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Background and Aims: Early gastric cancers (EGCs) after Helicobacter pylori (H. pylori) eradication often appear as reddish depressed lesions (RDLs); the same features are also appeared in benign stomachs after eradication. We compared clinic-pathological and endoscopic features of benign and neoplastic RDLs after H. pylori eradication., Methods: 228 neoplastic RDLs after H. pylori eradication were studied. All lesions were divided into neoplastic RDLs (differentiated carcinoma or adenoma, n=114) and benign RDLs (n=114) according to the histology. Clinical and pathological characteristics were compared in neoplastic and benign groups. Endoscopic diagnostic yields using the white light (WL) endoscopy, chromoendoscopy (CE) using indigo carmine dye and the magnifying endoscopy with narrow-band imaging (ME-NBI) were also evaluated in relation to the pathological diagnosis., Results: Size of neoplastic RDLs was larger than that of benign RDLs (p<0.01). Sensitivity, specificity and accuracy for predicting pathological types of RDLs was 70.1%, 52.6% and 61.4% for the WL, 65.8%, 63.1% and 65.4% for the CE, while the ME-NBI scored better with the 88.6%, 88.6%, 99.1% and 93.9% of sensitivity, specificity and accuracy. The accuracy of the ME-NBI was 99.9% (113/114) in the benign RDLs and 89.4% (101/114) for the neoplastic RDLs. Undiagnosed neoplastic RDLs using the ME-NBI were associated with more differentiated tumors such as adenoma and well-differentiated adenocarcinoma (tub1) and the presence of an unclear demarcation line., Conclusions: ME-NBI is useful to diagnose RDLs after H. pylori eradiation, while some of neoplastic lesions are difficult to diagnose using the ME-NBI.

Helicobacter pylori induces DNA methylation in gastric mucosa, which links to gastric cancer (GC) risk. In contrast, CpG island methylator phenotype (CIMP) is defined as high levels of cancer-specific methylation and provides distinct molecular and clinicopathological features of GC. The association between those two types of methylation in GC remains unclear. We examined DNA methylation of well-validated H. pylori infection associated genes in GC and its adjacent mucosa and investigated its association with CIMP, various molecular subtypes and clinical features. We studied 50 candidate loci in 24 gastric samples to identify H. pylori infection associated genes. Identified loci were further examined in 624 gastric tissue from 217 primary GC, 217 adjacent mucosa, and 190 mucosae from cancer-free subjects. We identified five genes (IGF2, SLC16A2, SOX11, P2RX7, and MYOD1) as hypermethylated in H. pylori infected gastric mucosa. In non-neoplastic mucosa, methylation of H. pylori infection associated genes was higher in patients with GC than those without. In primary GC tissues, higher methylation of H. pylori infection associated genes correlated with CIMP-positive and its related features, such as MLH1 methylated cases. On the other hand, GC with lower methylation of these genes presented aggressive clinicopathological features including undifferentiated histopathology, advanced stage at diagnosis. H. pylori infection associated DNA methylation is correlated with CIMP, specific molecular and clinicopathological features in GC, supporting its utility as promising biomarker in this tumor type., (© 2023 Wiley Periodicals LLC.)

Predicting Helicobacter pylori (Hp) status by endoscopic finding would be useful in recent clinical condition that the use of proton-pump inhibitors, anti-platelet, and anti-coagulant have become widespread. We aimed to elucidate the diagnostic accuracy of magnifying narrow-band imaging (M-NBI) endoscopy in distinguishing Hp status in patients with or without history of successful Hp eradication and compare this accuracy to the diagnostic accuracy of conventional white light (WL) endoscopy.Two hundred seven endoscopic examinations before and after Hp eradication were performed in prospective 163 patients. Endoscopic images by using the M-NBI and conventional WL were stored electronically and randomly allocated to 2 readers for evaluation. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and diagnostic accuracy were assessed by reference to Hp status assessed by conventional clinical test.Sensitivity, specificity, PPV, NPV, and accuracy for predicting Hp status for the conventional WL was 72.2%, 75.5%, 72.2%, 75.5%, and 73.9% for the first reader; 86.6%, 57.3%, 64.1%, 82.9%, and 71.0% for the second reader. On the other hand, sensitivity, specificity, PPV, NPV, and accuracy for predicting Hp status for the M-NBI was 96.9%, 93.6%, 93.1%, 97.1%, and 95.2% for the first reader; 92.8%, 93.6%, 92.8%, 93.6%, and 93.2% for the second reader, respectively. The diagnostic accuracy of M-NBI was significantly higher than that of WL (P < .0001 for both readers). Inter-observer agreement of M-NBI (k = 0.83) was also better than that of WL (k = 0.53).M-NBI was capable of distinguishing Hp status before and after eradication therapy.

Genome-wide association study identified two functional SNPs associated with gastric cancer especially the diffuse type. The first was a polymorphism (rs2294008) in prostate stem cell antigen ( PSCA ), and the other was a polymorphism (rs4072037) in mucin 1 ( MUC1 ). DNA methylation is associated with gastric cancer and Helicobacter pylori ( H. pylori )-induced gastritis, while hypermethylation of promoter CpG island (CGI) is a common characteristic of enlarged-fold gastritis induced by H. pylori , a risk factor of diffuse-type gastric cancer. We evaluated the association between PSCA and MUC1 polymorphisms with H. pylori- -related promoter CGI methylation in the nonneoplastic gastric mucosa. PSCA rs2294008 C/T and MUC1 rs4072037 A/G polymorphisms were genotyped in 410 cancer-free subjects in relation to promoter CGI methylation status of three candidate genes, of which the methylation status is associated with H. pylori infection ( IGF2, MYOD1 , and SLC16A12 ). Methylation levels of all three genes were significantly higher in subjects with PSCA rs2294008 T/T compared with the PSCA rs2294008 C/C (all P < 0.05). Such associations were more enhanced in H. pylori -positive subjects (all P < 0.01). The multivariate analysis demonstrated that PSCA C/T [OR, 2.37; 95% CI (confidence interval), 1.06-5.29; P = 0.035] and T/T genotypes (OR, 3.2; 95% CI, 1.41-7.25; P = 0.005) were significantly associated with methylation-high gastric mucosa as independent factors. MUC1 rs4072037 A/G polymorphism was not associated with methylation status of all three genes. PSCA C/T and T/T genotypes are associated with H. pylori -related promoter DNA methylation in the gastric mucosa. Impact: Our observations provided the evidence that PSCA polymorphism influence the susceptibility to gastric cancer through DNA methylation induction., (©2019 American Association for Cancer Research.)

Background and Aim: Early-stage gastric cancer (EGC) found after Helicobacter pylori (Hp) eradication often displays non-tumorous regenerative epithelium and/or maturated tumorous epithelium overlying the cancerous tissue, which may confuse endoscopic and histological diagnosis. Probe-based confocal laser endomicroscopy (pCLE) enables in vivo real-time optical biopsy. We compared the diagnostic yields for these EGC cases using conventional white light endoscopy (WL), magnifying endoscopy with narrow-band imaging (ME-NBI), pCLE, and endoscopic biopsy; we also compared the accuracy of the horizontal extent diagnosis between ME-NBI and pCLE., Methods: This study enrolled 30 patients with 36 EGC lesions after successful Hp eradication. Diagnostic yields of WL, ME-NBI, pCLE, and endoscopic biopsy were prospectively compared. Four points of cancerous margins (oral, anal, anterior, and posterior sites) were also prospectively evaluated with M-NBI and pCLE to determine the horizontal extent of the EGC., Results: Diagnostic yield was significantly higher with pCLE than with WL and endoscopic biopsy (97 vs 72%, 97 vs 72%, P = 0.0159, 0.0077, respectively), whereas it did not differ from ME-NBI (88.9%, P = 0.371). Height of non-tumorous regenerative epithelium or maturated atypical glands was 104.7 ± 34.2 μm in the pCLE-positive cases, whereas it was 188.3 ± 27.1 μm in a pCLE-negative case (P = 0.0004). Diagnostic accuracy of the horizontal margin of EGC was significantly higher with pCLE than with ME-NBI (92 vs 70%, P = 0.0159)., Conclusion: pCLE may be helpful for the diagnosis of ambiguous ECG found after Hp eradication because it enables real-time scanning throughout the lesion and detection of subsurface microstructure., (© 2017 Japan Gastroenterological Endoscopy Society.)

The molecular mechanisms of gastric carcinogenesis after Helicobacter pylori (H. pylori) eradication remain unclear. We examined the telomere length of gastric mucosa samples after successful H. pylori eradication in patients without and those with gastric cancer. Telomere length was measured by the real-time PCR among four different groups of biopsies: gastric body from subjects without history of H. pylori infection (Hp-: n = 23), gastric body from cancer-free subjects after H. pylori eradication (cancer-free body: n = 24), gastric body from early gastric cancer patients diagnosed after H. pylori eradication (EGC body: n = 35) and its paired samples from adjacent mucosa of cancerous area (EGC ADJ: n = 35). The Hp-group presented the longest telomeres among the all groups (Hp- vs. all others, all P < 0.05). Samples from EGC body group showed shorter telomere length than the samples from cancer-free body groups (P < 0.05). Conversely, samples from EGC ADJ group showed rather longer telomere length compared to the EGC body group (P < 0.05), which was also confirmed by the comparison of 35 matched samples (P = 0.0007). Among the samples after H. pylori eradication, shorter telomere length was associated with higher expression of IL-1B and NF-kB (P < 0.0001, 0.0006, respectively). Longer telomere length was also associated with higher expression of TNF-A (P = 0.01). Telomere shortening seems to be important initial steps in gastric cancer predisposition after H. pylori eradication, while it might shift to lengthening to acquire more aggressive pathway to develop cancer.

Background and Aim: Early-stage gastric cancer (EGC) found after H. pylori eradication often has non-tumorous epithelium on the tumorous tissue and/or surface differentiation of tumors, which may confuse endoscopic and histologic diagnosis. We investigated the diagnostic reliability of EGC using conventional white light endoscopy (WLE), chromoendoscopy (CE) using indigo carmine, and magnifying endoscopy with narrow band imaging (ME-NBI) in patients with EGC with or without history of prior H. pylori eradication therapy., Methods: Diagnostic reliability of EGC by using the WLE, CE and ME-NBI was investigated in 71 EGC lesions diagnosed after successful H. pylori eradication (eradication group) and 115 EGC lesions with current H. pylori infection (control group)., Results: Diagnostic reliability of EGC was lower in the eradication group than in the control group using all three modalities. In particular, the diagnostic accuracy of CE in the eradication group was especially lower compared to that of the control group (WLE: 74.6% vs. 86.1%, P=0.05; CE: 64.8% vs. 91.3%, P<0.0001; ME-NBI: 88.7% vs. 98.2%, P=0.01). The ME-NBI scored better in comparison with WLE and CE in the eradication group (both P<0.05). The indistinct EGC lesions in the eradicated group by using CE were associated with the presence of histological changes such as non-tumorous epithelium on the tumor and/or surface differentiation of tumors (P=0.005)., Conclusions: It should be noted that the diagnostic reliability of EGC after H. pylori eradication becomes lower especially using CE. Indistinguishable cases using CE are associated with histological findings such as non-tumorous epithelium on the tumor and/or surface differentiation of tumors.

Background: Gastric cancer develops after successful H. pylori eradication in patients with severe atrophic gastritis. We classified atrophic and non-atrophic mucosa of gastric body using magnifying NBI endoscopy in patients after successful H. pylori eradication., Materials and Methods: One hundred and twenty-five patients after successful H. pylori eradication (median period after eradication: 36 months) were enrolled. Magnifying NBI patterns in the uninvolved gastric body were divided into the following: restored-small, round pits, accompanied with honeycomb-like subepithelial capillary networks; atrophic-well-demarcated oval or tubulovillous pits with clearly visible coiled or wavy vessels. The subjects were also classified into the three types: Grade 0-restored pattern is shown in all or almost the entire area of gastric body; Grade 1-mixture of restored and atrophic pattern, there is a considerable portion of the atrophic area in the lesser curvature; Grade 2-atrophic pattern is shown in all or almost the entire area of the gastric body., Results: Sensitivity and specificity for atrophic type for detection of histological intestinal metaplasia were 95.9 and 98.3%, respectively. No association was observed between the prevalence of Grades 0, 1 and 2 and duration after eradication, while grades 1 and 2 were significantly frequent in gastric cancer patients diagnosed both before (27/35: 77%) and after (23/31: 74%) eradication, compared to the cancer-free subjects (15/59: 25%) (P < 0.001). The grades 1 and 2 were also common in patients who underwent H. pylori eradication for gastric ulcer., Conclusions: Magnifying the NBI pattern well correlates with pathological status of gastric mucosa after H. pylori eradication and may predict gastric cancer occurrence.

DNA methylation is associated with "field defect" in the gastric mucosa. To characterize "field defect" morphologically, we examined DNA methylation of non-neoplastic gastric mucosa in relation to their morphology seen by narrow-band imaging (NBI) with magnifying endoscopy. Magnifying NBI of non-neoplastic gastric body was classified as follows: normal-small and round pits with uniform subepithelial capillary networks; type 1-a little enlarged round pits with indistinct subepithelial capillary networks; type 2-remarkably enlarged pits with irregular vessels; and type 3-clearly demarcated oval or tubulovillous pits with bulky coiled or wavy vessels. Methylation of nine candidate genes (MYOD1, SLC16A12, GDNF, IGF2, MIR 124A1, CDH1, PRDM5, RORA and MLF1) were determined by bisulfite pyrosequencing. Infinium HumanMethylation450 array was used to characterize the methylation of >450,000 CpG sites. Mean Z score methylation of nine genes positively correlated with the changes of mucosal patterns from normal to types 1, 2, and 3 (P < 0.0001). Genome-wide analysis showed that development of mucosal patterns correlated with methylation accumulation especially at CpG islands. Genes with promoter CpG islands that were gradually methylated with the development of mucosal patterns significantly enriched the genes involved in zinc-related pathways. The results indicates that gastric mucosal morphology predicts a "field defect" in this tissue type. Accumulation of DNA methylation is associated with "field defect" in the non-neoplastic gastric mucosa. Endoscopic identification of "field defect" has important implications for preventing gastric cancer. Our results suggest that magnifying NBI of gastric mucosal morphology predicts a "field defect" in the gastric mucosa.

Background: Telomere length shortening in Helicobacter pylori (H. pylori) infected gastric mucosa constitutes the earliest steps toward neoplastic transformation. In addition to this genotoxic changes, epigenetic changes such as promoter CpG island (PCGI) methylation are frequently occurred in H. pylori infected gastric mucosa. The aim of this study was to investigate a potential link between H. pylori related PCGI methylation and telomere length shortening in the human gastric mucosa., Methods: Telomere length was measured in non-neoplastic gastric mucosa from 106 cancer-free subjects. To identify H. pylori related PCGI methylation, bisulfite pyrosequencing was used to quantify the methylation of 49 PCGIs from 47 genes and LINE1 repetitive elementResults: We identified five PCGIs (IGF2, SLC16A12, SOX11, P2RX7 and MYOD1), which the methylation is closely associated with H. pylori infection. Hypermethylation of all these PCGIs was associated with development of pathological state from normal to mild, active, and atrophic gastritis (P<0.001) and lower pepsinogen I/II ratio (P<0.05), an indicator for gastric mucosal atrophy. Telomere shortening was significantly associated with mean Z score methylation of five PCGIs (R=-0.39, P<0.0001) and four of these locus (IGF2: R=-0.35, P=0.0003, SLC16A12: R=-0.35, P=0.0002, P2RX7: R=-0.29, P=0.003, and MYOD1: R=-0.33, P=0.0005). Multivariate analysis revealed that telomere shortening held an increased risk for hypermethylation (odds ratio: 1.71, 95% confidence interval: 1.11-2.63, P=0.016)., Conclusion: Potential link between H. pylori related PCGI methylation and telomere shortening emphasize the importance of genotoxic-epigenetic interaction in the pathological state of H. pylori infected gastric mucosa., Competing Interests: We declare that we have no conflicts of interest.

Background/aims: We investigated the effect of IL-1β and TNF-α polymorphisms, and its synergistic effect with age, gender and H. pylori status on the gastric pre-malignant condition., Methodology: IL-1β-31(T>C) and -511(C>T) and TNF-α-857 (C>T) polymorphisms were genotyped in 123 cancer free subjects. Degree of histological gastritis in both antrum and corpus, and extension of endoscopic gastric atrophy were also evaluated., Results: Significant associations were found between degrees of mononuclear cell infiltration (p=0.007) and atrophy (p=0.01) in the antrum with IL-1β-31(T>C) polymorphism, and degree of endoscopic gastric atrophy with both IL-1β-31(T>C), -511(C>T) polymorphisms (p=0.03, 0.04, respectively). When subjects were divided into the 3 groups according to the histological severity of gastric mucosal atrophy: the non-atrophic gastritis (NA) group (atrophy score=0 and metaplasia score=0), the severe atrophic gastritis (SA) group (atrophy score>=2 or metaplasia score>=2), and the mild atrophic gastritis (MA) group (all others), synergistic effect was found between numbers of IL-1β-31C, IL-1β-511T variant alleles with co-factors on the development of gastric atrophy in the antrum (gender + H. pylori + number of IL-1β-31C allele: p=0.001, age + gender + H. pylori + number of IL-1β-31C allele: p=0.0008, gender + H. pylori + number of IL-1β-511T allele: p=0.016, age + gender + H. pylori + number of IL-1β-511T allele: p=0.013), while such association was found for TNF-α-857 T allele in the antrum and all genotypes in the corpus., Conclusions: IL-1β-31C, IL-1β-511T variant alleles may accelerate gastric mucosal inflammation and atrophy, not only by themselves, but also through the interaction with co-factors.

CpG island aberrant methylation is shown to be an important mechanism in gene silencing. The important role of NF-κB in the inflammatory response to H. pylori colonization has been indicated. We investigated the influence of NFKB1 polymorphisms, -94 ins/del (rs28362491) and -449 C>G (rs72696119), on the aberrant gene methylation under H. pylori infection. Gastric mucosal samples were obtained from sub-subjects without malignancies. Methylation status of genes (p14ARF, p16INK4a, DAPK and CDH1) was determined by methylation-specific PCR (MSP). The genotyping of NFKB1 was performed by PCR-SSCP. There was a strong allelic association between rs28362491 and rs72696119, and all H. pylori-infected -94 del/del homozygotes had a -449 GG genotype. The -94 del/del homozygosity was significantly associated with risk for development of CpG island high methylation (CIHM) (two or more gene methylations), especially DAPK and CDH1 methylations, and the number of methylated genes was significantly higher in -94 del/del homozygotes than in ins/del and ins/ins (ins carrier) H. pylori-infected elder subjects. In addition, this methylated gene number was significantly increased with age in H. pylori-infected del/del homozygotes, but not in infected ins carriers. Furthermore, the inflammation score was significantly higher in H. pylori-infected del/del homozygotes compared to ins carriers. NFKB1 -94 ins/del ATTG polymorphism (rs28362491) was significantly associated with the increased risk for the development of age-related gene methylation in non-cancerous gastric mucosa under H. pylori-induced inflammation.

Background: 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., Methods: 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., Results: 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., Conclusions: 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.

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 © 2011 S. Karger AG, Basel.)

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.

Objective: 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 pylori-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.

Background: Magnifying narrow-band imaging (NBI) endoscopy clearly visualizes superficial gastric mucosal patterns and capillary patterns., Objective: To investigate gastric mucosal patterns by using magnifying NBI endoscopy and identify any relationship between those patterns and Helicobacter pylori-induced gastritis., Design: Gastric mucosal patterns seen with magnifying NBI in uninvolved gastric corpus were divided into the following categories: normal--small, round pits with regular subepithelial capillary networks; type 1-slightly enlarged, round pits with unclear or irregular subepithelial capillary networks; type 2--obviously enlarged, oval or prolonged pits with increased density of irregular vessels; and type 3-well--demarcated oval or tubulovillous pits with clearly visible coiled or wavy vessels., Setting: Department of Gastroenterology, Fujita Health University., Patients: This study involved 106 participants undergoing upper endoscopy., Results: H pylori infection-positive ratios of normal and types 1, 2, and 3 patterns were 7.5%, 92.9%, 94.5%, and 66.7%, respectively. Sensitivity and specificity for types 1 + 2 + 3 for detection of H pylori positivity and type 3 for detection of intestinal metaplasia were 95.2%, 82.2%, 73.3%, and 95.6%, respectively. Development of mucosal patterns from normal to types 1, 2, and 3 was correlated with all histological parameters (P < .0001), lower pepsinogen I/II ratios (P < .0001), and degree of endoscopic atrophy (P < .0001). Sensitivity and specificity of type 3 for the prediction of severe histological atrophy was also better than those of serum pepsinogen level and standard endoscopy., Limitations: Only 1 endoscopist performed endoscopic procedures, and interobserver agreement could not be assessed., Conclusions: Magnifying NBI endoscopy is useful for predicting H pylori infection and the histological severity of gastritis and is valuable for predicting gastric atrophy in the entire stomach.

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.

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.

Objective: Superoxide has been implicated in the pathogenesis of Helicobacter pylori-related diseases through inflammation. NADPH oxidase, a major source of superoxide generation, plays a critical role in H. pylori-related gastric inflammation. The aim of this study was to clarify the effect of the p22PHOX C242T polymorphism, an essential component of NADPH oxidase in the risk of gastroduodenal diseases, on the severity of H. pylori-induced gastritis in a Japanese population., Material and Methods: The study comprised 436 patients attending the Endoscopy Center of Fujita Health University Hospital. The p22PHOX C242T polymorphism was determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Gastritis scores of antral gastric mucosa were assessed according to the updated Sydney system., Results: The 436 patients represented 106 gastric ulcers (24.3%), 48 duodenal ulcers (11.0%), and 282 non-ulcer subjects (64.7%). No association was found between p22PHOX polymorphism and the risk of ulcer diseases compared to non-ulcer subjects. However, among H. pylori-positive subjects, the degree of intestinal metaplasia tended to be lower in 242T carriers aged more than 60 years (p=0.0488). The same allele also decreased the risk of developing a more severe intestinal metaplasia in H. pylori-positive female subjects (p=0.0441)., Conclusions: Our data suggest that the p22PHOX 242T allele is associated with a reduced risk of developing a more severe intestinal metaplasia in subjects older than 60 years of age and in female subjects with H. pylori infection.

Background: The relationship between endoscopic appearances such as endoscopic gastritis and duodenitis and dyspeptic symptoms has not been clearly demonstrated. We aimed to clarify the association of endoscopic appearances with Helicobacter pylori infection, histological severity of gastritis, and dyspeptic symptoms in a Japanese population., Methods: We enrolled 87 dyspeptic and 93 nondyspeptic subjects in this study. All subjects underwent gastroscopy, and patients with active peptic ulcer disease, reflex esophagitis with erosion, polyps >1 cm, or cancer were excluded. Endoscopic appearances in patients with dyspeptic symptoms and in those without were assessed retrospectively on the basis of endoscopic images. The degree of atrophy by the Kimura-Takemoto classification system was also assessed. Helicobacter pylori infection status was examined by histology or antibody against H. pylori. Histological severity of inflammation and glandular atrophy in the antrum were assessed according to the updated Sydney System. The odds ratio (OR) and 95% confidence interval (CI) were calculated by logistic regression using the variables age, sex, H. pylori infection status, and all endoscopic appearances., Results: The degree of atrophy tended to be lower among dyspeptic patients (P = 0.06). Among all endoscopic appearances, the liner redness (friability) in the antrum (OR = 3.90, 95% CI = 1.20-12.64) and duodenal ulcer (DU) scarring (OR = 3.41, 95% CI = 1.08-10.79) were independently associated with dyspepsia. Histological severity of inflammation and glandular atrophy were not associated with dyspeptic symptoms. Also, no correlation was found between endoscopic appearances and any of the different subgroups of dyspeptic symptoms. Patients with friability in the antrum and DU scar, which correlated with dyspeptic symptom showed some of communal symptoms such as epigastric pain, epigastric discomfort, hypochondriac pain, early satiation/postprandial fullness, and belching, but they differed considerably with respect to H. pylori positivity and the histological severity of gastritis., Conclusions: Some endoscopic appearances such as friability in the antrum and DU scarring may be associated with dyspeptic symptoms, and endoscopic appearances may be useful markers to perform clinical implementation reflecting an individual's pathophysiology of dyspeptic symptoms.

To investigate the molecular mechanisms of gastric carcinogenesis after Helicobacter pylori (H. pylori) eradication, expression of miR-124a, miR-34b, and miR-34c was examined in nonneoplastic gastric specimens after successful H. pylori eradication. The magnifying narrow-band imaging (NBI) endoscopic features of gastric mucosa were also examined. The atrophic type, an informative endoscopic feature for histological intestinal metaplasia, showed lower expression of miR-124a. Lower expression of miR-124a correlated with hypermethylation of the miR-124a3 locus. The atrophic type represents gastric microarchitectures associated with irreversibility with H. pylori eradication and downregulation of miR-124a. [ABSTRACT FROM AUTHOR]

Molecular irreversibleness with Helicobacter pylori (H. pylori) infection might have a role in gastric tumorigenesis after H. pylori eradication. We performed comprehensive DNA methylation profiling of gastric mucosa after H. pylori eradication with or without gastric cancer. Using four different groups of biopsies obtained from gastric body without history of H. pylori infection (Hp‐), gastric body without cancer after H. pylori eradication (cancer‐free body), gastric body with early gastric cancer diagnosed after H. pylori eradication (EGC body) and their paired samples from adjacent mucosa of cancer (EGC ADJ), methylation status of five candidate genes (MYOD1, SLC16A12, IGF2, RORA and PRDM5) was examined by the bisulfite pyrosequencing. An Infinium Methylation EPIC BeadChip array was also used to characterize the methylation status of greater than 850,000 CpG sites. The EGC ADJ group showed highest methylation levels of five candidate genes among the four groups of biopsies. In the gastric body (cancer‐free body + EGC body), methylation levels were significantly decreased in patients with longer period after eradication, while such association was not observed in EGC ADJ group. Hyper methylated samples were associated with shorter telomere, an indicator for rapid cell turnover, and higher DNMT1 protein expression, an enzyme related to methyl transfer reaction. The genome‐wide methylation analysis demonstrated strikingly higher methylation levels especially at CpG islands in the EGC ADJ group. Exclusively hypermethylated promoter CpG islands in the same group frequently coded zinc finger proteins. Our data show that DNA methylation accumulation is associated with molecular irreversibleness and gastric carcinogenesis after H. pylori eradication. What's new? Molecular irreversibleness caused by Helicobacter pylori infection might play a role in gastric tumorigenesis sometimes observed after successful eradication, but the mechanisms remain unclear. This study documents DNA methylation accumulation in the mucosa adjacent to gastric cancer after H. pylori eradication, supporting the concept that DNA methylation is associated with molecular irreversibleness and gastric carcinogenesis and could help find biomarkers. The discovery of frequently methylated genes that code zinc finger proteins also emphasizes the importance of pathway‐specific molecular changes, and suggests that targeted epigenetic therapies could be useful in the treatment and chemoprevention of gastric cancer after H. pylori eradication. [ABSTRACT FROM AUTHOR]

The molecular mechanisms of gastric carcinogenesis after Helicobacter pylori (H. pylori) eradication remain unclear. We examined the telomere length of gastric mucosa samples after successful H. pylori eradication in patients without and those with gastric cancer. Telomere length was measured by the real-time PCR among four different groups of biopsies: gastric body from subjects without history of H. pylori infection (Hp-: n = 23), gastric body from cancer-free subjects after H. pylori eradication (cancer-free body: n = 24), gastric body from early gastric cancer patients diagnosed after H. pylori eradication (EGC body: n = 35) and its paired samples from adjacent mucosa of cancerous area (EGC ADJ: n = 35). The Hp-group presented the longest telomeres among the all groups (Hp- vs. all others, all P < 0.05). Samples from EGC body group showed shorter telomere length than the samples from cancer-free body groups (P < 0.05). Conversely, samples from EGC ADJ group showed rather longer telomere length compared to the EGC body group (P < 0.05), which was also confirmed by the comparison of 35 matched samples (P = 0.0007). Among the samples after H. pylori eradication, shorter telomere length was associated with higher expression of IL-1B and NF-kB (P < 0.0001, 0.0006, respectively). Longer telomere length was also associated with higher expression of TNF-A (P = 0.01). Telomere shortening seems to be important initial steps in gastric cancer predisposition after H. pylori eradication, while it might shift to lengthening to acquire more aggressive pathway to develop cancer. [ABSTRACT FROM AUTHOR]

Residual DNA methylation in the gastric mucosa after Helicobacter pylori ( H. pylori) eradication may have a role in gastric carcinogenesis. We examined the association between morphologic features and promoter methylation status of non-neoplastic gastric mucosa especially after H. pylori eradication. A total of 140 gastric specimens from 99 participants who had at least 6 months of post-eradication period were examined. The magnifying narrow-band imaging (NBI) endoscopic feature of gastric mucosa was divided into two types: restored-small, round pits, accompanied with honeycomb-like subepithelial capillary networks; atrophic-well-demarcated oval or tubulovillous pits with clearly visible coiled or wavy vessels. Methylation status of five candidate genes ( MYOD1, SLC16A12, IGF2, RORA, and PRDM5) were examined by bisulfite pyrosequencing. The atrophic type, informative endoscopic features of intestinal metaplasia, demonstrated higher methylation levels in all five genes compared to the restored type (all P < 0.0001). In the restored type, methylation levels were significantly lower among the samples with longer post-eradication period (for all genes, P < 0.0001), which was not observed in atrophic type (for all genes, P > 0.1). Multivariate analysis demonstrated that atrophic type or presence of intestinal held an independent factor for hyper methylation (odds ratio: 24.69, 95% confidence interval: 6.95-87.76, P < 0.0001). The atrophic type by the magnifying NBI and presence of intestinal metaplasia are the morphologic characteristics of residual DNA methylation of after H. pylori eradication, regardless of the post-eradication period and it might be considered as the epigenetic irreversible point with H. pylori eradication. [ABSTRACT FROM AUTHOR]

Background: The effect of H. pylori eradication in gastric cancer prevention can be attributed to the improvement of atrophic gastritis, which is a known risk of gastric cancer. However, gastric cancer has also been diagnosed after long-term H. pylori eradication. This study aimed to clarify the association between gastric atrophy and gastric cancer after H. pylori eradication, including its clinicopathological features. Methods: A total of 55 consecutive patients with 64 early gastric cancers (EGCs) diagnosed after H. pylori eradication were enrolled. The degree of endoscopic atrophy and the histological degrees of mononuclear cell infiltration, atrophy, and metaplasia in the corpus and adjacent mucosa of the EGCs were determined and scored. Results: The majority of EGCs (63/64) were located within the endoscopically assessed atrophic mucosa or along the atrophic border. The adjacent mucosa of the EGCs presented significantly higher degrees of all histological parameters than in the corpus (mononuclear cell infiltration, 0.86+/-0.09 vs. 0.51+/-0.11, P = 0.016; atrophy, 1.77+/-0.13 vs. 0.65+/-0.14, P<0.0001; metaplasia, 1.68+/-0.13 vs. 0.48+/-0.1, P<0.0001). The degree of endoscopic atrophy improved in the patients with longer post-H. pylori eradication periods; however, this trend was not observed for the histological parameters, and high degrees of atrophy and metaplasia were observed in the adjacent mucosa of the EGCs compared with the corpus during all periods (all P<0.05). The histological degrees of atrophy and metaplasia in the adjacent mucosa were particularly higher in the patients who underwent eradication due to gastric ulcers. Conclusions: Severe gastric atrophy remained in the adjacent mucosa of the EGCs after H. pylori eradication, which may be linked to gastric carcinogenesis. [ABSTRACT FROM AUTHOR]

Background. Gastric cancer is discovered even after successful eradication of H. pylori. We investigated clinic pathological features of early gastric cancers after H. pylori eradication. Methods. 51 early gastric cancers (EGCs) from 44 patients diagnosed after successful H. pylori eradication were included as eradication group. The clinic-pathological features were compared with that of 131 EGCs from 120 patients who did not have a history of H. pylori eradication (control group). Results. Compared with control group, clinic-pathological features of eradication group were characterized as depressed (p<0.0001), reddish (p=0.0001), and smaller (p=0.0095) lesions, which was also confirmed in the comparison of six metachronous lesions diagnosed after initial ESD and subsequent successful H. pylori eradication. Prevalence of both SM2 (submucosal invasion greater than 500 μm) and unexpected SM2 cases tended to be higher in eradication group (p=0.077, 0.0867, resp.). Prevalence of inconclusive diagnosis of gastric cancer during pretreatment biopsy was also higher in the same group (26.0% versus 1.6%, p<0.0001). Conclusions. Informative clinic pathological features of EGC after H. pylori eradication are depressed, reddish appearances, which should be treated as a caution because histological diagnosis of cancerous tissue is sometimes difficult by endoscopic biopsy. [ABSTRACT FROM AUTHOR]

Background: Aberrant methylation patterns in CpG island are known to be influential in gene silencing. Histamine plays important physiological roles in the upper gastrointestinal tract and acts via the H2 receptor. We report an investigation into the effect of HRH2 promoter polymorphism (rs2607474 G > A) on the methylation of DAPK and CDH1. Methods: Non cancerous gastric mucosa samples were obtained from 115 subjects with gastric cancer (GC) and 412 non-cancer subjects (non-GC). Methylation status of genes was determined by MSP. The genotyping of rs2607474 was performed by PCR-SSCP. Results: Methylation of DAPK and CDH1 was observed in 296 and 246 subjects, respectively. The frequency of CDH1 methylation in the subjects with GC was significantly lower in cancer lesion than in non cancerous mucosa, whereas that of DAPK methylation was not different. The allelic distribution of rs2607474 was 401GG, 119GA and 7AA. The GG homozygote was associated with a significantly increased risk for methylation of both DAPK and CDH1 (p < 0.0001 and p = 0.0009, respectively). In the non-GC subjects or more than 60 years of age, GG homozygote was more closely associated with both DAPK and CDH1 methylation. However, this genotype did not show an increased risk for the development of methylation of both genes in patients with GC. In H. pylori negative subjects, GG homozygote showed an increased risk for the methylation of both DAPK and CDH1 (p = 0.0074 and p = 0.0016, respectively), whereas this genotype was associated with an increased risk for the development of DAPK methylation in H. pylori positive subjects (p = 0.0018). In addition, in subjects older than 60 years of age, atrophy and metaplasia scores were significantly higher in the GG homozygote (p = 0.011 and p = 0.039, respectively) and a significant correlation was observed between age and atrophy or metaplasia. Conclusions: Our results suggest that rs2607474 GG homozygote confers a significantly increased risk for age- and inflammation-related DAPK and CDH1 methylation. [ABSTRACT FROM AUTHOR]

Introduction: It is suggested that minimal change (grade M) esophagitis is a spectrum of gastric acid reflux disease. We evaluated the clinical significance of grade M esophagitis, including its subtypes (reddish change: MR and whitish change: MW), especially with attempt to pathological conditions in the stomach that relates to gastric acid secretion. Materials and Methods: Using 241 subjects undergoing esophagogastroduodenoscopy for various indications, we investigated the association between grade M esophagitis with histological and serological severity of gastritis and endoscopic degree of atrophy. We also examined its association with ulcer diseases and various symptoms. Results: When grade M cases were divided into MR and MW, all MR cases had MW in considerable degrees. Dyspeptic symptoms were more likely to be associated with H. pylori negative grade M cases, while presence of duodenal ulcer and its scar were associated with Helicobacter pylori-positive grade M cases. In all subjects, histological parameters, especially in the corpus, were lower in grade M cases compared to normal appearance. In grade M cases, degree of acute and chronic inflammation, and atrophy in corpus were lowest in cases that have grade MR. Grade M cases were also associated with higher pepsinogen I/II ratio and lower endoscopic atrophy. Conclusions: Pathological conditions of the stomach relate to higher gastric acid secretion correlates with grade M esophagitis. In grade M cases, appearance of MR may reflect higher gastric acid secretion or severe acid reflux than cases that have grade MW only. [ABSTRACT FROM AUTHOR]

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. 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. 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). 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. [ABSTRACT FROM AUTHOR]

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. 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. 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∼, adjusted OR = 1.62, 95%CI = 1.05-2.49, p =.03). 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Host genetic factors may play a key role in determining the long-term outcome of the Helicobacter pylori infection. Toll-like receptor 4 (TLR4) and CD14-mediated recognition of lipo-polysaccharide (LPS) is required for efficient recognition of gram-negative bacterial infections. We investigated the effects of common polymorphisms of TLR4 Asp299Gly, Thr399Ile, and CD14 promoter-C159T on the risk of gastric cancer including its subtypes and clinicopathologic features. We also investigated the effects of these polymorphisms on histologic degree of H. pylori-induced gastritis. The study was performed in 149 gastric cancer (GC) cases [mean age 64.0 +/- 12.4, M:F = 109:40] and 94 patients without evidence of GC (mean age 64.1 +/- 12.3, M:F = 65:25, Peptic ulcer diseases = 43.6%, gastritis = 56.4%) as the control group. TLR4 Asp299Gly, Thr399Ile, and CD14 promoter-C159T were determined by PCR-RFLP in all the patients. Gastritis scores of non-cancerous gastric mucosa were assessed according to the updated Sydney system in H. pylori-positive subjects (n = 179). The frequencies of CD14-260 TT and T carrier were significantly lower in patents with intestinal-type gastric cancer than in controls (OR = 0.31; 95%CI = 0.12-0.78, OR = 0.38; 95%CI = 0.18-0.81, respectively). Compared to patients older than 61 years, the atrophy score in antrum was significantly lower in TT and CT patients. TLR4 Asp299Gly and Thr399Ile were not detected in all the patients. Our data suggests that CD14 promoter-159TT and T carrier were associated with a lower risk of developing gastric mucosal atrophy in H. pylori-infected patients of more than 61 years of age, and these genotypes may reduce the risk of intestinal-type gastric cancer. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Toll-like receptors (TLRs) play important roles in the signaling of many pathogen-related molecules and endogenous proteins associated with immune activation. -196 to -174del polymorphism affects the TLR2 gene and alters its promoter activity. We investigated the influence of TLR2 -196 to -174del polymorphism on the risk of gastro-duodenal diseases, on the severity of Helicobacter pylori-induced gastritis in a Japanese population. The study was performed on 309 patients with abdominal discomfort and 146 healthy controls. -196 to -174del polymorphism of TLR2 was investigated by allele-specific polymerase chain reaction method in all of the subjects. Gastritis scores of antral gastric mucosa were assessed according to the updated Sydney system in H. pylori-positive subjects (n = 156). Patients with abdominal discomfort was consisted of 80 gastric ulcers (25.9%), 38 duodenal ulcers (12.3%), five gastric + duodenal ulcers (1.6%), 105 patients with gastritis (34.0%) and 81 normal healthy stomachs (26.2%). We did not find any association between TLR2 polymorphism and risk of gastric ulcer, duodenal ulcer, gastric and duodenal ulcer and gastritis compared to healthy controls. However, the TLR2-196 to -174ins allele was associated with severity of intestinal metaplasia in more than 60 years of ages (P = 0.02). The same allele also increased the risks of developing more severe gastric mucosal atrophy and intestinal metaplasia in female subjects (P < 0.05, P = 0.07 respectively). No association was observed between TLR2 polymorphism and severity of neutrophil and mononuclear cell infiltration. Our data suggest that the TLR2-196 to -174ins allele was associated with more severe intestinal metaplasia in patients older than was correlated with severity of gastric mucosal atrophy and intestinal metaplasia in female subjects. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Aberrant DNA methylation is one of the major events in carcinogenesis. Promoter DNA methylation is also present in various non-neoplastic tissues including gastric epithelium as age-related phenomenon, suggesting that it occurs early in the process of tumorigenesis. Aim: We aimed to clarify the relationship of aberrant DNA methylation in non-neoplastic gastric epithelia with the risk of gastric cancer, Helicobactor pylori infection, and the degree of H. pylori-induced gastritis. Methods: 89 patients enrolled in this study. The status of aberrant DNA methylation was compared in two groups of patients: 43 cases with gastric cancer (mean age 65.9 years [29–91], F:M = 0.30, intestinal type [n = 25], diffuse type [n = 18]) and 46 age- and sex-matched patients without gastric cancer (peptic ulcer diseases [n = 11], gastritis [n = 35]) as a control group. Genomic DNA was extracted directly from non-neoplastic epithelia of antral biopsies obtained by endoscopy. The promoter methylation status of the p14 and p21 genes was determined by methylation-specific-polymerase chain reaction (MSP). The promoter methylation status of the p16 gene was quantified by digital densitographic analysis following MSP. The degree of gastritis in the antrum was assessed according to the updated Sydney system. The PG I/II ratio was calculated based on the data of serum PG I and PG II levels measured by radioimmunoassay. Results: In all 89 subjects, CpG island methylation was found in 25.8% for p14, 52.8% for p16, 1.1% for p21. Among non-cancer patients, the methylation frequency of the p14 gene was significantly higher in H. pylori-positive than in H. pylori-negative patients (38.5 vs. 10.0%, p = 0.03). The mean (± SD) methylation levels of the p16 gene in non-neoplastic gastric epithelium was significantly higher in gastric cancer cases both in all patients and in H. pylori-positive patients (0.45 ± 0.31 vs. 0.20 ± 0.17; p = 0.019, 0.45 ± 0.31 vs. 0.20 ± 0.17; p = 0.016, respectively). The methylation level of the p16 gene was also associated with the presence of intestinal-type gastric cancer (p = 0.017). The methylation level of the p16 gene was significantly higher in patients with intestinal metaplasia (IM) than those without (p = 0.04). Furthermore, the methylation level of the p16 gene was correlated with lower PG l/ll ratio (p = 0.04). The methylation of the p21gene was found in only 1 patient with gastric cancer. Conclusions: Our data suggest that promoter of the p14 gene may be one of the specific regions whose methylation is closely associated with H. pylori infection. Methylation levels of the p16 gene seem to be accumulated in the progression of gastric mucosal atrophy and IM, and thus may be associated with the presence of gastric cancer especially for intestinal-type histopathology. Copyright © 2007 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]