Predictors of vitamin D biochemical status in a large sample of middle-aged male smokers in Finland.

BACKGROUND/OBJECTIVES: As vitamin D deficiency is considered to be more common in regions with little solar ultraviolet (UV) light in winter, the aim of this study was to analyze predictors of vitamin D status by season within a large sample of male smokers from Finland, a country where there is negligible solar UV light in winter. SUBJECTS/METHODS: Vitamin D (measured by 25-hydroxyvitamin D (25(OH)D) nmol/l) and other serum constituents were assayed. Measured anthropometry, and self-reported dietary intake and physical activity (PA) were obtained and analyzed using stepwise multiple linear and logistic regression in 2271 middle-aged Finnish male smokers. RESULTS: In all, 27% of the population in winter and 17% in summer had serum 25(OH)D levels of <25 nmol/l, respectively. In summer, in multiple logistic regression analyses with adjustment for confounding and other predictors, high vitamin D intake (odds ratios (OR) 3.6; 95% confidence interval (CI) 1.5-8.5), some leisure time PA (OR 2.0; 95% CI 1.3-3.1) and having a body mass index (BMI) of >or=21 kg/m(2) compared with <21 kg/m(2) (OR 2.6; 95% CI 1.3-5.0), were associated with 25(OH)D >or=25 nmol/l. In winter, additional modifiable factors were occupational PA (OR 1.6; 95% CI 1.1-2.5) and high fish (OR 3.1; 95% CI 1.7-6.2) or poultry consumption (OR 1.7; 95% CI 1.2-2.5). Predictors from linear regression analyses of continuous levels of 25(OH)D were similar to the logistic regression analyses of 25(OH)D >or=25 nmol/l. CONCLUSION: In this Finnish sample more vitamin D intake, PA and having a BMI of >or=21 may have important modifiable roles in maintaining an adequate vitamin D status.

Polymorphisms in glutathione-S-transferase genes (GST-M1, GST-T1 and GST-P1) and susceptibility to prostate cancer among male smokers of the ATBC cancer prevention study.

Glutathione-S-transferase (GST) genes encode a family of detoxification enzymes that offer protection against endogenous and exogenous sources of reactive oxygen species (ROS). Germline variations in GST genes may alter the catalytic efficiency of GST isoenzymes leading to a potential increase in susceptibility to the genotoxic effects of ROS and electrophilic substances. A nested case-control study design was used to examine the association between the polymorphic GST genes and prostate cancer risk among Finnish male smokers of the ATBC Cancer Prevention Study. A case-case analysis was used to determine the association between these genetic polymorphisms and prostate cancer progression. Germline DNA was obtained from 206 prostate cancer cases and 194 controls frequency matched on age, intervention group and study clinic. Cases and controls were genotyped for three GST genes using MALDI-TOF mass spectrometry or multiplex polymerase chain reaction (PCR). Relative to the wild-type genotype, we observed a 36% reduction in prostate cancer risk associated with the GST-M1-null genotype (odds ratio (OR) 0.64, 95% confidence interval (CI) 0.43, 0.95). Unlike GST-M1, GST-T1-null (OR 0.74, 95% CI 0.42, 1.33) and GST-P1*B (OR 1.10, 95% CI 0.72, 1.69) were not strongly associated with prostate cancer risk. We did not observe any significant associations between the selected polymorphic GST genes and tumour grade or stage. In conclusion, we did not observe a direct association between polymorphic GST-T1 or GST-P1 and prostate cancer risk. Our observation of a relatively strong inverse association between the GST-M1-null genotype and prostate cancer risk needs to be confirmed in larger association studies.

Hormone replacement therapy and colorectal adenoma recurrence among women in the Polyp Prevention Trial.

BACKGROUND: Epidemiologic studies have suggested that estrogen may protect against the development of colorectal cancers and adenomatous polyps. We conducted a prospective study to evaluate the association between hormone replacement therapy (HRT) and adenoma recurrence among perimenopausal and postmenopausal women participating in the Polyp Prevention Trial, a randomized dietary intervention study of individuals with colorectal adenomas. METHODS: We used a questionnaire and interviews to collect detailed information, at baseline and at each of four annual study visits, from 620 women regarding hormone use, menopausal status, diet, alcohol consumption, and other risk factors. Adenoma recurrence was ascertained by complete colonoscopy at baseline and after 1 and 4 years. Logistic regression models were used to evaluate the association between hormone use and adenoma recurrence after adjusting for intervention group and for age and body mass index at baseline. All statistical tests were two-sided. RESULTS: Adenomas recurred in 200 women. There was no overall association between adenoma recurrence and either overall hormone use (odds ratio [OR] = 1.01; 95% confidence interval [CI] = 0.70 to 1.45), combined estrogen and progestin use (OR = 0.94; 95% CI = 0.57 to 1.56), or unopposed estrogen use (OR = 1.04; 95% CI = 0.68 to 1.59). HRT use was associated with a reduction in risk for recurrence of distal adenomas (OR = 0.56; 95% CI = 0.32 to 1.00) and a statistically nonsignificant increase in risk for recurrence of proximal adenomas (OR = 1.39; 95% CI = 0.85 to 2.26). We observed a statistically significant interaction between the HRT-adenoma recurrence association and age (P =.02). HRT was associated with a 40% reduced risk of adenoma recurrence among women older than 62 years (OR = 0.58; 95% CI = 0.35 to 0.97) but with an increased risk among women younger than 62 years (OR = 1.99; 95% CI = 1.11 to 3.55). CONCLUSIONS: HRT was not associated with a reduced risk for overall adenoma recurrence in this trial cohort, although there was a suggestion of an age interaction. The effect of age on the association needs to be confirmed in other adenoma recurrence trials.

Cyclooxygenase-2, P-glycoprotein-170 and drug resistance; is chemoprevention against multidrug resistance possible?

BACKGROUND: It is generally accepted that P-glycoprotein 170 (MDR1/Pgp170) expression in breast tumors results in poor response to chemotherapy due to its ability to export chemotherapeutic agents. Studies indicate that the use of non-steroidal anti-inflammatory drugs (NSAIDs) may enhance the anti-tumor activity of cancer chemotherapeutic agents and reduce the risk of many cancers. The best known function of NSAIDs is to block the enzyme cyclooxygenase (Cox), the rate limiting enzyme in the conversion of arachidonic acid to prostaglandins. In this study we investigated whether expression of the inducible isoform of Cox (Cox-2) is linked with the multidrug resistance phenotype in breast cancer. METHODS: Expression of Cox-2 and MDR1/Pgp170 was investigated in tumor specimens along with normal epithelium in breast cancer patients using immunohistochemisrty. Expression of Cox-2, MDR1/Pgp170, Protein Kinase C (PKC), and Activator Protein 1 (AP1) were investigated in a series of increasingly resistant human MCF-7 breast cancer cells compared to wild type using immunohistochemistry, Western blots, Northern blots, RT-PCR, and Southern blots. RESULTS: Immunohistochemical analyses of human breast tumor specimens revealed a strong correlation between expression of Cox-2 and MDR1/Pgp170. In drug resistant cell lines that over-express MDR1/Pgp170 there was also significant up-regulation of Cox-2 expression. In addition, PKC and AP1 subunits c-Jun and c-Fos were also upregulated. We hypothesized that increased prostaglandin production by Cox-2 induces PKC and the expression of transcriptional factor c-Jun, which in turn, induces the expression of MDR1/Pgp170. CONCLUSION: We propose that pretreatment with selective Cox-2 inhibitors may be useful in the prevention of multidrug resistance in response to cancer chemotherapy and should be further evaluated.

Influence of antioxidants and the CYP1A1 isoleucine to valine polymorphism on the smoking--lung cancer association.

To evaluate the association between CYP1A1 genotype and lung cancer risk and to assess the effect of CYP1A1 genotype and antioxidant supplementation on the smoking--lung cancer relationship we conducted a case-control study nested within a large cancer prevention trial cohort. Controls (n = 324) were matched to cases (n = 282) on age (+/- 5 years), intervention group and study clinic in a 1:1 ratio, using incidence density sampling. Genotype was determined by a PCR-based method and logistic regression was used to calculate relative risk estimates. Overall, we found no association between CYP1A1 genotype and lung cancer risk. CYP1A1 genotype did not modify the effect of smoking on lung cancer risk. However, in an examination of subgroups defined by randomized intervention assignment our findings suggest that alpha-tocopherol supplementation may reduce the risk of lung cancer associated with cumulative smoking exposure regardless of CYP1A1 genotype with the greatest effect seen among those with the variant CYP1A1 allele.

Variation in the promoter region of the myeloperoxidase gene is not directly related to lung cancer risk among male smokers in Finland.

In order to examine whether a polymorphism in the promoter region of the myeloperoxidase (MPO) gene is associated with lung cancer among male smokers, we conducted a case-control study nested within a Finnish clinical trial cohort. Although we found no evidence of an overall association between lung cancer risk and MPO genotype, the variant MPO genotype was associated with an increased risk of lung cancer among a subset of older men. These findings contrast with those from previous studies that report decreased lung cancer risk among MPO variant individuals.

Polymorphisms of the DNA repair gene XRCC1 and lung cancer risk.

We explored the association between polymorphisms of the DNA repair gene XRCC1 (codons 194, 280, and 399) and lung cancer risk in a case-control study nested within a cohort of tin miners. Cases were those diagnosed with lung cancer over 6 years of follow-up (n = 108). Two controls, matched on age and sex, were selected for each case by incidence density sampling. Of the three polymorphisms, only the XRCC1 Arg280His allele was associated with increased lung cancer risk (odds ratio, 1.8; 95% confidence interval, 1.0-3.4) after adjustment for radon and tobacco exposure. In addition, individuals with the variant Arg280His allele who were alcohol drinkers seemed to be at higher risk for lung cancer compared with those with the homozygous wild-type genotype. Conversely, individuals with the variant Arg194Trp allele who were alcohol drinkers seemed to be at lower risk for lung cancer compared with those with the homozygous wild-type genotype. Polymorphisms of XRCC1 appear to influence risk of lung cancer and may modify risk attributable to environmental exposures.

Effects of long-term alpha-tocopherol supplementation on serum hormones in older men.

BACKGROUND: alpha-tocopherol supplementation significantly reduced risk of prostate cancer in the Alpha-Tocopherol Beta-Carotene Cancer Prevention (ATBC) Study. Sex hormones are thought to be involved in the etiology of prostate cancer. We examined whether long-term supplementation with alpha-tocopherol modified serum hormone levels. METHODS: Men who were cancer-free consumed > or = 90% of the study capsules, and who had both baseline and follow-up blood available, were eligible for the study. One hundred men who received alpha-tocopherol were matched on age, study center, and length of time between blood draws to 100 men who received a placebo. Multivariate linear regression models which allowed for a separate intercept for each matched pair were used to evaluate the effect of alpha-tocopherol supplementation on follow-up hormone concentrations. RESULTS: Compared to men who received a placebo, we found significantly lower serum androstenedione (P = 0.04) and testosterone (P = 0.04) concentrations among men who received alpha-tocopherol, after controlling for baseline hormone level, follow-up serum cholesterol concentration, body mass index, smoking, and fasting time. Geometric mean (95% confidence interval; CI) androstenedione concentration among men who received alpha-tocopherol was 145 ng/dl (CI, 137-153) after adjusting for covariates, compared to 158 ng/dl (CI, 148-167) among men who received a placebo. Mean testosterone concentrations for men who received alpha-tocopherol and placebo were 539 (CI, 517-562) and 573 (CI, 549-598) ng/dl, respectively. CONCLUSIONS: These results suggest that long-term alpha-tocopherol supplementation decreases serum androgen concentrations, and could have been one of the factors contributing to the observed reduction in incidence and mortality of prostate cancer in the alpha-tocopherol treatment group of the ATBC Study.

Glutathione peroxidase codon 198 polymorphism variant increases lung cancer risk.

Human cellular glutathione peroxidase 1 (hGPX1) is a selenium-dependent enzyme that participates in the detoxification of hydrogen peroxide and a wide range of organic peroxides. We conducted a case-control study nested within the alpha-Tocopherol, beta-Carotene Cancer Prevention Study cohort to evaluate the association between the proline to leucine polymorphism at codon 198 of hGPX1 and lung cancer risk. Cases (n = 315) were matched to controls on age (+/-5 years), intervention group, and study clinic using incidence density sampling in a 1:1 ratio. The prevalence of the hGPX1 Pro198Leu variant allele was 58% for controls and 71% for cases (P < 0.001). Using conditional logistic regression, we found a significant association between hGPX1 genotype and lung cancer risk. The odds ratio for heterozygotes was 1.8 (95% confidence interval, 1.2-2.8) and 2.3 (95% confidence interval, 1.3-3.8) for homozygous variants compared to wild-type individuals. Due to its high prevalence, the hGPX1 variant may contribute significantly to lung cancer risk among Caucasians but not among ethnic Chinese who do not exhibit this polymorphism.

Serum carotenoids are associated with increased lung cancer risk among alcohol drinkers, but not among non-drinkers in a cohort of tin miners.

To examine the association between pre-diagnostic serum carotenoid levels and lung cancer risk and the effects of alcohol intake on the carotenoid-lung cancer relationship, we conducted a case-control study in an occupational cohort from the Yunnan Tin Corporation in China. During 6 years of follow-up, 339 cases of confirmed lung cancer were diagnosed. Among these cases, those who donated pre-diagnostic blood (n = 108) were eligible for this study. For each case, two individuals alive and free of cancer at the time of case diagnosis, matched on age, sex, and date of blood collection, were selected as controls. Serum beta-carotene (odds ratios (ORs) for tertiles: 1, 1.3, 2.0) and beta-cryptoxanthin (ORs for tertiles: 1, 1.8, 2.9) levels were positively associated with lung cancer risk after adjustment for tobacco use and radon exposure. Among alcohol drinkers, higher serum carotenoid levels were significantly associated with increased lung cancer risk (alpha-carotene OR 2.2, 95% confidence interval (CI) 1.1-4.4, beta-carotene OR 7.6, 95% CI 3.1-18.6, lutein/zeaxanthin OR 2.3, 95% CI 1.2-6.6 and beta-cryptoxanthin OR 7.6, 95% CI 2.7-21.5). Conversely, risk estimates among non-drinkers suggest a possible protective association for higher carotenoid levels.

Association between GSTM1*0 and squamous dysplasia of the esophagus in the high risk region of Linxian, China.

Individuals with specific phase I and phase II enzyme polymorphisms may be at increased risk for squamous cell carcinoma of the esophagus. However, to our knowledge there has been only one previous report that evaluates a potential role for these polymorphisms in increasing risk for preneoplastic squamous lesions of the esophagus. To explore this further, we examined polymorphisms in CYP1A1, CYP2E1, GSTM1 and GSTT1, both independently and in combination, for potential associations with the risk of biopsy-proven squamous dysplasia of the esophagus in asymptomatic adults from Linxian, a high risk region in China. Cases consisted of 56 individuals from an esophageal cancer screening study with an endoscopic biopsy diagnosis of mild or moderate squamous dysplasia. Each case was matched on age (+/- 1 year) and gender to a control. Controls were defined as screening study participants with an endoscopic biopsy diagnosis of normal mucosa or esophagitis. DNA was extracted from frozen cell samples obtained by cytologic balloon examination and genotyped using standard methods. Individuals who were GSTM1 null (homozygous for GSTM1*0) were found to have a tendency for an increased risk of esophageal squamous dysplasia (odds ratio=2.6, 95% CI, 0.9-7.4). No excess risks were observed for inheritance of other putative at risk genotypes CYP1A1*2B, CYP2E1*6 or GSTT1*0. The risk associated with the inheritance of combined genotypes was not significantly different than the risk estimates from the univariate analysis. These results are consistent with the notion that exposure to environmental carcinogens that are detoxified by GSTM1, such as polycyclic aromatic hydrocarbons, may contribute to the etiology of esophageal cancer in Linxian.

Effects of supplemental alpha-tocopherol and beta-carotene on colorectal cancer: results from a controlled trial (Finland)

BACKGROUND: Some epidemiological investigations suggest that higher intake or biochemical status of vitamin E and beta-carotene might be associated with reduced risk of colorectal cancer. METHODS: We tested the effects of alpha-tocopherol and beta-carotene supplementation on the incidence of colorectal cancer in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study, a double-blind, placebo-controlled trial among 29,133 50-69-year-old male cigarette smokers. Participants were randomly assigned to receive alpha-tocopherol (50 mg), beta-carotene (20 mg), both agents, or a placebo daily for 5-8 years. Incident colorectal cancers (n = 135) were identified through the nationwide cancer registry, and 99% were histologically confirmed. Intervention effects were evaluated using survival analysis and proportional hazards models. RESULTS: Colorectal cancer incidence was somewhat lower in the alpha-tocopherol arm compared to the no alpha-tocopherol arm, but this finding was not statistically significant (relative risk (RR) = 0.78, 95% confidence interval (CI) 0.55-1.09; log-rank test p = 0.15). Beta-carotene had no effect on colorectal cancer incidence (RR = 1.05, 95% CI 0.75-1.47; log-rank test p = 0.78). There was no interaction between the two substances. CONCLUSION: Our study found no evidence of a beneficial or harmful effect for beta-carotene in colorectal cancer in older male smokers, but does provide suggestive evidence that vitamin E supplementation may have had a modest preventive effect. The latter finding is in accord with previous research linking higher vitamin E status to reduced colorectal cancer risk.

Serum tocopherols, selenium and lung cancer risk among tin miners in China.

OBJECTIVE: To evaluate the association of prediagnostic serum antioxidants and lung cancer risk we conducted a case-control study nested in an occupational cohort of tin miners. METHODS: Male workers free of cancer enrolled in the cohort. During up to 6 years of follow-up, 339 lung cancer cases were diagnosed and, among these cases, those who donated blood prospectively (n = 108) were eligible for this study. For each case, two controls alive and free of cancer at the time of case diagnosis were matched on age and date of blood collection. RESULTS: Overall, we observed no association between serum alpha-tocopherol, gamma-tocopherol or selenium levels and lung cancer risk. However, a significant gradient of decreasing lung cancer risk with increasing serum alpha-tocopherol was apparent for men less than 60 years old (odds ratio by tertile: 1.0, 0.9, 0.2; trend p = 0.002). Alpha-tocopherol was also protective in men who reported no alcohol drinking (OR by tertile: 1.0, 0.6, 0.3; trend p = 0.008). CONCLUSION: Although there were no significant overall associations between prospectively collected serum alpha-tocopherol, gamma-tocopherol or selenium and incidence of lung cancer, results from this study suggest that higher alpha-tocopherol levels may be protective in men less than 60 years old and in those who do not drink alcohol.

The effect of beta-carotene supplementation on serum vitamin D metabolite concentrations.

In the alpha-Tocopherol, beta-Carotene Cancer Prevention (ATBC) study, a large randomized placebo-controlled trial designed to test the cancer prevention effects of alpha-tocopherol (50 mg/day) and beta-carotene (20 mg/day), participants receiving supplemental beta-carotene had significantly higher rates of lung cancer than those not receiving beta-carotene. It has been hypothesized that the supplemental beta-carotene may have interfered with the synthesis of vitamin D and that the resulting lower concentrations of vitamin D contributed to the elevated cancer incidence. We evaluated whether supplementation with beta-carotene altered the serum concentrations of either 25-hydroxyvitamin D or 1,25-dihydroxyvitamin D in the ATBC Study, by comparing on-study changes between baseline and follow-up serum samples among 20 randomly selected matched pairs of subjects from the beta-carotene and placebo groups. In a matched-pair analysis, the difference between the changes in both 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D in the beta-carotene supplement and placebo groups were small and statistically nonsignificant. These results provide no evidence that beta-carotene supplementation interferes with the endogenous production of 25-hydroxyvitamin D or 1,25-dihydroxyvitamin D and suggest that it is unlikely that an interaction between supplemental beta-carotene and vitamin D metabolites contributed to the modest increase in lung cancer incidence observed in the ATBC Study.

Prevalence of disease-related DNA polymorphisms among participants in a large cancer prevention trial.

Genetic susceptibility polymorphisms may be of substantial importance in the modulation of cancer risk. The prevalence for an array of polymorphic genes was determined in a cohort of male smokers who participated in a cancer prevention trial in Finland. A random sample of 120 individuals was selected from the trial cohort and the prevalence of variant alleles for nine genes was determined using a polymerase chain reaction-based approach. The prevalence values from this study were also compared with those of other populations derived from previous studies. Our results show that, with the exception of cytochrome P450-1A1 (CYP1A1) and cytochrome P450-2E1 (CYP2E1), all genes tested were sufficiently polymorphic to warrant an investigation of gene-environment studies. Most of the variant alleles, including alcohol dehydrogenase 3 (ADH3), glutathione-S-transferase (GSTM1), methionine synthase (MS), methylene tetrahydofolater reductase (MHTFR), CYP2E1 and CYP1A1, exhibited similar frequencies to other Caucasian populations. Interestingly, the prevalence of androgen receptor-CAG repeat (AR-CAG) and vitamin D receptor (VDR) polymorphisms differed significantly between the alpha-tocopherol, beta-carotene (ATBC) Study and other Caucasian populations. We present herein results from this survey and conclude that the ATBC study population in Finland is sufficiently heterogeneous to facilitate analysis of genetic polymorphisms and disease associations.

Diet and risk of colorectal cancer in a cohort of Finnish men.

OBJECTIVES: Based on previous epidemiological studies, high fat and meat consumption may increase and fiber, calcium, and vegetable consumption may decrease the risk of colorectal cancer. We sought to address these hypotheses in a male Finnish cohort. METHODS: We analyzed data from the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (ATBC Study) where 27, 111 male smokers completed a validated dietary questionnaire at baseline. After an average of 8 years of follow-up, we documented 185 cases of colorectal cancer. The analyses were carried out using the Cox proportional hazards model. RESULTS: The relative risk (RR) for men in the highest quartile of calcium intake compared with men in the lowest quartile was 0.6 (95% CI 0.4-0.9, p for trend 0.04). Likewise, the intake of milk protein and the consumption of milk products was inversely associated with risk of colorectal cancer. However, intake of dietary fiber was not associated with risk, nor was fat intake. Consumption of meat or different types of meat, and fried meat, fruits or vegetables were not associated with risk. CONCLUSIONS: In this cohort of men consuming a diet high in fat, meat, and fiber and low in vegetables, high calcium intake was associated with lowered risk of colorectal cancer.

Serum alpha-tocopherol and subsequent risk of lung cancer among male smokers.

BACKGROUND: Higher blood levels of alpha-tocopherol, the predominant form of vitamin E, have been associated in some studies with a reduced risk of lung cancer, but other studies have yielded conflicting results. To clarify this association, we examined the relationship between prospectively collected serum alpha-tocopherol and lung cancer in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study cohort. METHODS: The ATBC Study was a randomized, clinical trial of 29 133 white male smokers from Finland who were 50-69 years old and who had received alpha-tocopherol (50 mg), beta-carotene (20 mg), both, or neither daily for 5-8 years. Data regarding medical histories, smoking, and dietary factors were obtained at study entry, as was a serum specimen for baseline alpha-tocopherol determination. alpha-Tocopherol measurements were available for 29 102 of the men, among whom 1144 incident cases of lung cancer were diagnosed during a median observation period of 7.7 years. The association between alpha-tocopherol and lung cancer was evaluated with the use of multivariate proportional hazards regression. RESULTS: A 19% reduction in lung cancer incidence was observed in the highest versus lowest quintile of serum alpha-tocopherol (relative risk = 0.81; 95% confidence interval = 0. 67-0.97). There was a stronger inverse association among younger men (<60 years), among men with less cumulative tobacco exposure (<40 years of smoking), and possibly among men receiving alpha-tocopherol supplementation. CONCLUSIONS: In the ATBC Study cohort, higher serum alpha-tocopherol status is associated with lower lung cancer risk; this relationship appears stronger among younger persons and among those with less cumulative smoke exposure. These findings suggest that high levels of alpha-tocopherol, if present during the early critical stages of tumorigenesis, may inhibit lung cancer development.

Association between alcohol and lung cancer in the alpha-tocopherol, beta-carotene cancer prevention study in Finland.

OBJECTIVES: We evaluated the association between alcohol intake and lung cancer in a trial-based cohort in Finland, the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (ATBC Study). METHODS: During an average of 7.7 years of follow-up, 1059 lung cancer cases were diagnosed among the 27,111 male smokers with complete alcohol and dietary information. The relationship between alcohol and lung cancer was assessed in multivariate Cox regression models that adjusted for age, smoking, body mass index and intervention group. RESULTS: Nondrinkers, 11% of the study population, were at increased lung cancer risk compared to drinkers (RR = 1.2, 95% CI: 1.0-1.4), possibly due to the inclusion of ex-drinkers who had stopped drinking for health reasons. Among drinkers only, we observed no association between lung cancer and total ethanol or specific beverage (beer, wine, spirits) intake. We found no significant effect modification by level of smoking, dietary micronutrients or trial intervention group; however, for men in the highest quartile of alcohol intake, we observed a slight increase in risk for lighter smokers (<1 pack/day) and reduced risk among the heaviest smokers (>30 cigarettes/day). CONCLUSIONS: We concluded that alcohol consumption was not a risk factor for lung cancer among male cigarette smokers, and its effect was not significantly modified by other factors, notably smoking history.

Expression of cyclooxygenase-2 in human adenocarcinomas of the gastric cardia and corpus.

Several studies indicate that the use of non-steroidal anti-inflammatory drugs (NSAIDs) may reduce the risk of gastric corpus and possibly gastric cardia cancers. The best known action of NSAIDs is to block the enzyme cyclooxygenase, the rate limiting enzyme in the conversion of arachidonic acid to prostaglandins. We investigated the expression of cyclooxygenase-2 (Cox-2) in adenocarcinomas of the gastric cardia (N=19) and corpus (N=15) and in adjacent normal epithelium from a high risk Chinese population. Immunohistochemical detection of Cox-2 revealed positive staining in 36% of the gastric cardia cancer cases and 60% of the gastric corpus cancer cases, whereas histologically normal tissue from the same patients were negative. Smooth muscle, stroma and inflammatory cells were also positive. Our results suggest that Cox-2 is overexpressed in a large proportion of adenocarcinomas of the gastric corpus and in a smaller number of gastric cardia cancer cases.

The effect of alpha-tocopherol and beta-carotene supplementation on colorectal adenomas in middle-aged male smokers.

Epidemiological and experimental studies have indicated that dietary factors such as vitamin C, vitamin E, and beta-carotene are associated with the risk of colorectal cancer. This study was carried out within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (ATBC Study), whose participants were randomly assigned to four supplementation groups: (a) alpha-tocopherol (AT), 50 mg/day; (b) beta-carotene (BC), 20 mg/day; (c) both AT and BC; and (d) placebo. We included the 15,538 ATBC Study participants who had been randomized within the areas of three major cities in southern Finland. Cases of colorectal adenoma (n = 146) were identified by the pathology laboratories in the study areas, and these participants' medical records were collected and reviewed. Alpha-tocopherol supplementation increased the risk for adenomas (relative risk, 1.66; 95% confidence interval, 1.19-2.32), whereas beta-carotene supplementation had no effect on the risk (relative risk, 0.98; 95% confidence interval, 0.71-1.35). Slightly more prediagnosis rectal bleeding and intestinal pain occurred in those adenoma cases who received alpha-tocopherol supplements than in those who did not. Thus, some bias may have resulted, with alpha-tocopherol supplementation leading to more colonoscopies and, thus, to an increased detection of incident polyps in this group. This is further supported by the trial finding that alpha-tocopherol supplementation did not increase the risk of colorectal cancer.