Association between type of drinking water and upper gastrointestinal cancer incidence in the Linxian General Population.

BACKGROUND: This study aimed to explore the association between drinking water source and risk of upper gastrointestinal (UGI) cancer, including esophageal cancer (EC) and gastric cancer (GC), in the Linxian General Population Nutrition Intervention Trial (NIT) cohort. METHODS: In this study, we used data from the Linxian NIT cohort, which included 29,584 healthy adults aged 40 to 69 years. Subjects were enrolled in April 1986 and followed up until March 2016. Tap water drinking status and demographic characteristics were collected at baseline. Subjects who drank tap water were treated as the exposed group. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) were estimated using the Cox proportional hazard model. RESULTS: A total of 5,463 cases of UGI cancer were identified during the 30-year follow-up period. After adjusting for multiple factors, the incidence rate of UGI cancer in participants who drank tap water was significantly lower compared with individuals in the control (HR = 0.91, 95% CI: 0.86-0.97). A similar association was observed between tap water drinking and EC incidence (HR = 0.89, 95% CI: 0.82-0.97). The association between drinking tap water and risk of UGI cancer and EC incidence did not vary across the subgroup by age and gender (All Pinteraction > 0.05). For EC incidence, an interaction effect was observed for riboflavin/niacin supplements and drinking water source (Pinteraction = 0.03). No association was observed between drinking water source and GC incidence. CONCLUSIONS: In this prospective cohort study in Linxian, participants who drank tap water had a lower risk of EC incidence. As a source of drinking water, use of tap water may reduce the risk of EC by avoiding exposure to nitrate/nitrite. Measures should be taken to improve the quality of drinking water in high-incidence areas of EC. TRIAL REGISTRATION: The trial is registered with ClinicalTrials.gov (NCT00342654, 21/06/2006), and the trial name is Nutrition Intervention Trials in Linxian Follow-up Study.

Mortality after multivitamin supplementation: Nearly 35-year follow-up of the randomized Linxian Dysplasia Nutrition Intervention Trial.

BACKGROUND: The objective of this study was to update the association between multivitamin supplementation and total or cause-specific mortality in a population with a high prevalence of undernutrition in China. METHODS: The Linxian Dysplasia Nutrition Intervention Trial was a randomized, double-blind, placebo-controlled trial in which 3318 persons aged 40-69 years with esophageal squamous dysplasia were assigned to receive daily multivitamin supplementation or a placebo for 6 years and were followed for 29 years. The primary outcome was esophageal/gastric cardia cancer mortality. The data were analyzed with Cox proportional hazards regression models. Subgroup analyses were performed by common characteristics such as age and gender. RESULTS: The cumulative total mortality was 83.5%. Multivitamin supplementation did not affect total or cause-specific mortality in the participants as a whole (hazard ratio [HR], 0.96; 95% confidence interval [CI], 0.89-1.03). Subgroup analyses showed that no association between multivitamin supplementation and all-cause mortality was observed in men (HR, 0.90; 95% CI, 0.81-1.01), women (HR, 1.01; 95% CI, 0.91-1.12), younger participants (HR, 0.97; 95% CI, 0.87-1.08), or older participants (HR, 0.94; 95% CI, 0.85-1.04). Significant reductions in heart disease mortality (HR, 0.64; 95% CI, 0.47-0.87) and cerebrovascular disease mortality (HR, 0.74; 95% CI, 0.56-1.00) were seen in older men. In a subgroup of younger men and a subgroup of moderate or severe dysplasia, subjects receiving multivitamin supplementation had a lower risk of esophageal/cardia cancer mortality (HR for younger men, 0.76; 95% CI, 0.58-0.99; HR for moderate or severe dysplasia, 0.76; 95% CI, 0.58-1.00). No association between multivitamin supplementation and any cause-specific mortality was observed in a mild dysplasia population. CONCLUSIONS: Multivitamin supplementation in a population with esophageal squamous dysplasia was not associated with the risk of total mortality in the 35-year follow-up of this randomized controlled trial. In light of this and previous trials, multivitamin supplements should be used thoughtfully to improve health status of populations with esophageal squamous dysplasia. LAY SUMMARY: Multivitamin supplementation is common, yet its effect on mortality is unclear. The aim of this study was to update the long-term effects of multivitamin supplementation on total and cause-specific mortality during nearly 35 years of follow-up in the Linxian Dysplasia Nutrition Intervention Trial in China. Multivitamin supplementation in a population with esophageal squamous dysplasia was not associated with the risk of total mortality in the 35-year follow-up of this randomized controlled trial, and this indicates that multivitamin supplements should be used thoughtfully to improve health status.

Quantitative evaluation of radon, tobacco use and lung cancer association in an occupational cohort with 27 follow-up years.

BACKGROUND: Occupational radon cohorts provide important information about exposure at residential level, which are difficult to observe prospectively. However, evidence about radon-related lung cancer risks from initial exposure in childhood or interaction between radon and smoking is still limited. METHODS: A total of 6017 tin miners with at least 10 years of underground radon exposure were enrolled beginning in 1992 and followed for up to 27 years. Lung cancer risks were estimated by modeling total and intensity of radon exposure. RESULTS: A total of 933 lung cancer cases occurred in this cohort over 89,092 person-years of follow up. Excess relative risk increased by 0.96% per cumulative working level month (WLM). A unique aspect of this population was the early age at first radon exposure for workers. Results showed that lung cancer risk from initial radon exposure in childhood (<13 years old) was greater than risk when first exposure occurred at later ages (13-17, 18-24, and ≥ 25 years old). Moreover, risk declined with years since last exposure and attained age, but increased with age at last exposure. Importantly, these patterns were stable after adjustment for tobacco use or arsenic exposure. For joint effects of radon and other agents, our results support sub-multiplicative as the most likely model for interaction between radon and tobacco use or arsenic exposure. CONCLUSION: This study highlights the possible importance of radon exposure in childhood in cancer etiology and suggests another potential strategy to mitigate the global lung cancer burden.

Coffee and tea consumption and mortality from all causes, cardiovascular disease and cancer: a pooled analysis of prospective studies from the Asia Cohort Consortium.

BACKGROUND: Accumulating evidence suggests that consuming coffee may lower the risk of death, but evidence regarding tea consumption in Asians is limited. We examined the association between coffee and tea consumption and mortality in Asian populations. METHODS: We used data from 12 prospective cohort studies including 248 050 men and 280 454 women from the Asia Cohort Consortium conducted in China, Japan, Korea and Singapore. We estimated the study-specific association of coffee, green tea and black tea consumption with mortality using Cox proportional-hazards regression models and the pooled study-specific hazard ratios (HRs) using a random-effects model. RESULTS: In total, 94 744 deaths were identified during the follow-up, which ranged from an average of 6.5 to 22.7 years. Compared with coffee non-drinkers, men and women who drank at least five cups of coffee per day had a 24% [95% confidence interval (CI) 17%, 29%] and a 28% (95% CI 19%, 37%) lower risk of all-cause mortality, respectively. Similarly, we found inverse associations for coffee consumption with cardiovascular disease (CVD)-specific and cancer-specific mortality among both men and women. Green tea consumption was associated with lower risk of mortality from all causes, CVD and other causes but not from cancer. The association of drinking green tea with CVD-specific mortality was particularly strong, with HRs (95% CIs) of 0.79 (0.68, 0.91) for men and 0.78 (0.68, 0.90) for women who drank at least five cups per day of green tea compared with non-drinkers. The association between black tea consumption and mortality was weak, with no clear trends noted across the categories of consumption. CONCLUSIONS: In Asian populations, coffee consumption is associated with a lower risk of death overall and with lower risks of death from CVD and cancer. Green tea consumption is associated with lower risks of death from all causes and CVD.

Colorectal cancer in the Linxian China Nutrition Intervention Trial: Risk factors and intervention results.

BACKGROUND: Colorectal cancer (CRC) is among the most common cancers in economically developed countries and developing world. While dietary factors are associated with risk of CRC in the West and urban China, little is known about risk or protective factors in rural China. METHODS: The Linxian General Population Nutrition Intervention Trial (NIT) cohort was established over 30 years ago to test whether daily multivitamin/mineral supplements could reduce the incidence and mortality of esophageal/gastric cardia cancer. The cohort included a total of 29,553 healthy participants 40-69 years old who were randomly assigned to supplements or placebos via a 24 fractional factorial study design. We examined risk factors for the development of CRC as well as the effects of four different nutritional factors (Factor A: retinol, zinc; B: riboflavin, niacin; C: ascorbic acid, molybdenum; D: selenium, alpha-tocopherol, beta-carotene,) on CRC incidence following 5.25 years of supplementation in this randomized, placebo-controlled intervention trial. RESULTS: CRC risk increased with age and height as well as piped water usage, family history of CRC, and consumption of foods cooked in oil, eggs, and fresh fruits. No effect on CRC was seen for any of these four intervention factors tested in both genders, but CRC was reduced 37% in females who received Factor D (selenium/alpha-tocopherol/beta-carotene) (RR = 0.63, 95% CI = 0.43-0.92, P = 0.016) compared to females who did not receive Factor D. CONCLUSIONS: In this undernourished rural Chinese population, CRC risk factors in this Chinese cohort showed both similarities and differences compared to Western and urban Asian Chinese populations. Intervention results suggested a potential benefit for women supplemented with selenium/alpha-tocopherol/beta-carotene.

Association of tooth loss with liver cancer incidence and chronic liver disease mortality in a rural Chinese population.

BACKGROUND: Tooth loss has been reported to be associated with the risk of liver cancer in several prior studies in economically advantaged countries. Whether this relationship is also evident in economically disadvantaged populations is not known. METHODS: We analyzed data from the Nutrition Intervention Trials, two randomized placebo-controlled trials of vitamin/mineral supplementation in Linxian, China. Participants who reported having lost permanent teeth were examined to determine the number of teeth remaining. In the 30-year follow-up period, 329 liver cancers were diagnosed and 368 chronic liver disease deaths occurred. Tooth loss was categorized based on loess smoothed age-specific predicted quartiles. Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the two outcomes. RESULTS: Overall, persons in the highest quartile of age-specific tooth loss had an increased risk of liver cancer (HR = 1.27, 95%CI: 0.96, 1.67) which was not statistically significant. Results varied by sex and body mass index (BMI), however. Women in the highest quartile of age-specific tooth loss had a significantly increased risk (HR = 1.64, 95%CI: 1.04, 2.59), while men did not (HR = 1.08, 95%CI = 0.75, 1.57), and persons with a BMI > 23.0 kg/m2 (HR = 1.71, 95%CI: 1.00, 2.92) had a significantly increased risk, while persons with a BMI <23.0 kg/m2 did not (HR = 1.14, 95%CI: 0.82, 1.5). No relationships with chronic liver disease mortality were observed. CONCLUSIONS: In a rural, economically disadvantaged population, persons with the highest levels of age-specific tooth loss had an increased risk of liver cancer. The results, which were stronger among women and persons with greater BMI, suggest that periodontal disease may increase risk of liver cancer.

Effects of Nutrition Intervention on Total and Cancer Mortality: 25-Year Post-trial Follow-up of the 5.25-Year Linxian Nutrition Intervention Trial.

Background: A beneficial effect of supplementation with selenium, vitamin E, and beta-carotene was observed on total and cancer mortality in a Chinese population, and it endured for 10 years postintervention, but longer durability is unknown. Methods: A randomized, double-blind, placebo-controlled trial was conducted in Linxian, China, from 1986 to 1991; 29 584 residents age 40 to 69 years received daily supplementations based on a factorial design: Factors A (retinol/zinc), B (riboflavin/niacin), C (vitamin C/molybdenum), and/or D (selenium/vitamin E/beta-carotene), or placebo for 5.25 years, and followed for up 25 years. Hazard ratios (HRs) and 95% confidence intervals (CIs) for the intervention effects on mortalities were estimated using Cox proportional hazards models. Results: Through 2016, the interventions showed no effect on total mortality. The previously reported protective effect of Factor D against total mortality was lost 10 years postintervention. The protective effect of Factor D for gastric cancer was attenuated (HR = 0.93, 95% CI = 0.85 to 1.01), but a newly apparent protective effect against esophageal cancer was found for Factor B (HR = 0.92, 95% CI = 0.85 to 1.00, two-sided P = .04). Other protective/adverse associations were observed for cause-specific mortalities. Protective effects were found in people younger than age 55 years at baseline against non-upper gastrointestinal cancer death for Factor A (HR = 0.80, 95% CI = 0.69 to 0.92) and against death from stroke for Factor C (HR = 0.89, 95% CI = 0.82 to 0.96). In contrast, increased risk of esophageal cancer was found when the intervention began after age 55 years for Factors C (HR = 1.16, 95% CI = 1.04 to 1.30) and D (HR = 1.20, 95% CI = 1.07 to 1.34). Conclusions: Multiyear nutrition intervention is unlikely to have a meaningful effect on mortality more than a decade after supplementation ends, even in a nutritionally deprived population. Whether sustained or repeat intervention would provide longer effects needs further investigation.

Vertebral fractures among breast cancer survivors in China: a cross-sectional study of prevalence and health services gaps.

BACKGROUND: Breast cancer survivors are at high risk for fracture due to cancer treatment-induced bone loss, however, data is scarce regarding the scope of this problem from an epidemiologic and health services perspective among Chinese women with breast cancer. METHODS: We designed a cross-sectional study comparing prevalence of vertebral fractures among age- and BMI-matched women from two cohorts. Women in the Breast Cancer Survivors cohort were enrolled from a large cancer hospital in Beijing. Eligibility criteria included age 50-70 years, initiation of treatment for breast cancer at least 5 years prior to enrollment, and no history of metabolic bone disease or bone metastases. Data collected included sociodemographic characteristics; fracture-related risk factors, screening and preventive measures; breast cancer history; and thoracolumbar x-ray. The matched comparator group was selected from participants enrolled in the Peking Vertebral Fracture Study, an independent cohort of healthy community-dwelling postmenopausal women from Beijing. RESULTS: Two hundred breast cancer survivors were enrolled (mean age 57.5 ± 4.9 years), and compared with 200 matched healthy women. Twenty-two (11%) vertebral fractures were identified among breast cancer survivors compared with 7 (3.5%) vertebral fractures in the comparison group, yielding an adjusted odds ratio for vertebral fracture of 4.16 (95%CI 1.69-10.21, p < 0.01). The majority had early stage (85.3%) and estrogen and/or progesterone receptor positive (84.6%) breast cancer. Approximately half of breast cancer survivors reported taking calcium supplements, 6.1% reported taking vitamin D supplements, and only 27% reported having a bone density scan since being diagnosed with breast cancer. CONCLUSIONS: Despite a four-fold increased odds of prevalent vertebral fracture among Chinese breast cancer survivors in our study, rates of screening for osteoporosis and fracture risk were low reflecting a lack of standardization of care regarding cancer-treatment induced bone loss.

Multivitamin and mineral supplementation is associated with the reduction of fracture risk and hospitalization rate in Chinese adult males: a randomized controlled study.

Controversy exists in the literature regarding the efficacy of bone health-related nutrients, especially calcium and vitamin D, in preventing fractures. The aim of our present study was to determine the effect of multivitamin and mineral supplementation on fracture incidence among 3,318 participants from a nutritional intervention trial in Linxian, China. A total of 1,461 men and 1,857 women were enrolled and randomized to daily supplementation with 26 vitamins and minerals tablet or placebo pills for 6 years, followed by a 16-year post-interventional follow-up. The dates, sites, and causes of the fractures were collected retrospectively via a standardized questionnaire. Cox proportional hazard model was used to estimate hazard ratios and 95% confidence intervals of fracture incidence in the intervention versus the placebo group. A total of 221 fractures (57 in men and 164 in women) occurred during the entire study period of 21 years and 9 months. In men, the supplement reduced the risk of fracture by 63% during the trial period, and this protective effect was sustained and statistically significant when analysis included both the trial period and 5- or 10-year post-intervention follow-up (years 0-11, P = 0.04; years 0-16, P = 0.02, respectively). The protection against fracture was not apparent >10 years after cessation of the intervention. In women, no significant effect of supplementation on fracture incidence was seen in any of the study periods. These results demonstrate that a 6-year multivitamin and mineral intervention was associated with significant reduction of fracture risk and fracture-related hospitalization in men, but not in women.

Inpatient Treatment Patterns and Health Care Expenditures for Hepatocellular Carcinoma among the Population with Urban Basic Health Insurance in China.

OBJECTIVE: To identify inpatient treatment patterns and health care expenditures for hepatocellular carcinoma (HCC) among the population with urban basic health insurance (BHI) in China. METHODS: Hospitalizations for patients 18 years or older with discharge diagnosis of HCC from 2008 to 2011 and enrolled in the Chinese BHI plan were identified from the Chinese Health Insurance Research Association database. Treatment approaches and hospital expenditures were assessed for the full sample, and according to city level and hospital tier. Analyses were extrapolated to the national urban BHI population. RESULTS: A total of 3679 HCC hospitalizations were identified in the period 2008 to 2011, representing 615,359 hospitalizations among the urban BHI population. More than two-thirds of the patients received active treatment during hospitalization (68%, N = 418,394), most commonly with traditional Chinese medicine (51%) and/or transarterial intervention therapy (21%). Cases from larger level 1 cities and larger tier 3 hospitals reported greater use of active treatments (81% and 83%, respectively) than did those from smaller level 3 cities (46%) or tier 1 hospitals (56%). Hospital expenditures were higher in level 1 cities (mean [95% confidence interval] Chinese currency renminbi [¥] 17,119 [¥16,292-¥17,946]; US $2,506 [$2,385-$2,628]) than in level 3 cities (mean [95% confidence interval] ¥7,870 [¥5,775-¥9,964]; $1,152 [$846-$1,459]). CONCLUSIONS: Most patients with HCC received active treatment during hospitalization in China. There were substantial disparities, however, in the use of HCC treatments across different economic regions, and nearly a third received only palliative care. With the recent launch of health care reform, this study provides valuable insights into current resource use and costs for HCC in China to help prioritize areas of improvement.

Challenges to effective cancer control in China, India, and Russia.

Cancer is one of the major non-communicable diseases posing a threat to world health. Unfortunately, improvements in socioeconomic conditions are usually associated with increased cancer incidence. In this Commission, we focus on China, India, and Russia, which share rapidly rising cancer incidence and have cancer mortality rates that are nearly twice as high as in the UK or the USA, vast geographies, growing economies, ageing populations, increasingly westernised lifestyles, relatively disenfranchised subpopulations, serious contamination of the environment, and uncontrolled cancer-causing communicable infections. We describe the overall state of health and cancer control in each country and additional specific issues for consideration: for China, access to care, contamination of the environment, and cancer fatalism and traditional medicine; for India, affordability of care, provision of adequate health personnel, and sociocultural barriers to cancer control; and for Russia, monitoring of the burden of cancer, societal attitudes towards cancer prevention, effects of inequitable treatment and access to medicine, and a need for improved international engagement.

Epidemiologic study of compliance to postmastectomy radiation therapy guidelines in breast cancer patients in China between 1999 and 2008.

PURPOSE: To evaluate compliance with postmastectomy radiation therapy (PMRT) guidelines in breast cancer patients in China over a 10-year period. METHODS AND MATERIALS: A hospital-based, nationwide, multicenter retrospective epidemiologic study of primary breast cancer in women was conducted. Seven first-class, upper-level hospitals from different geographic regions of China were selected. One month was randomly selected to represent each year from 1999-2008 in every hospital. All inpatient cases within the selected months were reviewed and demographic, clinical, and pathologic characteristics and treatment patterns were collected. Patients enrolled in this study had to meet the following inclusion criteria: (1) treated with mastectomy and axillary dissection; (2) information regarding whether or not they received postmastectomy radiation therapy was available; and (3) information about staging was available. Patients were divided into 3 groups based on National Comprehensive Cancer Network guidelines. Utilization of PMRT in each group was analyzed and compared between different years and different hospitals. RESULTS: A total of 2310 patients were analyzed. There were 643 (27.8%) patients in the PMRT recommended group, 557 (24.1%) patients in the controversial group, and 1110 (48.1%) patients in the nonrecommended group. PMRT was used in 48.8% of patients in the recommended group, 15.6% in the controversial group, and 5.7% in the nonrecommended group. There was a trend toward increasing use of radiation therapy in the recommended and controversial groups from 1999-2008. The use of PMRT in the nonrecommended group remained relatively stable from 1999-2008. Fewer positive nodes and nonreceipt of chemotherapy or hormone therapy were associated with underuse of PMRT in the recommended group. In the controversial group, a higher ratio of positive nodes was associated with use of PMRT. CONCLUSIONS: There is an apparent underuse of PMRT in the PMRT recommended group. Efforts should be made to improve the compliance to PMRT guidelines.

The pathologic characteristics of breast cancer in China and its shift during 1999-2008: a national-wide multicenter cross-sectional image over 10 years.

In China, breast cancer is currently the most common malignancy and the sixth leading cause of cancer death in women. But, the characteristics of breast cancer in the whole population are not determined. The aim of this study was to perform a detailed study on pathologic characteristics of breast cancer representing the whole population in China during 1999-2008 and to compare the difference in invasive breast cancer between the Western and Chinese. We randomly collected 4,211 inpatient at seven hospitals in representative geographical regions of China during 1999-2008. All the hospitals had the ability of comprehensive cancer treatment. The pathologic characters including estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) status were surveyed. The shift of pathologic characters was evaluated and the data from China were also compared with those of the Western, both using Chi-square test. We found as follow. (i) The median age of the patients was 48 years and showed the similar characters of Asia. (ii) Breast cancer in China showed more invasive ductal carcinoma with larger tumor size, later stage, lower ER and PR expression and higher HER2 overexpression than those in the Western (p < 0.001). (iii) Both tumor size and stage at diagnosis decreased year by year (p < 0.001). Breast cancer in China showed more aggressive behavior than those in western countries, although tumor size and stage at diagnosis decreased by year during 1999-2008. We addressed the urgent needs for employ race-specific breast cancer screen, diagnosis methods, and therapeutic models in China.

Serum cytokine analysis in a positive chemoprevention trial: selenium, interleukin-2, and an association with squamous preneoplastic disease.

This study represents a multiplex cytokine analysis of serum from a 10-month randomized, controlled trial of 238 subjects that investigated the effects of selenomethionine and/or celecoxib in subjects with mild or moderate esophageal squamous dysplasia. The original chemoprevention study found that, among those with mild dysplasia, selenomethionine treatment favorably altered dysplasia grade. The current analysis found that selenomethionine downregulated interleukin (IL)-2 by 9% (P = 0.04), whereas celecoxib downregulated IL-7 by 11% (P = 0.006) and upregulated IL-13 by 17% (P = 0.008). In addition, an increase in IL-7 tertile from baseline to t10 was significantly associated with an increase in dysplasia grade, both overall [odds ratio (OR), 1.47; P = 0.03] and among those with mild dysplasia at t0 (OR, 2.53; P = 0.001). An increase in IL-2 tertile from baseline to t10 was also nonsignificantly associated with worsening dysplasia for all participants (OR, 1.32; P = 0.098) and significantly associated with worsening dysplasia among those with mild dysplasia at baseline (OR, 2.0; P = 0.01). The association of increased IL-2 with worsening dysplasia remained significant in those on selenomethionine treatment who began the trial with mild dysplasia (OR, 2.52; P = 0.03). The current study shows that selenomethionine supplementation decreased serum IL-2 levels, whereas celecoxib treatment decreased IL-7 levels and increased IL-13 levels during a 10-month randomized chemoprevention trial. An increase in IL-2 or IL-7 was associated with increased severity of dysplasia over the course of the trial, especially in those who began the trial with mild dysplasia. The favorable effect of selenomethionine on esophageal dysplasia in the original trial may have been mediated in part by its effect in reducing the levels of IL-2.

Total and cancer mortality after supplementation with vitamins and minerals: follow-up of the Linxian General Population Nutrition Intervention Trial.

BACKGROUND: The General Population Nutrition Intervention Trial was a randomized primary esophageal and gastric cancer prevention trial conducted from 1985 to 1991, in which 29,584 adult participants in Linxian, China, were given daily vitamin and mineral supplements. Treatment with "factor D," a combination of 50 microg selenium, 30 mg vitamin E, and 15 mg beta-carotene, led to decreased mortality from all causes, cancer overall, and gastric cancer. Here, we present 10-year follow-up after the end of active intervention. METHODS: Participants were assessed by periodic data collection, monthly visits by village health workers, and quarterly review of the Linxian Cancer Registry. Hazard ratios (HRs) and 95% confidence intervals (CIs) for the cumulative effects of four vitamin and mineral supplementation regimens were calculated using adjusted proportional hazards models. RESULTS: Through May 31, 2001, 276 participants were lost to follow-up; 9727 died, including 3242 from cancer (1515 from esophageal cancer and 1199 from gastric cancer). Participants who received factor D had lower overall mortality (HR = 0.95, 95% CI = 0.91 to 0.99; P = .009; reduction in cumulative mortality from 33.62% to 32.19%) and gastric cancer mortality (HR = 0.89, 95% CI = 0.79 to 1.00; P = .043; reduction in cumulative gastric cancer mortality from 4.28% to 3.84%) than subjects who did not receive factor D. Reductions were mostly attributable to benefits to subjects younger than 55 years. Esophageal cancer deaths between those who did and did not receive factor D were not different overall; however, decreased 17% among participants younger than 55 (HR = 0.83, 95% CI = 0.71 to 0.98; P = .025) but increased 14% among those aged 55 years or older (HR = 1.14, 95% CI = 1.00 to 1.30; P = .047) [corrected]. Vitamin A and zinc supplementation was associated with increased total and stroke mortality; vitamin C and molybdenum supplementation, with decreased stroke mortality. CONCLUSION: The beneficial effects of selenium, vitamin E, and beta-carotene on mortality were still evident up to 10 years after the cessation of supplementation and were consistently greater in younger participants. Late effects of other supplementation regimens were also observed.

Chemoprevention of primary liver cancer: a randomized, double-blind trial in Linxian, China.

BACKGROUND: Primary liver cancer is a common malignancy with a dismal prognosis. New primary prevention strategies are needed to reduce mortality from this disease. We examined the effects of supplementation with four different combinations of vitamins and minerals on primary liver cancer mortality among 29450 initially healthy adults from Linxian, China. METHODS: Participants were randomly assigned to take either a vitamin-mineral combination ("factor") or a placebo daily for 5.25 years (March 1986-May 1991). Four factors (at doses one to two times the US Recommended Daily Allowance)-retinol and zinc (factor A); riboflavin and niacin (factor B); ascorbic acid and molybdenum (factor C); and beta-carotene, alpha-tocopherol, and selenium (factor D)-were tested in a partial factorial design. The study outcome was primary liver cancer death occurring from 1986 through 2001. Adjusted Cox proportional hazards models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) of liver cancer death with and without each factor. All P values are two-sided. RESULTS: A total of 151 liver cancer deaths occurred during the analysis period. No statistically significant differences in liver cancer mortality were found comparing the presence and absence of any of the four intervention factors. However, both factor A and factor B reduced liver cancer mortality in individuals younger than 55 years at randomization (HR = 0.59, 95% CI = 0.34 to 1.00, and HR = 0.54, 95% CI = 0.31 to 0.93, respectively) but not in older individuals (HR = 1.06, 95% CI = 0.71 to 1.59, and HR = 1.12, 95% CI = 0.75 to 1.68, respectively). Factor C reduced liver cancer death, albeit with only borderline statistical significance in males (HR = 0.70, 95% CI = 0.47 to 1.02) but not in females (HR = 1.30, 95% CI = 0.72 to 2.37). Cumulative risks of liver cancer death were 6.0 per 1000 in the placebo arm, 5.4 per 1000 in the arms with two factors, and 2.4 per 1000 in the arm with all four factors. CONCLUSION: None of the factors tested reduced overall liver cancer mortality. However, three factors reduced liver cancer mortality in certain subgroups.

Cellular immune response is not associated with incident cancer or total mortality: a prospective follow-up.

The objective of this study was to determine whether immunologic competence, as measured by lymphocyte stimulation indices from three different ex vivo challenges, is associated with subsequent risk of cancer or total mortality in Linzhou, China, a population at high risk for upper gastrointestinal cancers. Cellular immune function tests were conducted on a subgroup of 381 trial participants after 5.25 years of intervention to evaluate whether nutrient supplementation affected the cellular immune system and found significantly higher T-lymphocyte mitogenic responsiveness to phytohemagglutinin-M among men receiving daily supplementation of beta-carotene (15 mg) plus selenium (50 mug) plus alpha-tocopherol (30 mg) (supplementation factor D) compared with those who did not receive this supplement (P<0.05). The current analysis reports 10 years of post-trial prospective follow-up of these 381 trial participants and identifies 53 incident cancers, 48 (92%) of which were upper gastrointestinal cancers, including 22 esophageal cancers, 22 gastric cardia cancers, and four noncardia gastric cancers. Ninety-one deaths occurred among the 381 participants, including 33 upper gastrointestinal cancer deaths, 23 heart disease deaths, 16 stroke deaths, and seven fatal accidents. Multivariate Cox proportional hazards models including variables for age at time of tests, sex, tobacco smoking, alcohol drinking, and original trial treatment group showed no significant associations between phytohemagglutinin-M, concanavalin-A, or anti-CD3 stimulation indices and subsequent cancer incidence or total mortality. This implies that immune competence, as measured by these stimulation indices, is not associated with incident cancer or total mortality in this population.

Lung cancer chemoprevention: a randomized, double-blind trial in Linxian, China.

We examined the effect of supplementation with four different combinations of vitamins and minerals in the prevention of lung cancer mortality among 29,584 healthy adults from Linxian, China. In accord with a partial factorial design, the participants were randomly assigned to take either a vitamin/mineral combination or a placebo for 5.25 years. The combinations tested in this trial were as follows: factor A, retinol and zinc; factor B, riboflavin and niacin; factor C, ascorbic acid and molybdenum; factor D, beta-carotene, alpha-tocopherol, and selenium. Lung cancer deaths (n = 147) identified during the trial period (1986-1991) and 10 years after the trial ended (1991-2001) were the study outcome. No significant differences in lung cancer death rates were found for any of the four combinations of supplements tested in this study, using log-rank tests (all P values are >0.20) or Cox proportional hazards models adjusted for age, sex, commune, and other treatments. No significant interactions were seen for age, sex, or smoking status. Supplementation with combinations of vitamins and minerals at nutrient-repletion levels for 5.25 years did not reduce lung cancer mortality in this nutrient-inadequate population in Linxian, China.

Selenomethionine treatment does not alter gene expression in normal squamous esophageal mucosa in a high-risk Chinese population.

Selenium is a promising cancer chemoprevention agent. A recent randomized controlled chemoprevention trial found that selenomethionine (SeMet) supplementation for 10 months favorably effected a change in esophageal dysplasia grade among participants who started the trial with mild dysplasia. To further explore the role of SeMet in this trial, we compared gene expression profiles by treatment group using Affymetrix HU 133A chips in before/after supplementation paired normal esophageal biopsies from a subset of 29 trial participants, 16 who received SeMet, and 13 who received placebo. Using P < 0.001 as a cutoff, 11 differentially expressed genes were found in the SeMet supplementation group but these genes did not include either known selenoprotein genes or genes previously shown to be modulated by selenium treatment. Because the number of differentially expressed genes (n = 11) was less than expected by chance (n = 18), we concluded that SeMet supplementation had no measurable effect on gene expression in the normal squamous esophagus of these subjects with dysplasia.