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-

This study aimed to elucidate groups at high risk of developing cancer among patients with serologically identified Helicobacter pylori infection and nonatrophic stomach. Annual endoscopy was performed for a mean of 5.4 years in 496 asymptomatic middle-aged men who were H. pylori antibody-positive and pepsinogen (PG) test-negative. Subjects were stratified according to the activity of H. pylori-associated gastritis measured by serum levels of PG and H. pylori antibody, and/or by endoscopic findings of rugal hyperplastic gastritis (RHG), and cancer development was investigated. During the study period, seven cases of cancer developed in the cohort (incidence rate, 261/100,000 person-years), with 85.7% developing in the group showing a PGI/II ratio 3.0, reflecting active inflammation-based high PGII levels. Cancer incidence was significantly higher in this group (750/100,000 person-years) than in groups with less active gastritis. Furthermore, cancer incidence for this group was significantly higher in the subgroup with high H. pylori antibody titers than in the lowtiter subgroup. Meanwhile, endoscopic findings revealed that 11.7% of subjects showed RHG reflecting localized highly active inflammation, and cancer risk was significantly higher in patients with RHG than in patients without. Combining the two serum tests and endoscopic examination for RHG allowed identification of subjects with more active gastritis and higher cancer risk. No cancer development was observed in these high-risk subjects after H. pylori eradication. Subjects with highly active gastritis identified by the two serological tests and endoscopic RHG constitute a group at high risk of cancer development with H. pylori-infected nonatrophic stomach.Gastric cancer is one of the leading causes of cancer-related deaths in Japan, with 50,017 deaths attributed to this cancer in 2009. 1 Helicobacter pylori infection is now widely accepted as playing a major role in the development of gastric cancer in areas showing high-risk for this cancer, including Japan. 2-5 H. pylori triggers chronic inflammation in the gastric mucosa, leading to a series of molecular and morphological events known as the atrophy-metaplasia-dysplasia-cancer sequence. [3][4][5] This carcinogenic sequence is considered to represent a major route of stomach carcinogenesis, and previous studies, including our own, have identified positive correlations between extent of chronic atrophic gastritis (CAG) and risk of gastric cancer. 6-13 Our longitudinal cohort study clearly indicated that progression of H. pylori-associated chronic gastritis increases cancer risk in a stepwise manner, and that patients with metaplastic gastritis, an end result of chronic H. pylori infection, show the highest annual cancer incidence rate of around 1% among asymptomatic middle-aged Japanese men. 11 Other

A total of 5,209 asymptomatic, middle-aged subjects, whose serum pepsinogen (PG) and Helicobacter pylori antibody levels had been assessed, were followed for 10 years. Subjects with positive serum H. pylori antibodies (>50 U/mL) had an increased cancer risk (HR 5 3.48, 95% CI 5 1.26-9.64). Risk of gastric cancer increased as the antibody level increased; the H. pylori-positive group with antibody levels >500 U/mL had the highest incidence rate (325/100,000 person-years). Cancer development also increased with a reduced serum PG I level or a reduced PG I/II ratio; the risk was significantly elevated with serum PG I level ≤30 ng/mL (HR 5 3.54, 95% CI 5 1.95-6.40) or PG I/II ratio ≤3.0 (HR 5 4.25, 95% CI 5 2.47-7.32). Furthermore, the risk of diffuse-type cancer increased as PG II level increased; it was significantly elevated with PG II level ≥30 ng/mL (HR 5 3.81, 95% CI 5 1.10-13.21). Using H. pylori antibody and PG levels, subgroups with an especially high or low cancer incidence rate could be identified. H. pylori-negative or indeterminate subjects with low PG level (PG I ≤30 ng/mL or PG I/II ratio ≤2.0) or H. pylori-positive subjects with antibody levels >500 U/mL and a low PG level were among the subgroups with a high cancer incidence rate (over 400/100,000 person-years). In contrast, H. pylorinegative subjects with a PG I level >70 ng/mL or a PG I/II ratio >3.0 had the lowest risk; none of these subjects developed cancer. Thus, serum PG levels and/or H. pylori antibody levels can be used to predict the risk of cancer in individuals with H. pylorirelated gastritis from the general population. ' 2008 Wiley-Liss, Inc.Key words: gastric cancer; pepsinogen; Helicobacter pylori; chronic atrophic gastritis; intestinal metaplasia Stomach carcinogenesis in high-risk populations, including the Japanese population, is believed to begin with chronic active inflammation of the stomach mucosa, proceeding to extensive atrophy together with intestinal metaplasia, then to dysplasia, and finally to cancer. 1 Currently, Helicobacter pylori (H. pylori) is considered a major factor in the establishment of the carcinogenic sequence in the stomach. 2-12 H. pylori-related gastritis usually starts in the antrum and expands proximally towards the body of the stomach. [13][14][15] During this process, both multifocal atrophy and intestinal metaplasia develop, eventually leading to chronic atrophic gastritis (CAG) with extensive intestinal metaplasia. Several studies dealing with endoscopic biopsies or chromoendoscopic testing found that the progression of CAG increases the risk for cancer. 12,[16][17][18][19][20] Thus, an accurate and reliable evaluation of the extent of CAG is considered to be important for identifying individuals at high risk of cancer. The diagnosis of CAG is based on histopathology of the stomach mucosa. However, gastric endoscopy with biopsy is an invasive test and inappropriate for mass population screening. In addition, since CAG together with intestinal metaplasia is a multifocal process, it is difficult to ac...