Progression Of Gastric Precancerous Lesions Research Articles

The homing receptor CD44 is involved in the progression of precancerous gastric lesions in patients infected with Helicobacter pylori and in development of mucous metaplasia in mice

Infection with Helicobacter pylori (H. pylori) leads to inflammatory events that can promote gastric cancer development. Immune cells transition from the circulation into the infected mucosa through the interaction of their receptors and ligands in the endothelial compartment. CD44 expression is increased in advanced gastric lesions. However, the association of this molecule with the progression of these lesions over time has not been investigated. In addition, there is a lack of understanding of the CD44-dependent cellular processes that lead to gastritis, and possibly to gastric cancer. Here we studied H. pylori-positive subjects with gastric lesions that ranged from multifocal atrophic gastritis to dysplasia to determine gene expression changes associated with disease progression over a period of 6 years. We report that CD44 expression is significantly increased in individuals whose gastric lesions progressed along the gastric precancerous cascade. We also show that CD44−/− mice develop less severe and less extensive H. pylori-induced metaplasia, and show fewer infiltrating Gr1+ cells compared to wild type mice. We present data suggesting that CD44 is associated with disease progression. Mechanisms associated with these effects include induction of interferon gamma responses.

Helicobacter pylori, cyclooxygenase-2 and evolution of gastric lesions: results from an intervention trial in China.

To investigate the role of cyclooxygenase (COX)-2/prostaglandin E2 (PGE2) in the process of Helicobacter pylori-induced gastric carcinogenesis, a prospective study based on an intervention trial was conducted in Linqu County, China. A total of 1401 subjects with histopathologic diagnosis were investigated at baseline, among those, 919 completed subsequent interventions (anti-H.pylori and/or celecoxib treatment). Expressions of COX-2 and Ki-67 were assessed by immunohistochemistry, and PGE2 levels were measured by enzyme immunoassay before and after interventions, respectively. We found a grade-response relationship between COX-2 expression level and risk of advanced gastric lesions at baseline. Stratified analysis indicated an additive interaction between COX-2 expression and H.pylori infection on the elevated risk of advanced gastric lesions. The odds ratios (ORs) for both factors combined were 9.31 [95% confidence interval (CI): 4.13-20.95] for chronic atrophic gastritis, 16.26 (95% CI: 7.29-36.24) for intestinal metaplasia and 21.13 (95% CI: 7.87-56.75) for dysplasia, respectively. After interventions, COX-2 expression and Ki-67 labeling index (LI) were decreased in anti-H.pylori group (OR: 1.65, 95% CI: 1.36-1.99 for COX-2; OR: 1.78, 95% CI: 1.49-2.12 for Ki-67) or anti-H.pylori followed by celecoxib group (OR: 1.41, 95% CI: 1.17-1.70 for COX-2; OR: 1.63, 95% CI: 1.37-1.94 for Ki-67). PGE2 levels were decreased in all treatment groups. Furthermore, the regression of gastric lesions was associated with the decrease of COX-2 expression or Ki-67 LI after interventions. Our findings indicate that H.pylori-induced COX-2/PGE2 pathways play an important role on the progression of precancerous gastric lesions in a Chinese population.

Consensus of gastroesophageal reflux disease in Taiwan with endoscopy-based approach covered by National Health Insurance

Summary Background and aims Gastroesophageal reflux disease (GERD) is emerging as a clinical complication in the Orient. The consensus comprises recommendations to GERD control under the advantage of endoscopy-based approach covered by the Taiwan National Health Insurance. Methods The steering committee defined the consensus scope to cover diagnostic, therapeutic, unresolved, controversial, or long-term proton pump inhibitor-related issues to GERD. The literature review emphasized domestic data, after which the draft statements and statement evidence levels were defined. Thirty-five experts of GERD in Taiwan formed the expert group to conduct the consensus conference by a modified Delphi process to vote anonymously to reach a consensus, defined by an agreement of ≥ 80% for each statement, and to set the recommendation grade. Results The consensus included 22 statements, including seven on diagnostic approach, seven on therapeutic suggestion, and eight on unresolved, controversial, or long-term proton pump inhibitor-related issues to GERD. The consensus highlighted that the endoscopy approach to GERD can define the disease spectrum and exclude malignant potential. The questionnaire survey can not only define GERD, but also monitor treatment response and quality of life. The consensus addressed suggestions for the unresolved issues related to extraesophageal presentation and adverse concerns of GERD after long-term use of proton pump inhibitors. In the endemic area of upper gastrointestinal cancers, Helicobacter pylori eradication is suggested to reduce progression of gastric precancerous lesions, and endoscopic surveillance of Barrett’s esophagus with dysplasia deserves prospective research. Conclusion The consensus comprises recommendations for the management of GERD in a high upper gastrointestinal cancer area with a national coverage of endoscopic approach.

Lysosomal-associated protein transmembrane 4 Beta-35 overexpression is a novel independent prognostic marker for gastric carcinoma.

ObjectiveThe purpose of this work was to analyze the relationships between the expression status of Lysosomal-associated protein transmembrane-4 beta 35 (LAPTM4B-35) in cancerous tissues and clinicopathological characteristics and prognosis of the patients with gastric carcinoma (GC).MethodsThe GC samples from 157 patients in a discovery cohort and 148 patients in a testing cohort with follow-up data were used to validate the feasibility of expression of LAPTM4B-35 protein in predicting GC prognosis. Immunohistochemical staining was used to determine the expression of LAPTM4B-35 protein in precancerous gastric lesions and gastric carcinomas. The correlation between the expression of LAPTM4B-35 and clinicopathologic characteristics of patients with gastric carcinoma was analyzed using chi-square test. Univariate and multivariate analyses were performed to determine the association between LAPTM4B-35 expression and prognosis.ResultsLAPTM4B-35 expression was increased steadily in sequential stages of precancerous gastric lesions. Positive LAPTM4B-35 expression was more frequently detected in patients with distant metastasis (P = 0.023) and III+IV TNM stages (P = 0.042) in the discovery cohort. Kaplan-Meier survival curves and univariate analysis showed that expression of LAPTM4B-35 had a significant impact on overall survival of patients with gastric carcinoma in discovery cohort (P<0.001) and testing cohort (P = 0.001). LAPTM4B-35 expression was an independent prognostic indicator for the overall survival of patients with gastric carcinoma in both cohorts.ConclusionsThe present research demonstrated that LAPTM4B-35 over-expression was an independent factor in gastric carcinoma prognosis. LAPTM4B gene may be a useful target of interventions slowing the progression of precancerous gastric lesions and a new therapy method to improve the prognosis of gastric carcinoma.

Temporal changes in serum biomarkers and risk for progression of gastric precancerous lesions: a longitudinal study.

Effectively managing precancerous lesions is crucial to reducing the gastric cancer (GC) burden. We evaluated associations of temporal changes in multiple serological markers (pepsinogen I [PGI], PGII, PGI/II ratio, gastrin-17 and anti-Helicobacter pylori IgG) with risk for progression of gastric precancerous lesions. From 1997 to 2011, repeated esophagogastroduodenoscopies with gastric mucosal biopsies and blood sample collections were conducted on 2,039 participants (5,070 person-visits) in the Zhuanghe Gastric Diseases Screening Program, Liaoning, China. Serum biomarkers were measured using ELISA, and gastric biopsies were evaluated using standardized histologic criteria. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using generalized estimating equations for correlated binary outcomes. The ORs for progression of gastric conditions comparing those whose serum PGI, PGII, and anti-H. pylori IgG levels increased ≥ 50% relative to those whose decreased ≥ 50% were, respectively 1.67 (CI, 1.22-2.28), 1.80 (CI, 1.40-2.33) and 1.93 (CI, 1.48-2.52). The OR for those whose PGI/II ratio decreased ≥ 50% relative to those whose increased ≥ 50% was 1.40 (CI, 1.08-1.81), and for those whose PGII and anti-H. pylori IgG levels both increased ≥ 50% relative to those whose levels both decreased ≥ 50% the OR was 3.18 (CI, 2.05-4.93). Changes in gastrin-17 were not statistically significantly associated with progression. These findings suggest that temporal changes in serum PGI, PGII, PGI/II ratio, and anti-H. pylori IgG levels (especially PGII and anti-H. pylori IgG combined) may be useful for assessing and managing risk for progression of gastric precancerous lesions.

Value of c-Met for predicting progression of precancerous gastric lesions in rural Chinese population

To investigate the value of c-Met in predicting progression of precancerous gastric lesions. A population-based study was conducted to detect the overexpression of c-Met by immunohisto- chemical analysis in 124 subjects with precancerous gastric lesions. Odds ratio (OR) and 95% confidence interval (95% CI) were calculated for the association of c-Met overexpression with the risk of advanced gastric lesions. The positive rates of c-Met were 55.7% in intestinal metaplasia (IM) and 64.8% in dysplasia (DYS), respectively. Stratified analysis indicated that the proportion of c-Met overexpression was 71.4% for IM progressive group, significantly higher than that for IM persistent group (40.0%, P<0.05). Compared to the IM persistent group, unconditional logistic regression showed that OR of c-Met overexpression for the IM progressive group was 7.416 (95% CI: 2.084-26.398). c-Met plays an important role in gastric carcinogenesis. Detection of c-Met is of value in predicting progression of precancerous gastric lesions from IM to DYS.

Helicobacter pylori cagA and vacA Genotypes as Predictors of Progression of Gastric Preneoplastic Lesions: A Long-Term Follow-Up in a High-Risk Area in Spain

There are no established predictive markers of progression of gastric preneoplastic lesions. The aim of this study was to analyze the relationship between Helicobacter pylori cagA and vacA genotypes and progression of gastric preneoplastic lesions. This was a follow-up study that carried out in a province of Spain with a high risk of gastric cancer. A total of 312 patients who underwent upper endoscopy with gastric biopsy in 1988-1994 with diagnoses of normal mucosa, non-atrophic gastritis (NAG), non-metaplastic multifocal atrophic gastritis (MAG), and complete or incomplete intestinal metaplasia (IM), and who accepted to undergo a new biopsy during 2005-2007 or had an end point during follow-up, were included in this study. Detection and characterization of H. pylori cagA and vacA genotypes was performed directly in baseline paraffin-embedded gastric biopsy specimens by PCR followed by reverse hybridization onto a line probe assay. Inter- and intra-observer variability of histological diagnosis was assessed. Analysis was done using unconditional logistic regression. The mean age of patients was 48.5 years (45% males) and the mean of follow-up was 12.8 years. H. pylori strains harboring cagA, vacA s1, and vacA m1 genotypes were more frequently found in patients with more advanced gastric preneoplastic lesions. Infection with cagA-positive, vacA s1, and vacA m1 strains was associated with progression of gastric preneoplastic lesions (multivariate odds ratio (OR)=2.28, 95% confidence interval (CI) 1.13-4.58; OR=2.90, 95% CI 1.38-6.13; and OR=3.38, 95% CI 1.34-8.53, respectively). Infection with strains that are simultaneously cagA positive and vacA s1/m1 was associated with progression of gastric precancerous lesions with an OR of 4.80 (95% CI 1.71-13.5) in relation to those infected with cagA-negative/vacA s2/m2 strains. H. pylori genotyping may be useful for the identification of patients at high risk of progression of gastric preneoplastic lesions and who need more intensive surveillance.

Interventional effect of Ginkgo biloba extract on the progression of gastric precancerous lesions in rats

To investigate the effect of Ginkgo biloba extract on gastric precancerous lesions in rats. 80 4-week-old Wistar rats were randomly divided into four groups: a control group, a model group, a low and a high dose Ginkgo biloba extract intervention group; 20 in each group. Gastric precancerous lesions were induced by giving them 100 mg/L N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) solution to drink ad libitum for 20 weeks. In addition to the MNNG, the intervention groups were lavaged with Ginkgo biloba extract (0.5 mg/kg/d in the low dose group, 1.5 mg/kg/d in the high dose group) for 20 weeks. Starting from week 21 all the rats were fed with normal rat chow and tap water. At the end of week 30 the rats were killed. The histopathological changes of their gastric mucosa, ISA, NGI, the serum and gastric mucosal SOD/MDA and the expressions of oncogenes were studied. The incidence of mild to severe intestinal metaplasia and dysplasia were significantly lower in the intervention groups than those in the model group (P < 0.01). The ISA and NGI in the intervention groups were significantly lower than those in the model group (P < 0.01). In the intervention groups the activity of SOD was increased and the concentration of MDA was decreased (P < 0.01). Expressions of Bcl-2, c-myc and FasL decreased in the intervention groups, whereas the expression of Fas increased. When compared with the model group, the differences were statistically significant (P < 0.01, P < 0.05, respectively). Ginkgo biloba extract can increase anti-oxidative activity and inhibit the progression of gastric precancerous lesions via the regulation of cell proliferation and apoptosis.

“Adjuvant” Therapy after Endoscopic Mucosal Resection of Early Gastric Cancer

“Adjuvant” Therapy after Endoscopic Mucosal Resection of Early Gastric Cancer

Anti-Helicobacter pylori therapy followed by celecoxib on progression of gastric precancerous lesions

To evaluate whether celecoxib, a selective cyclooxygenase 2 (COX-2) inhibitor, could reduce the severity of gastric precancerous lesions following Helicobacter pylori (H pylori) eradication. H pylori-eradicated patients with gastric precancerous lesions randomly received either celecoxib (n = 30) or placebo (n = 30) for up to 3 mo. COX-2 expression and activity was determined by immunostaining and prostaglandin E(2) (PGE(2)) assay, cell proliferation by Ki-67 immunostaining, apoptosis by TUNEL staining and angiogenesis by microvascular density (MVD) assay using CD31 staining. COX-2 protein expression was significantly increased in gastric precancerous lesions (atrophy, intestinal metaplasia and dysplasia, respectively) compared with chronic gastritis, and was concomitant with an increase in cell proliferation and angiogenesis. A significant improvement in precancerous lesions was observed in patients who received celecoxib compared with those who received placebo (P < 0.001). Of these three changes, 84.6% of sites with dysplasia regressed in patients treated with celecoxib (P = 0.002) compared with 60% in the placebo group, suggesting that celecoxib was effective on the regression of dysplasia. COX-2 protein expression (P < 0.001) and COX-2 activity (P < 0.001) in the gastric tissues were consistently lower in celecoxib-treated patients compared with the placebo-treated subjects. Moreover, it was also shown that celecoxib suppressed cell proliferation (P < 0.01), induced cell apoptosis (P < 0.01) and inhibited angiogenesis with decreased MVD (P < 0.001). However, all of these effects were not seen in placebo-treated subjects. Furthermore, COX-2 inhibition resulted in the up-regulation of PPARgamma expression, a protective molecule with anti-neoplastic effects. H pylori eradication therapy followed by celecoxib treatment improves gastric precancerous lesions by inhibiting COX-2 activity, inducing apoptosis, and suppressing cell proliferation and angiogenesis.

Treatment of Helicobacter pylori and prevention of gastric cancer

Gastric cancer is the second commonest fatal malignancy in the world with a high incidence in China. Helicobacter pylori infection is an important factor in the pathogenesis of gastric cancer. Epidemiological studies have shown a strong causal relationship between H. pylori infection and gastric cancer. Animal studies also show that eradication of H. pylori infection, especially at the early stage, is effective in preventing H. pylori-related gastric carcinogenesis. H. pylori eradication leads to regression and prevents the progression of gastric precancerous lesions, but only in a minority of cases. H. pylori eradication appears to be the most promising approach in gastric cancer prevention. The current available data in human studies showed that H. pylori eradication can reduce the risk of developing gastric cancer and this strategy is more useful in patients without atrophic gastritis or intestinal metaplasia. A longer follow-up and additional studies are needed for better understanding this issue.

Helicobacter pylori and the progression of gastric cancer: a 10-year cohort study

To search the role of Helicobacter pylori (H. pylori) in the progression of gastric carcinogenesis. A cohort study was conducted by cluster randomized sampling in Linqu County, a rural area in Shandong Province in northeast China, where the mortality of gastric cancer (GC) is among the highest in the world. In 1989-1990, a gastroscopic examination and serum test was launched among subjects aged 35-64 from 14 randomized villages. Histological diagnosis of gastric mucosa and enzyme-linked immunosorbent assay was used to detect gastric lesions and anti-H. pylori of all participants. A repeated gastroscopic screening was offered to all cohort members in 1994 and 1999 respectively, and all the GC cases, regardless of natural ones or ones by gastroscopy, were registered in the follow-up periods. Fifty-eight cases of GC were identified in 2469 subjects during the 10-year follow-up, 44 were observed in 1603 H. pylori-positive persons (2.74%) and 14 in 866 H. pylori-negative persons (1.62%). The incidence rate of GC in H. pylori-positive is significantly higher than in H. pylori-negative (OR = 1.871, 95% CI: 1.012 - 3.459). There was no significant difference in the progression of gastric carcinogenesis between H. pylori-positive and H. pylori-negative (P > 0.05) among subjects with normal or superficial gastritis (SG) at baseline. In contrast, the significant difference was found in baseline chronic gastritis (CAG) group (P < 0.01), and the GC incidence rate in H. pylori-positive (7/615) is higher than in H. pylori-negative (0/470, P = 0.019). The difference of gastric lesions between H. pylori-positive and H. pylori-negative in subjects with intestinal metaplasia (IM) and dysplasia (DYS) at baseline was statistically significant after a 10-year follow-up (P < 0.05, P < 0.01, respectively), but the GC incidence rate in H. pylori-positive is similar to the rate in H. pylori-negative at the two groups (17/573 and 7/224 in IM group, P = 0.907; 19/368 and 7/122 in DYS group, P = 0.806). H. pylori is a key risk factor that prompts the transition from chronic atrophic gastritis to advanced precancerous lesions and influences the whole progression of precancerous gastric lesions. H. pylori, perhaps can not cause GC directly, increases the risk of GC in company with other carcinogens. H. pylori seemingly has no important effect on the development of GC when gastric mucosa is normal or superficial gastritis, but this conclusion is required to be further confirmed.

Factorial Trial of Three Interventions to Reduce the Progression of Precancerous Gastric Lesions in Shandong, China: Design Issues and Initial Data

In the fall of 1995, 3411 subjects in 13 rural villages in Linqu County, Shandong Province, China, began participating in a blinded, randomized 2 3 factorial trial to determine whether interventions can reduce the prevalence of dysplasia and other precancerous gastric lesions. One intervention is treatment for infection by Helicobacter pylori with amoxicillin and omeprazole. A second is dietary supplementation with capsules containing vitamin C, vitamin E, and selenium. A third is dietary supplementation with capsules containing steam-distilled garlic oil and Kyolic aged garlic extract. Investigators will evaluate histopathologic endpoints after gastroscopies with biopsies from seven standard sites in 1999. Initial data from pill counts and sampled blood levels of vitamin E, vitamin C, and S-allylcysteine indicate excellent compliance. Subjects have tolerated all interventions well, although 3.1% of those assigned to amoxicillin and omeprazole developed rashes, compared to 0.3% to those in the control group. Preliminary breath tests demonstrate substantial reductions in gastric urease activity, an indication of infection by Helicobacter pylori, among those assigned to amoxicillin and omeprazole.