Izumi Inoue

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 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.

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.

Clinical features and risk factors of extrahepatic seeding after percutaneous radiofrequency ablation for hepatocellular carcinoma.

Aim:  To clarify the clinical features of and risk factors for extrahepatic seeding, a major complication following radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC).

Preventive effects of etodolac, a selective cyclooxygenase-2 inhibitor, on cancer development in extensive metaplastic gastritis, a Helicobacter pylori-negative precancerous lesion

The present study investigated the preventive effects of etodolac, a selective cyclo‐oxygenase (COX)‐2 inhibitor, on metachronous cancer development after endoscopic resection of early gastric cancer. Among 267 early gastric cancer patients who underwent endoscopic resection, 47 patients with extensive metaplastic gastritis were selected based on endoscopic findings and our previously described criteria of serum pepsinogen (PG) test‐positive and Helicobacter pylori antibody‐negative conditions. Nonrandomized etodolac treatment (300 mg/day) was administered to 26 patients (Group A), while the remaining 21 patients were untreated (Group B). No significant differences in age, sex distribution, lifestyle factors or extent of metaplastic gastritis at baseline were identified between groups. Patients were followed for metachronous cancer development with endoscopy every 6–12 months for up to 5 years. Mean (standard deviation) follow‐up period was 4.2 (0.9) years. In Group B, 5 cancers developed (incidence rate = 6,266/100,000 person‐years), significantly more than the 1 cancer in Group A (incidence rate = 898/100,000 person‐years; p < 0.05). Long‐term etodolac treatment did not influence the extent of metaplastic gastritis as revealed by endoscopic findings or by serum PG levels, but effectively reduced metachronous cancer development in patients with extensive metaplastic gastritis. These results strongly suggest that chemoprevention of cancer in the metaplastic stomach is possible by controlling COX‐2 expression.

Altered mucosal DNA methylation in parallel with highly active Helicobacter pylori-related gastritis

BackgroundChronic inflammation triggered by Helicobacter pylori causes altered DNA methylation in stomach mucosae, which is deeply involved in gastric carcinogenesis. This study aimed to elucidate the correlation between altered mucosal DNA methylation levels and activity of H. pylori-related gastritis, because inflammatory activity shows particular correlations with the development of diffuse-type cancer.MethodsMethylation levels in stomach mucosae of 78 healthy volunteers were determined by real-time methylation-specific PCR or bisulfite pyrosequencing. Examined loci were the promoter CpG islands of six genes (FLNc, HAND1, THBD, p41ARC, HRASLS, and LOX) and the CpG sites of non-coding repetitive elements (Alu and Satα) that are reportedly altered by H. pylori infection. Activity of H. pylori-related gastritis was evaluated using two serum markers: H. pylori antibody titer and pepsinogen II.ResultsMethylation levels of the six CpG islands were consistently increased, and those of the two repetitive elements were consistently decreased in a stepwise manner with the activity of gastric inflammation as represented by serum marker levels. Each serum marker level was well correlated with the overall DNA methylation status of stomach mucosa, and these two serologic markers were additive in the detection of the mucosa with severely altered DNA methylation.ConclusionsAlteration in mucosal DNA methylation level was closely correlated with activity of H. pylori-related gastritis as evaluated by serum markers. The observed correlation between altered DNA methylation levels and activity of H. pylori-related gastritis appears to be one of the relevant molecular mechanisms underlying the development of diffuse-type cancer.

Helicobacter pylori-related chronic gastritis as a risk factor for colonic neoplasms

To summarize the current views and insights on associations between Helicobacter pylori (H. pylori)-related chronic gastritis and colorectal neoplasm, we reviewed recent studies to clarify whether H. pylori infection/H. pylori-related chronic gastritis is associated with an elevated risk of colorectal neoplasm. Recent studies based on large databases with careful control for confounding variables have clearly demonstrated an increased risk of colorectal neoplasm associated with H. pylori infection. The correlation between H. pylori-related chronic atrophic gastritis (CAG) and colorectal neoplasm has only been examined in a limited number of studies. A recent large study using a national histopathological database, and our study based on the stage of H. pylori-related chronic gastritis as determined by serum levels of H. pylori antibody titer and pepsinogen, indicated that H. pylori-related CAG confers an increased risk of colorectal neoplasm, and more extensive atrophic gastritis will probably be associated with even higher risk of neoplasm. In addition, our study suggested that the activity of H. pylori-related chronic gastritis is correlated with colorectal neoplasm risk. H. pylori-related chronic gastritis could be involved in an increased risk of colorectal neoplasm that appears to be enhanced by the progression of gastric atrophy and the presence of active inflammation.