Does testosterone mediate the relationship between vitamin D and prostate cancer progression? A systematic review and meta-analysis.

PURPOSE: Observational studies and randomized controlled trials (RCTs) have shown an association between vitamin D levels and prostate cancer progression. However, evidence of direct causality is sparse and studies have not examined biological mechanisms, which can provide information on plausibility and strengthen the evidence for causality. METHODS: We used the World Cancer Research Fund International/University of Bristol two-stage framework for mechanistic systematic reviews. In stage one, both text mining of published literature and expert opinion identified testosterone as a plausible biological mechanism. In stage two, we performed a systematic review and meta-analysis to assess the evidence from both human and animal studies examining the effect of vitamin D on testosterone, and testosterone on advanced prostate cancer (diagnostic Gleason score of ≥ 8, development of metastasis) or prostate cancer-specific mortality. RESULTS: A meta-analysis of ten human RCTs showed evidence of an effect of vitamin D on total testosterone (standardised mean difference (SMD) = 0.133, 95% CI = - 0.003-0.269, I2 = 0.0%, p = 0.056). Five human RCTs showed evidence of an effect of vitamin D on free testosterone (SMD = 0.173, 95% CI = - 0.104-0.450, I2 = 52.4%, p = 0.220). Three human cohort studies of testosterone on advanced prostate cancer or prostate cancer-specific mortality provided inconsistent results. In one study, higher levels of calculated free testosterone were positively associated with advanced prostate cancer or prostate cancer-specific mortality. In contrast, higher levels of dihydrotestosterone were associated with lowering prostate cancer-specific mortality in another study. No animal studies met the study eligibility criteria. CONCLUSION: There is some evidence that vitamin D increases levels of total and free testosterone, although the effect of testosterone levels within the normal range on prostate cancer progression is unclear. The role of testosterone as a mechanism between vitamin D and prostate cancer progression remains inconclusive.

Change in obesity-related metabolic abnormalities associated with body mass index improvement through life-style intervention: A meta-regression.

The reduction in body mass index standard deviation score (BMI-SDS) associated with improvement in biomarkers relating to metabolic health in obese children is unknown. We aimed to establish the change in BMI-SDS associated with improved inflammation, liver function, and insulin resistance to inform clinical guidelines for pediatric weight management interventions and to assess the efficacy of future trials. A large-scale systematic review was conducted to identify relevant studies. Studies of children with a diagnosis of obesity according to defined BMI thresholds, participating in lifestyle interventions to reduce obesity, were included. Studies must have reported baseline (pre-) and postintervention (or change of) BMI-SDS and either fasting glucose, homeostatic model of insulin resistance (HOMA-IR), alanine aminotransferase (ALT), C-reactive protein (CRP), or interleukin-6 (IL-6). A series of meta-regressions were conducted to establish links between BMI-SDS change scores and change in metabolic markers of health. Sixty-eight articles were identified. From the meta-regression analyses, across all study subsets, greater mean falls in all four parameters, (HOMA-IR, Glucose, ALT, and CRP) were observed with greater mean loss of BMI-SDS, but the trends were only statistically significant for HOMA-IR and CRP (P = .003; P = .021). However, we could not find minimum changes in BMI-SDS that would ensure a fall in these outcomes. At this time, we are unable to recommend a definitive value of BMI-SDS reduction needed to improve the markers of metabolic health. Future trials should aim to report additional indices of derived BMI values, which may better reflect changes in actual adiposity.

Investigating the effects of lycopene and green tea on the metabolome of men at risk of prostate cancer: The ProDiet randomised controlled trial.

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 (R2 = 0.65 and 0.76 for lycopene and green tea respectively). Metabolites which were altered in response to lycopene supplementation were acetate [ß (standard deviation difference vs. placebo): 0.69; 95% CI = 0.24, 1.15; p = 0.003], valine (ß: -0.62; -1.03, -0.02; p = 0.004), pyruvate (ß: -0.56; -0.95, -0.16; p = 0.006) and docosahexaenoic acid (ß: -0.50; -085, -0.14; p = 0.006). Valine and diacylglycerol were lower in the lycopene dietary advice group (ß: -0.65; -1.04, -0.26; p = 0.001 and ß: -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.

Tobacco smoking and alcohol drinking at diagnosis of head and neck cancer and all-cause mortality: Results from head and neck 5000, a prospective observational cohort of people with head and neck cancer.

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.

Health behaviours of young mothers: Implications for health promotion and cancer prevention.

OBJECTIVE: Evidence suggests that younger mothers engage in poorer health behaviours, resulting in increased cancer risk. We aimed to better understand the health behaviours of younger mothers and the factors that influence their lifestyle choices, in order to improve cancer prevention within this population. METHODS: A multiple focus group, photo-elicitation-aided approach was used, in which young mothers (n = 27; aged 16-24 years) were provided with cameras and asked to capture 'a week in your life'. Photographs were developed and participants invited to an initial focus group where photographs were used to elicit discussion, exploring participants' health behaviours. Data were thematically analysed particularly identifying themes relating to barriers and facilitators of positive health behaviours. Participants were later invited to participate in a second focus group, to explore and validate identified themes further. RESULTS: Themes emerged from the data relating to (1) the mothers' personal perceptions of health, (2) health-related behaviours and (3) beliefs about cancer and its causes. Barriers to positive health behaviours included a lack of money, childcare and cookery skills; facilitators included the social media, commercial weight loss programmes and local community organisations. CONCLUSION: Study findings provide insight into the health behaviours and life choices of young mothers. They help illustrate health perceptions in relation to cancer risk, providing an understanding of how their daily routine and circumstance influence young women's decisions and lifestyle behaviour choices and highlighting barriers to, and facilitators of, positive health behaviours. Data hold potential to inform future health-related research among young mothers, particularly relating to cancer prevention intervention.

Dual-energy X-ray absorptiometry derived knee shape may provide a useful imaging biomarker for predicting total knee replacement: Findings from a study of 37,843 people in UK Biobank.

Objective: We aimed to create an imaging biomarker for knee shape using knee dual-energy x-ray absorptiometry (DXA) scans and investigate its potential association with subsequent total knee replacement (TKR), independently of radiographic features of knee osteoarthritis and established risk factors. Methods: Using a 129-point statistical shape model, knee shape (expressed as a B-score) and minimum joint space width (mJSW) of the medial joint compartment (binarized as above or below the first quartile) were derived. Osteophytes were manually graded in a subset of images and an overall score was assigned. Cox proportional hazards models were used to examine the associations of B-score, mJSW and osteophyte score with TKR risk, adjusting for age, sex, height and weight. Results: The analysis included 37,843 individuals (mean age 63.7 years). In adjusted models, B-score was associated with TKR: each unit increase in B-score, reflecting one standard deviation from the mean healthy shape, corresponded to a hazard ratio (HR) of 2.25 (2.08, 2.43), while a lower mJSW had a HR of 2.28 (1.88, 2.77). Among the 6719 images scored for osteophytes, mJSW was replaced by osteophyte score in the most strongly predictive model for TKR. In ROC analyses, a model combining B-score, osteophyte score, and demographics outperformed a model including demographics alone (AUC â€‹= â€‹0.87 vs 0.73). Conclusions: Using statistical shape modelling, we derived a DXA-based imaging biomarker for knee shape that was associated with kOA progression. When combined with osteophytes and demographic data, this biomarker may help identify individuals at high risk of TKR, facilitating targeted interventions.

Epigenetic biomarkers of ageing are predictive of mortality risk in a longitudinal clinical cohort of individuals diagnosed with oropharyngeal cancer.

BACKGROUND: Epigenetic clocks are biomarkers of ageing derived from DNA methylation levels at a subset of CpG sites. The difference between age predicted by these clocks and chronological age, termed "epigenetic age acceleration", has been shown to predict age-related disease and mortality. We aimed to assess the prognostic value of epigenetic age acceleration and a DNA methylation-based mortality risk score with all-cause mortality in a prospective clinical cohort of individuals with head and neck cancer: Head and Neck 5000. We investigated two markers of intrinsic epigenetic age acceleration (IEAAHorvath and IEAAHannum), one marker of extrinsic epigenetic age acceleration (EEAA), one optimised to predict physiological dysregulation (AgeAccelPheno), one optimised to predict lifespan (AgeAccelGrim) and a DNA methylation-based predictor of mortality (ZhangScore). Cox regression models were first used to estimate adjusted hazard ratios (HR) and 95% confidence intervals (CI) for associations of epigenetic age acceleration with all-cause mortality in people with oropharyngeal cancer (n = 408; 105 deaths). The added prognostic value of epigenetic markers compared to a clinical model including age, sex, TNM stage and HPV status was then evaluated. RESULTS: IEAAHannum and AgeAccelGrim were associated with mortality risk after adjustment for clinical and lifestyle factors (HRs per standard deviation [SD] increase in age acceleration = 1.30 [95% CI 1.07, 1.57; p = 0.007] and 1.40 [95% CI 1.06, 1.83; p = 0.016], respectively). There was weak evidence that the addition of AgeAccelGrim to the clinical model improved 3-year mortality prediction (area under the receiver operating characteristic curve: 0.80 vs. 0.77; p value for difference = 0.069). CONCLUSION: In the setting of a large, clinical cohort of individuals with head and neck cancer, our study demonstrates the potential of epigenetic markers of ageing to enhance survival prediction in people with oropharyngeal cancer, beyond established prognostic factors. Our findings have potential uses in both clinical and non-clinical contexts: to aid treatment planning and improve patient stratification.

What Change in Body Mass Index Is Required to Improve Cardiovascular Outcomes in Childhood and Adolescent Obesity through Lifestyle Interventions: A Meta-Regression.

Background: Using meta-regression, this article aims at establishing the minimum change in BMI-standard deviation score (SDS) needed to improve lipid profiles and blood pressure in children and adolescents with obesity, to aid future trials and guidelines. Methods: Studies with participants involved in lifestyle interventions, aged 4-19 years, with a diagnosis of obesity according to defined BMI thresholds, were considered for inclusion in a large systematic review. Interventions had to report pre- and post-intervention (or mean change in) BMI-SDS, plus either systolic blood pressure (SBP), high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and/or triglycerides (TGs). Random-effects meta-regression quantified the relationship between mean change in BMI-SDS and mean change in cardiovascular outcomes. Results: Seventy-one papers reported various cardiovascular measurements and mean change in BMI-SDS. Fifty-four, 59, 46, and 54 studies were analyzed, reporting a change in SBP, HDL, LDL, and TG, respectively. Reduction in mean BMI-SDS was significantly related to improvements in SBP, LDL, TG, and HDL (p < 0.05); BMI-SDS reductions of 1, 1.2, and 0.7 ensured a mean reduction of SBP, LDL, and TG, respectively, although an equivalent value for HDL improvement was indeterminate. Conclusion: Reductions in mean BMI-SDS of >1, >1.2, or >0.7 are likely to reduce SBP, LDL, and TG, respectively. Further studies are needed to clarify the optimal duration, intensity, and setting for interventions. Consistency is required regarding derived BMI values to facilitate future systematic reviews and meta-analyses.

Piloting the objective measurement of eating weight and speed at a population scale: a nested study within the Avon Longitudinal Study of Parents and Children.

Background: Effective measurement and adaption of eating behaviours, such as eating speed, may improve weight loss and weight over time. We assessed whether the Mandometer, a portable weighing scale connected to a computer that generates a graph of food removal rate from the plate to which it is connected, together with photo-imaging of food, might prove an effective approach to measuring eating behaviours at large scale. Methods: We deployed the Mandometer in the home environment to measure main meals over three days of 95 21-year-old participants of the Avon Longitudinal Study of Parents and Children. We used multi-level models to describe food weight and eating speed and, as exemplar analyses, examined the relationship of eating behaviours with body mass index (BMI), dietary composition (fat content) and genotypic variation (the FTO rs9939609 variant). Using this pilot data, we calculated the sample size required to detect differences in food weight and eating speed between groups of an exposure variable. Results: All participants were able to use the Mandometer effectively after brief training. In exemplar analyses, evidence suggested that obese participants consumed more food than those of "normal" weight (i.e., BMI 19 to <25 kg/m 2) and that A/A FTO homozygotes (an indicator of higher weight) ate at a faster rate compared to T/T homozygotes. There was also some evidence that those with a high-fat diet consumed less food than those with a low-fat diet, but no strong evidence that individuals with medium- or high-fat diets ate at a faster rate. Conclusions: We demonstrated the potential for assessing eating weight and speed in a short-term home setting and combining this with information in a research setting. This study may offer the opportunity to design interventions tailored for at-risk eating behaviours, offering advantages over the "one size fits all" approach of current failing obesity interventions.

Epigenetic prediction of complex traits and mortality in a cohort of individuals with oropharyngeal cancer.

BACKGROUND: DNA methylation (DNAm) variation is an established predictor for several traits. In the context of oropharyngeal cancer (OPC), where 5-year survival is ~ 65%, DNA methylation may act as a prognostic biomarker. We examined the accuracy of DNA methylation biomarkers of 4 complex exposure traits (alcohol consumption, body mass index [BMI], educational attainment and smoking status) in predicting all-cause mortality in people with OPC. RESULTS: DNAm predictors of alcohol consumption, BMI, educational attainment and smoking status were applied to 364 individuals with OPC in the Head and Neck 5000 cohort (HN5000; 19.6% of total OPC cases in the study), followed up for median 3.9 years; inter-quartile range (IQR) 3.3 to 5.2 years (time-to-event-death or censor). The proportion of phenotypic variance explained in each trait was as follows: 16.5% for alcohol consumption, 22.7% for BMI, 0.4% for educational attainment and 51.1% for smoking. We then assessed the relationship between each DNAm predictor and all-cause mortality using Cox proportional-hazard regression analysis. DNAm prediction of smoking was most consistently associated with mortality risk (hazard ratio [HR], 1.38 per standard deviation (SD) increase in smoking DNAm score; 95% confidence interval [CI] 1.04 to 1.83; P 0.025, in a model adjusted for demographic, lifestyle, health and biological variables). Finally, we examined the accuracy of each DNAm predictor of mortality. DNAm predictors explained similar levels of variance in mortality to self-reported phenotypes. Receiver operator characteristic (ROC) curves for the DNAm predictors showed a moderate discrimination of alcohol consumption (area under the curve [AUC] 0.63), BMI (AUC 0.61) and smoking (AUC 0.70) when predicting mortality. The DNAm predictor for education showed poor discrimination (AUC 0.57). Z tests comparing AUCs between self-reported phenotype ROC curves and DNAm score ROC curves did not show evidence for difference between the two (alcohol consumption P 0.41, BMI P 0.62, educational attainment P 0.49, smoking P 0.19). CONCLUSIONS: In the context of a clinical cohort of individuals with OPC, DNAm predictors for smoking, alcohol consumption, educational attainment and BMI exhibit similar predictive values for all-cause mortality compared to self-reported data. These findings may have translational utility in prognostic model development, particularly where phenotypic data are not available.

What change in body mass index is associated with improvement in percentage body fat in childhood obesity? A meta-regression.

OBJECTIVE: Using meta-regression this paper sets out the minimum change in body mass index-SD score (BMI-SDS) required to improve adiposity as percentage body fat for children and adolescents with obesity. DESIGN: Meta-regression. SETTING: Studies were identified as part of a large-scale systematic review of the following electronic databases: AMED, Embase, MEDLINE via OVID, Web of Science and CENTRAL via Cochrane library. PARTICIPANTS: Individuals aged 4-19 years with a diagnosis of obesity according to defined BMI thresholds. INTERVENTIONS: Studies of lifestyle treatment interventions that included dietary, physical activity and/or behavioural components with the objective of reducing obesity were included. Interventions of <2 weeks duration and those that involved surgical and/or pharmacological components (eg, bariatric surgery, drug therapy) were excluded. PRIMARY AND SECONDARY OUTCOME MEASURES: To be included in the review, studies had to report baseline and post-intervention BMI-SDS or change measurements (primary outcome measures) plus one or more of the following markers of metabolic health (secondary outcome measures): adiposity measures other than BMI; blood pressure; glucose; inflammation; insulin sensitivity/resistance; lipid profile; liver function. This paper focuses on adiposity measures only. Further papers in this series will report on other outcome measures. RESULTS: This paper explores the potential impact of BMI-SDS reduction in terms of change in percentage body fat. Thirty-nine studies reporting change in mean percentage body fat were analysed. Meta-regression demonstrated that reduction of at least 0.6 in mean BMI-SDS ensured a mean reduction of percentage body fat mass, in the sense that the associated 95% prediction interval for change in mean percentage body fat was wholly negative. CONCLUSIONS: Interventions demonstrating reductions of 0.6 BMI-SDS might be termed successful in reducing adiposity, a key purpose of weight management interventions. TRIAL REGISTRATION NUMBER: CRD42016025317.

Dietary behaviors and survival in people with head and neck cancer: Results from Head and Neck 5000.

BACKGROUND: The association between diet and head and neck cancer (HNC) survival is unclear. METHODS: Cox proportional hazard models measured the association between fruit, vegetable, and deep-fried food intake and HNC overall survival adjusting for clinical, social and lifestyle variables including smoking, alcohol, and HPV status. RESULTS: Fruit and vegetable intake and improved survival were associated in minimally adjusted analyses. Following adjustment for smoking and alcohol consumption (fully adjusted analyses), the association with survival disappeared for fruit (HR 0.91, 95% CI 0.67, 1.23; P for trend = .55) and attenuated for vegetables (HR 0.79, 95% CI 0.61, 1.03; P for trend = .04). We observed no association between survival and deep-fried food intake in minimally adjusted or fully adjusted analyses (HR 0.88 95% CI 0.72, 1.07; P for trend = .13). CONCLUSIONS: Vegetable intake and HNC survival are modestly associated. There is some confounding by tobacco and alcohol consumption.

Association between comorbidity and survival in head and neck cancer: Results from Head and Neck 5000.

BACKGROUND: People with head and neck cancer have higher comorbidity levels but it remains unclear if pretreatment comorbidity is an independent prognosticator in head and neck cancer. METHODS: Survival analyses were performed using data from participants in a UK multicentre cohort study with cancers of the oral cavity (n = 668), oropharynx (n = 1074), and larynx (n = 530). Survival analyses were incrementally adjusted for age, sex, marital status, income, education, stage, alcohol, and smoking. RESULTS: After adjusting for demographic, clinical, and behavioral confounders, higher baseline comorbidity was associated with reduced overall survival (mild comorbidity HR = 1.4, 95% CI = 1.1, 1.7; moderate comorbidity HR = 1.7, 95% CI = 1.3, 2.2; severe comorbidity HR = 2.8, 95% CI = 1.9, 4.; P-trend<.001). CONCLUSIONS: Our findings suggest that comorbidity is an independent prognosticator for overall survival in head and neck cancer. Comorbid illnesses should be considered in the assessment and treatment planning of people with head and neck cancer.

What change in body mass index is needed to improve metabolic health status in childhood obesity: protocol for a systematic review.

BACKGROUND: Childhood obesity is one of the most serious, global, public health challenges and has adverse health consequences in both the short-and long-term. The purpose of this study is to establish the change in body mass index (BMI) needed to achieve improvements in metabolic health status in obese children and adolescents attending lifestyle treatment interventions. METHODS: The following electronic databases will be searched from their inception: AMED, Embase, MEDLINE via OVID, Web of Science and CENTRAL via Cochrane library. Randomised controlled trials (RCTs) or cohort studies of lifestyle interventions (i.e. dietary, physical activity and/or behavioural therapy) for treating obesity in children and adolescents (4-18 years) will be included. Interventions that last less than 2 weeks and trials that include overweight participants or those with a secondary or syndromic cause of obesity will not be included. No language restrictions will be applied. Titles and abstracts will be assessed for eligibility by two reviewers, and data from full-text articles will be extracted using a standardised data extraction template. Reference lists of all included articles will be hand-searched for additional publications. A narrative synthesis of the findings will be presented, and meta-analysis will be conducted if considered appropriate. DISCUSSION: This will be the first systematic review of studies to establish the change in BMI required to improve metabolic health status in obese children and adolescents. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42016025317.