Wei-dong Liu

Fifteen-Year Effects of Helicobacter pylori, Garlic, and Vitamin Treatments on Gastric Cancer Incidence and Mortality

In the Shandong Intervention Trial, 2 weeks of antibiotic treatment for Helicobacter pylori reduced the prevalence of precancerous gastric lesions, whereas 7.3 years of oral supplementation with garlic extract and oil (garlic treatment) or vitamin C, vitamin E, and selenium (vitamin treatment) did not. Here we report 14.7-year follow-up for gastric cancer incidence and cause-specific mortality among 3365 randomly assigned subjects in this masked factorial placebo-controlled trial. Conditional logistic regression was used to estimate the odds of gastric cancer incidence, and the Cox proportional hazards model was used to estimate the relative hazard of cause-specific mortality. All statistical tests were two-sided. Gastric cancer was diagnosed in 3.0% of subjects who received H pylori treatment and in 4.6% of those who received placebo (odds ratio = 0.61, 95% confidence interval = 0.38 to 0.96, P = .032). Gastric cancer deaths occurred among 1.5% of subjects assigned H pylori treatment and among 2.1% of those assigned placebo (hazard ratio [HR] of death = 0.67, 95% CI = 0.36 to 1.28). Garlic and vitamin treatments were associated with non-statistically significant reductions in gastric cancer incidence and mortality. Vitamin treatment was associated with statistically significantly fewer deaths from gastric or esophageal cancer, a secondary endpoint (HR = 0.51, 95% CI = 0.30 to 0.87; P = .014).

Evolution of precancerous lesions in a rural Chinese population at high risk of gastric cancer

The pathogenesis of gastric cancer (GC), particularly of the intestinal type, is thought to involve a multistep and multifactorial process. Our objective was to determine the rates of transition from early to advanced gastric lesions in a population in Linqu County, China, where the GC rates are among the highest in the world. An endoscopic screening survey was launched in 1989–1990 among 3,399 residents aged 34–64 years with precancerous lesions diagnosed from biopsies taken from 7 standard locations in the stomach and from any suspicious sites. The cohort was subsequently followed, with endoscopic and histopathologic examinations conducted in 1994. Logistic regression analysis was used to estimate odds ratios (ORs) of progression to advanced lesions of various levels of severity as a function of age, sex and baseline pathology. The rates of progression were higher among older subjects, among men and among subjects with more extensive gastric lesions. 34 incident GCs were identified during the follow‐up period. The ORs of GC, adjusted for age and sex, varied from 17.1, for those with baseline diagnoses of superficial intestinal metaplasia (IM), to 29.3, for those with deep IM or mild dysplasia (DYS) or IM with glandular atrophy and neck hyperplasia, to 104.2, for those with moderate or severe DYS, as compared with subjects with superficial gastritis (SG) or chronic atrophic gastritis (CAG) at baseline. Our prospective study of a high‐risk population revealed sharp increases in the risk of GC and advanced precursor lesions according to the severity of lesions diagnosed at the start of follow‐up. Int. J. Cancer, 83:615‐619, 1999. Published 1999 Wiley‐Liss, Inc.

Effects of selective COX-2 inhibitor and Helicobacter pylori eradication on precancerous gastric lesions

Objective Helicobacter pylori infection and overexpression of cyclo-oxygenase-2 (COX-2) are associated with gastric cancer and its precursors. To evaluate the effect of a selective COX-2 inhibitor alone and combined with H pylori eradication on the evolution of precancerous gastric lesions, a randomised, placebo-controlled trial was conducted in Linqu County, Shandong Province, China. Methods A total of 1024 participants aged 35–64 years with H pylori infection and advanced gastric lesions were randomly assigned in a factorial design to two interventions or placebo: anti-H pylori treatment for 7 days, and a COX-2 inhibitor (celecoxib) for 24 months. The effects of the interventions were evaluated by the regression or progression of advanced gastric lesions. Results Of the 1024 participants who received anti-H pylori treatment or placebo, 919 completed a subsequent 24-month treatment with celecoxib or placebo. The H pylori eradication rate by per-protocol analysis was 78.2%. Compared with placebo, the proportions of regression of gastric lesions significantly increased in the celecoxib treatment (52.8% vs 41.2%) and anti-H pylori treatment (59.3% vs 41.2%) group, and OR by per-protocol analysis was 1.72 (95% CI 1.07 to 2.76) for celecoxib and 2.19 (95% CI 1.32 to 3.64) for H pylori eradication. No statistically significant effect was found for H pylori eradication followed by celecoxib on the regression of advanced gastric lesions (OR 1.48, 95% CI 0.91 to 2.40). Conclusion This population-based intervention trial revealed that celecoxib treatment or H pylori eradication alone had beneficial effects on the regression of advanced gastric lesions. No favourable effects were seen for H pylori eradication followed by celecoxib treatment. Trial registration HARECCTR0500053 in accordance with WHO ICTRP requirements.

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 23 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.

An intervention trial to inhibit the progression of precancerous gastric lesions: compliance, serum micronutrients and S-allyl cysteine levels, and toxicity.

Gastric cancer is the second most frequent cause of death from cancer in the world and the leading cause of death from cancer in China. In September 1995, we launched a randomized multi‐intervention trial to inhibit the progression of precancerous gastric lesions in Linqu County, Shandong Province, an area of China with one of the worlds highest rates of gastric cancer. Treatment compliance was measured by pill counts and quarterly serum concentrations of vitamin C, vitamin E and S‐allyl cysteine. In 1999, toxicity information was collected from each trial participant to evaluate treatment‐related side‐effects during the trial. Compliance rates were 93% and 92.9% for 39 months of treatment with the vitamins/mineral and garlic preparation, respectively. The means for serum concentrations of vitamins C and E were 7.2 μg/ml and 1695 μg/dl among subjects in the active treatment groups compared with 3.1 μg/ml and 752 μg/dl among subjects in the placebo treatment group, respectively. No significant differences in side‐effects were observed between the placebo treatment group and the vitamins/mineral and garlic preparation treatment groups during the 39‐month trial period.

A large randomised controlled intervention trial to prevent gastric cancer by eradication of Helicobacter pylori in Linqu County, China: baseline results and factors affecting the eradication

Objective To clarify the full range of benefits and adverse consequences of Helicobacter pylori eradication as a strategy for gastric cancer prevention, the community-based intervention trial was launched in Linqu County, China. Design A total of 184 786 residents aged 25–54 years were enrolled in this trial and received 13C-urea breath test. H. pylori positive participants were assigned into two groups, either receiving a 10-day quadruple anti-H. pylori treatment or lookalike placebos together with a single dosage of omeprazole and bismuth. Results The prevalence of H. pylori in trial participants was 57.6%. A total of 94 101 subjects completed the treatment. The overall H. pylori eradication rate was 72.9% in the active group. Gender, body mass index, history of stomach disease, baseline delta over baseline-value of 13C-urea breath test, missed medication doses, smoking and drinking were independent predictors of eradication failure. The missed doses and high baseline delta over baseline-value were important contributors in men and women (all Ptrend<0.001). However, a dose-response relationship between failure rate and smoking or drinking index was found in men (all Ptrend<0.001), while high body mass index (Ptrend<0.001) and history of stomach disease were significant predictors in women. The treatment failure rate increased up to 48.8% (OR 2.87, 95% CI 2.24 to 3.68) in men and 39.4% (OR 2.67, 95% CI 1.61 to 4.42) in women with multiple factors combined. Conclusions This large community-based intervention trial to eradicate H. pylori is feasible and acceptable. The findings of this trial lead to a distinct evaluation of factors influencing eradication that should be generally considered for future eradication therapies. Trial registration number ChiCTR-TRC-10000979 in accordance with WHO ICTRP requirements.

Helicobacter pylori prevalence and CagA status among children in two counties of China with high and low risks of gastric cancer.

BACKGROUND Studies in adult populations in selected countries with widely varying rates of gastric cancer have shown a weak correlation between gastric cancer mortality rates and the prevalence of CagA+ strains of H. pylori. However, only limited data are available in ethnically homogenous populations with varying rates in the same region. METHODS; We compared the prevalence of H. pylori in general and of CagA+ strains in particular among children in Shandong Province, China in areas at high (Linqu County) and low risk (Cangshan County) of gastric cancer. H. pylori status among children aged 3 to 12 years was determined by 13C-UBT, and CagA status was determined by enzyme-linked immunosorbent assay (ELISA). Because of the difficulty in obtaining blood from young children aged 3 to 4 years and from some children aged 5 years, CagA status was determined among part of children 5 years old and children 6 to 12 years old. RESULTS; Among 98 children aged 3 to 12 years in Linqu, 68 (69.4%) was H. pylori-positive, as compared with 29 (28.7%) among 101 children in Cangshan. Among children positive for 13C-UBT, the proportion of the CagA+ strains were identified was 46 (88.5%) of 52 in Linqu and 13 (81.3%) of 16 in Cangshan, respectively. CONCLUSIONS The prevalence of H. pylori was nearly three times higher among children in Linqu than in Cangshan, which may contribute to the large differential in gastric cancer rates for two neighboring populations in Shandong Province.

Helicobacter pylori Infection in Rural China: Exposure to Domestic Animals During Childhood and Adulthood

Little is known about the mode of transmission of Helicobacter pylori, one of the most common human bacterial infections. Some domestic animals, including the cat, have been suggested as a reservoir of H. pylori disease, but the data have been inconsistent. This paper evaluates the role of exposure to pets and other domestic animals in the etiology of H. pylori in a rural area of China with a high prevalence of H. pylori infection. In this double-blind, population-based, cross-sectional investigation, interviews were completed with 3,288 (1994 seropositive, 1,019 seronegative, 275 indeterminate) H. pylori-infected adults enrolled in a randomized intervention trial in Linqu County, Shandong Province, China. We found no evidence to suggest that exposure to pets or other domestic animals during either childhood or adulthood was related to the prevalence of H. pylori infection. In fact, odds ratios (ORs) were reduced for subjects who had kept a cat (OR = 0.7, 95% CI = 0.4-1.0) or any animal (OR = 0.5, 95% CI = 0.3-0.9) in the house as an adult, or a cat as a child (OR = 0.7, 95% CI =0.5-1.0). ORs were also reduced for all 11 types of animal studied that subjects had kept in their courtyard as an adult. These findings suggest that zoonotic transmission, including that from domestic cats, is an unlikely route of H. pylori infection in this rural Chinese population.Little is known about the mode of transmission of Helicobacter pylori, one of the most common human bacterial infections. Some domestic animals, including the cat, have been suggested as a reservoir of H. pylori disease, but the data have been inconsistent. This paper evaluates the role of exposure to pets and other domestic animals in the etiology of H. pylori in a rural area of China with a high prevalence of H. pylori infection. In this double-blind, population-based, cross-sectional investigation, interviews were completed with 3288 (1994 seropositive, 1019 seronegative, 275 indeterminate) H. pylori-infected adults enrolled in a randomized intervention trial in Linqu County, Shandong Province, China. We found no evidence to suggest that exposure to pets or other domestic animals during either childhood or adulthood was related to the prevalence of H. pylori infection. In fact, odds ratios (ORs) were reduced for subjects who had kept a cat (OR = 0.7, 95% CI = 0.4?1.0) or any animal (OR =0.5, 95% CI =0.3?0.9) in the house as an adult, or a cat as a child (OR =0.7, 95% CI = 0.5?1.0). ORs were also reduced for all 11 types of animal studied that subjects had kept in their courtyard as an adult. These findings suggest that zoonotic transmission, including that from domestic cats, is an unlikely route of H. pylori infection in this rural Chinese population.

A placebo-controlled trial of 10-day bismuth-based quadruple therapy to eradicate Helicobacter pylori infection; a pilot study for the large Linqu County trial.

Aim To explore a low-cost and highly-effective therapy for eradication of Helicobacter pylori (H. pylori), a placebo-controlled trial of quadruple therapy was conducted in a population at high risk of gastric cancer in Linqu County of Shandong Province, China. Methods Two hundred and seventy-seven adults aged 35–54 years with H. pylori infection in three villages were assigned to two groups: treatment (n=189 in two villages) and placebo (n=88 in one village). Participants received either a 10-day oral quadruple therapy regimen with omeprazole (20 mg, twice daily); tetracycline (750 mg, three times daily); metronidazole (500 mg, three times daily) and bismuth potassium citrate (300 mg, twice daily), or a similar lookalike placebo regimen. The status of H. pylori infection in each trial participant before and after six weeks of treatment was determined by a 13C-urea breath test. Results One hundred and seventy-four of 189 participants completed the quadruple therapy (92.1%) and 84 participants completed the placebo therapy (95.5%). The H. pylori eradication rate by intention-to-treat analysis was 76.7% (145 of 189) in the treatment group and 1.1% (1 of 88) in the placebo group, respectively; by per-protocol analysis it was 83.3% (145 of 174) in the treatment group and 1.2% (1 of 84) in the placebo group, respectively. Conclusion In a high-risk area of gastric cancer, we conducted a high compliance, tolerable, low side-effect and lowcost therapy of anti-H. pylori. The eradication rate of the 10-day quadruple treatment was more than 80% and significantly higher than the triple therapy regimen used in this population in an earlier trial.

Long-Term Garlic or Micronutrient Supplementation, but Not Anti-Helicobacter pylori Therapy, Increases Serum Folate or Glutathione Without Affecting Serum Vitamin B-12 or Homocysteine in a Rural Chinese Population

The effects of a 7.3-y supplementation with garlic and micronutrients and of anti-Helicobacter pylori treatment with amoxicillin (1 g twice daily) and omeprazole (20 mg twice daily) on serum folate, vitamin B-12, homocysteine, and glutathione concentrations were assessed in a rural Chinese population. A randomized, double-blind, placebo-controlled, factorial trial was conducted to compare the ability of 3 treatments to retard the development of precancerous gastric lesions in 3411 subjects. The treatments were: 1) anti-H. pylori treatment with amoxicillin and omeprazole; 2) 7.3-y supplementation with aged garlic and steam-distilled garlic oil; and 3) 7.3-y supplementation with vitamin C, vitamin E, and selenium. All 3 treatments were given in a 2(3) factorial design to subjects seropositive for H. pylori infection; only the garlic supplement and vitamin and selenium supplement were given in a 2(2) factorial design to the other subjects. Thirty-four subjects were randomly selected from each of the 12 treatment strata. Sera were analyzed after 7.3 y to measure effects on folate, vitamin B-12, homocysteine, and glutathione concentrations. Regression analyses adjusted for age, gender, and smoking indicated an increase of 10.2% (95%CI: 2.9-18.1%) in serum folate after garlic supplementation and an increase of 13.4% (95%CI: 5.3-22.2%) in serum glutathione after vitamin and selenium supplementation. The vitamin and selenium supplement did not affect other analytes and the amoxicillin and omeprazole therapy did not affect any of the variables tested. In this rural Chinese population, 7.3 y of garlic supplementation increased the serum folate concentration and the vitamin and selenium supplement increased that of glutathione, but neither affected serum concentrations of vitamin B-12 or homocysteine.