examined the expression of onco-related miRNAs in 131 sporadic exophytic adenomas or early cancers and in 52 sporadic flat elevated adenomas or early cancers to clarify the relationship between the expression of the miRNAs and the endoscopic morphological appearance of the colorectal tumors. The expression levels of miR-143, -145, and -34a were significantly reduced in most of the exophytic tumors compared with those in the flat elevated ones. In type 2 cancers, the miRNA expression profile was very similar to that of the exophytic tumors. The expression levels of miR-7 and -21 were significantly up-regulated in some flat elevated adenomas compared with those in exophytic adenomas. In contrast, in most of the miR-143 and -145 down-regulated cases of the adenoma-carcinoma sequence and in some of the de novo types of carcinoma, the up-regulation of oncogenic miR-7 and/or -21 contributed to the triggering mechanism leading to the carcinogenetic process. These findings indicated that the expression of onco-related miRNA was associated with the morphological appearance of colorectal tumors.

Background/Aims: Artificial ulcers remain a major complication after Endoscopic submucosal dissection (ESD). The development of more effective treatment regimen for this ulcer is required than the use of proton pump inhibitor (PPI) alone. Methodology: Patients with ESD-derived artificial ulcers were randomly assigned to two groups: a group of patients who received rabeprazole 20 mg daily for 8 weeks (PPI group) and a group of patients who received a combination of rebamipide 300 mg daily for 8 weeks and rabeprazole 20mg dairy for the first 4 weeks (reb+PPI group). The area reduction ratio and healing status of ulcers were evaluated endoscopically on postoperative 7, 28 and 56 days. Results: The overall ulcer area reduction ratio was higher in the reb+PPI group than in the PPI group, especially at an early stage. The ratio of progression to the H1 stage in the reb+PPI group was significantly higher than that in the PPI group, especially at an early stage. Conclusions: Treatment with 8 weeks of rebamipide plus the first 4 weeks of PPI demonstrated a reduction ratio of artificial ulcers superior to that with 8 weeks of PPI mono-therapy. This combination treatment is, therefore, one of the candidate treatment strategies against ESD-derived artificial ulcers.

Background: Epithelial-to-mesenchymal transition (EMT) is a phenomenon that allows the conversion of adherent epithelial cells to a mesenchymal cell phenotype, which enhances migratory capacity and invasiveness. Recent studies have suggested that EMT contributes to the pathogenesis of ulcerative colitis (UC). We investigated the promoter DNA methylation status of EMT-related genes in the colonic mucosa in UC. Methods: Colonic biopsies were obtained from the rectal inflammatory mucosa of 86 UC patients and the noninflammatory proximal colonic mucosa of 10 paired patients. Bisulfite pyrosequencing was used to quantify the methylation of 5 candidate CpG island promoters (NEUROG1, CDX1, miR-1247, CDH1, and CDH13) and LINE1. Results: Using an unsupervised hierarchical clustering analysis, inflamed rectal mucosa was well separated from mucosa that appeared normal. The CDH1 and CDH13 promoters were significantly associated with patient age (p = 0.04, 0.03, respectively). A similar trend was found between those genes and the duration of disease (CDH1: p = 0.07, CDH13: p = 0.0002, mean of both: p<0.00001). Several positive associations were found between hypermethylation and severe clinical phenotypes (CDX1 and miR-1247 and a refractory phenotype: p = 0.04 and 0.006, respectively. miR-1247 and CDH1 hyper methylation and a more severe Mayo endoscopic subscore: miR-1247: p = 0.0008, CDH1: p = 0.03, mean of both: p = 0.003). When the severe clinical phenotype was defined as having any of five phenotypes (hospitalized more than twice, highest Mayo endoscopic subscore, steroid dependence, refractory, or a history of surgery) miR-1247 hypermethylation was associated with the same phenotype (p = 0.008). Conclusions: Our data suggest that variability in the methylation status of EMT-related genes is associated with more severe clinical phenotypes in UC.

Background: Common single-nucleotide polymorphisms (SNPs) in pre-miRNAs (hsa-mir-196a2, hsa-mir-146a and hsa-mir-499) have been associated with various malignancies and their prognoses. We evaluated the associations of three selected SNPs (rs11614913, rs2910164, and rs3746444) in pre-miRNAs (hsa-mir-196a2, hsa-mir-146a and hsa-mir-499) with the prognosis of advanced gastric cancers (GCs) treated by chemotherapy. Materials and Methods: The rs11614913 (T>C), rs2910164 (C>T), and rs3746444 (A>G) SNPs were genotyped in 130 advanced GCs performing chemotherapy. Survival and response evaluation was based on overall survival (OS) and progression-free survival (PFS). Response rate (RR) was also evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST). Results: 63 patients performed gastrectomy after chemotherapy (neoadjuvant chemotherapy) and the remaining cases performed chemotherapy alone as treatment (chemotherapy alone). The majority of cases performed S-1-based chemotherapy as the first line treatment (n=119, 92%). The rs3746444 (A>G) SNP was significantly associated with OS by the log-rank test (p=0.018), while other SNPs were not associated with OS. The rs3746444 (A>G) SNP was also associated with OS and PFS among cases of neoadjuvant chemotherapy (p=0.038, 0.024, respectively). Multivariate survival analysis using the Cox's regression model revealed that non-responder by the RECIST (Hazard ratio (HR): 2.14 95% CI 1.06-4.19), upper third cancer (HR: 2.48 95% CI 1.12-5.49) and more advanced stage (HR: 4.12 95% CI 1.06-16.02) were predictive factors for worse OS, while the rs3746444 A allele carrier was predictive factor for better OS (HR: 0.33 95% CI 0.18-0.75). Conclusion: The rs3746444 A allele carrier in the hsa-mir-499 is associated with better prognosis in advanced GC performing chemotherapy.

Background: The neurochemical serotonin (5-HT) is an important signaling molecule in the gastrointestinal motor and sensory functions. A key regulator of 5-HT levels is the transmembrane serotonin transporter (5-HTT; SLC6A4) that governs the reuptake of 5-HT. Recent studies have indicated 5-HTT expression may be regulated by epigenetic mechanisms. We investigated DNA methylation status of SLC6A4 gene in the gastric mucosa from functional dyspepsia (FD) because of their potential role in dyspeptic symptoms. Methods: Endoscopic gastric biopsies were obtained from 78 subjects with no upper abdominal symptoms and 79 patients with FD. Bisulfite Pyrosequencing was carried out to determine the methylation status of promoter CpG islands (PCGIs), promoter non-CpG islands (PNCGIs) and gene body non-CpG islands (NPNCGIs) in the SLC6A4 gene. Gene expression was examined by real-time PCR. Results: In overall, methylation level of PCGIs was significantly lower in FD compared to control subjects (p = 0.04). On the other hand, methylation level of NPNCGIs was significantly higher in FD compared to control subjects (p = 0.03). Lower methylation level in PNCGIs was highlighted in the patients with PDS (p = 0.01), while higher methylation level in NPNCGIs was more prominent in the patients with EPS (p = 0.017). Methylation levels of PCGIs and PNCGIs were inversely correlated, while methylation levels of NPNCGIs was positively correlated with SLC6A4 mRNA levels in FD patients. Conclusions: Our data suggest that change in DNA methylation pattern of SLC6A4 in the gastric mucosa may have a role for developing FD. A role of epigenetics for developing FD needs to be further evaluated.

Small bowel tumors (SBTs) are uncommon, insidious in presentation, and frequently represent a diagnostic challenge. The advent of video capsule endoscopy (VCE) and double-balloon endoscopy (DBE) is a significant breakthrough for visual diagnosis of SBTs throughout the small bowel. Contrast-enhanced computed tomography (CECT) and fluoroscopic enteroclysis had significantly lower diagnostic yields of tumors that were 10 mm or smaller in diameter, but VCE and DBE had high diagnostic yields regardless of tumor size. Regarding SBTs larger than 10 mm in diameter, CECT had a significantly lower diagnostic yield of epithelial tumors compared to subepithelial tumors, whereas fluoroscopic enteroclysis and DBE had high diagnostic yields regardless of the tumor type. VCE had a slightly lower diagnostic yield of subepithelial tumors (78%) compared to epithelial tumors. Therefore, a combined examination method by using CECT and VCE is useful for screening of SBTs. In case suspicious of stenosis, patency capsule should be performed to confirm passage before VCE. DBE is useful for further precise examination including biopsy and ultrasonography by using miniature probe, and enteroscopic treatment. After medical, enteroscopic, and surgical treatment, VCE is helpful for follow-up. DBE is safe and useful in resecting the SBTs deep within the small bowel without laparotomy. Indications of enteroscopic resection may be benign tumors regardless of epithelial or subepithelial type, localizing in the mucosal or submucosal layer, which are symptomatic at present or possibly symptomatic or transforming in the future. Malignant tumors localized in the mucosal layer may be indications although detecting at an early stage is challenging. In this review article, we describe management of SBTs/polyps by various modalities.

AIM: To clarify the association between a polymorphism -449 C>G (rs72696119) in 5'-UTR of NFKB1 with ulcerative colitis (UC). METHODS: The studied population comprised 639 subjects, including patients with UC (UC cases, n = 174) and subjects without UC (controls, n = 465). We employed polymerase chain reaction-single strand conformation polymorphism to detect the gene polymorphism. RESULTS: The rs72696119 G allele frequencies in controls and UC cases were 33.4% and 38.5%, respectively (P = 0.10). Genotype frequency of the GG homozygote in UC cases was significantly higher than that in controls (P = 0.017), and the GG homozygote was significantly associated with susceptibility to UC [odds ratio (OR), 1.88; 95% CI, 1.13-3.14]. In male subjects, the GG homozygote was associated with an increased risk for UC (OR, 3.10; 95% CI, 1.47-6.54; P = 0.0053), whereas this association was not found in female subjects. In addition, the GG homozygote was significantly associated with the risk of non-continuous disease (OR, 2.06; 95% CI, 1.12-3.79; P = 0.029), not having total colitis (OR, 2.40; 95% CI, 1.09-3.80, P = 0.040), disease which developed before 20 years of age (OR, 2.80; 95% CI, 1.07-7.32, P = 0.041), no hospitalization (OR, 2.28; 95% CI, 1.29-4.05; P = 0.0090) and with a maximum of 8 or less on the UCDAI score (OR, 2.45; 95% CI, 1.23-4.93; P = 0.022). CONCLUSION: Our results provide evidence that NFKB1 polymorphism rs72696119 was significantly associated with the development of UC. This polymorphism influences the susceptibility to and pathophysiological features of UC. (C) 2012 Baishideng. All rights reserved.

Background/Aims: Although serum pepsinogen (PG) is considered as a marker of gastric atrophy, it also reflects gastric acid secretion, which closely influences dyspeptic symptoms. We investigated serum PG levels and PGI/PGII ratios in dyspeptic patients, in relation to various different subtypes of symptoms including Rome III classifications. Methodology: Serum PGs were measured in 75 subjects with dyspeptic symptoms and 42 asymptomatic healthy subjects. Results: PG II level was significantly higher (p=0.0001) and PG I/II ratio was significantly lower (p<0.0001) in subjects with H. pylori infection than those without, while no associations were found between PG levels and usage of H-2 receptor antagonists or proton-pump inhibitors. In all subjects with pain in stomach, abdominal bloating and PDS-like symptoms according to Rome III criteria, presented significantly higher levels of PGI, compared to subjects without symptoms (p=0.043, 0.015 and 0.037, respectively). In addition, burning sensation and abdominal pain presented significantly higher PGI/II ratios (p=0.0005 and 0.003, respectively), and higher PGI/II ratio was also positively correlated with a number of symptoms (p=0.04). When subjects were divided according to H. pylori infection status, higher PGI/II ratio was significantly associated with abdominal pain in H. pylori negative subjects (p=0.03), while higher PGI level was significantly associated with functional esophageal disorders (FEG) according to Rome III criteria, and higher number of dyspeptic symptoms in H. pylori positive subjects (p=0.016). Conclusions: Our data suggest that subjects with higher PGI level, and PGI/II ratio are more likely to develop several dyspeptic symptoms.

Background & Aim: The important role of IL-17 in inflammatory response to Helicobacter pylori (H. pylori) colonization has been indicated. We investigated the associations between gastro-duodenal diseases and polymorphisms of IL17A (rs2275913 G>A) and IL17F (rs763780 T>C). Methods: The study was performed in 548 subjects (363 controls and 185 peptic ulcer cases). The multiplex PCR-SSCP method was used to detect gene polymorphisms. Results: Overall, number of rs2275913 A allele was significantly associated with an increased risk for peptic ulcer (OR, 1.50; 95%CI, 1.11-2.01; p=0.0082). The frequency of rs2275913 GA+AA genotype was also significantly higher in ulcer cases than controls (OR, 1.72; 95%CI, 1.09-2.72; p=0.020). The rs2275913 GA+AA genotype conferred an increased risk for the severity of gastric mucosal atrophy in subjects younger than 60 years (OR, 2.83; 95%CI, 1.14-7.04; p=0.025). Both atrophy and metaplasia were increased with age in rs2275913 GA+AA genotype. In NSAIDs/aspirin users, number of rs2275913 A allele was associated with an increased risk for a peptic ulcer (OR, 3.98; 95%CI, 1.48-10.7; p=0.0061). There was no association of rs763780 with the development of peptic ulcer. Conclusions: Our results provide the evidence that rs2275913 is associated with an increased risk for peptic ulcer and the severity of the gastric mucosal atrophy in comparatively younger subjects. In addition, this allele is also associated with the increased risk for peptic ulcer in NSAIDs/aspirin users.

Background&Aim: Histamine plays important physiological roles in upper gastrointestinal tract and acts via the H2 receptor. A polymorphism -1018 G>A (rs2067474) was identified in an enhancer element of the HRH2 promoter. We attempted to clarify the associations of this polymorphism with the progression of gastric mucosal atrophy. Methods: Gastric mucosa samples were obtained from 398 subjects with no malignancies. The rs2067474 genotype was determined by PCR-SSCP method. The degree of gastritis was assessed in 366 subjects and serum pepsinogen (PG) I/II levels were measured in 108 subjects. The subjects with atrophy score >= 2 and metaplasia score >= 1 were classified into the severe atrophic gastritis group (SA group). Results: The -1018G>A minor allele frequencies in SA and non-SA groups were 8.02% and 13.3%, respectively (p=0.057). The -1018 GG homozygote had a significantly high risk for gastric mucosal atrophy (OR: 2.03, 95%CI: 1.03-4.01, p=0.042). In H. pylori positive subjects, GG homozygote was a more significant risk factor for gastric mucosa! atrophy (OR: 2.32, 95%CI: 1.12-4.81, p=0.023). In addition, in the subjects older than 60 years, GG homozygote had also a significant risk for gastric mucosal atrophy (OR: 2.63, 95%CI: 1.15-6.00, p=0.022). In -1018 GG homozygote, PG I/II ratio was significantly lower in H. pylori positive than negative subjects and was significantly decreased with age (p=0.0032 by ANOVA), whereas it was not in the A carrier. Conclusions: Our results suggest that HRH2 -1018 GG homozygote is a risk factor for the severity of gastric mucosal atrophy under the influence of H. pylori infection, especially in older subjects.

Background Combined chemotherapy with S-1 and docetaxel was implemented in patient with advanced or recurrent gastric cancer associated with peritoneal dissemination and malignant ascites. Methods S-1 was administered orally at 80 mg/m2 for 14 consecutive days and docetaxel was administered at 40 mg/m2 on day 1, followed by a 1-week rest, as one course, and the treatment was repeated until progression or severe toxicity. Results Three out of the five patients showed response to the treatment. The three patients with response had diffuse-type tumor according to the Lauren's classification. The median number of treatment courses was 4. The median survival time was 315 days, the median time to treatment failure was 225 days, and the 1-year survival rate was 20%. Conclusions These results suggest that combined therapy with S-1 and docetaxel is a promising treatment for advanced or recurrent gastric cancer with malignant ascites and peritoneal dissemination. © 2012, The Japanese Society of Strategies for Cancer Research and Therapy. All rights reserved.

Early gastric cancer located from the pyloric ring to inside the duodenal bulb (DB) is not easily treated by endoscopic submucosal dissection (ESD). The endoscope needs to be reversed inside the DB to set the resection line at a safe distance from the anal side. Because of the space limitations and limited flexibility of conventional endoscopy (CE), there have been increasing possibilities of complications. Here we report a new ESD technique using a transnasal endoscope (TN-E) that is reversed inside the DB. The subjects were 5 patients with early gastric cancer or adenoma, at locations ranging from the pyloric ring to inside the DB, who were all treated by ESD. We compared results in these patients (TN-E group) with results in five patients with similar disease characteristics who were treated by ESD before July 2008, when the TN-E treatment method was introduced (CE group). In the TN-E group, after marking by CE, we switched the endoscope to the TN-E, and performed the reversing procedure insidethe DB, and cut the anal side of the lesion in a semicircle. We switched back to CE to dissect the remaining half on the oral side. We compared the average resection time, en-bloc resection rate, and safety margin between the TN-E and CE groups. Reversing inside the DB and the anal-side procedures proved easy and there were no complications. No bleeding or perforation occurred. The average resection times and en-bloc resection rates were not different between the two groups. All the resections by the TN-E were more than 5 mm away from the tumor margin, whereas a resection rate with a safety margin of more than 5 mm was 80% by CE. In conclusion, the TN-E was safe and effective for use inside the DB. ESD using the TN-E contributed to accurate pathological diagnosis, because the size of the resected specimen was sufficient to prevent the burning effect caused by the ESD.

A high-salt diet is a risk factor for gastric cancers other than those caused by Helicobacter pylori. The angiotensinogen (AGT) M235T polymorphism has been associated with salt sensitivity. The aim of the present study was to clarify the association between the AGT M235T polymorphism and gastric cancer. The AGT M235T polymorphism was genotyped using PCR-RFLP analysis in 206 gastric cancers and 210 control biopsies. A logistic-regression analysis was performed to identify an odds ratio to determine whether a correlation exists between genetic polymorphism and risk in patients with gastric cancer as compared to the control samples. Statistical significance was determined using the Mann Whitney U and Chi-square tests. The genotype distribution was found to be MM=9 (4.4%), MT=57 (27.7%), and TT=140 (67.9%) in samples from patients with gastric cancer and MM=8 (3.8%), MT=60 (28.6%) and TT=142 (67.6%) in the control samples. The odds ratio of gastric cancer of the MM genotype associated with the T carrier was 1.0 (0.4-2.7) (P=0.95). The distribution pattern of AGT M235T polymorphism in the gastric cancer cases and controls was not found to be significantly different in this study. Thus, it can be concluded that other sites of AGT polymorphism or other salt sensitivity genes may be associated with gastric cancer.

Background: Genetic factors, related to DNA repair or xenobiotic pathways might confer different degrees of susceptibility to gastric carcinogenesis. CpG island hyper methylation (CIHM) is a major event in gastric carcinogenesis. We evaluated the association between XRCC1, GSTP1, GSTT1 and GSTM1 polymorphisms with CIHM status in non-neoplastic gastric mucosa. Methods: XRCC1 Arg399Gln, and Arg194Trp, GSTP1 Ile104Val, and GSTT1, GSTM1 null polymorphisms were genotyped in 415 cancer free subjects, in relation to four candidate CpG (p14, p16, DAP-kinase and CDH1) loci, assessed by Methylation-Specific-Polymerase Chain Reaction (MSP). CIHM high was defined as two or more CpG islands methylated. Results: Significant association between XRCC1 codon 399 Gln/Gln genotype and reduced susceptibility to CIHM of DAP-kinase (adjusted OR = 0.30, 95%CI = 0.13-0.71, p = .0055) and CIHM high (OR = 0.42, 95%CI = 0.19-0.97, p = .04). XRCC1 codon 399 Gin/Gln genotype also presented lower number of CIHM when compared with both Arg/Gln, and Arg/Arg + Arg/Gln genotypes (p = .02, .046, respectively) When subjects were divided according to age (> 50 and < 50), an association was found between GSTM1 null genotype and increased susceptibility to CIHM high in the 50 years and older generations (OR = 1.63, 95%CI = 1.01-2.62, p = .045). Conclusion: XRCC1 codon 399 Gln/Gln genotype is associated with reduced susceptibility to CIHM especially DAP-kinase. GSTM1 null genotype may increase the susceptibility to CIHM especially in older patients. Genetic factors, related to DNA repair or xenobiotic pathways may have a role in CIHM-related gastric carcinogenesis.

Background: Genetic factors related to DNA repair or xenobiotic pathways might confer different degrees of susceptibility to Helicobacter pylori (H. pylori)-related gastric carcinogenesis. The association between XRCC1 Arg399Gln, and Arg194Trp, GSTP1 Ile104Val, and GSTT1, GSTM1 null polymorphisms with gastric intestinal metaplasia, severity of histological gastritis, and peptic ulcer diseases were evaluated in a Japanese population. Patients and Methods: XRCC1 Arg399Gln and Arg194Trp, GSTP1 Ile104Val and GSTT1, GSTM1 null polymorphisms were genotyped in 280 cancer-free individuals, including 52 gastric and 31 duodenal ulcer patients. Results: Among the five polymorphisms, a significant association between the GSTT1 and GSTM1 null genotypes and increased risk of intestinal metaplasia was found (GSTT1 null: OR=2.42, 95% CI=1.28-4.60, p=0.007, GSTM1 null: OR=2.18, 95% CI=1.15-4.13, p=0.019). When the severity of gastric atrophy was classified into the following three groups: non-atrophy (NA) (atrophy score=0 and metaplasia score=0); severe atrophy (SA) (atrophy score >= 2 or metaplasia score >= 2) and mild atrophy (MA) (all others), both the GSTT1 and GSTM1 null genotypes held significantly higher risk for developing more severe gastric atrophy (GSTT1 null, SA vs. others: OR=1.95, 95% CI=1.07-3.52, p=0.028, GSTM1 null, NA vs. others: OR=2.57, 95% CI=1.16-5.67, p=0.019, SA vs. others: OR=1.90, 95% CI=1.06-3.42, p=0.032). A significant association was also found between GSTM1 null genotype and increased risk of ulcer diseases (all ulcers: OR=2.42, 95% CI=1.37-4.26, p=0.002, gastric ulcer: OR=2.18, 95% CI=1.11-4.29, p=0.025, duodenal ulcer: OR=2.62, 95% CI=1.15-6.00, p=0.023). Conclusion: Both the GSTT1 and GSTM1 null genotypes are associated with gastric pre-malignant conditions.

Background: CpG island hypermethylation (CIHM) in gene promoter is frequently observed in the colonic mucosa in ulcerative colitis (UC), and is strongly involved in UC-associated colorectal carcinogenesis (CRC). The influence of common single nucleotide polymorphisms (SNPs) related to inflammatory immune response on the individual susceptibility to CIHM status in the non-neoplastic rectal mucosa in UC patients was evaluated. Patients and Methods: Ten candidate SNPs, multidrug resistance 1 (MDR1) 3435 (C > T), regulated upon activation, normal T-cell expressed and secreted (RANTES)-28 (C > G), heat-shock protein (HSP)70-2 1267 (B > A), NADPH oxidase p22PHOX 242 (C > T), Toll-like receptor (TLR)2-196 to -174 (ins > del), CD14-159 (C > T), Mannan-binding lectin (MBL)2 codon 54 (G > A), tumor necrosis factor-alpha(TNF-alpha) -857 (C > T), inhyleukin-1 beta(IL-1 beta)-511 (C > T), and IL-beta-31 (T > C) were genotyped in 58 UC patients without neoplastic lesions, in relation to CIHM in the rectal mucosa of three candidate CpG (p14, p16 and E-cadherin: CDH1) loci, assessed by methylation-specific-polymerase chain reaction (MSP). High CIHM was defined as two or more CpG islands methylated. Results: The CD 14-159TT genotype held a significantly higher susceptibility to CIHM of the p16 promoter (OR=3.82, 95%CI=1.06-13.79, p=0.04) A significant association was also found between the IL-1 beta-31TC genotype and reduced susceptibility to high CIHM (OR=0.14, 95%CI=0.22-0.94, p=0.04). The p22PHOX 242CT genotype and MBL2 codon 54 A carrier (GA+AA) were significantly associated with a lower mean number of CIHM (p=0.029, 0.046, respectively). Conclusion: CD14 -159, IL-1 beta-31, p22PHOX 242 and MBL2 codon 54 SNP:: may influence the CIHM status in the rectal mucosa of UC patients and may therefore be substantially involved in UC-associated carcinogenesis.

Magnifying narrow-band imaging (NBI) endoscopy visualizes superficial gastric mucosal and capillary patterns. We aimed to investigate changes in gastric mucosal patterns seen by magnifying NBI endoscopy after Helicobacter pylori eradication. Gastric mucosal patterns in non-pathological gastric corpus were observed by magnifying NBI endoscopy before and 12 weeks after H. pylori eradication in thirty patients. By using paired photographs of each case, changes in NBI mucosal patterns during H. pylori eradication were judged in a consensus manner by three blinded endoscopists. At 12 weeks after H. pylori eradication, 20 of 24 subjects who had been successfully treated showed remarkable changes in gastric mucosal patterns (sensitivity 83.3%, specificity 100%). In the specimens from these subjects, the patterns of enlarged or elongated pits were improved to small oval or pinhole-like round pits, and the density of fine irregular vessels was decreased. Histological assessment showed alleviation of chronic inflammation in all subjects (p < 0.0001), while such a change was not observed for four subjects showing severe gastric atrophy and intestinal metaplasia. When the subjects were divided according to the presence of severe gastric atrophy, the diagnostic efficacy of magnifying NBI for predicting the results of H. pylori eradication was excellent in subjects without severe gastric atrophy and intestinal metaplasia (sensitivity and specificity, 100%). However, no change in the NBI mucosal pattern was observed in subjects with severe gastric atrophy and intestinal metaplasia, regardless of the H. pylori eradication result. At least in subjects without severe gastric atrophy or intestinal metaplasia, successful H. pylori eradication treatment shows improvements in gastric mucosal patterns with the use of magnifying NBI endoscopy early after successful treatment.

CpG island hypermethylation (CIHM) is frequently observed in the colonic mucosa in ulcerative colitis (UC) and is deeply involved in UC-associated colorectal carcinogenesis. We evaluated the influence of common polymorphisms related to DNA repair or xenobiotic pathway (XRCC1, GSTP1, GSTT1, and GSTM1) on the individual susceptibility to CIHM status in the non-neoplastic rectal mucosa in UC patients. XRCC1 Arg399Gln and Arg194Trp, GSTP1 Ile104Val, and GSTT1, GSTM1 null polymorphisms were genotyped in 84 UC patients without neoplastic lesions, in relation to CIHM in the rectal mucosa of three candidate CpG loci (p14, p16, and CDH1) assessed by methylation-specific polymerase chain reaction. XRCC1 codon 399 Arg/Gln genotype (odds ratio (OR) = 0.31, 95%CI = 0.12-0.81, p = 0.017) and 399 Gln carrier (GlnGln+Arg/Gln: OR = 0.30, 95%CI = 0.12-0.76, p = 0.01) were significantly associated with reduced susceptibility to CIHM of the CDH1 promoter. GSTP1 Val carrier (Ile Val+Val/Val) also held a significantly lower susceptibility to CIHM of the p16 promoter (OR = 0.26, 95%CI = 0.08-0.86, p = 0.028). In contrast, GSTT1 present genotype (OR = 3.16, 95%CI = 1.27-7.89, p = 0.01) was significantly associated with increased susceptibility to CIHM of the same gene. XRCC1 codon 399 Gln/Gln genotype was significantly associated with lower mean number of CIHM when compared to the Arg/Arg genotype (1.53 +/- 1.01 vs. 0.63 +/- 1.06, p = 0.024). In addition, the GSTP1 Ile/Val carrier (Ile/Val+Val/Val) was also significantly associated with lower mean number of CIHM (1.43 +/- 1.03 vs. 0.84 +/- 1.07, p = 0.03). XRCC1 Arg399Gln and GSTP1 Ile104Val polymorphisms may influence the CIHM status in the rectal mucosa of UC patients and may be substantially involved in UC-associated carcinogenesis.

Background: A number of association studies have focused on the effect of polymorphisnzs related to DNA repair or the xenobiotic pathway, on the susceptibility to gastric cancer (GC). Here, the possible association between common polymorphisms in the X-ray repair crosscomplementing groups (XRCC) 1, and glutathione-Stransferase (GST) genes and various clinicopathological characteristics, including overall survival, in GC patients were evaluated. Patients and Methods: XRCC1 Arg399G1n, and Arg194Trp, GSTP1 11e104Val, and GSITI, GSTM1 null polymorphisms were determined in 130 GC patients. Results: XRCC1 codon 194 Trp carriers (TrplTrp + ArgITrp) held a significantly higher risk of venous invasion (OR=3.76, 95%CI=1.05-13.51, p=0.043). A similar trend was also found for the XRCC1 codon 194 TrplTrp genotype (OR=2.15, 95% CI=0.87-5.34, p=0.099). The frequencies of the XRCCI codon 399 GInIGliz and ArgIGIn genotypes tended to be lower in lymphatic invasion-positive GC (XRCC1 codon 399 GInIG1n: OR=0.27, 95% CI=0.06-1.15, p=0.075, Gln/Gln + ArgIG1n: OR=0.46, 95% CI=0.20-1.06, p=0.069), while the frequencies of the XRCC1 codon 194 TrplTrp genotype tended to be higher in lymphatic invasionpositive GC (XRCCI codon 194 TrplTrp: OR=7.70, 95% CI=0.95-62.60, p=0.056). The patients with the GS7T1 null genotype showed significantly better overall survival than the patients with the GSTTI present genotype (p=0.019). Conclusion: XRCCI codon 194 Trp carrier status is correlated with more aggressive biological behavior of GC, such as venous invasion, and the GSTT1 null genotype is associated with better survival in GC patients.

Background There is evidence that changes in MDR1 function and/or expression contribute to the pathogenesis of inflammatory disorders of the gastrointestinal tract. Aims We aimed to investigate the effect of C3435T polymorphism of the MDR1 gene on histological chronic gastritis, and on the risk of peptic ulcer diseases. Methods Restriction fragment length polymorphism analysis was performed for polymorphisms at C3435T in the MDR1 gene in 556 cancer-free subjects including 116 gastric and 60 duodenal ulcers, and 380 non-ulcer subjects. Gastritis scores in the antrum were assessed according to the updated Sydney system in 384 subjects. Results We did not find a significant association between MDR1 genotype and gastritis scores in any of the 384 subjects. However, the 3435T carrier was significantly associated with a higher degree of neutrophil infiltration in H. pylori-positive subjects (CC vs. T carrier: p = 0.0495). When the H. pylori positive subjects were divided according to generation, the 3435T carrier was significantly associated with a higher degree of neutrophil infiltration in subjects more than 65 years of age (CC vs. T carrier: p = 0.03). Also, the MDR1 3435 TT genotype was significantly associated with a higher degree of atrophy and intestinal metaplasia in the same generation (atrophy, TT vs. C carrier: p = 0.038, intestinal metaplasia, TT vs. C carrier: p = 0.016). No association was found between MDR1 genotypes and risk of peptic ulcer diseases. Conclusions It appears that the C3435T polymorphism of MDR1 influences H. pylori-related inflammatory conditions in the stomach, especially in older subjects.

Common single-nucleotide polymorphisms (SNPs) in microRNAs (miRNA) have been shown to be associated with susceptibility to several human diseases. We evaluated the associations of three SNPs (rs11614913, rs2910164, and rs3746444) in pre-miRNAs (miR-196a2, miR-146a, and miR-499) with the risk of ulcerative colitis (UC) in a Japanese population. The rs11614913 (T > C), rs2910164 (C > G), and rs3746444 (A > G) SNPs were genotyped in 170 UC and 403 control subjects. The rs3746444 AG genotype was significantly higher among the UC group (odds ratio (OR) = 1.51, 95% CI = 1.03-2.21, p = 0.037). The rs3746444 AG genotype was associated with onset at an older age (OR = 1.70, 95% CI = 1.04-2.78, p = 0.035), left-sided colitis and pancolitis (left-sided colitis, OR = 2.10, 95% CI = 1.12-3.94, p = 0.024; pancolitis, OR = 1.81, 95% CI = 1.09-3.01, p = 0.028, left-sided colitis + pancolitis, OR = 1.91, 95% CI = 1.26-2.92, p = 0.003), higher number of times hospitalized (OR = 2.63, 95% CI = 1.22-5.69, p = 0.017), steroid dependence (OR = 2.63, 95% CI = 1.27-5.44, p = 0.014), and refractory phenotypes (OR = 2.76, 95% CI = 1.46-5.21, p = 0.002) while the rs3746444 AA genotype was inversely associated with the number of times hospitalized (2 similar to, OR = 0.36, 95% CI = 0.17-0.79, p = 0.012), steroid dependence (OR = 0.42, 95% CI = 0.21-0.88, p = 0.021), and refractory phenotypes (OR = 0.38, 95% CI = 0.20-0.72, p = 0.003). The rs1161913 TT genotype also held a significantly higher risk of refractory phenotype (T/T vs. T/C + C/C, OR = 2.21, 95% CI = 1.17-4.18, p = 0.016). Our results provided the first evidence that rs3746444 SNP may influence the susceptibility to UC, and both rs3746444 and rs11614913 SNPs may influence the pathophysiological features of UC.

Combining the narrow-band imaging (NBI) system and magnifying endoscopy allows simple and clear visualization of microscopic structures of the superficial mucosa and its capillary patterns, which may be useful for precise endoscopic diagnosis in the gastrointestinal tract, being more closely to histopathological diagnosis. In the non-neoplastic gastric mucosa, there have been reports showing a potential usefulness of magnifying NBI for the diagnosis of Helicobacter pylori infection, degree of histological gastritis, and intestinal metaplasia. We have shown that magnifying NBI appearances in the non-neoplastic gastric mucosa also predicts pepsinogen levels, which indicates extension of gastric atrophy in the entire stomach, and gastric cancer occurrence. Furthermore, we have shown that magnifying NBI appearances predicts the result of H. pylori treatment. Clear visualization of fine mucosal and capillary patterns, obtained by magnifying NBI, allows prediction of the histological condition, more in detail without biopsy, and it may also be useful for less invasive, and cost-effective endoscopic gastric cancer surveillance, and prediction of H. pylori eradication. Copyright (C) 2011 S. Karger AG, Basel

CpG island hypermethylation of tumor suppressor genes is highly involved in gastric carcinogenesis, and enhanced cell proliferation could accelerate this process. Cyclin D1 regulates cell cycle function and may play a role in methylation-related carcinogenesis. We investigated the association between Cyclin D1 gene G870A polymorphism and the methylation status of tumor suppressor genes in gastric cancer. Polymorphisms at G870A in the Cyclin D1 gene were genotyped, and methylation status of the p14, p16, DAP-kinase, and CDH1 genes were determined by methylation-specific-polymerase chain reaction in 139 gastric cancer tissues. CIHM high was defined as three or more methylated CpG islands. Although no association was found between methylation status and different stages and Lauren's subtypes, patients with CIHM of DAP-kinase showed significantly worse survival than those without (p = 0.017). In addition, the number of methylated sites was also associated with survival curves (p = 0.0397). The 870G carrier a significantly lower prevalence of CIHM high compared to the AA genotype in advanced-stage gastric cancer (adjusted OR = 0.32, p = 0.047). A weak correlation between the same genotypes and CIHM of p14 were found in the same subtype (adjusted OR = 0.32, p = 0.052). The mean methylation number was significantly lower in G carriers than in AA genotypes in advanced-stage gastric cancer (p = 0.017). Genetic polymorphism of CCND1 is associated with CIHM status in gastric cancer, especially in the advanced stage, but is independent of clinico-pathological features.

Background: Common single-nucleotide polymorphisms (SNPs) in microRNAs (miRNA) have been shown to be associated with susceptibility to several human cancers. We evaluated the associations of three SNPs (rs11614913, rs2910164, and rs3746444) in pre-miRNAs (miR-196a2, miR-146a, and miR-499) with the risk of gastric cancer (GC) and peptic ulcer diseases, and with the severity of Helicobacter pylori-induced gastritis in Japanese population. Methods: The rs11614913 (C > T), rs2910164 (G > C), and rs3746444 (A > G) SNPs were genotyped in 552 GC, and 697 non-cancer subjects, including 141 gastric and 73 duodenal ulcer, and 483 non-ulcer subjects. The degree of histologic gastritis was classified according to the updated Sydney System, and the serum pepsinogen levels were measured in selected 579 and 204 cases. Results: The rs2910164 CC genotype held a significantly higher risk of GC when compared to non-cancer subjects (adjusted odds ratio (OR) = 1.30, 95% confidence interval (CI) = 1.02-1.66, p =.03). Similarly, the rs2910164 C carrier was associated with higher risk of GC when compared to both non-cancer and non-ulcer subjects (OR = 1.39, 95%CI = 1.00-1.93, p =.05, adjusted OR = 1.57, 95%CI = 1.09-2.27, p =.016, respectively). The rs2910164 CC genotype was associated with non-cardia and upper third, diffuse type and advanced stage GC. The rs11614913 TT genotype was associated with higher degree of mononuclear cell infiltration (score 0-1 vs 2 similar to, adjusted OR = 1.62, 95%CI = 1.05-2.49, p =.03). Conclusions: The rs2910164 (G > C) SNP in the miR-146a is associated with susceptibility to GC. In addition, the rs11614913 (C > T) SNP in the miR-196a2 is associated with the degree of H. pylori-induced mononuclear cell infiltration.

Macrophage migration inhibitory factor (MIF) is a key proinflammatory mediator, which plays a pivotal role in inflammatory and immune diseases. We attempted to clarify the association of functional polymorphisms of MIF gene promoter with the development of gastro-duodenal ulcer. The study was performed in 471 stocked DNAs obtained from the subjects, including 93 healthy volunteers, with no evidence of gastric malignancy. We employed the PCR-SSCP method to detect gene polymorphisms. In all 471 DNAs, 92 and 43 were obtained from gastric and duodenal ulcer patients, respectively. By an unadjusted analysis, infection with Helicobacter pylori (H. pylori), male gender and non-steroidal anti-inflammatory drug (NSAID/aspirin) use were significantly associated with a risk for developing a gastric ulcer, whereas MIF promoter polymorphism were not. On the other hand, infection with H. pylori, male gender and 7-CATT repeat at position -794 were significantly associated with the development of a duodenal ulcer, whereas NSAID/aspirin use was not. By the analysis after adjustment for age, gender. NSAID/aspirin use and H. pylori infection status, 7/7-CATT homozygote had a significantly increased risk for the development of duodenal ulcers (OR, 6.31; 95% CT, 1.50-26.6; p=0.012). No factors were significantly associated with the development of peptic ulcers in NSAID/aspirin users. Our results suggested that tetranucleotide repeat polymorphism of MIF gene promoter might be associated with the development of duodenal ulcers.

Common single-nucleotide polymorphisms (SNPs) in microRNAs (miRNAs) have been shown to be associated with susceptibility to several types of human cancer. We evaluated the association between three SNPs (rs11614913, rs2910164 and rs3746444) in pre-miRNAs (miR-196a2, miR-146a and miR-499) and various clinicopathological characteristics, including CpG island hypermethylation (CIHM) status and overall survival in gastric cancer (GC) patients. rs11614913 (T>C), rs2910164 (C>G) and rs3746444 (A>G) SNPs were genotyped in 127 GC patients. OHM of p14, p16, DAP-kinase and CDH1 genes was determined by methylation-specific polymerase chain reaction in the cancer tissues. A significant marginal association was found between the rs11614913 CC genotype and polypoid or elevated type morphology in early-stage GC (OR=6.29, 95% CI 1.18-33.47, p=0.03). The rs2910164 CC and CG genotypes were associated with increased susceptibility to CIHM of DAP-kinase OR=5.48, 95% CI 1.30-23.10, p=0.02; CC, OR=6.93, 95% Cl 1.37-35.02, p=0.02; OD, OR=4.24, 95% CI 0.87-20.78, p=0.07). The 11614913 TT and TC genotypes were associated with a higher number of CIHM (no. of CIHM 0-1 vs. 2-4; TT+TC, OR=3.67, 95% CI 0.98-13.72, p=0.05; TC, OR=4.08, 95% CI 1.04-15.97, p=0.04). When the subjects were divided according to age group, the combined rs11614913 TT+TC genotype tended to be associated with worse overall survival than the CC genotype in patients younger than 65 years of age (p=0.05). The combined rs2910164 CG+GG genotype also tended to be associated with worse overall survival than the CC genotype in the same age group (p=0.09). It appears that rs11614913 and rs2910164 SNPs in pre-miRNAs (miR-196a2 and miR-146a) affect the clinicopathological characteristics of GC, including its morphological appearance. CIHM status and overall survival.

Inflammatory changes in the gastric mucosa are commonly observed in Japanese patients with functional dyspepsia (FD). However, detailed data regarding the possible association between the genetic factors of inflammation related molecules and FD are not available. Toll like receptor 2 (TLR2) and mannan-binding lectin (MBL) protein play important roles in the innate immune activation. We aimed to clarify the association between common polymorphisms of TLR2 and MBL2 genes with FD in Japanese subjects. TLR2 -196 to -174 del and MBL2 codon54 G/A polymorphisms were genotyped in 111 FD patients according to Rome III criteria and 106 asymptomatic controls. Non-significant correlation was found between TLR2 and MBL2 polymorphisms with FD. However, in Helicobacter pylori (H. pylon) positives, we found significant inverse association between TLR2 -196 to -174 del carrier and FD among H. pylori positive subjects (Adjusted odds ratio (OR) = 0.48, 95% confidence interval (CI) = 0.23-0.996,p = 0.0488). We also found significant inverse association between the same genotype with postprandial distress syndrome (PDS) among H. pylori positive subjects (Adjusted OR = 0.22, 95% CI = 0.07-0.69, p = 0.0099). Our data suggest that TLR2 -196 to -174 del carriers's status but not MBL2 codon54 G/A is inversely related to the risk with FD in H. pylori-infected subjects.

Macrophage migration inhibitory factor (MIF) is a key proinflammatory mediator. Two functional polymorphisms were identified in the promoter region of MIF gene. We attempted to clarify the associations between these polymorphisms and ulcerative colitis (UC). The study was performed in 111 patients with UC and 209 subjects without UC. We employed the PCR-SSCP method to detect gene polymorphisms. Overall, 5/5-CATT genotype was a decreased risk for the development of UC (OR, 0.51; 95% Cl, 0.26-0.99). In addition, 7/7-CATT genotype was significantly associated with chronic continuous phenotype and distal colitis phenotype (OR, 5.49; 95% Cl, 1.19-25.3, and OR, 6.10; 95% Cl, 1.32-28.2, respectively), whereas 5/5-CATT genotype had an inhibitory effect on the development of UC after 20 years of age (OR, 0.33; 95% Cl, 0.14-0.82). On the other hand, G-173C polymorphism did not affect the susceptibility to and the phenotypes of UC. Our results suggested that tetranucleotide CATT repeat of MIF gene promoter may be associated with the development of UC and the severity of inflammation in patients with UC. (C) 2010 Elsevier Ltd. All rights reserved.

We investigated the methylation status of multidrug resistance 1 (MDR1) gene promoter in noncancerous gastric mucosa in relation to gastric cancer (GC) occurrence. Methylation of the MDR1 promoter was estimated in 127 GC and 82 non-GC patients. A significant association was found between higher methylation ratio and occurrence of GC. Higher methylation ratio was also associated with occurrence of GC in both Helicobacter pylori-positive and Helicobacter pylori-negative subjects. Higher MR was also associated with Helicobacter pylori infection. Methylation status of MDR1 gene in noncancerous gastric mucosa would be useful for predicting GC occurrence.

Background: Therapeutic strategies for flat elevated (0-IIa) lesions in the stomach diagnosed as adenoma by biopsy are currently not established, because some difficulties have previously been reported in the evaluation of vascular patterns alone for the differential diagnosis between adenoma and carcinoma. Objective: We attempted to evaluate the 0-IIa lesions diagnosed as adenoma by using magnifying endoscopy with narrow-band imaging (MENBI) to distinguish them as either adenoma or carcinoma. Setting: Department of Gastroenterology, Fujita Health University. Patients: Fourteen adenomatous lesions (6 adenomas and 8 carcinomas confirmed postoperatively) diagnosed with preoperative biopsies from patients who had undergone endoscopic submucosal dissection were evaluated. Interventions: We selected 5 sites per lesion for MENBI. Selected sites were divided into superficial structures (SSs) and irregular microvascular patterns (IMVPs). Main Outcome Measurements: The rate of SSs and IMVPs in adenoma and carcinoma. Results: Significant SSs were tubular in the adenoma and unclear in the carcinoma. Regarding IMVP subcategories, (1) slight intrastructual irregular microvascular patterns (ISIMVPs) accounted for 97%, (2) severe ISIMVPs accounted for 0%, (3) Fine networks accounted for 3%, and (4) corkscrews accounted for 0% of cases in the adenomas. The corresponding proportions in the carcinomas were (1) 40%, (2) 15%, (3) 45%, and (4) 0%. Severe ISIMVPs and fine networks were significant Findings for carcinomas. Limitations: The number of cases was limited. Conclusions: Our combined evaluation method using MENBI offers the ability to establish proper therapeutic strategies for lesions that are difficult to identify as adenoma or carcinoma.

CpG island hyper-methylation (CIHM) is one of the major events in the gastric carcinogenesis. IL-17A, -17F and MIF have a crucial role in the gastric inflammation and carcinogenesis. Recently, we showed that the genetic polymorphisms of MIF-794-CATT repeat are associated with CIHM status in the non-neoplastic gastric mucosa. Consequently, the CIHM status in the gastric cancer tissue, in relation to IL-17A (-197G>A), -17F (7488T>C), and MIF (-173G>C and -794 tetranucleotide repeats) polymorphisms was investigated. Gastric cancer tissues were obtained from 102 patients. CIHM of p 14, p 16, DAP-kinase and CDH1 genes were determined by methylation-specific polymerase chain reaction (MSP). CIHM high was defined as three or all CpG islands methylated. We employed the PCR-SSCP (multiplex PCR for IL-17A and -17F) method to detect the gene polymorphisms. We did not find significant association between CIHM status and IL-17F (7488T>C and MIF (-173G>C polymorphisms. However, concerning the IL-17A (-197G>A) polymorphism, we found that IL-17A G carrier (GG+GA) held a significantly higher risk of CIHM of p16 (OR = 11.22, 95% CI=1.38-91.17, p=0.024) and CIHM high (OR=3.51, 95% CI=1.15-10.68, p=0.027). An association was also found between the 7-CATT repeat carrier (5/7 + 6/7 + 7/7) of the MIF polymorphism (-794-CATT) and reduced risk of CIHM of CDH1 (OR=0.36, 95% CI=O. 14-0.92, p=0.032). No association was found between CHIM status and homozygote genotypes of each repeat (-794-CATT 5/5, 6/6, and 7/7). The present results provided evidence that the genetic polymorphisms of IL-17A, and MIF-794-CATT repeat are associated with CIHM status in the gastric cancer. Genetic polymorphisms of IL-17A, and MIF-794-CATT repeat may be involved in methylation-related carcinogenesis in the stomach.

There have been reports showing a protective role of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) against gastrointestinal cancers. E-cadherin (CDH1) is an adhesion molecule involved in tumour invasion/metastasis. Silencing of CDH1 by promoter CpG island methylation was shown in gastric cancer, precancerous lesion, and Helicobacter pylori-infected chronic gastritis. We investigated the methylation status of CDH1 in noncancerous gastric mucosa in chronic aspirin user, and assessed its effect on methylation-associated carcinogenesis. Gastric mucosa samples from antrum were obtained from 217 cancer-free subjects, including 37 chronic aspirin users and 180 subjects with no history of chronic or occasional intake of aspirin. Methylation-specific polymerase chain reaction (PCR), i.e., MSP, was performed for CDH1 gene promoter. In all 217 subjects, CDH1 methylation was detected for 69 subjects (31.7%). CDH1 methylation more frequently occurred in H. pylori-infection-positive subjects (P < 0.0001), while chronic aspirin users had a significantly lower risk of CDH1 methylation [nonuser versus user 36.1% versus 10.8%; odds ratio (OR) = 0.21, 95% confidence interval (CI) = 0.07-0.63, P = 0.005]. Logistic regression analysis showed that chronic aspirin use was the independent factor for lower risk of CDH1 methylation (adjusted OR = 0.21, 95% CI = 0.07-0.66, P = 0.008). Chronic aspirin use was associated with lower risk of CDH1 methylation in H. pylori-positive subjects (nonuser versus user 49.5% versus 19.0%; OR = 0.24, 95% CI = 0.08-0.76, P = 0.01). Similar trend was also found in H. pylori-negative subjects (P = 0.07). No association was found between CDH1 methylation status, and duration and dose of aspirin. Our data suggest that chronic aspirin use is associated with reduced risk of CDH1 methylation in human gastric mucosa. Aspirin may have suppressive role against methylation-related gastric carcinogenesis.

Capsaicin/vanilloid (transient receptor potential vanilloid 1, (TRPV1) receptor has been shown to be expressed in gastrointestinal tract and play a role as a member of sensory ion channel superfamily. The G315C polymorphism affects the TRPV1 gene and alters its protein level. We aimed to investigate the effect of TRPV1 G315C polymorphism on functional dyspepsia (FD) in a Japanese population. © 2010 Lippincott Williams &amp Wilkins, Inc.

CpG island hypermethylation (CIHM) of tumor suppressor genes is one of the major events in the gastric carcinogenesis. We aimed to investigate the association between CIHM status of tumor suppressor genes and clinicopathological and morphological characteristics of gastric cancer. Patients and Methods: CIHM of p14, p16, Death-associated protein kinase (DAPK) and E-cadherin (CDHI) genes were determined by methylation-specific-polymerase chain Reaction in 146 gastric cancer tissues. CIHM-high was defined as three or more methylated CpG islands. Results: CIHM pf p14 was found in 70 (47.9%) cases, in 26 (17.8%) for p16, in 104 (71.2%) for CDHI and in 127 (87.0%) for DAPK. CIHM-high was also found in 63 cases (43.2%). No association was found between between CIHM status and different staging, Lauren's subtypes, anatomic location, venous and lymphatic invasion, lymph node metastasis, distant metastasis, or peritoneal dissemination. However, among early gastric cancer cases, the depressed type with ulceration presented a significantly lower prevalence of CIHM of DAPK. In addition, Borrmann type IV cases presented significantly lower prevalence of CIHM-high among advanced gastric cancer. The Borrmann type IV cases also presented lower mean methylation number Conclusion: The present results suggest that CIHM of DAPK and CIHM-high were associated with the morphological appearance of depressed type with ulceration in early gastric cancer, and Borrmann type IV advanced gastric cancer, respectively.

Background/Aim: We investigated the relationship of gastric cancer (GC) and CpG island hypermethylation (CIHM) in tumor suppressor genes of non-neoplastic gastric mucosa. Methods: Gastric mucosa samples were obtained from 125 GC and 180 non-GC subjects. CIHM of p14, p16, DAP-kinase and CDH1 genes were determined by methylation-specific polymerase chain reaction. High CIHM was defined as three or all methylated CpG islands. Results: Rates of CIHM of p14, CDH1, DAP-kinase, and high CIHM were significantly higher in all GC samples than non-GC samples (p14: 32.2 vs. 50.4%; OR = 1.70, 95% CI = 1.03-2.80, p = 0.04, CDH1: 36.1 vs. 84.0%; OR = 8.65, 95% CI = 14.74-15.77, p < 0.0001, DAP-kinase: 42.2 vs. 83.2%; OR = 5.98, 95% CI = 3.37-10.62, p < 0.0001, and high CIHM: 44.4 vs. 80.8%; OR = 4.40, 95% CI = 2.51-7.72, p < 0.0001). CIHM in CDH1 and DAP-kinase were associated with a greater risk of GC including all of its different subtypes. An increased number of CIHM was associated with an increased risk of all GC (1 CIHM; OR = 2.33, 95% CI = 0.82-6.64, p = 0.11, 2 CIHM; OR = 4.89, 95% CI = 1.79-13.37, p = 0.002, 3 CIHM; OR = 9.43, 95% CI = 3.20-27.78, p < 0.0001, and all CIHM OR = 24.71, 95% CI = 6.70-91.18, p < 0.0001). Three and all CIHM were closely associated with a higher risk of intestinal-type GC, Helicobacter pylori-positive infection status, male gender, and middle and older GC while 3 CIHM was closely associated with a higher risk of diffuse-type GC, H. pylori-negative infection status and younger GC. Conclusions: CIHM of CDH1 and DAP-kinase in non-neoplastic gastric mucosa corresponded to a risk of GC regardless of histological subtype, H. pylori infection status, gender and generation. An increased number of CIHM correlates with a higher GC risk including its various clinico-pathological subtypes. Copyright (C) 2010 S. Karger AG, Basel

We report the case of a 56-year-old woman who had a gastrointestinal stromal tumor (GIST) of the stomach. She was admitted to our hospital for epigastric pain, nausea, and severe acute anemia (hemoglobin level 4.3 g/dl). Esophagogastroduodenoscopy revealed a narrow stalk-like based, hemorrhagic and uneven protruding lesion in the lesser curvature of the gastric upper corpus. Although the tumor was less than 2 cm in diameter and was probably a benign GIST according to histology, laparoscopy-assisted local resection was needed because the patient had continuous severe anemia and epigastric pain. Histological assessment showed that the elongated spindle-like tumor cells originated from the intrinsic muscle layer, and was shown with growth to the mucosal side, cropping out to the surface in most areas of the protruding lesion. Only a small part of the tumor was within nontumoral gastric mucosa. Most of the tumor cells demonstrated immunoreactivity for KIT and CD34 in the cytoplasm but not for αSMA, S100, and desmin. Mitotic activity (0/50 high power field) and the labeling index for MIB-1 (about 1%) were low. The GIST of the stomach described in this report was a rare case with a narrow stalk-like based, uneven protruding mass presenting with severe acute anemia despite small size. Copyright © 2010 S. Karger AG.

Objectve Although inflammatory changes in the gastric mucosa are commonly observed in Japanese patients with functional dyspepsia (FD), detailed data regarding the relationship between the genetic regulatory factors of inflammation and FD are not available. Superoxide has been implicated in the pathogenesis of Helicobacter pylrori-related diseases through inflammation. Nicotinamide adenine dinucleotide phosphate oxidase, a major source of superoxide generation plays a critical role in H. pylori-related gastric inflammation. We aimed to clarify the association between C242T polymorphism of p22PHOX, an essential component of nicotinamide adenine dinucleotide phosphate oxidase and FD in a Japanese population. Methods Eighty-nine FD according to Rome III criteria and 95 asymptomatic participants enrolled in this study. The p22PHOX C242T polymorphism was determined by polymerase chain reaction restriction fragment length polymorphism. H. pylori infection status was examined by histology or antibody against H. pylori. Results Nonsignificant correlation was found between p22PHOX polymorphism and FD. In H. pylori positives, however, C242T carriers significantly associated lower risk of FD (25.9 vs. 6.2%; C/C vs. T carriers; odds ratio=0.19, 95% confidence interval = 0.05-0.71, P=0.009). This significant association remained after logistic regression analysis with adjustment for sex and age (odds ratio= 0.20, 95% confidence interval = 0.05-0.73). No significant correlation was found between p22PHOX polymorphism and a different subgroup of FD. Conclusion Our data suggest that C242T carriers status is inversely related to the risk of FD in H. pylori-infected patients. Eur J Gastroenterol Hepatol 21:1363-1368 (C) 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins.

DNA methylation is one of the major events in the early process of gastric carcinogenesis and it also occurs in non-neoplastic gastric mucosa. MTHFR plays a central role in biotransformation of folate to form S-adenosylmethionine, the universal methyl donor in cells and affects DNA methylation status. We investigated the association between common functional polymorphism of MTHFR C677T and DNA methylation status in H. pylori-infected non-neoplastic gastric mucosa. For 99 gastric mucosa samples from H. pylori positive non-cancer subjects, we assessed the association between MTHFR C677T genetic polymorphism and promoter methylation status of the four candidate promoters (p14, p16, DAP-kinase, and CDH1). In most all of the subjects, weak correlation was found between the p16 promoter methylation and MTHFR 677T carriers (age, sex-adjusted OR = 2.57, P = 0.053). When subjects were divided into two groups according to age, the MTHFR T carrier held a significantly higher risk of p16 promoter methylation, especially in 66 years or older generation (sex-adjusted OR = 14.28, P = 0.02). In addition, mean number of methylated CpG cites were significantly higher in T carrier than CC genotype in the same generation (P = 0.0418). Our data suggest that MTHFR 677T carrier influences the risk of DNA methylation in gastric mucosa in the long-term outcome of the H. pylori infection.