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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.)

Competing Interests: The authors declare that they have no conflict of interest.

Objective In general, surface ulceration in gastric gastrointestinal stromal tumor (GIST) is considered a malignant feature; however, the mechanism underlying its formation has not been evaluated in detail. In this study, we analyzed the factors involved in ulceration using resected specimens of gastric GIST. Methods A total of 48 samples were retrospectively analyzed. We examined the association of surface ulceration of gastric GIST with the MIB-1 labeling index, mitotic number, tumor size, endoscopic ultrasound (EUS) findings and growth pattern on computed tomography (CT). Results The proportion of men was significantly higher in the ulceration group than in the non-ulceration group (p=0.04146), whereas age was not significantly different between the groups. Tumor was significantly larger in the ulceration group than in the non-ulceration group (p=0.0048). There was no correlation between tumor size and ulcer number. The MIB-1 index was not related to ulceration, nor were EUS findings. The number of mitotic cells tended to be higher in the ulceration group than in the non-ulceration group (p=0.05988). Intraluminal growth pattern was strongly associated with ulceration (p=0.00019). After a multivariate analysis, the growth pattern was the only factor associated with ulceration of gastric GIST. Conclusion Although formation of surface ulceration in gastric GIST was partially associated with the degree of malignancy, the growth pattern was the most important factor associated with ulceration in gastric GIST.

Objectives: Comprehensive assessments of the long-term outcomes of endoscopic submucosal dissection (ESD) for early gastric cancer (EGC) in the elderly are unavailable. We aimed to create a scoring system to predict the long-term prognosis after ESD for EGC among patients aged ≥75 years., Methods: We conducted retrospective studies of two cohorts: a single-center cohort (2006-2011) for developing the scoring system, and a multicenter cohort for validating the developed system (2012-2016). In the development cohort, factors related to death after ESD were identified using multivariable Cox regression analysis, and a predictive scoring system was developed. In the validation cohort, the scoring system was validated in 295 patients., Results: In the development cohort, Charlson comorbidity index (CCI) ≥3 (hazard ratio [HR] 3.017), high psoas muscle index (PMI) (HR 2.206), and age ≥80 years (HR 1.978) were significantly related to overall survival after ESD. Therefore, high CCI, low PMI, and age ≥80 years were assigned 1 point each. The patients were categorized into low (≤1 point) and high (≥2 points) score groups based on their total scores. In the validation cohort, 184 and 111 patients were assigned to the low- and high-score groups, respectively. In comparisons based on Kaplan-Meier curves, the 5-year survival rate was 91.5% in the low-score group and 57.8% in the high-score group (log-rank test; P < 0.001)., Conclusion: Our scoring system including high CCI, low PMI, and age ≥80 years could stratify the long-term prognosis of elderly patients aged ≥75 years after ESD for EGC., (© 2022 Japan Gastroenterological Endoscopy Society.)

Background and Aim: The management of bleeding during endoscopic submucosal dissection (ESD) is critical and related to the procedure time. We collaborated on a new image enhancement algorithm with parameter optimization for clinical use being developed by FUJIFILM Co. and processed white light image data offline to evaluate the effectiveness of this technology. This study aims to evaluate the clinical usefulness of this technology., Methods: Eighteen video scenes of bleeding points from five gastric ESDs were selected and processed by the new image enhancement algorithm. The time until a bleeding point was found, visibility of a bleeding point, and color abnormality of the submucosal layer were evaluated by ESD experts, ESD trainees, and endoscopy trainees. The color differences between the bleeding point and the surroundings in CIE-L*a*b* color space were calculated in the original and enhanced images., Results: The time until a bleeding point was found in the enhanced videos was significantly shorter than that in the original videos (11.10 s vs 13.85 s) (P = 0.017). On a 5-point (-2 to +2) Likert scale of visibility, the enhanced image was slightly superior to the original (+0.45), and the appearance of the submucosa was comparable between images (+0.14). The color difference among the bleeding areas on the enhanced images was significantly larger than that on the original images (10.93 vs 8.36)., Conclusion: This novel image enhancement algorithm emphasizes the color difference between a bleeding point and the surrounding area, which would help find bleeding points faster during ESD for the less experienced endoscopists., (© 2022 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Rationale: API2-MALT1 positive gastric mucosa-associated lymphoid tissue (MALT) lymphomas are considered to have favorable prognosis. We report a case of API2-MALT1 positive gastric MALT lymphoma, treated by endoscopic submucosal dissection (ESD)., Patient Concerns: A 51-year-old man underwent esophagogastroduodenoscopy (EGD) for the annual health checkup examination., Diagnoses: The EGD showed a reddish depressed lesion with small reddish spots in the lower gastric body. There was no endoscopic atrophy in the entire stomach and Helicobacter pylori (H. pylori) serum test was negative. Infiltration of small lymphocytes was shown in the gastric tissues obtained by the endoscopic biopsy. The fluorescence in situ hybridization using the biopsy samples confirmed the presence of genetic translocation of API2-MALT1, suggesting that the lesion is API2-MALT1 positive MALT lymphoma., Interventions: Since endoscopic ultrasound suggested that the lesion was localized within the lamina propria mucosae, we performed ESD to achieve the en bloc resection of the lesion., Outcomes: Conclusive diagnosis of gastric MALT lymphoma was made based on the resected specimen. Lateral and vertical margins were negative. No lymphoma cells were detected using endoscopic biopsy after 5 years., Lessons: Our report suggests that ESD can be considered as alternative treatment for API2-MALT1 positive gastric MALT lymphoma if the lesion was localized within the gastric mucosa., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Aim: To investigate the associations between LINE1 methylation, an indicator for genome-wide hypomethylation, molecular and clinicopathological characteristics of gastric cancer (GC) patients. Patients & methods: LINE1 methylation statuses were examined in paired cancerous, non-neoplastic mucosa from 217 GC and gastric mucosa from separate group of 224 noncancer patients. CpG island methylator phenotype, TP53 and KRAS mutation, MLH1 methylation status and promoter hypermethylation of GC related and H. pylori -related genes were examined. Results: Lower LINE1 methylation was observed in primary GC compared with non-neoplastic gastric mucosa and associated with CpG island methylator phenotype, TP53 mutation, MLH1 methylation and promoter hypermethylation of GC related and H. pylori -related genes. Conclusion: Lower LINE1 methylation correlates specific molecular subtypes and promoter hypermethylation in GC.

Both genetic and epigenetic abnormalities play important roles in gastric cancer (GC) development. We investigated whether the molecular subtypes of gastric cancer by combining genetic and epigenetic anomalies define its clinicopathological features and prognosis. The CpG island methylator phenotype (CIMP), MLH1 methylation, TP53, and KRAS mutation statuses were characterized in 214 GCs in relation to their clinicopathological features and prognosis. The molecular subtypes based on CIMP and TP53 hot spot mutation status (R175, G245, R248, R273, and R282) best predicted prognosis of GC. These subtypes contained 120 CIMP-positive (CIMP+) TP53 hot spot mutation-negative (TP53 hot spot-) cases, 81 CIMP-negative (CIMP-) TP53 hot spot- cases, 8 CIMP+TP53 hot spot mutation-positive (TP53 hot spot+) cases, and 5 CIMP- TP53 hot spot+ cases. The CIMP-TP53 hot spot+ group presented the worst overall survival (OS) and progression-free survival (PFS), followed by the CIMP+TP53 hot spot+, CIMP-TP53 hot spot- and CIMP+TP53 hot spot- groups (both P < 0.0001). These subtypes also correlated well with several aggressive clinicopathological features in that order. The molecular subtypes were independent factors for predicting overall survival (hazard ratio = 1.66, 95% CI = 1.07-2.57, P = 0.006). The molecular subtypes combining the CIMP and TP53 hot spot mutation status provide distinct clinicopathological features and prognostic impacts in GC., (© 2018 Wiley Periodicals, Inc.)

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., (© 2018 UICC.)

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.

Objective: Helicobacter pylori eradication is expected to prevent gastric cancer. However, morphological alterations after eradication often hinder accurate diagnosis. Therefore, we evaluated endoscopic and histological changes in gastric tumors after eradication of H. pylori in a time-dependent manner., Methods: We classified 144 cases of endoscopic submucosal dissection (ESD) of early gastric cancer into the following categories: (i) patients positive for H. pylori with no eradication history, (ii) patients positive for H. pylori who underwent ESD 2 months after eradication, (iii) patients negative for H. pylori with an eradication history of at least 6 months before ESD, and (iv) patients negative for H. pylori with an unknown history. We compared endoscopic and histological factors between the groups., Results: The characteristics of cancers positive for H. pylori were exploding shape, superficial high-grade atypical epithelium, and a surface proliferating zone. H. pylori eradication induced a series of endoscopic and histological changes, including shape -depression, appearance of surface regenerative and lower-grade atypical epithelium, and a downward shift of the proliferative zone within a period as short as 2 months., Conclusion: H. pylori eradication rapidly causes cancer regression and leads to tumor shrinkage, diminished atypism, and shortened proliferative zone, resulting in drastic morphological changes., (© 2019 S. Karger AG, Basel.)

DNA methylation of leukocyte DNA has been proposed to be a biomarker for cancer that can be used to target patients for appropriate clinical implementation. We investigated IGF2 DMR and LINE1 methylation in the leukocyte DNA and their association with clinicopathological features and prognosis of gastric cancer (GC) patients. Methylation status of IGF2 DMR and LINE1 in the leukocyte DNA was quantified using bisulfite pyrosequencing in 207 GC patients. Methylation of both IGF2 DMR and the LINE1 was significantly higher in the undifferentiated histologic type compared to the differentiated histologic type (both P = 0.0002). Hypermethylation of both the IGF2 DMR and the LINE1 was associated with more aggressive features of GC such as advanced stage (IGF2 DMR, P = 0.0002; LINE1, P < 0.0001), lymphatic invasion positive (IGF2 DMR, P = 0.004; LINE1, P = 0.002), venous invasion positive (IGF2 DMR, LINE1, both P = 0.03), lymph node metastasis positive (IGF2 DMR, P = 0.01; LINE1, P = 0.001), peritoneal dissemination positive (IGF2 DMR, P = 0.04; LINE1, P = 0.002), liver metastasis positive (IGF2 DMR, P = 0.008; LINE1, P = 0.001), and other distant metastasis positive (IGF2 DMR, P = 0.04). Our data suggest that high LINE1 and IGF2 DMR methylation status would be a phenomenon that is observed with the progression of GC, supporting their potential utility as a biomarker in GC patients.

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.

Background/aim: Telomere shortening in leukocytes has been thought to be associated with reduced immune response capacity and increased chromosome instability. Several studies indicate that telomere length in the peripheral blood leukocyte DNA can predict clinical outcome of several cancers. We evaluated the potential association between telomere shortening in the leukocyte DNA and clinicopathological features and prognosis of gastric cancer (GC) in Japanese patients., Materials and Methods: Telomere length in leukocyte DNA was measured using quantitative real-time polymerase chain reaction (PCR) in 207 GC patients. The association between telomere length and clinicopathological features and prognosis was evaluated., Results: These short-telomere group was significantly associated with advanced stage (p=0.015), worse overall survival (OS) and progression-free survival (PFS) (p=0.046 and 0.026, respectively). The same group was also weakly associated with overall and peritoneal recurrences (p=0.052 and 0.059, respectively)., Conclusion: Telomere shortening in leukocyte DNA is associated with advanced stage and poor prognosis of GC, which may reflect their reduced immune response capacity or increased chromosome instability., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Chemotherapy may improve outcomes in gastric cancer (GC), especially for the patients with advanced stage. To explore useful predictive factor for GC performing chemotherapy, we compared the tumor responses assessed using computed tomography (CT) with endoscopy based criteria., Methods: 192 GC patients performing chemotherapy were retrospectively studied. CT based response assessment was performed after 2 courses of treatment. Endoscopic evaluation according to The Japanese classification of gastric carcinoma was also performed at same period. Data were correlated with overall survival (OS) and progression-free survival (PFS)., Results: Majority of the cases (n = 178, 93%) received S-1 based chemotherapy as the first line treatment. 55 (29%) and 91 (47%) cases were considered to be CT and endoscopic responders. Endoscopic responder was more clearly associated with better OS and PFS compared to CT based responder by the log-rank test (P<0.0001 vs. 0.01 and P<0.0001 vs. 0.008, respectively). The association was more striking among patients performing neoadjuvant chemotherapy (P<0.0001 vs. 0.15 and P<0.0001 vs. 0.1, respectively). Multivariate survival analysis using Cox's regression model revealed that endoscopic non-responder was the independent predictive factor, being more strongly associated with worse OS when compared to CT non-responder (hazard ratio: 4.60 vs. 1.77, 95% confidence interval: 2.83-7.49 vs.1.08-2.89, P<0.0001 vs. 0.02). More advanced T, N stage and cases who had peritoneal dissemination were significantly associated with endoscopic non-responder (all P values <0.01)., Conclusion: Endoscopy based evaluation of primary lesions are clearly associated with prognosis in patients with GC who perform chemotherapy.

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., Competing Interests: The authors have declared that no competing interests exist.

Background and Aim: TP53 gene is frequently mutated in gastric cancer (GC), but the relationship with clinicopathological features and prognosis is conflicting. Here, we screened TP53 mutation spectrum of 214 GC patients in relation to their clinicopathological features and prognosis., Results: TP53 nonsilent mutations were detected in 80 cases (37.4%), being frequently occurred as C:G to T:A single nucleotide transitions at 5'-CpG-3' sites. TP53 mutations occurred more frequently in differentiated histologic type than in undifferentiated type in the early stage (48.6% vs. 7%, P=0.0006), while the mutations correlated with venous invasion among advanced stage (47.7% vs. 20.7%, P=0.04). Subset of GC with TP53 hot spot mutations (R175, G245, R248, R273, R282) presented significantly worse overall survival and recurrence free survival compared to others (both P=0.001)., Methods: Matched biopsies from GC and adjacent tissues from 214 patients were used for the experiment. All coding regions of TP53 gene (exon2 to exon11) were examined using Sanger sequencing., Conclusion: Our data suggest that GC with TP53 mutations seems to develop as differentiated histologic type and show aggressive biological behavior such as venous invasion. Moreover, our data emphasizes the importance of discriminating TP53 hot spot mutations (R175, G245, R248, R273, R282) to predict worse overall survival and recurrence free survival of GC patients., Competing Interests: No conflicts of interest exist.

Telomere shortening occurs in many organs and tissues and is accelerated by oxidative injury and rapid cell turnover. Short telomeres initiate chromosomal instability and may eventually contribute to tumorigenesis. To evaluate telomere length as potential biomarker for gastric cancer (GC) risk, we measured average telomere length using quantitative real-time PCR in GC tissues and in non-neoplastic mucosa from patients with GC and without GC. We obtained of 217 GC patients matched biopsies from the GC and adjacent tissues as well as gastric biopsies of 102 subjects without GC. Relative telomere length was measured in genomic DNA by real-time PCR. Relative telomere length decreased gradually in Helicobacter pylori (H. pylori) negative and positive gastric mucosa of GC free subjects compared with adjacent mucosa and cancer tissue from GC patients (4.03 ± 0.3 vs. 2.82 ± 0.19 vs. 0.82 ± 0.07 vs. 0.29 ± 0.09, P < 0.0001). In non-neoplastic mucosa of GC patients, shorter telomeres were found significantly more often than in that of GC free subjects (age, sex, and H. pylori adjusted odds ratio = 7.81, 95 % confidence interval = 4.71-12.9, P < 0.0001). Telomere shortening in non-neoplastic mucosa was associated with chronic inflammation (P = 0.0018) and intestinal metaplasia (P < 0.0001). No significant associations were found between relative telomere length and clinicopathological features of GC and overall survival. Telomere shortening in gastric mucosa reflects a field effect in an early stage of carcinogenesis and is associated with an increased risk of GC. Telomere length in GC is not associated with clinicopathological features or prognosis.

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

Background: Common single-nucleotide polymorphisms (SNPs) in pre-miRNAs (hsa-mir-196a2, hsa-mir-146a and hsa-mir-499) have been associated with various malignancies and their prognoses. We evaluated the associations of three selected SNPs (rs11614913, rs2910164, and rs3746444) in pre-miRNAs (hsa-mir-196a2, hsa-mir-146a and hsa-mir-499) with the prognosis of advanced gastric cancers (GCs) treated by chemotherapy., Materials and Methods: The rs11614913 (T>C), rs2910164 (C>T), and rs3746444 (A>G) SNPs were genotyped in 130 advanced GCs performing chemotherapy. Survival and response evaluation was based on overall survival (OS) and progression-free survival (PFS). Response rate (RR) was also evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST)., Results: 63 patients performed gastrectomy after chemotherapy (neoadjuvant chemotherapy) and the remaining cases performed chemotherapy alone as treatment (chemotherapy alone). The majority of cases performed S-1-based chemotherapy as the first line treatment (n=119, 92%). The rs3746444 (A>G) SNP was significantly associated with OS by the log-rank test (p=0.018), while other SNPs were not associated with OS. The rs3746444 (A>G) SNP was also associated with OS and PFS among cases of neoadjuvant chemotherapy (p=0.038, 0.024, respectively). Multivariate survival analysis using the Cox's regression model revealed that non-responder by the RECIST (Hazard ratio (HR): 2.14 95%CI 1.06-4.19), upper third cancer (HR: 2.48 95%CI 1.12-5.49) and more advanced stage (HR: 4.12 95%CI 1.06-16.02) were predictive factors for worse OS, while the rs3746444 A allele carrier was predictive factor for better OS (HR: 0.33 95%CI 0.18-0.75)., Conclusion: The rs3746444 A allele carrier in the hsa-mir-499 is associated with better prognosis in advanced GC performing chemotherapy., (Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Background/aims: Combining the magnifying endoscopy and the narrow-band imaging (NBI) system is an endoscopic imaging technique for the enhanced visualization of mucosal microscopic structure and capillaries of the superficial mucosal layer. Light blue crest (LBC) and, ridge/villous pattern have been thought to be suggestive signs for gastric intestinal metaplasia (IM) of magnifying NBI endoscopy. Since the IM is related to gastric cancer risk (GC), the prevalence of LBC and ridge/villous pattern in the nonneoplastic gastric antrum was examined in relation to gastric cancer (GC) risk and serological severity of gastritis., Methodology: In 100 subjects including 13 GC patients, gastric mucosal pattern were examined using magnifying NBI. The mucosal patterns in the antrum were classified according to the presence of LBC or ridge/villous pattern. Serum pepsinogen (PG) levels were also examined., Results: The sensitivity and specificity for predicting IM was the best when LBC and ridge/villous patterns were combined (sensitivity 95.2%, specificity 98.7%). Both LBC and ridge/villous pattern showed lower serum PGI and PGI/II ratio than those without (P = 0.046, 0.0005, respectively.) In particular, PGI/II ratio was lowest in ridge/villous pattern. The LBC and ridge/villous pattern showed higher incidence of all GC and diffuse GC compared to those without (P = 0.002, 0.002, respectively)., Conclusions: LBC and ridge/villous pattern in uninvolved gastric antrum by magnifying NBI endoscopy are useful signs for predicting gastric atrophy in the entire stomach and GC risk.

In the present study, we report an association between gastric cancer and polymorphisms in NFKB1 (rs28362941 and rs78696119). We employed the PCR-SSCP method to detect gene polymorphisms in 479 gastric cancer cases and 880 controls. The rs28362941 del/del homozygote was significantly associated with gastric cancer development; in particular it was closely associated with diffuse type gastric cancer. The rs78696119 GG homozygote was also associated with the diffuse type of gastric cancer. In young subjects, both polymorphisms were significantly associated with the development of gastric cancer. In addition, both polymorphisms were related to tumor progression such as tumor invasion and lymph node metastasis. The inflammatory cell infiltration into non-cancerous gastric mucosa was greater in the subjects with the rs28362491 del/del or rs78696119 GG genotype when compared to those with the other genotypes. In conclusion, functional polymorphisms of NFKB1 are associated with an increased risk of gastric cancer; in particular they are closely associated with the development of diffuse type of gastric cancer via severe gastric inflammation. These polymorphisms also appear to be associated with gastric cancer progression.

Whole blood DNA methylation analysis has been proposed to be a risk marker for cancer that can be used to target patients for preventive interventions. To test this, we examined whole blood DNA methylation of 16 CpG island promoters and LINE1 repetitive element in patients with gastric cancer and control subjects. Bisulfite pyrosequencing was used to quantify the methylation of 14 CpG island promoters (MINT25, RORA, GDNF, CDH1, RARAB2, ER, CDH13, MYOD1, SFRP1, P2RX7, SLC16A12, IGF2, DPYS, and N33) and LINE1 from 72 patients with gastric cancer, 67 control, and 52 healthy young individuals. Quantitative methylation-specific real-time PCR was also conducted for 3 CpG island promoters (MINT25, MYO3A, and SOX11). Among all sites tested, only a marginal increase in the methylation of the SFRP1 promoter was observed in the blood of patients with gastric cancer when compared with the control group (11.3 % vs 10.5%; age-adjusted P value: P = 0.009), and this association was also seen in a validation set of 91 patients with gastric cancer (11.5% vs 10.5%; age-adjusted P value: P = 0.001). The methylation of 9 sites (GDNF, CDH1, RARAB2, CDH13, MYOD1, SFRP1, SLC16A12, DPYS, N33, and LINE1) and their mean Z score was correlated with higher age (R = 0.41, P < 0.0001) and marginally with telomere shortening (R = -0.18, P = 0.01) but not with gastric cancer risk (other than SFRP1 methylation). Variability in whole blood DNA methylation of cancer markers is primarily associated with aging, reflecting turnover of white blood cells, and has no direct link to gastric cancer predisposition. SFRP1 methylation in whole blood may be associated with gastric cancer risk.

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.

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.

Histamine plays important physiological roles in the upper gastrointestinal tract and acts via the H2 receptor. The -1018 G>A (rs2067474) in an enhancer element of the promoter and non-synonymous rs79385261 (Asn46Thr) were identified in HRH2. We attempted to clarify the associations of these polymorphisms with gastric carcinogenesis. The study was performed in 321 patients with gastric cancer and 599 subjects with no evidence of gastric malignancies on upper gastroduodenal endoscopy. The genotypes were determined using a one-tube multiplex PCR-SSCP method. The degree of gastritis was assessed in 496 subjects and serum pepsinogen (PG) I/II levels were measured in 124 subjects without gastric cancer. The minor allele of Asn46Thr could not be detected. The frequencies of the -1018 A allele in the non-GC and GC groups were 13.5% and 8.26%, respectively (p=0.00077). Overall, -1018 GG homozygotes had an increased risk for developing gastric cancer (OR 1.68; 95% CI 1.17-2.42; p=0.0052), especially intestinal type cancer (OR 1.94; 95% CI 1.23-3.08; p=0.0047). In subjects aged >60 years, the adjusted risk for gastric cancer among individuals who were -1018 GG homozygotes was 1.87 (range 1.19-2.93; p=0.0065) compared with A carriers. In the gastric cancer cases located in the antrum and at comparative advanced stage, -1018 GG homozygosity was a significantly increased risk factor. In subjects >60 years, the metaplasia score was significantly higher in -1018 GG homozygotes than A carriers. Both atrophy and metaplasia scores were significantly increased with age only in -1018 GG homozygotes. The PG I/II ratio was significantly decreased in H. pylori positive GG homozygotes than negative GG homozygotes and positive A carriers. Our results suggest that -1018 GG homozygosity of HRH2 may be associated with the severity of gastric mucosal atrophy. This genotype has an increased risk for the subsequent development of gastric cancer, especially intestinal type, at advanced age.

We report an association between gastric cancer (GC) and polymorphisms in IL17A, rs2275913 (-197 G > A), rs3748067 (*1249 C > T), and pri-miR-938, rs2505901 (T > C). We employed the multiplex PCR-SSCP method to detect gene polymorphisms in 337 GC cases and 587 controls. The minor allele frequency of rs2275913 was significantly higher, and those of rs3748067 and rs2505901 significantly lower, in GC cases than controls. The rs2275913 AA homozygote was associated with an increased risk (OR, 2.38; 95%CI, 1.63-3.46; p < 0.0001) for the development of both intestinal and diffuse types of GC. The rs3748067 T polymorphism was associated with a decreased risk for intestinal GC (OR, 0.511; 95%CI, 0.272-0.962; p = 0.037), whereas rs2505901 C locus carried a decreased risk overall for GC (OR, 0.733; 95%CI, 0.545-0.985; p = 0.039). In addition, rs3748067 T allele was inversely correlated with lymph node metastasis. Our results suggest that polymorphisms in both IL17A and pri-miR-938 contribute to cancer risk susceptibility and therefore can affect the development of gastric cancer., (Copyright © 2012 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)

Background: Several study showed usefulness of microscopic capillaries, seen by magnifying narrow band imaging (NBI) endoscopy for predicting histopathology among superficial depressed or flat elevated gastric neoplasia (GN). Here we assessed the diagnostic efficacy of magnifying NBI for predicting histopathology among gastric protruding/or polypoid lesions., Methods: Using endoscopic pictures of magnifying NBI from 95 protruding/or polypoid lesions (19 fundic gland polyps: FGP, 47 hyperplastic polyps: HP, and 29 GN), fine mucosal patterns were classified into four categories: small round, prolonged, villous or ridge, and unclear patterns, and micro vascular patterns were classified into five categories: honey comb, dense vascular, fine net work, core vascular, and unclear patterns., Results: Most suggestive micro vascular patterns for predicting FGP, and HP were honeycomb (sensitivity 94.7%, specificity 97.4%), and dense vascular patterns (sensitivity 93.6%, specificity 91.6%), respectively. Fine net work, core vascular, and unclear patterns presented higher specificity (97%, 100%, and 100%) for predicting GN, and diagnostic efficacy of combined of those patterns was favorable (sensitivity 86.2%, specificity 97.0%)., Conclusion: Micro vascular patterns by using magnifying NBI provides meaningful information for predicting the histopathology of gastric protruding/or polypoid lesions.

So far, a number of association studies have focused on the effect of polymorphisms in IL-1β and TNF-α genes on the susceptibility to gastric cancer (GC). Here, we evaluate the possible association between common polymorphisms in the IL-1β and TNF-α genes with various clinicopathological characteristics, including overall survival of GC patients. Restriction fragment length polymorphism analysis was performed for IL-1β-31(T > C) and IL-1β-511(C > T) and TNF-α-857 (C > T) polymorphisms in 130 GC patients. IL-1β-31CC and IL-1β-511TT genotypes held a significantly lower risk of lymphatic invasion (IL-1β-31CC vs. others: adjusted OR = 0.39, 95% CI = 0.15-0.96, P = 0.04, IL-1β-511TT vs. others: adjusted OR = 0.23, 95% CI = 0.08-0.67, P = 0.007). The IL-1β-31CC and IL-1β-511TT genotypes were weakly associated with reduced risk of venous invasion (IL-1β-31CC vs. others: adjusted OR = 0.35, 95% CI = 0.12-1.05, P = 0.06, IL-1β-511TT vs. others: adjusted OR = 0.32, 95% CI = 0.08-1.20, P = 0.09). The IL-1β-511TT genotype was also weakly associated with reduced risk of lymph node metastasis (IL-1β-511TT vs. others: adjusted OR = 0.42, 95% CI = 0.17-1.04, P = 0.06). When the TNF-α-857CT and TNF-α-857-TT genotypes were considered as T carrier, the patients with TNF-α-857T carrier showed significantly better overall survival than patients with CC genotype (P = 0.011). GC patients who have both IL-1β-31 CC and IL-1β-511 TT genotypes and have at least one of protective genotypes (IL-1β-31 CC, IL-1β-511 TT, TNF-α-857 T carrier) were also associated with better prognostic factors, such as lymphatic and venous invasion better survival. IL-1β-31CC, IL-1β-511TT genotype, and TNF-α-857T carrier may have protective effect against GC progression.

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

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

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

Background: A number of association studies have focused on the effect of polymorphisms related to DNA repair or the xenobiotic pathway, on the susceptibility to gastric cancer (GC). Here, the possible association between common polymorphisms in the X-ray repair cross-complementing groups (XRCC) 1, and glutathione-S-transferase (GST) genes and various clinicopathological characteristics, including overall survival, in GC patients were evaluated., Patients and Methods: XRCC1 Arg399Gln, and Arg194Trp, GSTP1 Ile104Val, and GSTT1, GSTM1 null polymorphisms were determined in 130 GC patients., Results: XRCC1 codon 194 Trp carriers (Trp/Trp + Arg/Trp) held a significantly higher risk of venous invasion (OR = 3.76, 95%CI = 1.05-13.51, p = 0.043). A similar trend was also found for the XRCC1 codon 194 Trp/Trp genotype (OR = 2.15, 95% CI = 0.87-5.34, p = 0.099). The frequencies of the XRCC1 codon 399 Gln/Gln and Arg/Gln genotypes tended to be lower in lymphatic invasion-positive GC (XRCC1 codon 399 Gln/Gln: OR = 0.27, 95% CI = 0.06-1.15, p = 0.075, Gln/Gln + Arg/Gln: OR = 0.46, 95% CI = 0.20-1.06, p = 0.069), while the frequencies of the XRCC1 codon 194 Trp/Trp genotype tended to be higher in lymphatic invasion-positive GC (XRCC1 codon 194 Trp/Trp: OR = 7.70, 95% CI = 0.95-62.60, p = 0.056). The patients with the GSTT1 null genotype showed significantly better overall survival than the patients with the GSTT1 present genotype (p = 0.019)., Conclusion: XRCC1 codon 194 Trp carrier status is correlated with more aggressive biological behavior of GC, such as venous invasion, and the GSTT1 null genotype is associated with better survival in GC patients.

Background: Common single-nucleotide polymorphisms (SNPs) in microRNAs (miRNA) have been shown to be associated with susceptibility to several human cancers. We evaluated the associations of three SNPs (rs11614913, rs2910164, and rs3746444) in pre-miRNAs (miR-196a2, miR-146a, and miR-499) with the risk of gastric cancer (GC) and peptic ulcer diseases, and with the severity of Helicobacter pylori-induced gastritis in Japanese population., Methods: The rs11614913 (C>T), rs2910164 (G>C), and rs3746444 (A>G) SNPs were genotyped in 552 GC, and 697 non-cancer subjects, including 141 gastric and 73 duodenal ulcer, and 483 non-ulcer subjects. The degree of histologic gastritis was classified according to the updated Sydney System, and the serum pepsinogen levels were measured in selected 579 and 204 cases., Results: The rs2910164 CC genotype held a significantly higher risk of GC when compared to non-cancer subjects (adjusted odds ratio (OR) = 1.30, 95% confidence interval (CI) = 1.02-1.66, p =.03). Similarly, the rs2910164 C carrier was associated with higher risk of GC when compared to both non-cancer and non-ulcer subjects (OR = 1.39, 95%CI = 1.00-1.93, p =.05, adjusted OR = 1.57, 95%CI = 1.09-2.27, p =.016, respectively). The rs2910164 CC genotype was associated with non-cardia and upper third, diffuse type and advanced stage GC. The rs11614913 TT genotype was associated with higher degree of mononuclear cell infiltration (score 0-1 vs 2∼, adjusted OR = 1.62, 95%CI = 1.05-2.49, p =.03)., Conclusions: The rs2910164 (G>C) SNP in the miR-146a is associated with susceptibility to GC. In addition, the rs11614913 (C>T) SNP in the miR-196a2 is associated with the degree of H. pylori-induced mononuclear cell infiltration., (© 2010 Blackwell Publishing Ltd.)

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

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

Background: Therapeutic strategies for flat elevated (0-IIa) lesions in the stomach diagnosed as adenoma by biopsy are currently not established, because some difficulties have previously been reported in the evaluation of vascular patterns alone for the differential diagnosis between adenoma and carcinoma., Objective: We attempted to evaluate the 0-IIa lesions diagnosed as adenoma by using magnifying endoscopy with narrow-band imaging (MENBI) to distinguish them as either adenoma or carcinoma., Setting: Department of Gastroenterology, Fujita Health University., Patients: Fourteen adenomatous lesions (6 adenomas and 8 carcinomas confirmed postoperatively) diagnosed with preoperative biopsies from patients who had undergone endoscopic submucosal dissection were evaluated., Interventions: We selected 5 sites per lesion for MENBI. Selected sites were divided into superficial structures (SSs) and irregular microvascular patterns (IMVPs)., Main Outcome Measurements: The rate of SSs and IMVPs in adenoma and carcinoma., Results: Significant SSs were tubular in the adenoma and unclear in the carcinoma. Regarding IMVP subcategories, (1) slight intrastructual irregular microvascular patterns (ISIMVPs) accounted for 97%, (2) severe ISIMVPs accounted for 0%, (3) fine networks accounted for 3%, and (4) corkscrews accounted for 0% of cases in the adenomas. The corresponding proportions in the carcinomas were (1) 40%, (2) 15%, (3) 45%, and (4) 0%. Severe ISIMVPs and fine networks were significant findings for carcinomas., Limitations: The number of cases was limited., Conclusions: Our combined evaluation method using MENBI offers the ability to establish proper therapeutic strategies for lesions that are difficult to identify as adenoma or carcinoma., (2010 American Society for Gastrointestinal Endoscopy. Published by Mosby, Inc. All rights reserved.)

CpG island hyper-methylation (CIHM) is one of the major events in the gastric carcinogenesis. IL-17A, -17F and MIF have a crucial role in the gastric inflammation and carcinogenesis. Recently, we showed that the genetic polymorphisms of MIF-794-CATT repeat are associated with CIHM status in the non-neoplastic gastric mucosa. Consequently, the CIHM status in the gastric cancer tissue, in relation to IL-17A (-197G>A), -17F (7488T>C), and MIF (-173G>C and -794 tetranucleotide repeats) polymorphisms was investigated. Gastric cancer tissues were obtained from 102 patients. CIHM of p14, p16, DAP-kinase and CDH1 genes were determined by methylation-specific polymerase chain reaction (MSP). CIHM high was defined as three or all CpG islands methylated. We employed the PCR-SSCP (multiplex PCR for IL-17A and -17F) method to detect the gene polymorphisms. We did not find significant association between CIHM status and IL-17F (7488T>C) and MIF (-173G>C) polymorphisms. However, concerning the IL-17A (-197G>A) polymorphism, we found that IL-17A G carrier (GG+GA) held a significantly higher risk of CIHM of p16 (OR=11.22, 95% CI=1.38-91.17, p=0.024) and CIHM high (OR=3.51, 95% CI=1.15-10.68, p=0.027). An association was also found between the 7-CATT repeat carrier (5/7 + 6/7 + 7/7) of the MIF polymorphism (-794-CATT) and reduced risk of CIHM of CDH1 (OR=0.36, 95% CI=0.14-0.92, p=0.032). No association was found between CHIM status and homozygote genotypes of each repeat (-794-CATT 5/5, 6/6, and 7/7). The present results provided evidence that the genetic polymorphisms of IL-17A, and MIF-794-CATT repeat are associated with CIHM status in the gastric cancer. Genetic polymorphisms of IL-17A, and MIF-794-CATT repeat may be involved in methylation-related carcinogenesis in the stomach.

Unlabelled: CpG island hypermethylation (CIHM) of tumor suppressor genes is one of the major events in the gastric carcinogenesis. We aimed to investigate the association between CIHM status of tumor suppressor genes and clinicopathological and morphological characteristics of gastric cancer., Patients and Methods: CIHM of p14, p16, Death-associated protein kinase (DAPK) and E-cadherin (CDH1) genes were determined by methylation-specific-polymerase chain Reaction in 146 gastric cancer tissues. CIHM-high was defined as three or more methylated CpG islands., Results: CIHM pf p14 was found in 70 (47.9%) cases, in 26 (17.8%) for p16, in 104 (71.2%) for CDH1 and in 127 (87.0%) for DAPK. CIHM-high was also found in 63 cases (43.2%). No association was found between between CIHM status and different staging, Lauren's subtypes, anatomic location, venous and lymphatic invasion, lymph node metastasis, distant metastasis, or peritoneal dissemination. However, among early gastric cancer cases, the depressed type with ulceration presented a significantly lower prevalence of CIHM of DAPK. In addition, Borrmann type IV cases presented significantly lower prevalence of CIHM-high among advanced gastric cancer. The Borrmann type IV cases also presented lower mean methylation number., Conclusion: The present results suggest that CIHM of DAPK and CIHM-high were associated with the morphological appearance of depressed type with ulceration in early gastric cancer, and Borrmann type IV advanced gastric cancer, respectively.

From epidemiological evidence a high salt diet is a risk factor for gastric cancer, independent of Helicobacter pylori infection, and animal studies have shown that salt promotes carcinogenesis. The G-protein β 3(GNB3) C825T polymorphism has been linked with hypertension, salt sensitivity and multiple diseases. Our aim in this study was to clarify any association of the GNB3 C825T polymorphism with gastric cancer risk in Japanese. We examined 161 patients with gastric cancer and 183 control subjects. All underwent stomach biopsy by endoscopic procedures, and extracted DNA was genotyped using a primer pair including the GNB3 C825T polymorphism area by PCR-based restriction fragment length polymorphism (PCR-RFLP). Logistic-regression analysis was performed to assess the impact of the genetic polymorphism. Overall comparison of genotype frequency showed the CT genotype in control patients to be relatively infrequent, but no statistically significant differences were found. However, on comparison of subtypes of gastric cancer (intestinal and diffuse), a significantly increased risk of diffuse type of gastric cancer was foudn for the TT genotype (odds ratio compared to CC, 3.1, 95%CI 1.1-8.6, p=0.03). In conclusion, the TT genotype of GNB3 was associated with diffuse type of gastric cancer. The mechanism of the GNB3 polymorphism interaction with gastric cancer development needs to be clarified by future study.

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

A complex interaction of host genetic and environmental factors may be relevant in the development of Helicocobacter pylori-related gastric carcinogenesis. We investigated the effect of vascular endothelial growth factor (VEGF) gene polymorphisms on the risk of gastric cancer (GC) and peptic ulcer diseases in a Japanese population. The G1612A(rs10434) and C936T(rs3025039) polymorphisms in the 3' untranslated region (3'-UTR) of VEGF gene were genotyped in a total of 844 subjects including 385 GC, 143 ulcer including 98 gastric ulcer (GU), 45 duodenal ulcer (DU), and 316 nonulcer subjects. The 1612A carrier held a significantly higher risk of GC when compared to both noncancer and nonulcer (overall noncancer vs. GC; OR = 1.61, 95% CI = 1.17-2.21, P = 0.0038, nonulcer vs. GC; OR = 1.54, 95% CI = 1.07-2.22, P = 0.0197). The 1612A carrier was more closely associated with an increased risk of noncardiac cancer (OR = 1.64, 95% CI = 0.17-2.21, P = 0.0038), lower third cancer (OR = 1.97, 95% CI = 1.30-3.00, P = 0.002), and Lauren's diffuse-type cancer (OR = 1.75, 95% CI = 1.24-2.46, P = 0.001), while the same genotype was not associated with the progression of GC. The C936T genotype was not associated with a risk of GC and its progression. Both the G1612A and C936T genotypes were not associated with the risk of peptic ulcer diseases. Our data suggest that the G1612A, but not C936T polymorphisms in the 3'-UTR of VEGF gene is associated with the susceptibility to GC in the Japanese population.

Background: A complex interaction of genetic and environmental factors is relevant in gastric carcinogenesis. Previous studies reported that the expression of RANTES is enhanced in Helicobacter pylori-infected gastric mucosa. Elevated serum level of RANTES in gastric cancer patients was also reported. We aimed to clarify the effect of RANTES promoter polymorphism on the risk of gastric cancer (GC) in a Japanese population., Materials and Methods: A total of 191 GC and 335 non-cancer patients including H. pylori-positive gastritis (n=180) and H. pylori- negative healthy stomach (n=155) were genotyped for polymorphisms at -28 C/G in the RANTES gene promoter region., Results: RANTES promoter genotype distributions were not significantly different among GC, overall non-cancer patients, healthy stomach and gastritis. In the comparison of genotype frequency between GC and healthy stomach, only a weak correlation was found between -28G/G genotype and GC in individuals more than 70 years of age (odds ratio (OR)=7.65, 95% confidence interval (CI)=0.78-75.0, p=0.07), with advanced stage (OR=6.58, 95% CI=0.72-59.77, p=0.07), lymph node metastasis (OR=7.20, 95% CI=0.79-65.46, p=0.06) and peritoneal dissemination (OR=10.93, 95% CI=0.96-124.64, p=0.07)., Conclusion: The effect of -28 C/G polymorphism in the RANTES gene promoter on GC development may not to be very strong. The role of RANTES promoter polymorphism in gastric carcinogenesis needs further evaluation.

Interleukin-17A (IL-17A) and IL-17F play a role in tissue inflammation by inducing release of proinflammatory and neutrophil-mobilizing cytokines. We investigated the associations between gastric cancer and polymorphisms of IL-17A (rs2275913, G-197A) and -17F (rs763780, 7488 T/C) genes. The study was performed in 811 subjects (524 without gastric cancer and 287 with gastric cancer). We used the multiplex PCR-SSCP method to detect gene polymorphisms. Overall, the number of IL-17A/-197A allele was significantly correlated to the development of gastric cancer (OR, 1.42; 95% CI, 1.09-1.85; p = 0.010). The frequency of IL-17A/-197 A/A homozygote was also significantly higher in gastric cancer group than in non-cancer group (OR, 3.02; 95% CI, 1.86-4.91; p < 0.0001). The IL-17A/G-197A polymorphism was more closely correlated to intestinal-type cancer than diffuse-type cancer. In addition, IL-17A/-197A allele carriers had an increased risk of the development of gastric mucosal atrophy (OR, 1.68; 95% CI, 1.06-2.65; p = 0.026), and a positive relationship between the inflammation score and the number of -197A allele was observed (p = 0.022). We concluded that G-197A polymorphism of IL-17A gene was significantly associated with the development of gastric cancer, especially intestinal-type cancer.