Introduction: Risk prediction of gastric cancers is important to implement appropriate screening procedures. Although aberrant DNA methylation is deeply involved in gastric carcinogenesis, its induction by Helicobacter pylori, a strong gastric carcinogen, is unclear. Here, we analyzed the effect of H. pylori infection on the quantity of methylated DNA molecules in noncancerous gastric mucosae and examined its association with gastric cancer risk. Experimental Design: Gastric mucosae were collected from 154 healthy volunteers (56 H. pylori negative and 98 H. pylori positive) and 72 cases with differentiated-type gastric cancers (29 H. pylori negative and 43 H. pylori positive) by endoscopy. The numbers of DNA molecules methylated and unmethylated for eight regions of seven CpG islands (CGI) were quantified by quantitative PCR after bisulfite modification, and fractions of methylated molecules (methylation levels) were calculated. Results: Among healthy volunteers, methylation levels of all the eight regions were 5.4-to 303-fold higher in H. pylori positives than in H. pylori negatives (P < 0.0001). Methylation levels of the LOX, HAND1, andTHBD promoter CGIs and p41ARC exonic CGI were as high as 7.4% or more in H. pylori^positive individuals. Among H. pylori^negative individuals, methylation levels of all the eight regions were 2.2-to 32-fold higher in gastric cancer cases than in age-matched healthy volunteers (P V 0.01). Among H. pylori^positive individuals, methylation levels were highly variable, and that of only HAND1 was significantly increased in gastric cancer cases (1.4-fold, P = 0.02). Conclusions: It was indicated that H. pylori infection potently induces methylation of CGIs to various degrees. Methylation levels of specific CGIs seemed to reflect gastric cancer risk in H. pylori^negative individuals.Gastric cancer is one of the most common malignancies worldwide and remains a leading cause of cancer death in Asia and some European countries (1). To reduce its mortality, early detection by endoscopy and curative resection are important (2). However, considering the potential risk and costs of early detection by endoscopic examination, implementation reflecting an individual's risk for developing a gastric cancer would be ideal. Also, endoscopic mucosal resection, which conserves the noncancerous gastric mucosae, is becoming popular, and the problem of metachronous gastric cancer recurrence is being recognized (3). Again, if the future risk of developing metachronous cancers in a specific case can be estimated, the information will be useful in the decision on either surgical resection or endoscopic mucosal resection for the case.The major etiologic risk factor for gastric cancers is Helicobacter pylori infection, which increases gastric cancer risk 2.2-to 21-fold (4 -6). In an animal model with Mongolian gerbil chronic infection with H. pylori rarely induces gastric cancers by itself, but markedly enhances their incidences after initiation with a mutagen, such as N-methyl-N-nitrosourea (7). Thi...

SH solutions were the most suitable ones for producing and maintaining long-term mucosal elevation, while the superiority of hypertonic solutions over normal saline was not clearly demonstrated.

Background : Although the strip biopsy method and aspiration method are popular endoscopic mucosal resection techniques for its convenience and reliability, they have limitations in resectable tumor size and location. Endoscopic submucosal dissection techniques using the diathermic needle knife or the insulated-tip diathermic knife have been introduced to overcome this disadvantage, but they have high risks for bleeding and perforation. Therefore, we have developed a new endoscopic submucosal dissection technique using the tip of an electrosurgical snare (thin type) and assessed its efficacy. Methods : Fifty-nine lesions with differentiated-type gastric cancer without ulceration were treated with our technique at the University Hospital. The tip of an electrosurgical snare (thin type) was used for mucosal incision and submucosal dissection as a flexible diathermic knife. Results : The size of tumor was 5-85 mm in diameter (mean size: 29 mm) and the location varied from cardia to antrum. Among 59 lesions, 56 lesions (56/59, 95%) were resected completely in an en-bloc fashion with much less perforation (2/ 59, 3.4%) and bleeding (1/59, 1.7%) regardless of their size and location. Conclusion : New endoscopic submucosal dissection technique using the tip of an electrosurgical snare (thin type) is safe and reliable. We were able to resect early gastric cancer with a much higher en-bloc resection rate and fewer complications using this technique.

Our study investigated the relationship between gastric cancer development and activity of Helicobacter pylori-associated chronic gastritis or the resulting chronic atrophic gastritis (CAG). A cohort of 4,655 healthy asymptomatic subjects, in whom serum pepsinogen (PG) and H. pylori antibody titer had been measured to assess the activity and stage of H. pylori-associated chronic gastritis, was followed for up to 16 years, and cancer development was investigated. In subjects with a serologically diagnosed healthy stomach (H. pylori-negative/CAG-negative), cancer incidence rate was low, at 16/100,000 person-years. With the establishment of H. pylori infection and progression of chronic gastritis, significant stepwise cancer risk elevations were seen from CAG-free subjects (H. pylori-positive/CAG-negative) [hazard ratio (HR) 5 8.9, 95% confidence interval (CI) 5 2.7-54.7] to subjects with CAG (H. pylori-positive/CAG-positive) (HR 5 17.7, 95% CI 5 5.4-108.6) and finally to subjects with metaplastic gastritis (H. pylori-negative/CAG-positive) (HR 5 69.7, 95% CI 5 13.6-502.9). In H. pylori-infected CAG-free subjects, significantly elevated cancer risk was observed in the subgroup with active inflammation-based high PG II level or potent immune responsebased high H. pylori antibody titer; the former was associated with a particularly high risk of diffuse-type cancer, and both subgroups showed high cancer incidence rates of around 250/100,000 person-years, comparable to that in subjects with CAG. No such risk elevation was observed in H. pylori-infected subjects with CAG. These results clearly indicate that gastric cancer develops mainly from the gastritis-atrophy-metaplasia-cancer sequence and partly from active inflammation-based direct carcinogenesis, and that serum levels of PG and H. pylori antibody titer provide indices of cancer development in H. pylori-infected subjects.Despite worldwide declines in the incidence of gastric cancer and associated mortality over the past 50 years, this pathology remains one of the leading causes of cancer-related death in Eastern Asia, including Japan, South America and Eastern Europe.1-4 In Japan, more than 100,000 new cases of gastric cancer are diagnosed every year, and the Japanese Ministry of Health, Labor and Welfare reported that 50,136 deaths attributed to the cancer in 2010.5 Gastric cancer thus remains a major health problem in Japan. Development of gastric cancer represents a classical example of host-genetic and environmental interactions and is characterized by a multistep process of molecular and morphological events known as the gastritisatrophy-metaplasia-dysplasia-cancer sequence.6,7 Based on a large number of epidemiological and clinicopathological studies and also on animal experiments using Mongolian gerbils, this sequence, which predominantly leads to intestinal-type cancer, is considered to represent a major route of stomach carcinogenesis, particularly in areas of high cancer risk, such as Japan. Although other environmental and lifestyle factors together wi...

A longitudinal cohort study was conducted in Helicobactor pyloriinfected middle-aged Japanese males to evaluate the preventive effects of H. pylori eradication on the development of gastric cancer according to the extent of chronic atrophic gastritis (CAG). The extent of CAG was monitored by baseline serum pepsinogen (PG) levels. We followed 3,656 subjects with persistent H. pylori infection and 473 subjects with successful H. pylori eradication for cancer development for a mean (SD) of 9.3 (0.7) years. Groups with and without extensive CAG were categorized based on PG test-positive criteria to detect extensive CAG of PG I 70 ng/ml and PG I/II ratio 3.0. During the study period, 5 and 55 gastric cancers developed in H. pylori-eradicated and the noneradicated subjects, respectively, indicating no significant reduction in cancer incidence after H. pylori eradication. Among the noneradicated subjects, 1,329 were PG test-positive and 2,327 were PG test-negative. Gastric cancer was confirmed in 30 and 25 subjects, respectively. Among subjects whose infection was eradicated, 155 were PG test-positive and 318 were PG test-negative. Of these subjects, gastric cancer was confirmed in 3 and 2 subjects, respectively. Significant reduction in cancer incidence after eradication was observed only in PG test-negative subjects (p < 0.05; log-rank test). The results of this study strongly indicate that cancer development after eradication depends on the presence of extensive CAG before eradication and that H. pylori eradication is beneficial to most PG test-negative subjects with mild CAG as defined by the aforementioned criteria. ' 2009 UICC

Background: Gastric cancer screening using the pepsinogen filter test is receiving wide recognition in Japan owing to convenience, freedom from discomfort or risk, efficiency, and economy. Because the long-term outcomes of cancer development in extensive atrophic gastritis detected by pepsinogen test are unclear, testpositive and test-negative subjects were investigated in a longitudinal cohort study. Methods: Subjects comprised 5,209 middle-aged men with measured serum pepsinogen levels who were followed for 10 years. Cancer development based on ''atrophy-positive'' and ''atrophy-negative'' criteria used for cancer screening was investigated. Results: During the study, 63 cases of cancer developed in the cohort, representing an incidence rate of 125 per 100,000 person-years. Pepsinogen test screening using the most widely used atrophy-positive criterion (pepsinogen I, V70 ng/mL; pepsinogen I/II ratio, V3.0) displayed 58.7% sensitivity, 73.4% specificity, and 2.6% positive predictive value. Cancer inci-

Background: Due to the remarkable progress of endoscopic resection techniques, endoscopic submucosal dissection (ESD) has been widely performed for larger mucosal tumors that would result in large artificial ulcers. The healing process of peptic ulcers has been previously studied in detail; however, no precise investigation for artificial ulcers after ESD has been reported. To confirm the validity of the treatment from the aspect of wound healing, we aimed to clarify the healing process of large gastric artificial ulcers after ESD. Methods: Seventy patients with gastric mucosal tumors treated by ESD were enrolled. The size, location and time of scar formation of the ulcers were reviewed using endoscopic pictures taken from the same view and angle. Follow-up endoscopy was performed at 1, 4, 8 and 12 weeks after ESD. For postoperative medication, all patients received normal doses of proton pump inhibitors and sucralfate for 8 weeks. Results:The average size of the resected specimen was 34.7 mm (20-90 mm). Irrespective of ulcer size and location, all of the cases healed up to scarring stages within 8 weeks. Conclusions: Gastric artificial ulcers after ESD healed within 8 weeks regardless of size and location using normal doses of medication as peptic ulcers. The fact that even giant ulcers after ESD heal within 8 weeks could be helpful information for candidates for ESD and for postoperative management of patients after ESD.

ObjectiveBleeding after endoscopic submucosal dissection (ESD) for early gastric cancer (EGC) is a frequent adverse event after ESD. We aimed to develop and externally validate a clinically useful prediction model (BEST-J score: Bleeding after ESD Trend from Japan) for bleeding after ESD for EGC.DesignThis retrospective study enrolled patients who underwent ESD for EGC. Patients in the derivation cohort (n=8291) were recruited from 25 institutions, and patients in the external validation cohort (n=2029) were recruited from eight institutions in other areas. In the derivation cohort, weighted points were assigned to predictors of bleeding determined in the multivariate logistic regression analysis and a prediction model was established. External validation of the model was conducted to analyse discrimination and calibration.ResultsA prediction model comprised 10 variables (warfarin, direct oral anticoagulant, chronic kidney disease with haemodialysis, P2Y12 receptor antagonist, aspirin, cilostazol, tumour size >30 mm, lower-third in tumour location, presence of multiple tumours and interruption of each kind of antithrombotic agents). The rates of bleeding after ESD at low-risk (0 to 1 points), intermediate-risk (2 points), high-risk (3 to 4 points) and very high-risk (≥5 points) were 2.8%, 6.1%, 11.4% and 29.7%, respectively. In the external validation cohort, the model showed moderately good discrimination, with a c-statistic of 0.70 (95% CI, 0.64 to 0.76), and good calibration (calibration-in-the-large, 0.05; calibration slope, 1.01).ConclusionsIn this nationwide multicentre study, we derived and externally validated a prediction model for bleeding after ESD. This model may be a good clinical decision-making support tool for ESD in patients with EGC.