Hideyuki Tamai

Progression of chronic atrophic gastritis associated with Helicobacter pylori infection increases risk of gastric cancer

We conducted a longitudinal cohort study to determine the association of Helicobacter pylori infection and the progression of chronic atrophic gastritis (CAG) with gastric cancer. A cohort of 4,655 healthy asymptomatic subjects was followed for a mean period of 7.7 years. H. pylori infection was established by serum specific antibodies and the presence of CAG was confirmed by serum pepsinogen. During the follow‐up period, 45 gastric cancer cases were detected (incidence rate, 126/100,000 person‐years). A univariate analysis after adjustment for age showed that both H. pylori and CAG were significantly associated with gastric cancer. To clarify the interaction between H. pylori and CAG, an analysis stratified by H. pylori‐ and CAG–status was performed. No cancer developed in the H. pylori(−)/CAG(−) group during the study period. This supports the theory that it is quite rare for any type of gastric cancer to develop in an H. pylori‐free healthy stomach. With the progression of H. pylori‐induced gastritis, the risk of gastric cancer increased in a stepwise fashion from CAG‐free gastritis [H. pylori(+)/CAG(−) group] (HR=7.13, 95%CI=0.95‐53.33) to CAG [H. pylori(+)/CAG(+) group] (HR=14.85, 95%CI=1.96–107.7) and finally to severe CAG with extensive intestinal metaplasia [H. pylori(−)/CAG(+) group] (HR=61.85, 95%CI=5.6–682.64) in which loss of H. pylori from the stomach is observed. Therefore, it is probable that H. pylori alone is not directly associated with stomach carcinogenesis. Instead, H. pylori appears to influence stomach carcinogenesis through the development of CAG. The observed positive correlation between the extent of H. pylori‐induced gastritis and the development of cancer was strong, especially for the intestinal type. These results are compelling evidence that severe gastritis with extensive intestinal metaplasia is a major risk factor for gastric cancer, and they confirm the previously described model of stomach carcinogenesis: the gastritis‐metaplasia‐carcinoma sequence.

Contrast-Enhanced Ultrasonography in the Diagnosis of Solid Renal Tumors

The purpose of this study was to evaluate the usefulness of contrast‐enhanced ultrasonography (CEUS) in the diagnosis of solid renal tumors.

Eradication of Helicobacter pylori prevents cancer development in subjects with mild gastric atrophy identified by serum pepsinogen levels

A longitudinal cohort study was conducted in Helicobactor pylori‐infected 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.

Cancer High-Risk Subjects Identified by Serum Pepsinogen Tests: Outcomes after 10-Year Follow-up in Asymptomatic Middle-Aged Males

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, test-positive 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, ≤70 ng/mL; pepsinogen I/II ratio, ≤3.0) displayed 58.7% sensitivity, 73.4% specificity, and 2.6% positive predictive value. Cancer incidence rate was 276 per 100,000 person-years for the atrophy-positive group and 70 per 100,000 person-years for the atrophy-negative group. Incidence rate was higher in groups fulfilling stricter positive criteria detecting more extensive atrophy, reaching 424 per 100,000 person-years. In addition, 9.2% of atrophy-negative subjects with pepsinogen I of >70 ng/mL and pepsinogen I/II ratio of ≤3.0 (reflecting putative inflammation-based high pepsinogen II level) are at high risk for cancer, particularly diffuse-type cancer, with a cancer incidence rate comparable with atrophy-positive subjects (216 per 100,000 person-years). Conclusion: Atrophy-positive subjects by pepsinogen filter test, particularly those fulfilling stricter criteria, and atrophy-negative subjects with low pepsinogen I/II ratio reflecting putative extensive active inflammation constitute populations at high risk for gastric cancer, requiring thorough endoscopic examination. (Cancer Epidemiol Biomarkers Prev 2008;17(4):838–45)

Cancer development based on chronic active gastritis and resulting gastric atrophy as assessed by serum levels of pepsinogen and Helicobacter pylori antibody titer

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) = 8.9, 95% confidence interval (CI) = 2.7–54.7] to subjects with CAG (H. pylori‐positive/CAG‐positive) (HR = 17.7, 95% CI = 5.4–108.6) and finally to subjects with metaplastic gastritis (H. pylori‐negative/CAG‐positive) (HR = 69.7, 95% CI = 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 response‐based 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.

Gastric acid reduction leads to an alteration in lower intestinal microflora

To clarify the alterations in lower intestinal microflora induced by gastric acid reduction, the dynamics of 12 major genera or groups of bacteria comprising the microflora in feces and colonic contents were examined by quantitative real-time PCR in proton pump inhibitor-treated rats and in asymptomatic human subjects with hypochlorhydria. In both rat and human experiments, most genera or groups of intestinal microflora (facultative and obligate anaerobes) proliferated by gastric acid reduction, and marked and significant increases in the Lactobacilli group and Veillonella, oropharyngeal bacteria, were observed. In rats, potent gastric acid inhibition led to a marked and significant increase of intestinal bacteria, including the Bacteroidesfragilis group, while Bifidobacterium, a beneficial bacterial species, remained at a constant level. These results strongly indicate that the gastric acid barrier not only controls the colonization and growth of oropharyngeal bacteria, but also regulates the population and composition of lower intestinal microflora.

Gastric cancer screening of a high-risk population in Japan using serum pepsinogen and barium digital radiography

With the aim of developing more efficient gastric cancer screening programs for use in Japan, we studied a new screening program that combines serum pepsinogen (PG) testing and barium digital radiography (DR). A total of 17 647 middle‐aged male subjects underwent workplace screening over a 7‐year period using a combination of PG testing and DR. This programs effectiveness, as well as other characteristics of the program, was analyzed. Forty‐nine cases of gastric cancer were detected (comprising 88% early cancer cases). The detection rate was 0.28%, and the positive predictive value was 0.85%. The PG test detected 63.3% of cases, DR detected 69.4% of cases, and both tests were positive in 32.7% of cancer cases. The two methods were almost equally effective, and were considerably more effective than conventional screening using photofluorography. Each screening method detected a distinct gastric cancer subgroup; the PG test efficiently detected asymptomatic small early cancer with intestinal type histology, while DR was efficient at detecting cancers with depressed or ulcerated morphology and diffuse type histology. The cost for the detection of a single cancer was much less than that for conventional screening. In fact, it is possible to further reduce the cost of detecting a single cancer to a cost comparable to that of surgically resecting a single gastric cancer. Thus, it is probable that a highly efficient gastric cancer screening system can be implemented by combining the two screening methods. Such a screening program would be beneficial in a population at high risk for gastric cancer. (Cancer Sci 2005; 96: 713 – 720)

Risk of gastric cancer in asymptomatic, middle-aged Japanese subjects based on serum pepsinogen and Helicobacter pylori antibody levels.

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 = 3.48, 95% CI = 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 = 3.54, 95% CI = 1.95–6.40) or PG I/II ratio ≤3.0 (HR = 4.25, 95% CI = 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 = 3.81, 95% CI = 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. pylori‐negative 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. pylori‐related gastritis from the general population.

Elevated risk of colorectal adenoma with Helicobacter pylori-related chronic gastritis: a population-based case-control study

This study investigated correlations between Helicobacter pylori infection or chronic atrophic gastritis (CAG) and risk of colorectal adenoma in a population‐based case‐control study. Subjects comprised asymptomatic, middle‐aged, male Japanese factory workers who participated in an annual health check‐up program, including cancer screening with colonoscopy. We selected 239 colorectal adenoma cases based on histological evaluation and 239 age‐matched adenoma‐free controls, and evaluated colorectal adenoma risk according to stage of H. pylori‐related chronic gastritis as determined by serum tests for H. pylori antibody titer and pepsinogen. Subjects with colorectal adenoma were more likely to be smokers and have hypercholesterolemia. H. pylori infection was a risk factor for adenoma as a whole (crude odds ratio [OR]: 2.26, 95% confidence interval [CI]: 1.44–3.55). Analysis of distal adenoma cases showed that adenoma risk was significantly increased in the presence of H. pylori infection, but there was no further increase in risk with CAG. In contrast, proximal adenoma risk increased stepwise with the presence and progression of H. pylori‐related chronic gastritis and showed a maximal and significant increase with CAG (crude OR: 4.51, 95% CI: 1.43–14.2). Subjects with more extensive and severe gastritis showed still higher risk not only for proximal but also for distal adenoma. H. pylori‐related chronic gastritis is likely to be involved in the development of colorectal neoplasms, and its progression appears to increase the risk, particularly for proximal adenomas. Knowing the H. pylori‐related chronic gastritis stage will probably be useful for evaluation of risk for colorectal neoplasia.

Development of gastric cancer in nonatrophic stomach with highly active inflammation identified by serum levels of pepsinogen and Helicobacter pylori antibody together with endoscopic rugal hyperplastic gastritis

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 low‐titer 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.