Search

Background Epidemiological and experimental evidence has linked chronic inflammation to cancer aetiology. It is unclear whether associations for specific inflammatory biomarkers are causal or due to bias. In order to examine whether altered genetically predicted concentration of circulating cytokines are associated with cancer development, we performed a two-sample Mendelian randomisation (MR) analysis. Methods Up to 31,112 individuals of European descent were included in genome-wide association study (GWAS) meta-analyses of 47 circulating cytokines. Single nucleotide polymorphisms (SNPs) robustly associated with the cytokines, located in or close to their coding gene (cis), were used as instrumental variables. Inverse-variance weighted MR was used as the primary analysis, and the MR assumptions were evaluated in sensitivity and colocalization analyses and a false discovery rate (FDR) correction for multiple comparisons was applied. Corresponding germline GWAS summary data for five cancer outcomes (breast, endometrial, lung, ovarian, and prostate), and their subtypes were selected from the largest cancer-specific GWASs available (cases ranging from 12,906 for endometrial to 133,384 for breast cancer). Results There was evidence of inverse associations of macrophage migration inhibitory factor with breast cancer (OR per SD = 0.88, 95% CI 0.83 to 0.94), interleukin-1 receptor antagonist with endometrial cancer (0.86, 0.80 to 0.93), interleukin-18 with lung cancer (0.87, 0.81 to 0.93), and beta-chemokine-RANTES with ovarian cancer (0.70, 0.57 to 0.85) and positive associations of monokine induced by gamma interferon with endometrial cancer (3.73, 1.86 to 7.47) and cutaneous T-cell attracting chemokine with lung cancer (1.51, 1.22 to 1.87). These associations were similar in sensitivity analyses and supported in colocalization analyses. Conclusions Our study adds to current knowledge on the role of specific inflammatory biomarker pathways in cancer aetiology. Further validation is needed to assess the potential of these cytokines as pharmacological or lifestyle targets for cancer prevention.

Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction.

Background: The ProtecT trial reported intention-to-treat analysis of men with localised prostate cancer (PCa) randomly allocated to active monitoring (AM), radical prostatectomy, and external beam radiotherapy. Objective: To determine report outcomes according to treatment received in men in randomised and treatment choice cohorts. Design, Setting, and Participants: This study focuses on secondary care. Men with clinically localised prostate cancer at one of nine UK centres were invited to participate in the treatment trial comparing AM, radical prostatectomy, and radiotherapy. Intervention: Two cohorts included 1643 men who agreed to be randomised; 997 declined randomisation and chose treatment. Outcome Measurements and Statistical Analysis: Health-related quality of life impacts on urinary, bowel, and sexual function were assessed using patient-reported outcome measures. Analysis was carried out based on treatment received for each cohort and on pooled estimates using meta-analysis. Differences were estimated with adjustment for known prognostic factors using propensity scores. Results and Limitations: According to treatment received, more men receiving AM died of PCa (AM 1.85%, surgery 0.67%, radiotherapy 0.73%), whilst this difference remained consistent with chance in the randomised cohort (p = 0.08); stronger evidence was found in the exploratory analyses (randomised plus choice cohort) when AM was compared with the combined radical treatment group (p = 0.003). There was also strong evidence that metastasis (AM 5.6%, surgery 2.4%, radiotherapy 2.7%) and disease progression (AM 20.35%, surgery 5.87%, radiotherapy 6.62%) were more common in the AM group. Compared with AM, there were higher risks of sexual dysfunction (95% at 6 mo) and urinary incontinence (55% at 6 mo) after surgery, and of sexual dysfunction (88% at 6 mo) and bowel dysfunction (5% at 6 mo) after radiotherapy. The key limitations are the potential for bias when comparing groups defined by treatment received and outdating of the interventions being evaluated during the lengthy follow-up required in trials of screen-detected PCa. Conclusions: Analyses according to treatment received showed increased rates of disease-related events and lower rates of patient-reported harms in men managed by AM compared with men managed by radical treatment, and stronger evidence of greater PCa mortality in the AM group. Patient Summary: More than 90 out of every 100 men with localised prostate cancer do not die of prostate cancer within 10 yr, irrespective of whether treatment is by means of monitoring, surgery, or radiotherapy. Side effects on sexual and bladder function are much better after active monitoring, but the risks of spreading of prostate cancer are more common.

Supplemental Digital Content is available in the text., Whether prostate cancer (PCa) may be preventable by dietary interventions can be assessed in randomized trials using intermediate biomarkers of cancer risk or progression. We investigated whether lycopene or green tea modify circulating insulin-like growth factor (IGF) peptides in men at increased risk of PCa. Participants (aged 50–69 years) in one centre in the UK wide PCa testing and treatment trial (ProtecT) with prostate specific antigen between 2.0 and 2.95 ng/ml or negative biopsies, were randomized to daily lycopene (n = 44 assigned 15 mg capsules/day; 44 assigned a lycopene-rich diet; 45 assigned placebo) and green tea (n = 45 assigned 600 mg/day epigallocatechin gallate; 45 assigned green tea drink; 43 assigned placebo) for 6 months. The interventions significantly elevated the primary outcomes, serum epigallocatechin gallate and lycopene at 6 months of follow-up. We report here an exploratory analysis in which serum IGF-I, IGF-II, IGF binding protein (BP)-2 and IGFBP-3 were measured at baseline and 6 months of postintervention. A total of 133 men were randomized (34% of eligible men approached) and 130 had follow-up IGF peptides (98%). In intention-to-treat analyses, there was only weak evidence that lycopene or green tea influenced some aspects of serum IGF-I, IGF-II, IGFBP-2 or IGFBP-3. In men randomized to lycopene supplements, IGFBP-2 was nonsignificantly (50.9 ng/ml; 95% confidence interval: −51.2–152.9, P = 0.3) higher in comparison to placebo, whereas in men randomized to green tea supplements, IGFBP-3 was nonsignificantly (205.2 ng/ml; 95% confidence interval: −583.3–172.9, P = 0.3) lower than with placebo. In this small, pilot randomized controlled trial, there was little evidence that lycopene or green tea interventions influenced serum levels of IGF-I, IGF-II, IGFBBP-3 and IGFBP-2. However, the effects were imprecisely estimates and some observed trends may justify larger trials.

Circulating 25‐hydroxyvitamin D (25OHD) is an appealing potential intervention for cancer risk and has been associated with oral and oropharyngeal cancer risk but evidence is inconsistent. The availability of genetic variants, uncorrelated with known confounders, but predictive of 25OHD and genetic data in a large oral and oropharyngeal cancer collaboration aids causal inference when assessing this association. A total of 5,133 oral and oropharyngeal cancer cases and 5,984 controls with genetic data were included in the study. Participants were based in Europe, North America and South America and were part of the Genetic Associations and Mechanisms in Oncology (GAME‐ON) Network. Five genetic variants reliably associated with circulating 25OHD were used to create a relative genetic measure of 25OHD. In the absence of measured 25OHD, two‐sample Mendelian randomization using individual level outcome data were used to estimate causal odds ratios (OR) for cancer case status per standard deviation increase in log25OHD. Analyses were replicated in an independent population‐based cohort (UK Biobank). In the GAME‐ON study, there was little evidence of a causal association between circulating 25OHD and oral cancer (OR = 0.86 [0.68;1.09], p = 0.22), oropharyngeal cancer (OR = 1.28 [0.72;2.26], p = 0.40) or when sites were combined (OR = 1.01 [0.74;1.40], p = 0.93). Replication in UK Biobank and pooled estimates produced similar results. Our study suggests that a clinically relevant protective effect of 25OHD on oral and oropharyngeal cancer risk is unlikely and supplementation of the general population with 25OHD is unlikely to be beneficial in preventing these cancers., What's new? Evidence for a role of vitamin D in head and neck cancers is contradictory, and randomized controlled trials are not well suited to investigate the potential effect of 25‐hydroxyvitamin D (25OHD) supplementation. For the first time, this study used Mendelian randomization with genetic variants associated with 25OHD and uncorrelated with known confounders to derive the causal effect of 25OHD on oral cavity and oropharyngeal cancer risk. The findings suggest that a clinically‐relevant protective effect of 25OHD on oral and oropharyngeal cancer risk is unlikely, making supplementation of the general population with 25OHD unlikely to be beneficial in preventing these cancers.

Background: Clinically diagnosed eating disorders may have adverse cardiometabolic consequences, including overweight or obesity and high blood pressure. However, the link between problematic eating attitudes in early adolescence, which can lead to disordered eating behaviors, and future cardiometabolic health is, to our knowledge, unknown. Objective: We assessed whether variations in midchildhood eating attitudes influence the future development of overweight or obesity and high blood pressure. Design: Of 17,046 children who participated in the Promotion of Breastfeeding Intervention Trial (PROBIT), we included 13,557 participants (79.5% response rate) who completed the Children’s Eating Attitudes Test (ChEAT) at age 11.5 y and in whom we measured adiposity and blood pressure at ages 6.5, 11.5, and 16 y. We assessed whether ChEAT scores ≥85th percentile (indicative of problematic eating attitudes) compared with scores

Background High body mass index (BMI) is associated with mortality, but the pervasive problem of confounding and reverse causality in observational studies limits inference about the direction and magnitude of causal effects. We aimed to obtain estimates of the causal association of BMI with all-cause and cause-specific mortality. Methods and findings In a record-linked, intergenerational prospective study from the general population of Sweden, we used two-sample instrumental variable (IV) analysis with data from 996,898 fathers (282,407 deaths) and 1,013,083 mothers (153,043 deaths) and their sons followed up from January 1, 1961, until December 31, 2004. Sons’ BMI was used as the instrument for parents’ BMI to compute hazard ratios (HRs) for risk of mortality per standard deviation (SD) higher parents’ BMI. Using offspring exposure as an instrument for parents’ exposure is unlikely to be affected by reverse causality (an important source of bias in this context) and reduces confounding. IV analyses supported causal associations between higher BMI and greater risk of all-cause mortality (HR [95% confidence interval (CI)] per SD higher fathers’ BMI: 1.29 [1.26–1.31] and mothers’ BMI: 1.39 [1.35–1.42]) and overall cancer mortality (HR per SD higher fathers’ BMI: 1.20 [1.16–1.24] and mothers’ BMI: 1.29 [1.24–1.34]), including 9 site-specific cancers in men (bladder, colorectum, gallbladder, kidney, liver, lung, lymphatic system, pancreas, and stomach) and 11 site-specific cancers in women (gallbladder, kidney, liver, lung, lymphatic system, ovaries, pancreas, stomach, uterus, cervix, and endometrium). There was evidence supporting causal associations between higher BMI in mothers and greater risk of mortality from kidney disease (HR: 2.17 [1.68–2.81]) and lower risk of mortality from suicide (HR: 0.77 [0.65–0.90]). In both sexes, there was evidence supporting causal associations between higher BMI and mortality from cardiovascular diseases (CVDs), stroke, diabetes, and respiratory diseases. We were unable to test the association between sons’ and mothers’ BMIs (as mothers’ data were unavailable) or whether the instrument was independent of unmeasured or residual confounding; however, the associations between parents’ mortality and sons’ BMI were negligibly influenced by adjustment for available confounders. Conclusions Consistent with previous large-scale meta-analyses and reviews, results supported the causal role of higher BMI in increasing the risk of several common causes of death, including cancers with increasing global incidence. We also found positive effects of BMI on mortality from respiratory disease, prostate cancer, and lung cancer, which has been inconsistently reported in the literature, suggesting that the causal role of higher BMI in mortality from these diseases may be underestimated. Furthermore, we expect different patterns of bias in the current observational and IV analyses; therefore, the similarities between our findings from both methods increases confidence in the results. These findings support efforts to understand the mechanisms underpinning these effects to inform targeted interventions and develop population-based strategies to reduce rising obesity levels for disease prevention., Kaitlin Wade and colleagues investigate associations between BMI and cause-specific mortality in a large cohort of parent-son pairs., Author summary Why was this study done? Whilst high body mass index (BMI) clearly increases the risk of mortality, there have been inconsistencies in the literature, which mainly rely on observational epidemiological studies that are limited in their ability to draw causal inferences. To overcome the pervasive problem of confounding and reverse causation in such studies, we aimed to obtain more reliable causal estimates of the association of BMI and both all-cause and cause-specific mortality using two-sample instrumental variable (IV) analyses. What did the researchers do and find? In a large, record-linked, intergenerational prospective study comprising data from the general population of Sweden from 996,898 fathers (282,407 deaths) and 1,013,082 mothers (153,043 deaths) and their sons, we used sons’ BMI as an instrument for parents’ BMI to compute hazard ratios (HRs) for the risk of mortality per standard deviation (SD) higher parents’ BMI. IV analyses supported the causal role of higher BMI and greater risk of all-cause mortality and mortality from cardiovascular diseases (CVDs), stroke, diabetes, respiratory diseases, and cancer, the latter including 9 site-specific cancers in men (bladder, colorectum, gallbladder, kidney, liver, lung, lymphatic system, pancreas, and stomach) and 11 site-specific cancers in women (gallbladder, kidney, liver, lung, lymphatic system, ovaries, pancreas, stomach, uterus, cervix, and endometrium). There was also evidence supporting a causal association between higher BMI in mothers and greater risk of mortality from kidney disease and lower risk of mortality from suicide. What do these findings mean? For cancer-specific mortality, many IV-derived effect estimates were in the same direction and of greater magnitude as those derived from previous large-scale meta-analyses and reviews focusing on both mortality outcomes and the development of specific cancers. Results also implied a positive effect of BMI on mortality from respiratory disease, prostate cancer, and lung cancer, which has been inconsistently reported in the literature, suggesting that the causal role of higher BMI in mortality from these diseases may be underestimated. These results support efforts to reduce obesity levels for disease prevention, particularly cancer.

Lycopene and green tea consumption have been observationally associated with reduced prostate cancer risk, but the underlying mechanisms have not been fully elucidated. We investigated the effect of factorial randomisation to a 6-month lycopene and green tea dietary advice or supplementation intervention on 159 serum metabolite measures in 128 men with raised PSA levels (but prostate cancer-free), analysed by intention-to-treat. The causal effects of metabolites modified by the intervention on prostate cancer risk were then assessed by Mendelian randomisation, using summary statistics from 44,825 prostate cancer cases and 27,904 controls. The systemic effects of lycopene and green tea supplementation on serum metabolic profile were comparable to the effects of the respective dietary advice interventions (R-2 = 0.65 and 0.76 for lycopene and green tea respectively). Metabolites which were altered in response to lycopene supplementation were acetate [beta (standard deviation difference vs. placebo): 0.69; 95% CI = 0.24, 1.15; p = 0.003], valine (beta: -0.62; -1.03, -0.02; p = 0.004), pyruvate (beta: -0.56; -0.95, -0.16; p = 0.006) and docosahexaenoic acid (beta: -0.50; -085, -0.14; p = 0.006). Valine and diacylglycerol were lower in the lycopene dietary advice group (beta: -0.65; -1.04, -0.26; p = 0.001 and beta: -0.59; -1.01, -0.18; p = 0.006). A genetically instrumented SD increase in pyruvate increased the odds of prostate cancer by 1.29 (1.03, 1.62; p = 0.027). An intervention to increase lycopene intake altered the serum metabolome of men at risk of prostate cancer. Lycopene lowered levels of pyruvate, which our Mendelian randomisation analysis suggests may be causally related to reduced prostate cancer risk.

Background Evidence from studies on prostate cancer progression have identified vitamin D to be a potentially important nutrient. However, the World Cancer Research Fund and American Institute for Cancer Research have reported the quality of this evidence to be limited and warrant further investigation. We plan to use the recently developed WCRF International/University of Bristol mechanistic systematic review framework to determine whether the observed association between vitamin D and prostate cancer exists through a plausible biological pathway. Methods This protocol sets out how we will perform a systematic review of the literature in human and animal studies. We will search the electronic databases MEDLINE, EMBASE, PubMed, and BIOSIS Citation Index without restrictions on year of publication or language. We will extract data from observational and experimental studies examining two inter-linked pathways in the relationship between vitamin D and prostate cancer progression: (1) vitamin D and testosterone, and (2) testosterone and prostate cancer progression. We focus on testosterone as its actions form a potentially novel intermediate mechanism that was identified via our online literature mining tools. The outcomes of interest include incidence or prevalence of prostate cancer, measures of prostate cancer progression (including biochemical recurrence, local, or distal metastases), and prostate cancer-specific mortality. We will assess study quality and the level of certainty of the evidence. We will analyse data where possible, using meta-analysis with forest plots or albatross plots; otherwise, a narrative synthesis will be performed. Discussion To our knowledge, this will be the first systematic synthesis of the evidence underpinning the vitamin D-testosterone-prostate cancer mechanistic pathway. The results of the review may inform future research, intervention trials, and public health messages. Electronic supplementary material The online version of this article (10.1186/s13643-018-0908-1) contains supplementary material, which is available to authorized users.

Chromosome 8q24 is a susceptibility locus for multiple cancers, including prostate cancer. Here we combine genetic data across the 8q24 susceptibility region from 71,535 prostate cancer cases and 52,935 controls of European ancestry to define the overall contribution of germline variation at 8q24 to prostate cancer risk. We identify 12 independent risk signals for prostate cancer (p, Chromosome 8q24 is known to be a major susceptibility region for prostate cancer risk. Here the authors analyze genetic data across the 8q24 region from 71,535 prostate cancer patients identifying 12 risk loci, three previously unreported, highlighting the contribution of germline variation at this locus.

Tobacco smoking and alcohol consumption are well‐established risk factors for head and neck cancer. The prognostic role of smoking and alcohol intake at diagnosis have been less well studied. We analysed 1,393 people prospectively enrolled into the Head and Neck 5000 study (oral cavity cancer, n=403; oropharyngeal cancer, n=660; laryngeal cancer, n=330) and followed up for a median of 3.5 years. The primary outcome was all‐cause mortality. We used Cox proportional hazard models to derive minimally adjusted (age and gender) and fully adjusted (age, gender, ethnicity, stage, comorbidity, body mass index, HPV status, treatment, education, deprivation index, income, marital status, and either smoking or alcohol use) mortality hazard ratios (HR) for the effects of smoking status and alcohol intake at diagnosis. Models were stratified by cancer site, stage and HPV status. The fully‐adjusted HR for current versus never‐smokers was 1.7 overall (95% confidence interval [CI] 1.1, 2.6). In stratified analyses, associations of smoking with mortality were observed for oropharyngeal and laryngeal cancers (fully adjusted HRs for current smokers: 1.8 (95% CI=0.9, 3.40 and 2.3 (95% CI=0.8, 6.4)). We found no evidence that people who drank hazardous to harmful amounts of alcohol at diagnosis had a higher mortality risk compared to non‐drinkers (HR=1.2 (95% CI=0.9, 1.6)). There was no strong evidence that HPV status or tumour stage modified the association of smoking with survival. Smoking status at the time of a head and neck cancer diagnosis influenced all‐cause mortality in models adjusted for important prognostic factors., What's new? Smoking and alcohol use are risk factors for developing head‐and‐neck cancer (HNC) and are known to influence mortality in general. However, the prognostic role of smoking status and alcohol intake at time of diagnosis on HNC survival is less clear. In this study, the authors provide a comprehensive, prospective analysis of mortality risk in different tumour sites, adjusting for important prognostic factors such as stage, comorbidity, and HPV infection. These results may provide insight to inform and improve prediction of clinical outcomes.

BACKGROUND: Observational studies have suggested an association between circulating vitamin D concentrations [25(OH)D] and risk of breast and prostate cancer, which was not supported by a recent Mendelian randomization (MR) analysis comprising 15 748 breast and 22 898 prostate-cancer cases. Demonstrating causality has proven challenging and one common limitation of MR studies is insufficient power. METHODS: We aimed to determine whether circulating concentrations of vitamin D are causally associated with the risk of breast and prostate cancer, by using summary-level data from the largest ever genome-wide association studies conducted on vitamin D (N = 73 699), breast cancer (Ncase = 122 977) and prostate cancer (Ncase = 79 148). We constructed a stronger instrument using six common genetic variants (compared with the previous four variants) and applied several two-sample MR methods. RESULTS: We found no evidence to support a causal association between 25(OH)D and risk of breast cancer [OR per 25 nmol/L increase, 1.02 (95% confidence interval: 0.97-1.08), P = 0.47], oestrogen receptor (ER)+ [1.00 (0.94-1.07), P = 0.99] or ER- [1.02 (0.90-1.16), P = 0.75] subsets, prostate cancer [1.00 (0.93-1.07), P = 0.99] or the advanced subtype [1.02 (0.90-1.16), P = 0.72] using the inverse-variance-weighted method. Sensitivity analyses did not reveal any sign of directional pleiotropy. CONCLUSIONS: Despite its almost five-fold augmented sample size and substantially improved statistical power, our MR analysis does not support a causal effect of circulating 25(OH)D concentrations on breast- or prostate-cancer risk. However, we can still not exclude a modest or non-linear effect of vitamin D. Future studies may be designed to understand the effect of vitamin D in subpopulations with a profound deficiency.

Background There is ongoing debate about the harms and benefits of a national prostate cancer screening programme. Several model-based cost-effectiveness analyses have been developed to determine whether the benefits of prostate cancer screening outweigh the costs and harms caused by over-detection and over-treatment, and the different approaches may impact results. Methods To identify models of prostate cancer used to assess the cost-effectiveness of prostate cancer screening strategies, a systematic review of articles published since 2006 was conducted using the NHS Economic Evaluation Database, Medline, EMBASE and HTA databases. The NICE website, UK National Screening website, reference lists from relevant studies were also searched and experts contacted. Key model features, inputs, and cost-effectiveness recommendations were extracted. Results Ten studies were included. Four of the studies identified some screening strategies to be potentially cost-effective at a PSA threshold of 3.0 ng/ml, including single screen at 55 years, annual or two yearly screens starting at 55 years old, and delayed radical treatment. Prostate cancer screening was modelled using both individual and cohort level models. Model pathways to reflect cancer progression varied widely, Gleason grade was not always considered and clinical verification was rarely outlined. Where quality of life was considered, the methods used did not follow recommended practice and key issues of overdiagnosis and overtreatment were not addressed by all studies. Conclusion The cost-effectiveness of prostate cancer screening is unclear. There was no consensus on the optimal model type or approach to model prostate cancer progression. Due to limited data availability, individual patient-level modelling is unlikely to increase the accuracy of cost-effectiveness results compared with cohort-level modelling, but is more suitable when assessing adaptive screening strategies. Modelling prostate cancer is challenging and the justification for the data used and the approach to modelling natural disease progression was lacking. Country-specific data are required and recommended methods used to incorporate quality of life. Influence of data inputs on cost-effectiveness results need to be comprehensively assessed and the model structure and assumptions verified by clinical experts. Electronic supplementary material The online version of this article (10.1186/s12885-017-3974-1) contains supplementary material, which is available to authorized users.

Atopic diseases, including asthma and atopic eczema, are the most common chronic conditions of childhood.To investigate whether an intervention to promote prolonged and exclusive breastfeeding protects against asthma, atopic eczema, and low lung function in adolescence.Follow-up of the Promotion of Breastfeeding Intervention Trial (PROBIT), a cluster randomized trial in 30 Belarusian maternity hospitals and affiliated polyclinics; recruitment of 17 046 healthy term infants took place from June 15, 1996, to December 31, 1997. Data analysis was conducted from May 9, 2016, to April 21, 2017. The primary analytic approach was by modified intention-to-treat analysis.Randomization to receive a breastfeeding promotion intervention vs usual care.Spirometry and flexural eczema on standardized skin examination by study pediatricians were the primary outcomes; secondary outcomes were self-reported asthma diagnosis ever, and wheezing and flexural eczema symptoms in the previous year.A total of 13 557 (79.5%) participants were followed up from September 15, 2012 to July 15, 2015. The intervention (7064 [79.7%]) and control (6493 [79.4%]) groups were similar at follow-up (3590 [50.8%] and 3391 [52.2%] male; mean [SD] age, 16.2 [0.6] and 16.1 [0.5] years, respectively). In the intervention group, 0.3% (21 of 7064) had flexural eczema on skin examination and mean (SD) forced expiratory volume in the first second of expiration/forced vital capacity (FEV1/FVC) ratio z score was -0.10 (1.82), compared with 0.7% (43 of 6493) and 0.35 (1.34), respectively, in the control group. In modified intention-to-treat analysis, accounting for clustering by polyclinic, a 54% lower risk of flexural eczema on skin examination was observed in the intervention compared with the control group (odds ratio [OR], 0.46; 95% CI, 0.25 to 0.86). Self-reported flexural eczema symptoms in the past year (OR, 0.57; 95% CI, 0.27 to 1.18), asthma (OR, 0.76; 95% CI, 0.47 to 1.23), and wheezing in the past year (OR, 0.66; 95% CI, 0.37 to 1.18) were less frequently reported in the intervention compared with the control group, but 95% CIs were wide and included the null. There was no significant difference in the FEV1/FVC ratio z score (β -0.15; 95% CI, -0.76 to 0.45). All results were similar with additional adjustment for baseline characteristics, on instrumental variable analysis, and with multiple imputation among all 17 046 randomized participants.A breastfeeding promotion intervention reduced flexural dermatitis risk but had no detectable effect on lung function or questionnaire-derived measures of atopic eczema or asthma in adolescence in a setting where atopic eczema and allergies are rare.clinicaltrials.gov Identifier: NCT01561612.

Prostate cancer is the most common cancer in men in developed countries, and is a target for risk reduction strategies. The effects of alcohol consumption on prostate cancer incidence and survival remain unclear, potentially due to methodological limitations of observational studies. In this study, we investigated the associations of genetic variants in alcohol‐metabolising genes with prostate cancer incidence and survival. We analysed data from 23,868 men with prostate cancer and 23,051 controls from 25 studies within the international PRACTICAL Consortium. Study‐specific associations of 68 single nucleotide polymorphisms (SNPs) in 8 alcohol‐metabolising genes (Alcohol Dehydrogenases (ADHs) and Aldehyde Dehydrogenases (ALDHs)) with prostate cancer diagnosis and prostate cancer‐specific mortality, by grade, were assessed using logistic and Cox regression models, respectively. The data across the 25 studies were meta‐analysed using fixed‐effect and random‐effects models. We found little evidence that variants in alcohol metabolising genes were associated with prostate cancer diagnosis. Four variants in two genes exceeded the multiple testing threshold for associations with prostate cancer mortality in fixed‐effect meta‐analyses. SNPs within ALDH1A2 associated with prostate cancer mortality were rs1441817 (fixed effects hazard ratio, HRfixed = 0.78; 95% confidence interval (95%CI):0.66,0.91; p values = 0.002); rs12910509, HRfixed = 0.76; 95%CI:0.64,0.91; p values = 0.003); and rs8041922 (HRfixed = 0.76; 95%CI:0.64,0.91; p values = 0.002). These SNPs were in linkage disequilibrium with each other. In ALDH1B1, rs10973794 (HRfixed = 1.43; 95%CI:1.14,1.79; p values = 0.002) was associated with prostate cancer mortality in men with low‐grade prostate cancer. These results suggest that alcohol consumption is unlikely to affect prostate cancer incidence, but it may influence disease progression., What's new? Alcohol may spur prostate cancer progression, though it does not appear to affect incidence, according to new analysis. Variation in genes involved in alcohol metabolism affect how much the body is exposed to carcinogenic metabolites. These authors examined 68 genetic variants in alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) genes, seeking a link with prostate cancer risk. While they found no evidence that these variants alter prostate cancer incidence, they did show that SNPs in the ALDH1A2 gene affect prostate cancer mortality. From a public health standpoint, these results suggest reducing alcohol consumption could slow prostate cancer disease progression.

ObjectivesTo compare the completeness and agreement of prostate cancer data recorded by the National Cancer Registration and Analysis Service (NCRAS) with research-level data specifically abstracted from medical records from the Cluster randomised trial of PSA testing for Prostate cancer (CAP) trial.DesignCross-sectional comparison studyParticipantsWe included 1,356 men from the CAP trial cohort who were linked to the NCRASregistry.Primary and secondary outcome measuresCompleteness of prostate cancer data in NCRAS and CAP and agreement for TNMstage (T1/T2; T3; T4/N1/M1) and Gleason grade (4-6; 7; 8-10), measured bydifferences in proportions and Cohen’s Kappa statistic. Data were also stratified by year and pre- versus post-2010, when NCRAS reporting standards changed.ResultsCompared to CAP, completeness was lower in NCRAS for Gleason grade (41.2% vs 76.7%, difference 35.5 95% CI 32.1, 39.0) and TNM stage (29.9% vs 67.6%, difference 37.6 95% CI 34.1, 41.1). NCRAS completeness for Gleason grade (pre- versus post-2010 31.69% vs 64%; difference 32.31 95% CI 26.76, 37.87) and TNM stage (19.31% vs 55.50%; difference 36.19 95% CI 30.72, 41.67) improved over time. Agreement for Gleason grade was high (Cohen’s Kappa, κ=0.90 95% CI 0.88, 0.93), but lower for TNM stage (κ=0.41 95% CI 0.37, 0.51) overall. There was a trend towards improved agreement on Gleason grade, but not TNM stage, when comparing pre- and post-2010.ConclusionNCRAS case identification was very high, however data on prostate cancer grade was less complete than CAP, and agreement for TNM stage was modest. Although the completeness of NCRAS data has improved since 2010, the higher completeness rate in CAP demonstrate that gains could potentially be achieved in routine registry data. This study’s findings highlight a need for improved recording of stage and grade data in the source medical records.

Objectives To evaluate the accuracy of routine data for costing inpatient resource use in a large clinical trial and to investigate costing methodologies. Design Final-year inpatient cost profiles were derived using (1) data extracted from medical records mapped to the National Health Service (NHS) reference costs via service codes and (2) Hospital Episode Statistics (HES) data using NHS reference costs. Trust finance departments were consulted to obtain costs for comparison purposes. Setting 7 UK secondary care centres. Population A subsample of 292 men identified as having died at least a year after being diagnosed with prostate cancer in Cluster randomised triAl of PSA testing for Prostate cancer (CAP), a long-running trial to evaluate the effectiveness and cost-effectiveness of prostate-specific antigen (PSA) testing. Results Both inpatient cost profiles showed a rise in costs in the months leading up to death, and were broadly similar. The difference in mean inpatient costs was £899, with HES data yielding ∼8% lower costs than medical record data (differences compatible with chance, p=0.3). Events were missing from both data sets. 11 men (3.8%) had events identified in HES that were all missing from medical record review, while 7 men (2.4%) had events identified in medical record review that were all missing from HES. The response from finance departments to requests for cost data was poor: only 3 of 7 departments returned adequate data sets within 6 months. Conclusions Using HES routine data coupled with NHS reference costs resulted in mean annual inpatient costs that were very similar to those derived via medical record review; therefore, routinely available data can be used as the primary method of costing resource use in large clinical trials. Neither HES nor medical record review represent gold standards of data collection. Requesting cost data from finance departments is impractical for large clinical trials. Trial registration number ISRCTN92187251; Pre-results.

Purpose: This study aimed to quantify the probability of overdiagnosis of prostate cancer by polygenic risk. Genet Med 17 10, 789–795. Methods: We calculated the polygenic risk score based on 66 known prostate cancer susceptibility variants for 17,012 men aged 50–69 years (9,404 men identified with prostate cancer and 7,608 with no cancer) derived from three UK-based ongoing studies. We derived the probabilities of overdiagnosis by quartiles of polygenic risk considering that the observed prevalence of screen-detected prostate cancer is a combination of underlying incidence, mean sojourn time (MST), test sensitivity, and overdiagnosis. Genet Med 17 10, 789–795. Results: Polygenic risk quartiles 1 to 4 comprised 9, 18, 25, and 48% of the cases, respectively. For a prostate-specific antigen test sensitivity of 80% and MST of 9 years, 43, 30, 25, and 19% of the prevalent screen-detected cancers in quartiles 1 to 4, respectively, were likely to be overdiagnosed cancers. Overdiagnosis decreased with increasing polygenic risk, with 56% decrease between the lowest and the highest polygenic risk quartiles. Genet Med 17 10, 789–795. Conclusion: Targeting screening to men at higher polygenic risk could reduce the problem of overdiagnosis and lead to a better benefit-to-harm balance in screening for prostate cancer. Genet Med 17 10, 789–795.

OBJECTIVES: Cross-sectional studies suggest that around 6% of men undergo prostate-specific antigen (PSA) testing each year in UK general practice (GP). This longitudinal study aims to determine the cumulative testing pattern of men over a 10-year period and whether this testing can be considered equivalent to screening for prostate cancer (PCa). SETTING, PARTICIPANTS AND OUTCOME MEASURES: Patient-level data on PSA tests, biopsies and PCa diagnoses were obtained from the UK Clinical Practice Research Datalink (CPRD) for the years 2002 to 2011. The cumulative risks of PSA testing and of being diagnosed with PCa were estimated for the 10-year study period. Associations of a man's age, region and index of multiple deprivation with the cumulative risk of PSA testing and PCa diagnosis were investigated. Rates of biopsy and diagnosis, following a high test result, were compared with those from the programme of PSA testing in the Prostate Testing for Cancer and Treatment (ProtecT) study. RESULTS: The 10-year risk of exposure to at least one PSA test in men aged 45 to 69 years in UK GP was 39.2% (95% CI 39.0 to 39.4%). The age-specific risks ranged from 25.2% for men aged 45-49 years to 53.0% for men aged 65-69 years (p for trend

Evidence that breastfeeding reduces child obesity risk and lowers blood pressure (BP) is based on potentially confounded observational studies.To investigate the effects of a breastfeeding promotion intervention on adiposity and BP at age 16 years and on longitudinal growth trajectories from birth.Cluster-randomized Promotion of Breastfeeding Intervention Trial. Belarusian maternity hospitals and affiliated polyclinics (the clusters) were allocated into intervention (n = 16) or control arms (n = 15) in 1996 and 1997. The trial participants were 17 046 breastfeeding mother-infant pairs; of these, 13 557 children (79.5%) were followed up at 16 years of age between September 2012 and July 2015.Breastfeeding promotion, modeled on the Baby-Friendly Hospital Initiative.Body mass index (BMI, calculated as weight in kilograms divided by height in meters squared); fat and fat-free mass indices and percentage of body fat from bioimpedance; waist circumference; overweight and obesity; height; BP; and longitudinal growth trajectories. The primary analysis was modified intention-to-treat (without imputation for losses to follow-up) accounting for within-clinic clustering.We examined 13 557 children at a median age of 16.2 years (48.5% were girls). The intervention substantially increased breastfeeding duration and exclusivity compared with the control arm (exclusively breastfed: 45% vs 6% at 3 months, respectively). Mean differences at 16 years between intervention and control groups were 0.21 (95% CI, 0.06-0.36) for BMI; 0.21 kg/m2 (95% CI, -0.03 to 0.44) for fat mass index; 0.00 kg/m2 (95% CI, -0.21 to 0.22) for fat-free mass index; 0.71% (95% CI, -0.32 to 1.74) for percentage body fat; -0.73 cm (-2.48 to 1.02) for waist circumference; 0.05 cm (95% CI, -0.85 to 0.94) for height; -0.54 mm Hg (95% CI, -2.40 to 1.31) for systolic BP; and 0.71 mm Hg (95% CI, -0.68 to 2.10) for diastolic BP. The odds ratio for overweight/obesity (BMI ≥85th percentile vs85th percentile) was 1.14 (95% CI, 1.02-1.28) and the odds ratio for obesity (BMI ≥95th percentile vs95th percentile) was 1.09 (95% CI, 0.92-1.29). The intervention resulted in a more rapid rate of gain in postinfancy height (1 to 2.8 years), weight (2.8 to 14.5 years), and BMI (2.8 to 8.5 years) compared with the control arm. The intervention had little effect on BMI z score changes after 8.5 years.A randomized intervention that increased the duration and exclusivity of breastfeeding was not associated with lowered adolescent obesity risk or BP. On the contrary, the prevalence of overweight/obesity was higher in the intervention arm. All mothers initiated breastfeeding, so findings may not apply to comparisons of the effects of breastfeeding vs formula feeding.isrctn.org: ISRCTN37687716; and clinicaltrials.gov: NCT01561612.

Background: Accurate cause of death assignment is crucial for prostate cancer epidemiology and trials reporting prostate cancer-specific mortality outcomes. Methods: We compared death certificate information with independent cause of death evaluation by an expert committee within a prostate cancer trial (2002-2015). Results: Of 1,236 deaths assessed, expert committee evaluation attributed 523 (42%) to prostate cancer, agreeing with death certificate cause of death in 1,134 cases (92%, 95% CI: 90%, 93%). The sensitivity of death certificates in identifying prostate cancer deaths as classified by the committee was 91% (95% CI: 89%, 94%); specificity was 92% (95% CI: 90%, 94%). Sensitivity and specificity were lower where death occurred within one year of diagnosis, and where there was another primary cancer diagnosis.Conclusion: UK death certificates accurately identify cause of death in men with prostate cancer, supporting their use in routine statistics. Possible differential misattribution by trial arm supports independent evaluation in randomised trials.

Coffee consumption has been shown in some studies to be associated with lower risk of prostate cancer. However, it is unclear if this association is causal or due to confounding or reverse causality. We conducted a Mendelian randomisation analysis to investigate the causal effects of coffee consumption on prostate cancer risk and progression. We used two genetic variants robustly associated with caffeine intake (rs4410790 and rs2472297) as proxies for coffee consumption in a sample of 46,687 men of European ancestry from 25 studies in the PRACTICAL consortium. Associations between genetic variants and prostate cancer case status, stage and grade were assessed by logistic regression and with all-cause and prostate cancer-specific mortality using Cox proportional hazards regression. There was no clear evidence that a genetic risk score combining rs4410790 and rs2472297 was associated with prostate cancer risk (OR per additional coffee increasing allele: 1.01, 95% CI: 0.98,1.03) or having high-grade compared to low-grade disease (OR: 1.01, 95% CI: 0.97,1.04). There was some evidence that the genetic risk score was associated with higher odds of having nonlocalised compared to localised stage disease (OR: 1.03, 95% CI: 1.01, 1.06). Amongst men with prostate cancer, there was no clear association between the genetic risk score and all-cause mortality (HR: 1.00, 95% CI: 0.97,1.04) or prostate cancer-specific mortality (HR: 1.03, 95% CI: 0.98,1.08). These results, which should have less bias from confounding than observational estimates, are not consistent with a substantial effect of coffee consumption on reducing prostate cancer incidence or progression.

Circulating insulin-like growth factors (IGFs) and their binding proteins (IGFBPs) are associated with prostate cancer. Using genetic variants as instruments for IGF peptides, we investigated whether these associations are likely to be causal. We identified from the literature 56 single nucleotide polymorphisms (SNPs) in the IGF axis previously associated with biomarker levels (8 from a genome-wide association study [GWAS] and 48 in reported candidate genes). In ∼700 men without prostate cancer and two replication cohorts (N ∼ 900 and ∼9,000), we examined the properties of these SNPS as instrumental variables (IVs) for IGF-I, IGF-II, IGFBP-2 and IGFBP-3. Those confirmed as strong IVs were tested for association with prostate cancer risk, low (< 7) vs. high (≥ 7) Gleason grade, localised vs. advanced stage, and mortality, in 22,936 controls and 22,992 cases. IV analysis was used in an attempt to estimate the causal effect of circulating IGF peptides on prostate cancer. Published SNPs in the IGFBP1/IGFBP3 gene region, particularly rs11977526, were strong instruments for IGF-II and IGFBP-3, less so for IGF-I. Rs11977526 was associated with high (vs. low) Gleason grade (OR per IGF-II/IGFBP-3 level-raising allele 1.05; 95% CI: 1.00, 1.10). Using rs11977526 as an IV we estimated the causal effect of a one SD increase in IGF-II (∼265 ng/mL) on risk of high vs. low grade disease as 1.14 (95% CI: 1.00, 1.31). Because of the potential for pleiotropy of the genetic instruments, these findings can only causally implicate the IGF pathway in general, not any one specific biomarker.

Prostate cancer is the most common cancer in men in developed countries, and is a target for risk reduction strategies. The effects of alcohol consumption on prostate cancer incidence and survival remain unclear, potentially due to methodological limitations of observational studies. In this study, we investigated the associations of genetic variants in alcohol-metabolising genes with prostate cancer incidence and survival. We analysed data from 23,868 men with prostate cancer and 23,051 controls from 25 studies within the international PRACTICAL Consortium. Study-specific associations of 68 single nucleotide polymorphisms (SNPs) in 8 alcohol-metabolising genes (Alcohol Dehydrogenases (ADHs) and Aldehyde Dehydrogenases (ALDHs)) with prostate cancer diagnosis and prostate cancer-specific mortality, by grade, were assessed using logistic and Cox regression models, respectively. The data across the 25 studies were meta-analysed using fixed-effect and random-effects models. We found little evidence that variants in alcohol metabolising genes were associated with prostate cancer diagnosis. Four variants in two genes exceeded the multiple testing threshold for associations with prostate cancer mortality in fixed-effect meta-analyses. SNPs within ALDH1A2 associated with prostate cancer mortality were rs1441817 (fixed effects hazard ratio, HRfixed = 0.78; 95% confidence interval (95%CI):0.66,0.91; p values = 0.002); rs12910509, HRfixed = 0.76; 95%CI:0.64,0.91; p values = 0.003); and rs8041922 (HRfixed = 0.76; 95%CI:0.64,0.91; p values = 0.002). These SNPs were in linkage disequilibrium with each other. In ALDH1B1, rs10973794 (HRfixed = 1.43; 95%CI:1.14,1.79; p values = 0.002) was associated with prostate cancer mortality in men with low-grade prostate cancer. These results suggest that alcohol consumption is unlikely to affect prostate cancer incidence, but it may influence disease progression.

Genetic risk scores were used as unconfounded instruments for specific lipid traits (Mendelian randomization) to assess whether circulating lipids causally influence prostate cancer risk. Data from 22,249 prostate cancer cases and 22,133 controls from 22 studies within the international PRACTICAL consortium were analyzed. Allele scores based on single nucleotide polymorphisms (SNPs) previously reported to be uniquely associated with each of low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglyceride (TG) levels, were first validated in an independent dataset, and then entered into logistic regression models to estimate the presence (and direction) of any causal effect of each lipid trait on prostate cancer risk. There was weak evidence for an association between the LDL genetic score and cancer grade: the odds ratio (OR) per genetically instrumented standard deviation (SD) in LDL, comparing high- (≥7 Gleason score) versus low-grade (

Coffee consumption has been shown in some studies to be associated with lower risk of prostate cancer. However, it is unclear if this association is causal or due to confounding or reverse causality. We conducted a Mendelian randomisation analysis to investigate the causal effects of coffee consumption on prostate cancer risk and progression. We used two genetic variants robustly associated with caffeine intake (rs4410790 and rs2472297) as proxies for coffee consumption in a sample of 46,687 men of European ancestry from 25 studies in the PRACTICAL consortium. Associations between genetic variants and prostate cancer case status, stage and grade were assessed by logistic regression and with all‐cause and prostate cancer‐specific mortality using Cox proportional hazards regression. There was no clear evidence that a genetic risk score combining rs4410790 and rs2472297 was associated with prostate cancer risk (OR per additional coffee increasing allele: 1.01, 95% CI: 0.98,1.03) or having high‐grade compared to low‐grade disease (OR: 1.01, 95% CI: 0.97,1.04). There was some evidence that the genetic risk score was associated with higher odds of having nonlocalised compared to localised stage disease (OR: 1.03, 95% CI: 1.01, 1.06). Amongst men with prostate cancer, there was no clear association between the genetic risk score and all‐cause mortality (HR: 1.00, 95% CI: 0.97,1.04) or prostate cancer‐specific mortality (HR: 1.03, 95% CI: 0.98,1.08). These results, which should have less bias from confounding than observational estimates, are not consistent with a substantial effect of coffee consumption on reducing prostate cancer incidence or progression., What's new? Does coffee consumption reduce prostate cancer risk? It's biologically plausible that it could, but studies showing a link have relied on observational evidence, which could be affected by confounding factors. These authors set out to isolate coffee's contribution. They focused on two genetic variants that correspond with caffeine intake, and used them as proxies for coffee drinking. Alleles are not affected by behavior or demographic factors, nor can behavior changes after diagnosis change whether a person carries an allele. The authors found no correlation between either of the alleles and prostate cancer risk, suggesting drinking coffee may not protect against prostate cancer.

BackgroundIndividual studies have suggested that circulating carotenoids, retinol, or tocopherols may be associated with prostate cancer risk, but the studies have not been large enough to provide precise estimates of associations, particularly by stage and grade of disease.ObjectiveThe objective of this study was to conduct a pooled analysis of the associations of the concentrations of 7 carotenoids, retinol, α-tocopherol, and γ-tocopherol with risk of prostate cancer and to describe whether any associations differ by stage or grade of the disease or other factors.DesignPrincipal investigators of prospective studies provided individual participant data for prostate cancer cases and controls. Risk by study-specific fifths of each biomarker was estimated by using multivariable-adjusted conditional logistic regression in matched case-control sets.ResultsData were available for up to 11,239 cases (including 1654 advanced stage and 1741 aggressive) and 18,541 controls from 15 studies. Lycopene was not associated with overall risk of prostate cancer, but there was statistically significant heterogeneity by stage of disease, and the OR for aggressive disease for the highest compared with the lowest fifth of lycopene was 0.65 (95% CI: 0.46, 0.91; P-trend = 0.032). No other carotenoid was significantly associated with overall risk of prostate cancer or with risk of advanced-stage or aggressive disease. For retinol, the OR for the highest compared with the lowest fifth was 1.13 (95% CI: 1.04, 1.22; P-trend = 0.015). For α-tocopherol, the OR for the highest compared with the lowest fifth was 0.86 (95% CI: 0.78, 0.94; P-trend < 0.001), with significant heterogeneity by stage of disease; the OR for aggressive prostate cancer was 0.74 (95% CI: 0.59, 0.92; P-trend = 0.001). γ-Tocopherol was not associated with risk.ConclusionsOverall prostate cancer risk was positively associated with retinol and inversely associated with α-tocopherol, and risk of aggressive prostate cancer was inversely associated with lycopene and α-tocopherol. Whether these associations reflect causal relations is unclear.

INTRODUCTION:Prostate-specific antigen (PSA) testing is a widely accepted screening method for prostate cancer, but with low specificity at thresholds giving good sensitivity. Previous research identified four single nucleotide polymorphisms (SNPs) principally associated with circulating PSA levels rather than with prostate cancer risk (TERT rs2736098, FGFR2 rs10788160, TBX3 rs11067228, KLK3 rs17632542). Removing the genetic contribution to PSA levels may improve the ability of the remaining biologically-determined variation in PSA to discriminate between high and low risk of progression within men with identified prostate cancer. We investigate whether incorporating information on the PSA-SNPs improves the discrimination achieved by a single PSA threshold in men with raised PSA levels. MATERIALS AND METHODS:Men with PSA between 3-10 ng/mL and histologically-confirmed prostate cancer were categorised as high or low risk of progression (Low risk: Gleason score≤6 and stage T1-T2a; High risk: Gleason score 7-10 or stage T2C). We used the combined genetic effect of the four PSA-SNPs to calculate a genetically corrected PSA risk score. We calculated the Area under the Curve (AUC) to determine how well genetically corrected PSA risk scores distinguished men at high risk of progression from low risk men. RESULTS:The analysis includes 868 men with prostate cancer (Low risk: 684 (78.8%); High risk: 184 (21.2%)). Receiver operating characteristic (ROC) curves indicate that including the 4 PSA-SNPs does not improve the performance of measured PSA as a screening tool for high/low risk prostate cancer (measured PSA level AUC = 59.5% (95% CI: 54.7,64.2) vs additionally including information from the 4 PSA-SNPs AUC = 59.8% (95% CI: 55.2,64.5) (p-value = 0.40)). CONCLUSION:We demonstrate that genetically correcting PSA for the combined genetic effect of four PSA-SNPs, did not improve discrimination between high and low risk prostate cancer in men with raised PSA levels (3-10 ng/mL). Replication and gaining more accurate estimates of the effects of the 4 PSA-SNPs and additional variants associated with PSA levels and not prostate cancer could be obtained from subsequent GWAS from larger prospective studies.

Only a minority of the genetic components of prostate cancer risk have been explained. Some observed associations of SNPs with prostate cancer might arise from associations of these SNPs with circulating prostate-specific antigen (PSA) because PSA values are used to select controls.We undertook a genome-wide association study (GWAS) of screen-detected prostate cancer (ProtecT: 1,146 cases and 1,804 controls); meta-analyzed the results with those from the previously published UK Genetic Prostate Cancer Study (1,854 cases and 1,437 controls); investigated associations of SNPs with prostate cancer using either "low" (PSA0.5 ng/mL) or "high" (PSA ≥ 3 ng/mL, biopsy negative) PSA controls; and investigated associations of SNPs with PSA.The ProtecT GWAS confirmed previously reported associations of prostate cancer at three loci: 10q11.23, 17q24.3, and 19q13.33. The meta-analysis confirmed associations of prostate cancer with SNPs near four previously identified loci (8q24.21,10q11.23, 17q24.3, and 19q13.33). When comparing prostate cancer cases with low PSA controls, alleles at genetic markers rs1512268, rs445114, rs10788160, rs11199874, rs17632542, rs266849, and rs2735839 were associated with an increased risk of prostate cancer, but the effect-estimates were attenuated to the null when using high PSA controls (Pheterogeneity in effect-estimates0.04). We found a novel inverse association of rs9311171-T with circulating PSA.Differences in effect-estimates for prostate cancer observed when comparing low versus high PSA controls may be explained by associations of these SNPs with PSA.These findings highlight the need for inferences from genetic studies of prostate cancer risk to carefully consider the influence of control selection criteria.

It has been hypothesised that postnatal weight and length/height gain are variously related to wheeze, asthma and atopy; however, supporting evidence is limited and inconsistent.Weights and lengths/heights of 12,171 term infants were measured from birth to 12 months and at 6.5 yr and extracted from polyclinic records prospectively obtained between 12 and 60 months. Atopic phenotypes were ascertained at 6.5 yr with the International Study of Asthma and Allergy in Childhood questionnaire and skin prick tests. Logistic regression models investigated whether rates of weight and length/height gain from infancy to mid-childhood were associated with atopy phenotypes that have occurred ever or in the last 12 months.After controlling for confounders and prior weight and length/height gain, all weight gain variables except birth weight were positively associated with ever having wheezed (p 0.1). A one s.d. increase in weight gain rate between 0 and 3 months was associated with a 12% increase (2-23%) in allergic rhinitis ever. No other consistent patterns of association were found for weight gain or length/height gain rate between 0 and 60 months with atopic outcomes at 6.5 yr. In contrast, all atopy outcomes except for ever having asthma were associated with current weight and height, even after controlling for prior growth.Current height and weight are more strongly associated with the development of atopic phenotypes in childhood than patterns of infant and early childhood growth, which may well reflect reverse causality (atopy effects on growth) or residual confounding by an unknown common cause of growth and atopy.

This paper aims to investigate whether the stage shift (where more cancers are detected at an earlier stage) in prostate-specific antigen (PSA)-detected cancers differs by Gleason score.Between 2002 and 2005, 1514 men aged 50-69 years were identified with prostate cancer following community-based PSA testing as part of the ProtecT study. In the same period, 2021 men aged 50-69 years with clinically diagnosed prostate cancer were registered at a population-based cancer registry in the East of England. Using logistic regression analysis and controlling for age, the odds ratio (OR) for advanced stage (TNM stage T3 and above) prostate cancer among the PSA-detected group was compared with the clinically diagnosed tumours. The evidence that stage shift differs by Gleason score was assessed using the likelihood ratio test for interaction.Advanced stage disease among the PSA-detected cancers was less common than among the clinically detected cancers (OR = 0.47, 95% CI 0.39-0.56). PSA-detected tumours had a substantial shift to earlier-stage disease where the Gleason score was7 (OR = 0.52; 95% CI 0.36-0.77, P0.001) but showed no such shift where the Gleason score was 7 or more (OR = 0.84; 95% CI 0.66-1.07, P = 0.1). There was evidence of interaction between detection mode and Gleason score (P = 0.03).The observed stage shift could be partially explained by length bias or overdiagnosis. These findings may have implications on understanding pathways of prostate cancer progression and on identifying potential targets for screening, pending further investigation of complexities of associations between PSA testing, Gleason score, and stage.

There is continuing controversy over the most appropriate treatment for screen detected and clinically localized prostate cancer, and increasing interest in monitoring such men initially with radical treatment targeted at cancers showing signs of progressive potential but while they are still curable. Current evidence on monitoring protocols and biomarkers used to predict disease progression was systematically reviewed.The MEDLINE and Excerpta Medica (EMBASE) bibliographic databases were searched from 1988 to October 2004, supplemented by manual searches of reference lists, focusing on studies reporting monitoring of men with localized prostate cancer.A total of 48 potentially eligible articles were found but only 5 studies, in which there was a total of 451 participants, restricted entry criteria to men with clinically localized (T1-T2) prostate cancer. Monitoring protocols varied with little consensus, although the majority used prostate specific antigen and digital rectal examination, while some added re-biopsy to assess progression. Actuarial probabilities of freedom from disease progression at 4 to 5 years of followup were 67% to 72%. However, up to 50% of men abandoned monitoring within 2 years, largely because of anxiety related to increasing prostate specific antigen rather than objective evidence of disease progression. There was no robust evidence to support prostate specific antigen doubling times or velocity to identify men in whom disease may progress. Studies were characterized by small sample size, short-term followup, observer bias and uncertain validity around variable definitions of progression.Current evidence suggests that some form of monitoring would be a suitable treatment option in men with localized prostate cancer but there is little consensus over what markers should be used in such a program or how progression should be properly defined. The search for a method that safely identifies men with prostate cancer who could avoid radical intervention must continue.

To estimate the rates of common adverse events in patients treated with the proton pump inhibitors omeprazole, lansoprazole and pantoprazole in general practice in England.In prescription-event monitoring cohort studies, data on dispensed prescriptions prescribed by general practitioners in England soon after each drug was launched were linked to subsequent clinical events recorded by the prescriber. 16 205 patients prescribed omeprazole between June 1989 and June 1990, 17 329 patients prescribed lansoprazole between May and November 1994, and 11 541 patients prescribed pantoprazole between December 1996 and June 1997 were studied.The commonest adverse events in the omeprazole, lansoprazole and pantoprazole cohorts were diarrhoea (incidence: 0. 18, 0.39 and 0.23 per 1000 days of exposure, respectively); nausea/vomiting (incidence: 0.16, 0.22 and 0.18 per 1000 days of exposure, respectively); abdominal pain (incidence: 0.17, 0.21 and 0. 17 per 1000 days of exposure, respectively); and headache (incidence rates: 0.10, 0.17 and 0.15 per 1000 days of exposure, respectively). The remaining adverse events occurred at rates of less than 0.11 per 1000 days of exposure. There were little absolute differences in the rates of most events between the three proton pump inhibitors. However, diarrhoea was more commonly associated with lansoprazole compared with omeprazole (rate difference: 0.21 per 1000 days of exposure; 95% CI 0.17, 0.25; rate ratio: 2.11; 1.78, 2.51), and there was a clear age-response relationship.Adverse events occurred relatively infrequently in all three cohorts. There were only small absolute differences in event rates between the three drugs, although these data suggest the hypothesis that lansoprazole is associated with more frequent occurrence of diarrhoea, particularly in the elderly.

Meloxicam is a novel nonsteroidal anti-inflammatory drug (NSAID) which may be associated with fewer adverse upper gastrointestinal events than other NSAIDs because it preferentially inhibits the inducible enzyme cyclo-oxygenase-2 relative to the constitutive isoform, cyclo-oxygenase-1. The aims of the study were to: determine the rate of adverse events associated with meloxicam in general practice, stratify these rates by selected risk factors, and to identify signals of previously unsuspected adverse events associated with meloxicam.As part of the national prescription-event monitoring pharmacovigilance system for newly launched drugs in general practice, all patients prescribed meloxicam in England between December 1996 and March 1997 were identified by the central Prescription Pricing Authority. We sent short questionnaires to all prescribers asking about adverse events experienced within 6 months of the first prescription.There were 19 087 patients in the study. The rate of dyspepsia during the first month of exposure was 28.3 per 1000 patient-months. There were 33 reports of upper gastrointestinal haemorrhage during treatment (rate: 0.4 per 1000 months). A history of gastrointestinal disorder in the previous year was associated with an increased rate of dyspepsia (rate ratio: 3.0; 95% confidence interval: 2.6, 3.4), abdominal pain (2.1; 1.6, 2.6), and peptic ulcer (4.0; 1.4, 13.2). Prior NSAID use was associated with a 20-30% decrease in the rate of dyspepsia and abdominal pain in patients starting meloxicam, while patients prescribed concomitant gastroprotective agents had a two to three-fold increased rate of dyspepsia, abdominal pain and peptic ulceration. Other rare events were thrombocytopenia (n = 2); interstitial nephritis (n = 1) and idiosyncratic liver abnormalities (n = 1).In the absence of gastro-intestinal risk factors the incidence of gastro-intestinal disturbance was low. Such risk factors should be carefully reviewed prior to prescribing meloxicam.

Background Epidemiological studies suggest a potential role for obesity and determinants of adult stature in prostate cancer risk and mortality, but the relationships described in the literature are complex. To address uncertainty over the causal nature of previous observational findings, we investigated associations of height- and adiposity-related genetic variants with prostate cancer risk and mortality. Methods We conducted a case–control study based on 20,848 prostate cancers and 20,214 controls of European ancestry from 22 studies in the PRACTICAL consortium. We constructed genetic risk scores that summed each man’s number of height and BMI increasing alleles across multiple single nucleotide polymorphisms robustly associated with each phenotype from published genome-wide association studies. Results The genetic risk scores explained 6.31 and 1.46 % of the variability in height and BMI, respectively. There was only weak evidence that genetic variants previously associated with increased BMI were associated with a lower prostate cancer risk (odds ratio per standard deviation increase in BMI genetic score 0.98; 95 % CI 0.96, 1.00; p = 0.07). Genetic variants associated with increased height were not associated with prostate cancer incidence (OR 0.99; 95 % CI 0.97, 1.01; p = 0.23), but were associated with an increase (OR 1.13; 95 % CI 1.08, 1.20) in prostate cancer mortality among low-grade disease (p heterogeneity, low vs. high grade p heterogeneity = 0.03). Conclusions We found little evidence of a substantial effect of genetically elevated height or BMI on prostate cancer risk, suggesting that previously reported observational associations may reflect common environmental determinants of height or BMI and prostate cancer risk. Genetically elevated height and BMI were associated with increased mortality (prostate cancer-specific and all-cause, respectively) in men with low-grade disease, a potentially informative but novel finding that requires replication.

Purpose Vitamin D pathway single nucleotide polymorphisms (SNPs) are potentially useful proxies for investigating whether circulating vitamin D metabolites [total 25-hydroxyvitamin-D, 25(OH)D; 1,25-dihydroxyvitamin, 1,25(OH)2D] are causally related to prostate cancer. We investigated associations of sixteen SNPs across seven genes with prostate-specific antigen-detected prostate cancer. Methods In a nested case–control study (within the ProtecT trial), we estimated odds ratios and 95 % confidence intervals (CIs) quantifying associations between SNPs and prostate cancer. Subgroup analyses investigated whether associations were stronger in men who had high/low sun exposure [a proxy for 25(OH)D]. We quantified associations of SNPs with stage (T1–T2/T3–T4) and grade (

BACKGROUND: Several obesity-related factors have been associated with renal cell carcinoma (RCC), but it is unclear which individual factors directly influence risk. We addressed this question using genetic markers as proxies for putative risk factors and evaluated their relation to RCC risk in a mendelian randomization (MR) framework. This methodology limits bias due to confounding and is not affected by reverse causation. METHODS AND FINDINGS: Genetic markers associated with obesity measures, blood pressure, lipids, type 2 diabetes, insulin, and glucose were initially identified as instrumental variables, and their association with RCC risk was subsequently evaluated in a genome-wide association study (GWAS) of 10,784 RCC patients and 20,406 control participants in a 2-sample MR framework. The effect on RCC risk was estimated by calculating odds ratios (ORSD) for a standard deviation (SD) increment in each risk factor. The MR analysis indicated that higher body mass index increases the risk of RCC (ORSD: 1.56, 95% confidence interval [CI] 1.44-1.70), with comparable results for waist-to-hip ratio (ORSD: 1.63, 95% CI 1.40-1.90) and body fat percentage (ORSD: 1.66, 95% CI 1.44-1.90). This analysis further indicated that higher fasting insulin (ORSD: 1.82, 95% CI 1.30-2.55) and diastolic blood pressure (DBP; ORSD: 1.28, 95% CI 1.11-1.47), but not systolic blood pressure (ORSD: 0.98, 95% CI 0.84-1.14), increase the risk for RCC. No association with RCC risk was seen for lipids, overall type 2 diabetes, or fasting glucose. CONCLUSIONS: This study provides novel evidence for an etiological role of insulin in RCC, as well as confirmatory evidence that obesity and DBP influence RCC risk.

Genetic models for cancer have been evaluated using almost exclusively European data, which could exacerbate health disparities. A polygenic hazard score (PHS1) is associated with age at prostate cancer diagnosis and improves screening accuracy in Europeans. Here, we evaluate performance of PHS2 (PHS1, adapted for OncoArray) in a multi-ethnic dataset of 80,491 men (49,916 cases, 30,575 controls). PHS2 is associated with age at diagnosis of any and aggressive (Gleason score ≥ 7, stage T3-T4, PSA ≥ 10 ng/mL, or nodal/distant metastasis) cancer and prostate-cancer-specific death. Associations with cancer are significant within European (n = 71,856), Asian (n = 2,382), and African (n = 6,253) genetic ancestries (p < 10-180). Comparing the 80th/20th PHS2 percentiles, hazard ratios for prostate cancer, aggressive cancer, and prostate-cancer-specific death are 5.32, 5.88, and 5.68, respectively. Within European, Asian, and African ancestries, hazard ratios for prostate cancer are: 5.54, 4.49, and 2.54, respectively. PHS2 risk-stratifies men for any, aggressive, and fatal prostate cancer in a multi-ethnic dataset.

Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction.