Endoscopic features of lymphoid follicles in the colonic mucosa using the image enhanced endoscopy and its association with colorectal adenoma.

BACKGROUND/AIM: Lymphoid follicles hyperplasia (LH) is sometimes observed in the normal colon as small, round, yellowish-white nodules. LH is associated with food hypersensitivity and bowel symptoms and histologically characterized as intense infiltration of lymphocytes or plasmacytes. It is suggested that LH represents inflammatory immune response in the colonic mucosa. We investigated the presence of LH in the normal colonic mucosa and its association with incidence of colorectal lesions including colorectal cancer, adenoma and hyperplastic polyp. PATIENTS/METHODS: 605 participants undergoing colonoscopy for various indications were enrolled. Presence of LH in the proximal colon (appendix, cecum and the ascending colon) was observed using the blue laser imaging (BLI) endoscopy, a new generation image enhanced endoscopy (IEE) system. LH was defined as well demarcated white nodules. Elevated LH with erythema was distinguished as LH severe. Association between presence of LH and occurrence of colorectal lesions was investigated. RESULTS: Prevalence of all colorectal lesions and adenoma were significantly lower in LH severe group compared to the LH negative group (P = 0.0008, 0.0009, respectively). Mean number of all colorectal lesions and adenoma were also lower in LH severe group compared to the LH negative group (P = 0.005, 0.003 respectively). The logistic regression with adjustment for gender and age demonstrated that presence of LH severe held significantly lower risk of all colorectal lesions (OR = 0.48, 95%CI = 0.27-0.86) and adenoma (OR = 0.47, 95%CI = 0.26-0.86). CONCLUSION: LH in the colonic mucosa visualized by IEE is useful endoscopic finding to predict risk of colorectal adenoma.

Endoscopic features of lymphoid follicles using blue laser imaging (BLI) endoscopy in the colorectum and its association with chronic bowel symptoms.

BACKGROUND/AIM: In the colorectum, lymphoid follicles hyperplasia (LH) is sometimes observed as small, round, yellowish-white nodules. The novel image-enhanced endoscopy system named blue laser imaging (BLI) provides enhanced the contrast of surface vessels using lasers for light illumination. We investigated the endoscopic features of LH observed by using BLI endoscopy and its association with chronic bowel symptoms. PATIENTS/METHODS: 300 participants undergoing colonoscopy for various indications were enrolled. Entire colorectum was observed by using BLI-bright mode with non-magnification view. LH was defined as well demarcated white nodules. Elevated LH with erythema was distinguished as LH severe. RESULTS: LHs were observed more clearly by using BLI-bright mode compared to conventional white light colonoscopy and were also histologically confirmed as intense infiltration of lymphocytes or plasmacytes. LH was observed in 134 subjects (44.6%) and 67 (22.3%) were LH severe. LH was associated younger age (Odds ratio (OR) = 1.05, 95%Confidence Interval (95%CI) = 1.03-1.07, P<0.0001) and chronic bowel symptoms including constipation, hard stools, diarrhea and loose stools (all LH: OR = 4.03, 95%CI = 2.36-6.89, P<0.0001, LH severe: OR = 5.31, 95%CI = 2.64-10.71, P<0.0001). LH severe was closely associated with both constipation associated symptoms (OR = 3.94, 95%CI = 1.79-8.66, P = 0.0007) and diarrhea associated symptoms (OR = 5.22, 95%CI = 2.09-13.05, P = 0.0004). In particular, LH severe in the ascending colon was strongly associated with bowel symptoms (P<0.0001). CONCLUSION: LH, visualized by using BLI endoscopy was associated with bowel symptom, raising the possibility of pathogenic role of this endoscopic finding in the functional lower gastrointestinal disorders.

Role of heat-shock protein (HSP) 70-2 genotype in peptic ulcer in Japanese population.

BACKGROUND/AIMS: There have been reports showing the protective role of inducible heat-shock protein (HSP) 70 in gastric epithelial cells. An A to G transition at the 1267 position HSP70-2 gene has been shown to be associated with a different level of HSP70 mRNA expression. We aimed to clarify the effect of HSP70-2 polymorphism on the risk of peptic ulcer diseases in a Japanese population. METHODOLOGY: A total of 519 subjects participated in this study. All subjects underwent upper gastroscopy. Restriction fragment length polymorphism analysis was performed for polymorphisms at 1267 of HSP70-2 gene in all the subjects. RESULTS: After gastroscopy, 109, 53 and 357 subjects were diagnosed as gastric ulcer, duodenal ulcer and non-ulcer subjects, respectively. Although, there were no significant differences of HSP70-2 genotype distributions among nonulcer subjects, overall ulcer, gastric and duodenal ulcers when the subjects were divided into two groups according to age distribution, logistic regression analysis showed that the BB genotype increased the risk of duodenal ulcer in subjects 60 years and older. (Gender, status of H. pylori infection and NSAID use adjusted OR=3.12, 95%CI=1.33-7.35, p=0.009). CONCLUSIONS: It appears that polymorphism of HSP70-2 gene is not directly associated with the susceptibility to peptic ulcer diseases but BB genotype is associated with an increased risk of duodenal ulcer in older subjects in the Japanese population.

Gastrointestinal Stromal Tumor of the Stomach with Narrow Stalk-Like Based, Uneven Protruding Appearance Presenting with Severe Acute Anemia despite Small Size.

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.

Chronic aspirin use suppresses CDH1 methylation in human gastric mucosa.

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.

Impact of catechol-O-methyltransferase (COMT) gene polymorphism on promoter methylation status in gastric mucosa.

UNLABELLED: DNA methylation is one of the major events in the early process of gastric carcinogenesis and also occurs in non-neoplastic gastric mucosa. Catechol-O-methyltransferase (COMT) catalyzes the methylation of various endobiotic and xenobiotic substances, and protects DNA from oxidative damage. The association between a common functional polymorphism of COMT Val158Met and DNA methylation status in the stomach was investigated. PATIENTS AND METHODS: One hundred and sixty-nine gastric mucosa samples from non-cancer patients were obtained by endoscopy. The promoter methylation status of p14 and p16 was determined by methylation-specific PCR (MSP). The COMT Val158Met polymorphism was detected by PCR-restriction fragment length polymorphism (RFLP). RESULTS: CpG island methylation was observed in 32.5% of the p14, and 37.9% of the p16. The methylation status of both p14 and p16 was not associated with gender or age, while p16 methylation was strongly associated with Helicobacter pylori infection (OR=4.71, 95% CI=2.35-9.46, p<0.0001). The Val/Val genotype held a significantly higher risk of p16 methylation (OR=3.27, 95% CI=1.05-10.25, p=0.0418). CONCLUSION: The COMT polymorphism may influence the susceptibility to gene methylation in the gastric mucosa. The promoter CpG island of p16 gene, but not of p14 may be one of the specific regions whose methylation is closely influenced by the COMT polymorphism.

COMT gene Val158Met polymorphism influences the severity of intestinal metaplasia in H. pylori infected older subjects.

BACKGROUND/AIMS: A complex interaction of host genetic and environmental factors may be relevant in the development of Helocobacter pylori (H. pylori) related gastroduodenal diseases. Catechol-O-methyltransferase (COMT) is expressed catalyzes the methylation of various endobiotic and xenobiotic substances and thus might protect DNA from oxidative damage. We aimed to clarify the effect of COMT functional polymorphism on the severity of histological gastritis in a Japanese population. METHODOLOGY: 203 subjects were included in this study. Restriction fragment length polymorphism analysis was performed for polymorphisms at codon 158 in the COMT gene. Gastritis scores of antral gastric mucosa were assessed according to the updated Sydney system. RESULTS: COMT genotype distribution in the study subjects was 158Val/Val (51.2%), 84Val/Met (41.4%), and 15Met/Met (7.4%). It was within the Hardy-Weinberg equilibrium (p = 0.73). In over all subjects, the degree of intestinal metaplasia tended to be lower among 158Met/Met when compared to Val/Val (Val/Val vs. Met/Met; 0.59 +/- 0.93 vs. 0.13 +/- 0.52, p = 0.052). Among H. pylori infected subjects, the degree of intestinal metaplasia was significantly lower among 158Met carriers in 50 years or older age (Val/Val vs. Met carriers; 1.20 +/- 1.06 vs. 0.75 +/- 1.08, p = 0.0436). No significant association was found between COMT genotypes and the degree of gastritis in different gender CONCLUSION: Our data suggest that COMT gene 158Met polymorphism is associate with a reduced risk of developing more severe intestinal metaplasia in H. pylori infected older subjects.

Effect of polymorphisms in the 3'-untranslated region (3'-UTR) of VEGF gene on gastric pre-malignant condition.

BACKGROUND: A complex interaction of host genetic and environmental factors may be relevant in Helicocobacter pylori-related gastric carcinogenesis. We investigated the effect of VEGF gene polymorphisms on the risk of gastric pre-malignant condition. PATIENTS AND METHODS: The G1612A and C936T polymorphisms in the 3'-untranslated region (3'-UTR) of the VEGF gene were genotyped in 337 cancer-free individuals. The presence of intestinal metaplasia in the gastric antrum was assessed in all. Gastritis scores were also assessed according to the updated Sydney system. RESULTS: The 1612 GA genotype held a significantly higher incidence of intestinal metaplasia in H. pylori-positive individuals more than 65 years of age (OR = 4.05, 95% CI = 1.08-15.15, p = 0.038). The degree of intestinal metaplasia was also higher among individuals with 1612 GA in the same generation (GG vs. GA; 0.98 +/- 0.87 vs. 1.55 +/- 0.96, p = 0.026). CONCLUSION: The G1612A but not the C936T polymorphism of the VEGF gene is associated with gastric pre-malignant condition in older individuals.

Mannan-binding lectin B allele is associated with a risk of developing more severe gastric mucosal atrophy in Helicobacter pylori-infected Japanese patients.

OBJECTIVE: Mannan-binding lectin (MBL) is an important constituent of the innate immune system, and deficiency of MBL has been reported to increase the overall susceptibility of an individual to infectious disease. Codon 54 G/A variant of exon 1 (B allele) affects MBL2 gene and alters its activity. We investigated the influence of MBL2 variant on the risk of gastroduodenal diseases and on the severity of Helicobacter pylori-induced gastritis in a Japanese population. METHODS: One hundred and two gastric ulcers, 48 duodenal ulcers, 275 nonulcer participants were included in this study. B allele of the MBL2 gene was detected by polymerase chain reaction based restriction fragment length polymorphism. The severity of the histological chronic gastritis in antral biopsy specimens were classified according to the updated Sydney system. RESULTS: MBL2 B allele was significantly associated with severity of gastric mucosal atrophy and intestinal metaplasia (atrophy, G/G vs. G/A vs. A/A; P=0.02, A/A vs. others; P=0.009, intestinal metaplasia; G/G vs. G/A vs. A/A; P=0.03, A/A vs. others; P=0.004). When participants were divided into the following three groups according to the severity of gastric atrophy: the nonatrophic gastritis (NA) group, the severe atrophic gastritis (SA) group, and mild atrophic gastritis (MA) group, the frequency of A/A was significantly higher in the SA group than in others (SA vs. MA; odds ratio=8.42, 95% confidence interval=1.05-67.45, SA vs. others; odds ratio=10.06, 95% confidence interval=1.26-80.45). CONCLUSION: Our data suggest that the MBL2 codon 54 B allele is associated with a risk of developing more severe gastric mucosal atrophy in H. pylori-infected Japanese patients.

Increased number of methylated CpG islands correlates with Helicobacter pylori infection, histological and serological severity of chronic gastritis.

BACKGROUND: Promoter hypermethylation of tumor suppressor genes is one of the major events in gastric carcinogenesis. Promoter hypermethylation is also present in non-neoplastic gastric epithelium as age-related phenomenon and some reports suggest the potential association between promoter hypermethylation and Helicobacter pylori infection. Here, we examined whether methylation of multiple promoter CpG islands would occur by H. pylori infection and correlate with histological or serological severity of chronic gastritis. METHODS: One hundred and ninety-one gastric mucosa samples were obtained by endoscopy. The promoter methylation status of the p14, p16, DAP-kinase and CDH1 genes were determined by methylation-specific-polymerase chain reaction. The degree of gastritis in the antrum was assessed according to the updated Sydney system in 150 participants. The pepsinogen (PG) I/II ratio was calculated based on the data of serum PG I and PG II levels measured by radioimmunoassay in 54 selected cases. RESULTS: CpG island methylation was found in 32.5% for p14, 35.1% for p16, 43.5% for DAP-kinase and 36.1% for CDH1, whereas non, 1, 2, 3, and all methylation of four promoter CpG sites were present in 46 (24.1%), 59 (30.9%), 46 (24.1%), 30 (15.7%), and 10 (5.2%) participants, respectively. A strong association between the increased number of methylated CpG islands and H. pylori infection was observed (P<0.0001). An increased number of methylated CpG islands was also associated with severity of neutrophil infiltration (P<0.0001), mononuclear cell infiltration (P<0.0001) and atrophy (P=0.0021) in all, and severity of neutrophil infiltration (P=0.0177) and mononuclear cell infiltration (P=0.0004) in H. pylori-positive participants. An increased number of methylated CpG islands correlated with lower PG I/II ratio in all (P=0.0105) and H. pylori-infected participants (P=0.074). CONCLUSION: Multiple promoter CpG islands would be methylated by H. pylori infection, and an increased number of methylated CpG sites correlate with histological and serological severity of chronic gastritis.

Selenoprotein S (SEPS1) gene -105G>A promoter polymorphism influences the susceptibility to gastric cancer in the Japanese population.

BACKGROUND: Inflammation is a key factor in the process of carcinogenesis from chronic gastritis induced by Helicobacter pylori. Selenoprotein S (SEPS1) is involved in the control of the inflammatory response in the endoplasmic reticulum (ER). Recently the -105G>A polymorphism in the promoter of SEPS1 was shown to increase pro-inflammatory cytokine expression. We examined the association between this polymorphism and the risk of gastric cancer. METHODS: We took stomach biopsies during endoscopies of 268 Japanese gastric cancer patients (193 males and 75 females, average age 65.3), and 306 control patients (184 males and 122 females, average age 62.7) and extracted the DNA from the biopsy specimens. All subjects provided written informed consent. For the genotyping of the SEPS1 promoter polymorphism at position -105G>A, PCR-RFLP methods were used and the PCR products were digested with PspGI. Logistic-regression analysis was used to estimate odds ratios (OR) and 95% confidence intervals (CI), adjusting for age, sex, and H. pylori infection status. RESULTS: Among cases, the distribution of genotypes was as follows: 88.4% were GG, 11.2% were GA, and 0.4% were AA. Among controls, the distribution was as follows: 92.5% were GG, 7.2% were GA, and 0.3% were AA. Among males, carrying the A allele was associated with an increased odds of gastric cancer, compared with the GG genotype (OR: 2.0, 95% CI 1.0-4.1, p = 0.07). Compared with the GG genotype, carrying the A allele was significantly associated with increased risks of intestinal type gastric cancer (OR: 2.0, 95%CI 1.0-3.9, p < 0.05) as well as of gastric cancer located in the middle third of the stomach (OR: 2.0, 95%CI 1.0-3.9, p < 0.05). CONCLUSION: The -105G>A promoter polymorphism of SEPS1 was associated with the intestinal type of gastric cancer. This polymorphism may influence the inflammatory conditions of gastric mucosa. Larger population-based studies are needed for clarifying the relation between inflammatory responses and SEPS1 polymorphism.

MTHFR 677T carrier influences the methylation status of H. pylori-infected gastric mucosa in older subjects.

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.

Protective role of genetic polymorphism of heat shock protein 70-2 for gastric cancer risk.

BACKGROUND: Heat shock protein 70-2 (HSP70-2) has a cytoprotective role in various conditions and also protects the gastric mucosa. Recently, polymorphism of HSP70-2 at position 1267 was suggested to be associated with carcinogenesis. We investigated the association of this polymorphism with the risk of gastric cancer in the present study. METHODS: We examined 223 patients (159 men and 64 women, mean age 64.8 years) with gastric cancer who underwent gastrointestinal endoscopy at our department. The controls were 200 age-matched patients (140 men and 60 women) without gastric cancer diagnosed by gastrointestinal endoscopy. Genotyping was done by PCR-based restriction fragment length polymorphism analysis, and the PCR products were digested with PstI. The two allelic forms, corresponding to the presence or absence of the PstI site, were designated as the P1 allele and P2 allele, respectively. Logistic regression analysis was performed to calculate an odds ratios (ORs) for differences of HSP70-2 polymorphism between the two groups. RESULTS: Among the 223 patients with gastric cancer, 46 (20.6%) had P1/P1, 177 (79.4%) were P1 carriers, and 6 (2.7%) were P2/P2. In the control group, 33 (16.5%) patients had P1/P1 polymorphism, 167 (83.5%) were P1 carriers, and 12 (6.0%) were P2/P2. The OR for gastric cancer of subjects with P2/P2 polymorphism relative to P1 carriers was 0.43 (95% CI = 0.16-1.17) (P = 0.097). Among females, the OR for gastric cancer of subjects with P2/P2 polymorphism relative to P1 carriers was 0.10 (95% CI = 0.012-0.838) (P = 0.014). This polymorphism was also associated with a lower risk of middle third cancer (OR = 0.13; 95% CI = 0.02-1.00). CONCLUSIONS: P2/P2 polymorphism of HSP70-2 at position 1267 was associated with a lower risk of gastric cancer in females.

Effect of RANTES promoter genotype on the severity of intestinal metaplasia in Helicobacter pylori-infected Japanese subjects.

BACKGROUND: A complex interaction of host genetic and environmental factors may be relevant in the development of Helicobacter pylori (H. pylori)-related gastro-duodenal diseases. RANTES is a potent chemoattractant peptide for memory T lymphocytes and eosinophils, and has been shown to be enhanced in H. pylori-infected gastric mucosa. We aimed to clarify the effect of RANTES functional promoter polymorphism on the risk of gastro-duodenal diseases in a Japanese population. METHODS: Four hundred and eighty-three subjects, comprising 106 gastric ulcer, 52 duodenal ulcer, and 325 non-ulcer subjects, were included in this study. Restriction fragment length polymorphism (RFLP) analysis was performed for polymorphisms at -28 C/G in the RANTES gene promoter region. Gastritis scores of antral gastric mucosa were assessed according to the updated Sydney system. RESULTS: There were no significant differences in the RANTES promoter genotype distributions among non-ulcer subjects, ulcer patients, and gastric and duodenal ulcers. However, the degree of intestinal metaplasia was significantly lower among G carriers in H. pylori-infected subjects aged 60 years or older (C/C vs. G carriers; 1.28 +/- 1.02 vs. 0.83 +/- 0.89, P = 0.0357). In addition, we also found that the same genotype held a lower risk of more severe intestinal metaplasia in H. pylori-infected female subjects (C/C vs. G carriers; 0.91 +/- 1.03 vs. 0.41 +/- 0.73, P = 0.0443). CONCLUSION: The polymorphism of RANTES promoter is not associated with the susceptibility to peptic ulcer diseases, but the -28 G carrier is associated with a reduced risk of developing more severe intestinal metaplasia in H. pylori-positive subjects aged 60 years and older and in female subjects.

No association between a genetic variant of the p22PHOX component of NADPH oxidase C242T and ulcerative colitis.

BACKGROUND/AIMS: Reactive oxygen species has been implicated in the development of ulcerative colitis (UC). NADPH oxidase, a major source of superoxide generation play a critical role in H. pylori related gastric inflammation. We aimed to clarify the effect of C242T polymorphism of p22PHOX, an essential component of NADPH oxidase on the risk of UC in a Japanese population. METHODOLOGY: 123 UC patients and 459 healthy control (HC) subjects participated in this study. The p22PHOX C242T polymorphism was determined by polymerase chain reaction-restriction fragment length polymorphism. RESULTS: In the HC group, the p22 PHOX genotype distribution was 379C/C (82.6%), 79C/T (17.2%), and 5T/T (1.2%). Meanwhile, the p22 PHOX geno type distribution in UC group was 96C/C (78.0%), 26C/T (21.1%), and 1T/T (0.9%). No significant difference of the p22 PHOX genotype distribution was observed between HC and UC groups. (C/C vs. T/T; OR=0.80, 95% CI=0.09-6.84, C/C vs. C/T; OR=1.37, 95% CI=0.83-2.25, C/C vs. T carriers; OR=1.33, 95% CI=0.82-2.18, T/T vs. others; OR=0.74, 95% CI =0.09-6.43). No association was also found between p22PHOX gene polymorphism and different clinicopathological features of UC such as gender, age, age of onset, clinical type, extension of colitis and response to treatment. CONCLUSIONS: It appears that the C242T polymorphism of p22 PHOX is not associated with the incidence of gastric cancer in the Japanese population.

Oral spherical adsorptive carbon for the treatment of intractable anal fistulas in Crohn's disease: a multicenter, randomized, double-blind, placebo-controlled trial.

OBJECTIVES: Anal fistulas are common in individuals with Crohn's disease (CD). We sought to evaluate the efficacy of oral spherical adsorptive carbon (AST-120) (Kremezin; Kureha Corporation, Tokyo, Japan) for the treatment of intractable anal fistulas in patients with CD. METHODS: In this multicenter, randomized, double-blind, placebo-controlled trial, patients with CD and at least one active anal fistula under treatment were assigned to receive either AST-120 or placebo for 8 wk. Improvement was defined as a reduction of 50% or more from baseline in the number of draining fistulas observed at both 4 and 8 wk. Remission was defined by closure of all draining fistulas at both 4 and 8 wk. The Perianal Disease Activity Index (PDAI) and Crohn's Disease Activity Index (CDAI) were also assessed. RESULTS: In total, 62 patients were randomized, of whom 57 received AST-120 (N = 27) or placebo (N = 30). The improvement rate in the AST-120 group (37.0%) was significantly greater than that in the placebo group (10.0%) (P= 0.025). The corresponding remission rates were 29.6% and 6.7%, respectively (P= 0.035). PDAI significantly improved at both 4 and 8 wk with AST-120, compared to placebo (P= 0.004 and P= 0.005, respectively). CDAI was also significantly improved at both 4 and 8 wk in the AST-120 group, compared to the placebo group (P= 0.007 and P= 0.001, respectively). AST-120 treatment was well tolerated and no life-threatening adverse events were observed. CONCLUSION: AST-120 is useful for the control of intractable anal fistulas in CD patients.

Aberrant DNA methylation in ulcerative colitis without neoplasia.

BACKGROUND/AIMS: DNA methylation has been reported to correlate with the development of colitis associated cancer. We detected the promoter methylation of estrogen receptor gene (ER), TP53, p14, p16, p21 and hMLH1 in ulcerative colitis without neoplasia. METHODOLOGY: A total of 49 specimens from 36 patients, including 36 at rectal inflammatory mucosa and 13 at terminal ileum were obtained by colonoscopic biopsies. Methylation specific polymerase chain reaction were performed to detect the methylation in promoters of the above six genes. RESULTS: Methylation rate of ER promoter was significantly higher in the rectal mucosa than that in the ileum (76.3% vs. 46.2%, P=0.044). Moreover, ER methylation in rectal mucosa was significantly higher in relapse-remitting type compared to one attack only type cases (P=0.008), and also increased in cases longer than 7 years (P=0.036). Methylation rates of p14 or p16 were higher in rectal mucosa than those in the ileum, but the differences were not of statistic significance. Meanwhile, methylation in TP53 promoter was found in only one case, while p21 and hMLH1 methylation were negative in all cases. CONCLUSIONS: Methylation in promoters of ER, p14 and p16 occurs in rectal inflammatory mucosa without neoplasia. Examination of ER methylation in rectal mucosa may be useful for predicting cases at high risk of neoplasia.

Mannan-binding lectin (MBL) polymorphism and gastric cancer risk in Japanese population.

BACKGROUND: Mannan-binding lectin (MBL) is believed to be an important constituent of the innate immune system. It has been reported that the codon 54 G/A polymorphism of exon-1 affects the MBL2 gene and alters its activity. AIMS: We investigated the association between polymorphism of the MBL2 gene and gastric cancer risk as well as Helicobacter pylori infection in a Japanese population. METHODS: The study cohort comprised 388 gastric cancer patients and 144 healthy volunteers. Polymorphism at codon 54 of exon 1 of the MBL2 gene was investigated by PCR-based restriction fragment length polymorphism analysis. RESULTS: There was no significant difference in the distribution of the MBL2 genotype among the gastric cancer patients and healthy controls. However, the carrier of the A allele was more prevalent among patients with a more advanced stage gastric cancer [odds ratio (OR) 1.68, 95% confidence interval (CI) 1.05-2.67; P = 0.03] and also had an increased risk of gastric cancer among patients 65 years of age or younger (OR = 1.6, 95%CI = 1.01-2.52, <0.05). CONCLUSION: The codon 54 polymorphism of the MBL2 gene is associated with more advanced phenotypes of gastric cancer and the risk of gastric cancer in Japanese patients 65 years of age or younger.

Influence of peroxisome proliferator-activated receptor (PPAR)gamma Plo12Ala polymorphism as a shared risk marker for both gastric cancer and impaired fasting glucose (IFG) in Japanese.

Activation of peroxisome proliferator-activated receptor gamma (PPARgamma) has been shown to inhibit the proliferation of gastric cancer cells. A common polymorphism at codon 12 of this gene (Pro12Ala) has been shown to confer protection against diabetes and colorectal cancer. We investigated the influence of PPARgamma gene Plo12Ala polymorphism on the risk of gastric cancer and on the severity of Helicobacter pylori-induced gastritis as well as impaired fasting glucose (IFG) in Japanese. About 215 patients with gastric cancer (GC) and 201 patients without GC enrolled in this study. Plo12Ala polymorphism of PPARgamma was investigated by PCR-RFLP in all of the subjects. The gastritis score of noncancerous antral mucosa was calculated by the updated Sydney system. The diagnosis of IFG was based on repeated evidence of serum fasting glucose (SFG) concentration of greater than or equal to 110 mg/dl. The Plo12Ala genotype of PPARgamma showed a significantly higher frequency in GC patients than in controls (OR = 2.43; 95%CI = 1.04-5.67). In contrast, the Plo12Ala genotype held a lower risk of IFG (OR = 0.33; 95%CI = 0.13-0.83). The same genotype was associated with an increased risk of non-cardiac gastric cancer (OR = 2.39; 95%CI = 1.02-5.65), lower third gastric cancer (OR = 3.56; 95%CI = 1.31-9.71), advanced cancer (OR = 2.93; 95%CI = 1.13-7.58), and Lauren's intestinal cancer (OR = 2.94; 95%CI = 1.13-7.66). Among 151 gastric cancer subjects, the atrophy and metaplasia scores of the antral mucosa adjacent to cancer showed a tendency to be higher in those with the 12Ala allele. Our study suggests that the PPARgamma Pro12Ala polymorphism may be a shared risk marker of both IFG and gastric cancer in Japanese.