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A cohort of 4,655 healthy asymptomatic subjects, in whom serum pepsinogen (PG) and <jats:italic>H. pylori<\/jats:italic> antibody titer had been measured to assess the activity and stage of <jats:italic>H. pylori<\/jats:italic>\u2010associated chronic gastritis, was followed for up to 16 years, and cancer development was investigated. In subjects with a serologically diagnosed healthy stomach (<jats:italic>H. pylori<\/jats:italic>\u2010negative\/CAG\u2010negative), cancer incidence rate was low, at 16\/100,000 person\u2010years. With the establishment of <jats:italic>H. pylori<\/jats:italic> infection and progression of chronic gastritis, significant stepwise cancer risk elevations were seen from CAG\u2010free subjects (<jats:italic>H. pylori<\/jats:italic>\u2010positive\/CAG\u2010negative) [hazard ratio (HR)\u2009=\u20098.9, 95% confidence interval (CI)\u2009=\u20092.7\u201354.7] to subjects with CAG (<jats:italic>H. pylori<\/jats:italic>\u2010positive\/CAG\u2010positive) (HR\u2009=\u200917.7, 95% CI\u2009=\u20095.4\u2013108.6) and finally to subjects with metaplastic gastritis (<jats:italic>H. pylori<\/jats:italic>\u2010negative\/CAG\u2010positive) (HR\u2009=\u200969.7, 95% CI\u2009=\u200913.6\u2013502.9). In <jats:italic>H. pylori<\/jats:italic>\u2010infected CAG\u2010free subjects, significantly elevated cancer risk was observed in the subgroup with active inflammation\u2010based high PG II level or potent immune response\u2010based high <jats:italic>H. pylori<\/jats:italic> antibody titer; the former was associated with a particularly high risk of diffuse\u2010type cancer, and both subgroups showed high cancer incidence rates of around 250\/100,000 person\u2010years, comparable to that in subjects with CAG. No such risk elevation was observed in <jats:italic>H. pylori<\/jats:italic>\u2010infected subjects with CAG. These results clearly indicate that gastric cancer develops mainly from the gastritis\u2010atrophy\u2010metaplasia\u2010cancer sequence and partly from active inflammation\u2010based direct carcinogenesis, and that serum levels of PG and <jats:italic>H. pylori<\/jats:italic> antibody titer provide indices of cancer development in <jats:italic>H. pylori<\/jats:italic>\u2010infected subjects.<\/jats:p>","DOI":"10.1002\/ijc.28470","type":"journal-article","created":{"date-parts":[[2013,9,5]],"date-time":"2013-09-05T15:03:26Z","timestamp":1378393406000},"page":"1445-1457","source":"Crossref","is-referenced-by-count":138,"title":["Cancer development based on chronic active gastritis and resulting gastric atrophy as assessed by serum levels of pepsinogen and <i>Helicobacter pylori<\/i> antibody titer"],"prefix":"10.1002","volume":"134","author":[{"given":"Takeichi","family":"Yoshida","sequence":"first","affiliation":[{"name":"Second Department of Internal Medicine School of Medicine Wakayama 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