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BackgroundThis review is the third update of the Cochrane review "Selenium for preventing cancer". Selenium is a naturally occurring element with both nutritional and toxicological properties. Higher selenium exposure and selenium supplements have been suggested to protect against several types of cancer.ObjectivesTo gather and present evidence needed to address two research questions:1. What is the aetiological relationship between selenium exposure and cancer risk in humans?2. Describe the efficacy of selenium supplementation for cancer prevention in humans.Search methodsWe updated electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 2), MEDLINE (Ovid, 2013 to January 2017, week 4), and Embase (2013 to 2017, week 6), as well as searches of clinical trial registries.Selection criteriaWe included randomised controlled trials (RCTs) and longitudinal observational studies that enrolled adult participants.Data collection and analysisWe performed random-effects (RE) meta-analyses when two or more RCTs were available for a specific outcome. We conducted RE meta-analyses when five or more observational studies were available for a specific outcome. We assessed risk of bias in RCTs and in observational studies using Cochrane's risk assessment tool and the Newcastle-Ottawa Scale, respectively. We considered in the primary analysis data pooled from RCTs with low risk of bias. We assessed the certainty of evidence by using the GRADE approach.Main resultsWe included 83 studies in this updated review: two additional RCTs (10 in total) and a few additional trial reports for previously included studies. RCTs involved 27,232 participants allocated to either selenium supplements or placebo. For analyses of RCTs with low risk of bias, the summary risk ratio (RR) for any cancer incidence was 1.01 (95% confidence interval (CI) 0.93 to 1.10; 3 studies, 19,475 participants; high-certainty evidence). The RR for estimated cancer mortality was 1.02 (95% CI 0.80 to 1.30; 1 study, 17,444 participants). For the most frequently investigated site-specific cancers, investigators provided little evidence of any effect of selenium supplementation. Two RCTs with 19,009 participants indicated that colorectal cancer was unaffected by selenium administration (RR 0.99, 95% CI 0.69 to 1.43), as were non-melanoma skin cancer (RR 1.16, 95% CI 0.30 to 4.42; 2 studies, 2027 participants), lung cancer (RR 1.16, 95% CI 0.89 to 1.50; 2 studies, 19,009 participants), breast cancer (RR 2.04, 95% CI 0.44 to 9.55; 1 study, 802 participants), bladder cancer (RR 1.07, 95% CI 0.76 to 1.52; 2 studies, 19,009 participants), and prostate cancer (RR 1.01, 95% CI 0.90 to 1.14; 4 studies, 18,942 participants). Certainty of the evidence was high for all of these cancer sites, except for breast cancer, which was of moderate certainty owing to imprecision, and non-melanoma skin cancer, which we judged as moderate certainty owing to high heterogeneity. RCTs with low risk of bias suggested increased melanoma risk.Results for most outcomes were similar when we included all RCTs in the meta-analysis, regardless of risk of bias. Selenium supplementation did not reduce overall cancer incidence (RR 0.99, 95% CI 0.86 to 1.14; 5 studies, 21,860 participants) nor mortality (RR 0.81, 95% CI 0.49 to 1.32; 2 studies, 18,698 participants). Summary RRs for site-specific cancers showed limited changes compared with estimates from high-quality studies alone, except for liver cancer, for which results were reversed.In the largest trial, the Selenium and Vitamin E Cancer Trial, selenium supplementation increased risks of alopecia and dermatitis, and for participants with highest background selenium status, supplementation also increased risk of high-grade prostate cancer. RCTs showed a slightly increased risk of type 2 diabetes associated with supplementation. A hypothesis generated by the Nutritional Prevention of Cancer Trial - that individuals with low blood selenium levels could reduce their risk of cancer (particularly prostate cancer) by increasing selenium intake - has not been confirmed. As RCT participants have been overwhelmingly male (88%), we could not assess the potential influence of sex or gender.We included 15 additional observational cohort studies (70 in total; over 2,360,000 participants). We found that lower cancer incidence (summary odds ratio (OR) 0.72, 95% CI 0.55 to 0.93; 7 studies, 76,239 participants) and lower cancer mortality (OR 0.76, 95% CI 0.59 to 0.97; 7 studies, 183,863 participants) were associated with the highest category of selenium exposure compared with the lowest. Cancer incidence was lower in men (OR 0.72, 95% CI 0.46 to 1.14, 4 studies, 29,365 men) than in women (OR 0.90, 95% CI 0.45 to 1.77, 2 studies, 18,244 women). Data show a decrease in risk of site-specific cancers for stomach, colorectal, lung, breast, bladder, and prostate cancers. However, these studies have major weaknesses due to study design, exposure misclassification, and potential unmeasured confounding due to lifestyle or nutritional factors covarying with selenium exposure beyond those taken into account in multi-variable analyses. In addition, no evidence of a dose-response relation between selenium status and cancer risk emerged. Certainty of evidence was very low for each outcome. Some studies suggested that genetic factors might modify the relation between selenium and cancer risk - an issue that merits further investigation.Authors' conclusionsWell-designed and well-conducted RCTs have shown no beneficial effect of selenium supplements in reducing cancer risk (high certainty of evidence). Some RCTs have raised concerns by reporting a higher incidence of high-grade prostate cancer and type 2 diabetes in participants with selenium supplementation. No clear evidence of an influence of baseline participant selenium status on outcomes has emerged in these studies.Observational longitudinal studies have shown an inverse association between selenium exposure and risk of some cancer types, but null and direct relations have also been reported, and no systematic pattern suggesting dose-response relations has emerged. These studies suffer from limitations inherent to the observational design, including exposure misclassification and unmeasured confounding.Overall, there is no evidence to suggest that increasing selenium intake through diet or supplementation prevents cancer in humans. However, more research is needed to assess whether selenium may modify the risk of cancer in individuals with a specific genetic background or nutritional status, and to investigate possible differential effects of various forms of selenium.

BackgroundIn 2012, more than 400,000 urinary bladder cancer cases occurred worldwide, making it the 7(th) most common type of cancer. Although many previous studies focused on the relationship between diet and bladder cancer, the evidence related to specific food items or nutrients that could be involved in the development of bladder cancer remains inconclusive. Dietary components can either be, or be activated into, potential carcinogens through metabolism, or act to prevent carcinogen damage.Methods/designThe BLadder cancer, Epidemiology and Nutritional Determinants (BLEND) study was set up with the purpose of collecting individual patient data from observational studies on diet and bladder cancer. In total, data from 11,261 bladder cancer cases and 675,532 non-cases from 18 case-control and 6 cohort studies from all over the world were included with the aim to investigate the association between individual food items, nutrients and dietary patterns and risk of developing bladder cancer.DiscussionThe substantial number of cases included in this study will enable us to provide evidence with large statistical power, for dietary recommendations on the prevention of bladder cancer.

BackgroundThis review is an update of the first Cochrane publication on selenium for preventing cancer (Dennert 2011).Selenium is a metalloid with both nutritional and toxicological properties. Higher selenium exposure and selenium supplements have been suggested to protect against several types of cancers.ObjectivesTwo research questions were addressed in this review: What is the evidence for:1. an aetiological relation between selenium exposure and cancer risk in humans? and2. the efficacy of selenium supplementation for cancer prevention in humans?Search methodsWe conducted electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL, 2013, Issue 1), MEDLINE (Ovid, 1966 to February 2013 week 1), EMBASE (1980 to 2013 week 6), CancerLit (February 2004) and CCMed (February 2011). As MEDLINE now includes the journals indexed in CancerLit, no further searches were conducted in this database after 2004.Selection criteriaWe included prospective observational studies (cohort studies including sub-cohort controlled studies and nested case-control studies) and randomised controlled trials (RCTs) with healthy adult participants (18 years of age and older).Data collection and analysisFor observational studies, we conducted random effects meta-analyses when five or more studies were retrieved for a specific outcome. For RCTs, we performed random effects meta-analyses when two or more studies were available. The risk of bias in observational studies was assessed using forms adapted from the Newcastle-Ottawa Quality Assessment Scale for cohort and case-control studies; the criteria specified in the Cochrane Handbook for Systematic Reviews of Interventions were used to evaluate the risk of bias in RCTs.Main resultsWe included 55 prospective observational studies (including more than 1,100,000 participants) and eight RCTs (with a total of 44,743 participants). For the observational studies, we found lower cancer incidence (summary odds ratio (OR) 0.69, 95% confidence interval (CI) 0.53 to 0.91, N = 8) and cancer mortality (OR 0.60, 95% CI 0.39 to 0.93, N = 6) associated with higher selenium exposure. Gender-specific subgroup analysis provided no clear evidence of different effects in men and women (P value 0.47), although cancer incidence was lower in men (OR 0.66, 95% CI 0.42 to 1.05, N = 6) than in women (OR 0.90, 95% CI 0.45 to 1.77, N = 2). The most pronounced decreases in risk of site-specific cancers were seen for stomach, bladder and prostate cancers. However, these findings have limitations due to study design, quality and heterogeneity that complicate interpretation of the summary statistics. Some studies suggested that genetic factors may modify the relation between selenium and cancer risk-a hypothesis that deserves further investigation.In RCTs, we found no clear evidence that selenium supplementation reduced the risk of any cancer (risk ratio (RR) 0.90, 95% CI 0.70 to 1.17, two studies, N = 4765) or cancer-related mortality (RR 0.81, 95% CI 0.49 to 1.32, two studies, N = 18,698), and this finding was confirmed when the analysis was restricted to studies with low risk of bias. The effect on prostate cancer was imprecise (RR 0.90, 95% CI 0.71 to 1.14, four studies, N = 19,110), and when the analysis was limited to trials with low risk of bias, the interventions showed no effect (RR 1.02, 95% CI 0.90 to 1.14, three studies, N = 18,183). The risk of non-melanoma skin cancer was increased (RR 1.44, 95% CI 0.95 to 1.17, three studies, N = 1900). Results of two trials-the Nutritional Prevention of Cancer Trial (NPCT) and the Selenium and Vitamin E Cancer Trial (SELECT)-also raised concerns about possible increased risk of type 2 diabetes, alopecia and dermatitis due to selenium supplements. An early hypothesis generated by NPCT that individuals with the lowest blood selenium levels at baseline could reduce their risk of cancer, particularly of prostate cancer, by increasing selenium intake has not been confirmed by subsequent trials. As the RCT participants were overwhelmingly male (94%), gender differences could not be systematically assessed.Authors' conclusionsAlthough an inverse association between selenium exposure and the risk of some types of cancer was found in some observational studies, this cannot be taken as evidence of a causal relation, and these results should be interpreted with caution. These studies have many limitations, including issues with assessment of exposure to selenium and to its various chemical forms, heterogeneity, confounding and other biases. Conflicting results including inverse, null and direct associations have been reported for some cancer types.RCTs assessing the effects of selenium supplementation on cancer risk have yielded inconsistent results, although the most recent studies, characterised by a low risk of bias, found no beneficial effect on cancer risk, more specifically on risk of prostate cancer, as well as little evidence of any influence of baseline selenium status. Rather, some trials suggest harmful effects of selenium exposure. To date, no convincing evidence suggests that selenium supplements can prevent cancer in humans.

Background: Although a potential inverse association between vegetable intake and bladder cancer risk has been reported, epidemiological evidence is inconsistent. This research aimed to elucidate the association between vegetable intake and bladder cancer risk by conducting a pooled analysis of data from prospective cohort studies.Methods: Vegetable intake in relation to bladder cancer risk was examined by pooling individual-level data from 13 cohort studies, comprising 3203 cases among a total of 555,685 participants. Pooled multivariate hazard ratios (HRs), with corresponding 95% confidence intervals (CIs), were estimated using Cox proportional hazards regression models stratified by cohort for intakes of total vegetable, vegetable subtypes (i.e. non-starchy, starchy, green leafy and cruciferous vegetables) and individual vegetable types. In addition, a diet diversity score was used to assess the association of the varied types of vegetable intake on bladder cancer risk.Results: The association between vegetable intake and bladder cancer risk differed by sex (P-interaction = 0.011) and smoking status (P-interaction = 0.038); therefore, analyses were stratified by sex and smoking status. With adjustment of age, sex, smoking, energy intake, ethnicity and other potential dietary factors, we found that higher intake of total and non-starchy vegetables were inversely associated with the risk of bladder cancer among women (comparing the highest with lowest intake tertile: HR = 0.79, 95% CI = 0.64-0.98, P = 0.037 for trend, HR per 1 SD increment = 0.89, 95% CI = 0.81-0.99; HR = 0.78, 95% CI = 0.63-0.97, P = 0.034 for trend, HR per 1 SD increment = 0.88, 95% CI = 0.79-0.98, respectively). However, no evidence of association was observed among men, and the intake of vegetable was not found to be associated with bladder cancer when stratified by smoking status. Moreover, we found no evidence of association for diet diversity with bladder cancer risk.Conclusion: Higher intakes of total and non-starchy vegetable are associated with reduced risk of bladder cancer for women. Further studies are needed to clarify whether these results reflect causal processes and potential underlying mechanisms. [ABSTRACT FROM AUTHOR]

Background Higher intakes of whole grains and dietary fiber have been associated with lower risk of insulin resistance, hyperinsulinemia, and inflammation, which are known predisposing factors for cancer. Objectives Because the evidence of association with bladder cancer (BC) is limited, we aimed to assess associations with BC risk for intakes of whole grains, refined grains, and dietary fiber. Methods We pooled individual data from 574,726 participants in 13 cohort studies, 3214 of whom developed incident BC. HRs, with corresponding 95% CIs, were estimated using Cox regression models stratified on cohort. Dose–response relations were examined using fractional polynomial regression models. Results We found that higher intake of total whole grain was associated with lower risk of BC (comparing highest with lowest intake tertile: HR: 0.87; 95% CI: 0.77, 0.98; HR per 1-SD increment: 0.95; 95% CI: 0.91, 0.99; P for trend: 0.023). No association was observed for intake of total refined grain. Intake of total dietary fiber was also inversely associated with BC risk (comparing highest with lowest intake tertile: HR: 0.86; 95% CI: 0.76, 0.98; HR per 1-SD increment: 0.91; 95% CI: 0.82, 0.98; P for trend: 0.021). In addition, dose–response analyses gave estimated HRs of 0.97 (95% CI: 0.95, 0.99) for intake of total whole grain and 0.96 (95% CI: 0.94, 0.98) for intake of total dietary fiber per 5-g daily increment. When considered jointly, highest intake of whole grains with the highest intake of dietary fiber showed 28% reduced risk (95% CI: 0.54, 0.93; P for trend: 0.031) of BC compared with the lowest intakes, suggesting potential synergism. Conclusions Higher intakes of total whole grain and total dietary fiber are associated with reduced risk of BC individually and jointly. Further studies are needed to clarify the underlying mechanisms for these findings. [ABSTRACT FROM AUTHOR]

Dietary intakes of B vitamins and other components involved in one-carbon metabolism, which is necessary for DNA replication, DNA repair, and regulation of gene expression, may be associated with carcinogenesis. We investigated associations between intakes of 11 nutrients (thiamine, riboflavin, niacin, pantothenic acid, vitamin B6, biotin, folate, vitamin B12, methionine, choline, and betaine) and gastric cancer risk. A total of 159 incident gastric cancer cases were identified from the Melbourne Collaborative Cohort Study (N = 41,513) and matched with 159 controls on year of birth, sex, and country of birth using incidence density sampling. Dietary intakes of nutrients were estimated at baseline (1990–1994) using a 121-item food frequency questionnaire. Odds ratios (ORs) and 95% confidence intervals were estimated using conditional logistic regression models adjusting for Helicobacter pylori infection, and other potential confounders. We observed a positive association between intake of niacin and overall gastric cancer risk (OR = 1.33, 95%CI: 1.01–1.75 per SD increment). For thiamine, heterogeneity by subtype (cardia and non-cardia) was found (Phet = 0.05), with weak evidence of an inverse association with cardia cancer risk. Our results do not support increasing intakes of B vitamins or other nutrients involved in one-carbon metabolism to reduce gastric cancer risk in a well-nourished population. [ABSTRACT FROM AUTHOR]

B‐group vitamins, as components of the one carbon metabolism pathway, are involved in DNA synthesis, repair and methylation. Our aim was to investigate associations between circulating plasma levels of B vitamins and urothelial cell carcinoma (UCC). We conducted a nested case–control study of UCC within the Melbourne Collaborative Cohort Study. B vitamins were measured in pre‐diagnostic plasma samples. Conditional logistic regression was used to estimate odds ratios (OR) for UCC risk associated with circulating B vitamins in 363 matched cases and controls. In a case‐only analysis (N = 390), hazard ratios (HR) for overall survival associated with plasma B vitamins were estimated using Cox regression. There were no strong associations between UCC risk and pre‐diagnostic levels of plasma B vitamins. No heterogeneity in UCC risk was observed by subtype (invasive or superficial), sex, smoking status or alcohol intake. There was no heterogeneity by country of birth for most B vitamins, except for folate (p‐homogeneity = 0.03). In UCC cases, there were no strong associations between plasma B vitamins and overall survival. We found no associations between pre‐diagnostic plasma concentrations of B‐group vitamins and UCC risk or survival. What's new? B vitamins are involved in DNA synthesis, repair, and methylation, and therefore they might affect cancer risk. While they appear to be protective against some cancers, data on the effect of B‐vitamins on bladder cancer have been inconsistent. In this prospective study, the authors examined levels of circulating B vitamins in patients with urothelial‐cell carcinoma (UCC) and matched controls. However, they found no association between pre‐diagnostic concentrations of B vitamins and UCC risk or survival. [ABSTRACT FROM AUTHOR]