Background
Helicobacter pylori
(
HP
) infection potently induces aberrant DNA methylation in gastric mucosae, and its accumulation is associated with gastric cancer risk. Cross-sectional analysis of ...methylation levels (fraction of methylated DNA molecules) and temporal analysis of methylation incidence suggested that methylation levels decrease after
HP
infection discontinues. We aimed to demonstrate the decrease in methylation levels.
Methods
Thirty-five patients with
HP
infection who had undergone curative endoscopic resection and 11 healthy volunteers were recruited. Methylation levels were quantified by real-time methylation-specific PCR. Histology was evaluated according to the updated Sydney System.
Results
In the 20 patients with successful eradication, the
FLNc
methylation level, along with infiltration of inflammatory cells, decreased from 0.6 to 0.4% at 6 weeks (
P
= 0.049) and remained low at 1 year. The
THBD
methylation level (30.1%) remained high at 6 weeks, but decreased to 19.0% at 1 year (
P
= 0.0032). Nine healthy volunteers with successful eradication tended to show a decrease of both
FLNc
and
THBD
at 6 weeks. However, the methylation levels after the decrease were still higher than those of healthy individuals without
HP
infection. In the 15 patients with persistent infection, the methylation levels remained the same. Before eradication, the
THBD
methylation level correlated with the degree of inflammatory cell infiltration (
P
<
0.05).
Conclusions
Methylation levels in gastric mucosae decreased to certain levels after
HP
eradication in profiles unique to individual markers. Involvement of chronic inflammation in methylation induction was suggested.
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.
What's new?
Infection with the bacteria H. pylori is the most common risk factor for developing gastric cancer. The infection causes chronic inflammation leading to a sequence of gastritis, atrophy, metaplasia, dysplasia, cancer. This study follows up a cohort of 6,000 men after 16 years and showed that cancer risk increased with the progression of inflammation and atrophy, which can be measured by serum tests. These tests, the authors suggest, would be useful in assessing risk among people infected with H. pylori.
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.
Aim: To clarify the clinical features of and risk factors for extrahepatic seeding, a major complication following radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC).
Methods: Our ...prospective database of 351 nodules in 257 patients with HCC who had undergone RFA between April 2001 and April 2008 was reviewed. The following variables were assessed to identify the risk factors for extrahepatic seeding: age, sex, viral markers, Child–Pugh class, tumor size, number of tumors, RFA indication (tumor size ≤3 cm, number of tumors ≤3), tumor biopsy prior to RFA, degree of histological differentiation, tumor markers, tumor location, number of sessions, and combined transcatheter arterial chemoembolization.
Results: The median follow‐up period was 36.5 months, during which the rate of seeding after was 5.1% and the 5‐year cumulative seeding rate was 8.4%. The survival rate after neoplastic seeding was 21% at 5 years. Univariate analysis of the risk factors for neoplastic seeding showed significant differences in tumor size, RFA indication, subcapsular lesion, number of sessions, tumor biopsy prior to RFA, and des‐gamma‐carboxy prothrombin value. However, multivariate analysis showed that the only independent risk factor was RFA indication.
Conclusions: The prognosis of patients with neoplastic seeding was poor. In particular, RFA performed for HCC not satisfying the RFA indication showed a high risk of seeding, and careful consideration should be given to the optimal treatment method and avoiding direct puncture of subcapsular tumors.
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.
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.
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, < or =70 ng/mL; pepsinogen I/II ratio, < or =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 < or =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).
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.
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.
The presence of high levels of aberrant DNA methylation in gastric mucosae correlates with risk of gastric cancer. Some gastric cancers are known to have methylation of multiple CpG islands (CGI), ...which is referred to as the CGI methylator phenotype (CIMP). In the present study, we aimed to clarify the possible association between the CIMP in cancers and high methylation levels in their background mucosae by accurate quantitative methylation analysis of 14 carefully selected promoter CGI. Methylation levels were measured in 66 cancers and their background mucosae, along with 19 normal mucosae of healthy volunteers. Methylation in cancers was classified as absent (methylation level = 0%) or positive. The number of methylated CGI in a cancer showed a continuous distribution, and cancers were classified as CIMP high (21 cases), CIMP low (30 cases), or CIMP negative (15 cases). CIMP‐high gastric cancer patients had significantly better survival rates than CIMP‐negative patients. Of the Epstein–Barr virus‐positive gastric cancers studied, eight out of nine presented as CIMP high. Methylation in background mucosae showed a unimodal distribution, and was assessed by their degree. The gastric mucosae of cancer patients showed higher levels than normal gastric mucosae of healthy volunteers. Finally, the CIMP‐high, CIMP‐low, and CIMP‐negative statuses in cancers were not associated with methylation levels of individual genes and their means in the background mucosae. These showed that the CIMP statuses in gastric cancers had no association with methylation levels in the background gastric mucosae. (Cancer Sci 2007; 98: 1853–1861)
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.
PDF
