Analgesic use and the risk of renal cell carcinoma - Findings from the Consortium for the Investigation of Renal Malignancies (CONFIRM) study.

PURPOSE: The incidence of renal cell carcinoma (RCC) is rising. Use of analgesics such as non-steroidal anti-inflammatory drugs (NSAIDs) and paracetamol may affect renal function. The aim of this study was to assess associations between analgesic use and risk of RCC. METHODS: A population-based case-control family design was used. Cases were recruited via two Australian state cancer registries. Controls were siblings or partners of cases. Analgesic use was captured by self-completed questionnaire. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for RCC risk associated with regular analgesic use (at least 5 times per month for 6 months or more) and duration and frequency of use. RESULTS: The analysis included 1064 cases and 724 controls. Regular use of paracetamol was associated with an increased risk of RCC (OR 1.41, 95%CI 1.13-1.77). Regular use of NSAIDs was associated with increased risk of RCC for women (OR 1.71, 95% CI 1.23-2.39) but not men (OR 0.83, 95% CI 0.58-1.18; p-interaction=0.003). There was no evidence of a dose-response for duration of use of paracetamol (linear trend p = 0.77) and weak evidence for non- aspirin NSAID use by women (linear trend p = 0.054). CONCLUSION: This study found that regular use of paracetamol was associated with increased risk of RCC. NSAID use was associated with increased risk only for women.

Measures of body fatness and height in early and mid-to-late adulthood and prostate cancer: risk and mortality in The Pooling Project of Prospective Studies of Diet and Cancer.

BACKGROUND: Advanced prostate cancer etiology is poorly understood. Few studies have examined associations of anthropometric factors (e.g. early adulthood obesity) with advanced prostate cancer risk. PATIENTS AND METHODS: We carried out pooled analyses to examine associations between body fatness, height, and prostate cancer risk. Among 830 772 men, 51 734 incident prostate cancer cases were identified, including 4762 advanced (T4/N1/M1 or prostate cancer deaths) cases, 2915 advanced restricted (same as advanced, but excluding localized cancers that resulted in death) cases, 9489 high-grade cases, and 3027 prostate cancer deaths. Cox proportional hazards models were used to calculate study-specific hazard ratios (HR) and 95% confidence intervals (CI); results were pooled using random effects models. RESULTS: No statistically significant associations were observed for body mass index (BMI) in early adulthood for advanced, advanced restricted, and high-grade prostate cancer, and prostate cancer mortality. Positive associations were shown for BMI at baseline with advanced prostate cancer (HR = 1.30, 95% CI = 0.95-1.78) and prostate cancer mortality (HR = 1.52, 95% CI = 1.12-2.07) comparing BMI ≥35.0 kg/m2 with 21-22.9 kg/m2. When considering early adulthood and baseline BMI together, a 27% higher prostate cancer mortality risk (95% CI = 9% to 49%) was observed for men with BMI <25.0 kg/m2 in early adulthood and BMI ≥30.0 kg/m2 at baseline compared with BMI <25.0 kg/m2 in early adulthood and BMI <30.0 kg/m2 at baseline. Baseline waist circumference, comparing ≥110 cm with <90 cm, and waist-to-hip ratio, comparing ≥1.00 with <0.90, were associated with significant 14%-16% increases in high-grade prostate cancer risk and suggestive or significant 20%-39% increases in prostate cancer mortality risk. Height was associated with suggestive or significant 33%-56% risks of advanced or advanced restricted prostate cancer and prostate cancer mortality, comparing ≥1.90 m with <1.65 m. CONCLUSION: Our findings suggest that height and total and central adiposity in mid-to-later adulthood, but not early adulthood adiposity, are associated with risk of advanced forms of prostate cancer. Thus, maintenance of healthy weight may help prevent advanced prostate cancer.

Novel associations between blood DNA methylation and body mass index in middle-aged and older adults.

BACKGROUND/OBJECTIVES: There is increasing evidence of a relationship between blood DNA methylation and body mass index (BMI). We aimed to assess associations of BMI with individual methylation measures (CpGs) through a cross-sectional genome-wide DNA methylation association study and a longitudinal analysis of repeated measurements over time. SUBJECTS/METHODS: Using the Illumina Infinium HumanMethylation450 BeadChip, DNA methylation measures were determined in baseline peripheral blood samples from 5361 adults recruited to the Melbourne Collaborative Cohort Study (MCCS) and selected for nested case-control studies, 2586 because they were subsequently diagnosed with cancer (cases) and 2775 as controls. For a subset of 1088 controls, these measures were repeated using blood samples collected at wave 2 follow-up, a median of 11 years later; weight was measured at both time points. Associations between BMI and blood DNA methylation were assessed using linear mixed-effects regression models adjusted for batch effects and potential confounders. These were applied to cases and controls separately, with results combined through fixed-effects meta-analysis. RESULTS: Cross-sectional analysis identified 310 CpGs associated with BMI with P<1.0 × 10-7, 225 of which had not been reported previously. Of these 225 novel associations, 172 were replicated (P<0.05) using the Atherosclerosis Risk in Communities (ARIC) study. We also replicated using MCCS data (P<0.05) 335 of 392 associations previously reported with P<1.0 × 10-7, including 60 that had not been replicated before. Associations between change in BMI and change in methylation were observed for 34 of the 310 strongest signals in our cross-sectional analysis, including 7 that had not been replicated using the ARIC study. CONCLUSIONS: Together, these findings suggest that BMI is associated with blood DNA methylation at a large number of CpGs across the genome, several of which are located in or near genes involved in ATP-binding cassette transportation, tumour necrosis factor signalling, insulin resistance and lipid metabolism.

The Influence of Age the BMI and All-Cause Mortality Association: A Meta-Analysis.

OBJECTIVES: To assess BMI range with the lowest mortality for those aged <65 years and those ≥65 years, utilising cohort studies that spanned the entire adult age range. DESIGN: A two-stage random effects meta-analysis of studies that reported mortality in cohorts both ≥65 years and <65 years. Setting / Participants: Community living adults aged ≥65 and <65 years. RESULTS: Eight studies were included with a total of 370 416 subjects (306 340 aged <65 years; 64 076 ≥65 years). In the older age group, mortality risk increased at BMIs lower than 22 (BMI range 21.0-21.9: hazard ratio (HR) (95% confidence interval (CI)): 1.05 (1.03, 1.07)), which was not seen in younger adults. In the younger group, mortality increased from BMI range 28.0-28.9 (HR (95% CI): 1.13 (1.00, 1.29)), but mortality did not tend to increase significantly in the older group at BMIs above 23. CONCLUSION: The recommended healthy weight range is appropriate for younger and middle aged adults but a higher BMI range should be recommended for older adults based on mortality.

Study protocol for a natural experiment in a lower socioeconomic area to examine the health-related effects of refurbishment to parks including built-shade (ShadePlus).

INTRODUCTION: Parks in disadvantaged suburbs often have low quality and few amenities, which is likely to result in them being underutilised for recreation and physical activity. Refurbishment of parks, including shade, walking paths and other amenities, may have broad health-related benefits. METHODS AND ANALYSIS: The study design, methods and planned analyses for a natural experiment examining the effects of refurbishments including built-shade added to parks in disadvantaged outer suburbs of Melbourne are described. Three intervention parks and three comparison parks matched for equivalence of park and neighbourhood characteristics were selected. Using mixed methods, the outcomes will be assessed during three consecutive spring-summer periods (T1: 2013-2014; T2: 2014-2015: T3: 2015-2016). Primary outcomes included: observed park use, physical activity and shade use. Self-reported social connectedness, community engagement and psychological well-being were assessed as secondary outcomes. ETHICS AND DISSEMINATION: This study was approved by Cancer Council Victoria's Human Research Ethics Committee. Studies such as ShadePlus can improve understanding of the broader effects of park refurbishments (including physical activity levels and sun protection behaviours, as well as social connectedness and psychological well-being). The study findings will be disseminated through established urban planning and parks and recreation networks, peer review publications and conference presentations.

Total and beverage-specific alcohol intake and the risk of aggressive prostate cancer: a case-control study.

BACKGROUND: Ethanol in alcoholic beverages is a known carcinogen, but its association with aggressive prostate cancer (APC) is uncertain. Recent studies have shown a modest increase in risk of APC associated with heavy alcohol intake while association for beverage types remain inconsistent. METHODS: Using a case-control design and self-administered questionnaire, we examined the association between APC (high grade and/or advanced stage) and frequency and quantity of alcohol intake 2 years prior to enrolment. Furthermore, we delineated the relationships for beverage-specific intakes of beer, red wine, white wine and spirits. RESULTS: The study included 1282 APC cases and 951 controls. Beer intake frequency of ⩾5 days per week was associated with increased risk compared with no beer intake (odds ratio=1.66, 95% confidence interval: 1.12-2.48) whereas wine was protective at all frequencies of consumption compared with those with no wine intake. For every 10 g per week ethanol intake from beer increase, the odds of advanced PC rose by 3% (OR=1.03, 95% CI: 1.02-1.05). No such increased risk was observed for red or white wine while a marginal dose-response relationship was found for spirits (OR=1.03, 95% CI: 0.99-1.07). CONCLUSIONS: Heavy beer and possibly spirits consumption is associated with increased risk while no dose-response relationship was found for red or white wine. Wine drinkers at all frequencies have a decreased risk of APC compared with those who did not drink wine.

Prospective validation of the breast cancer risk prediction model BOADICEA and a batch-mode version BOADICEACentre.

BACKGROUND: Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) is a risk prediction algorithm that can be used to compute estimates of age-specific risk of breast cancer. It is uncertain whether BOADICEA performs adequately for populations outside the United Kingdom. METHODS: Using a batch mode version of BOADICEA that we developed (BOADICEACentre), we calculated the cumulative 10-year invasive breast cancer risk for 4176 Australian women of European ancestry unaffected at baseline from 1601 case and control families in the Australian Breast Cancer Family Registry. Based on 115 incident breast cancers, we investigated calibration, discrimination (using receiver-operating characteristic (ROC) curves) and accuracy at the individual level. RESULTS: The ratio of expected to observed number of breast cancers was 0.92 (95% confidence interval (CI) 0.76-1.10). The E/O ratios by subgroups of the participant's relationship to the index case and by the reported number of affected relatives ranged between 0.83 and 0.98 and all 95% CIs included 1.00. The area under the ROC curve was 0.70 (95% CI 0.66-0.75) and there was no evidence of systematic under- or over-dispersion (P=0.2). CONCLUSION: BOADICEA is well calibrated for Australian women, and had good discrimination and accuracy at the individual level.

Effect of physical activity and body size on survival after diagnosis with colorectal cancer.

BACKGROUND: Physical inactivity and obesity increase the risk of colorectal cancer but little is known about whether they influence prognosis after diagnosis. METHODS: Incident cases of colorectal cancer were identified among participants of the Melbourne Collaborative Cohort Study, a prospective cohort study of 41 528 Australians recruited from 1990 to 1994. Participants diagnosed with their first colorectal cancer between recruitment and 1 August 2002 were eligible. At the time of study entry, body measurements were taken and participants were interviewed about their physical activity. Information on tumour site and stage, treatments given, recurrences, and deaths were obtained from systematic review of the medical records. RESULTS: A total of 526 cases of colorectal cancer were identified. Median follow up among survivors was 5.5 years, and 208 deaths had occurred, including 181 from colorectal cancer. After adjusting for age, sex, and tumour stage, exercisers had an improved disease specific survival (hazard ratio 0.73 (95% confidence interval (CI) 0.54-1.00)). The benefit of exercise was largely confined to stage II-III tumours (hazard ratio 0.49 (95% CI 0.30-0.79)). Increasing per cent body fat resulted in an increase in disease specific deaths (hazard ratio 1.33 per 10 kg (95% CI 1.04-1.71)). Similarly, increasing waist circumference reduced disease specific survival (hazard ratio 1.20 per 10 cm (95% CI 1.05-1.37)). CONCLUSIONS: Increased central adiposity and a lack of regular physical activity prior to the diagnosis of colorectal cancer is associated with poorer overall and disease specific survival.

Physical activity, insulin-like growth factor 1, insulin-like growth factor binding protein 3, and survival from colorectal cancer.

BACKGROUND: Recent reports have shown that physical activity improves the outcome of patients with colorectal cancer as well as breast and prostate cancer. However, the mechanisms whereby physical activity reduces cancer mortality are not well established. METHODS: Incident cases of colorectal cancer were identified among participants of the Melbourne Collaborative Cohort Study, a prospective cohort study of 41,528 Australians recruited from 1990 to 1994. Information on tumour site and stage, treatments given, recurrences, and deaths were obtained from systematic review of the medical records. Baseline assessments of physical activity and body size were made, and cases with available plasma had pre-diagnosis insulin-like growth factor 1 (IGF-1) and insulin-like growth factor binding protein 3 (IGFBP-3) levels measured. We assessed associations between these hormones and colorectal cancer specific deaths with respect to physical activity. RESULTS: A total of 526 cases of colorectal cancer were identified, of which 443 had IGF-1/IGFBP-3 levels measured. Median follow up among survivors was 5.6 years. For the physically active, increasing IGFBP-3 by 26.2 nmol/l was associated with a 48% reduction in colorectal cancer specific deaths (adjusted hazard ratio (HR) 0.52 (0.33-0.83); p = 0.006). No association was seen for IGF-1 (adjusted HR 0.90 (0.55-1.45); p = 0.65). For the physically inactive, neither IGF-1 nor IGFBP-3 was associated with disease specific survival. CONCLUSIONS: This study supports the hypothesis that the beneficial effects of physical activity in reducing colorectal cancer mortality may occur through interactions with the insulin-like growth factor axis and in particular IGFBP-3.

A comparison of estradiol levels between women with a hysterectomy and ovarian conservation and women with an intact uterus.

OBJECTIVES: To compare the distribution of estradiol levels between women with a hysterectomy and ovarian conservation and women with an intact uterus. METHODS: A large cross-sectional study of women aged between 40 and 69 years, residing in Melbourne, Australia. Estradiol levels were available for 152 women with a hysterectomy and ovarian conservation and 1423 women with an intact uterus. All of the women were 'never-users' of hormone replacement therapy. RESULTS: For women under 55 years of age, we observed that those with a hysterectomy and ovarian conservation had slightly higher estradiol levels compared with those with an intact uterus after adjustment for age, body mass index, smoking status and alcohol intake (ratio of geometric means of estradiol levels = 1.24; 95% confidence interval = 1.00-1.53). For women who were 55 years or greater, the distribution of estradiol levels varied little by hysterectomy status. CONCLUSIONS: Our data do not suggest that women with hysterectomy and ovarian conservation have markedly different estradiol levels compared to women with an intact uterus.

Determinants of bone density in 30- to 65-year-old women: a co-twin study.

UNLABELLED: Reported effects of body composition and lifestyle on bone mineral density in pre-elderly adult women have been inconsistent. In a co-twin study, we measured bone mineral density, lean and fat mass, and lifestyle factors. Analyzing within pair differences, we found negative associations between bone mineral density and tobacco use (2.3-3.3% per 10 pack-years) and positive associations with sporting activity and lean and fat mass. INTRODUCTION: Reported effects of body composition and lifestyle of bone mineral density in pre-elderly adult women have been inconsistent. METHODS: In a co-twin study of 146 female twin pairs aged 30 to 65 years, DXA was used to measure bone mineral density at the lumbar spine, total hip, and forearm, total body bone mineral content, and lean and fat mass. Height and weight were measured. Menopausal status, dietary calcium intake, physical activity, current tobacco use, and alcohol consumption were determined by questionnaire. Within-pair differences in bone measures were regressed through the origin against within-pair differences in putative determinants. RESULTS: Lean mass and fat mass were associated with greater bone mass at all sites. A discordance of 10 pack-years smoking was related to a 2.3-3.3% (SE, 0.8-1.0) decrease in bone density at all sites except the forearm, with the effects more evident in postmenopausal women. In all women, a 0.8% (SE, 0.3) difference in hip bone mineral density was associated with each hour per week difference in sporting activity, with effects more evident in premenopausal women. Daily dietary calcium intake was related to total body bone mineral content and forearm bone mineral density (1.4 +/- 0.7% increase for every 1000 mg). Lifetime alcohol consumption and walking were not consistently related to bone mass. CONCLUSION: Several lifestyle and dietary factors, in particular tobacco use, were related to bone mineral density. Effect sizes varied by site. Characterization of determinants of bone mineral density in midlife and thereafter may lead to interventions that could minimize postmenopausal bone loss and reduce osteoporotic fracture risk.

Changes in body composition as determinants of longitudinal changes in bone mineral measures in 8 to 26-year-old female twins.

Between 1990 and 1998, we conducted a longitudinal study of 286 female twins aged 8 to 25 years at baseline (60 monozygotic (MZ) pairs, 44 dizygotic (DZ) pairs and 78 unpaired twins), measured on average 2.4 times (range 2-6) with an average of 1.8 years between measurements (range 0.7-6.7 years). Areal bone mineral density (ABMD) at the lumbar spine, total hip and femoral neck, total body bone mineral content (BMC), total body soft tissue composition (lean mass and fat mass) were measured by dual-energy X-ray absorptiometry, and height and menarchial status were also recorded. Median annual changes in height were negligible at 4 years post-menarche. During the 'linear growth' period up to 4 years post-menarche, ABMD at the lumbar spine, total hip and femoral neck increased with annual change in lean mass by 1.7 (S.E.0.1), 1.4 (0.1) and 1.0 (0.1) percent per kilogram per year, respectively (all p<0.001), independently of changes in fat mass or height. During the 'post-linear growth' period, ABMD at the total hip and femoral neck increased with annual change in fat mass by 0.3 (0.1) and 0.5 (0.1) percent per kilogram per year (all p < 0.01), independent of change in lean mass. Annual changes in total body BMC were associated with annual changes in lean mass (1.9 (0.2) percent per kilogram), in fat mass (1.3 (0.2) percent per kilogram) and in height (0.7) (0.2) percent per centimeter) during linear growth, and in fat mass (1.0 (0.1)) and lean mass (0.6 (0.1)) percent per kilogram post-linear growth (all p < 0.001). We conclude that changes in bone mineral measures are strongly associated with changes in lean mass during linear growth, while post-linear growth, changes in fat mass are the predominant, although weaker, predictor. These findings suggest that the strong cross-sectional association between bone mineral measures and lean mass is established during growth and development, and that fat mass emerges as a more powerful determinant of bone change in healthy adult females.

ACE inhibitors, beta-blockers, calcium blockers, and diuretics for the control of systolic hypertension.

The objective of this study was to determine which of the common groups of antihypertensive drugs is most effective at lowering systolic blood pressure (SBP) in elderly patients with previously untreated hypertension and the percentage of patients controlled with single or sequential monotherapy. Subjects were recruited from patients attending other outpatient clinics and entered into the study if their SBP was more than 150 mm Hg after three visits. Patients were given a low and high dose of each of the main classes of drugs or placebo for 1 month each. The study was a balanced, randomized crossover design with five periods: placebo; angiotensin converting enzyme inhibitors; beta-blocking drugs; calcium-blocking drugs; and thiazide diuretics. Blood pressure (BP) was measured 24 to 26 h after the previous dose. A questionnaire for side effects was administered at each visit. Seventy-four patients entered the study. beta-Blockers could not be used in 15 patients because of asthma or bronchospasm and these had two placebo periods. There were 9 of 66 patients on P, 9 of 46 on beta-blockers, 4 of 65 on calcium-blocking drugs, 4 of 65 on diuretic, and 1 of 62 patients on ACE inhibitors who did not progress to the higher dose because of side effects. Decreases in SBP compared to randomized placebo were calcium-blocking drugs 15 mm Hg = diuretic 13 mm Hg > ACE inhibitors 8 mm Hg = beta-blockers 5 mm Hg. Blood pressure decrease correlated with placebo BP (P < .0005, r = 0.53 to 0.70). When corrected for placebo, target SBP (<140 mm Hg) was reached in between 6% to 15% of patients on monotherapy. Sequential monotherapy achieved target in 29%. Angiotensin converting enzyme inhibitors, calcium-blocking drugs, and diuretics had no more side effects than placebo. Patients on beta-blockers had more side effects and the well-being score was reduced. Diuretics and calcium-blocking drugs are more effective in elderly patients at lowering SBP pressure. beta-Blockers were relatively ineffective, were frequently contraindicated, and had more side effects. Monotherapy achieved control in only a small number of patients. In elderly people with essential hypertension, therapy should be instituted with diuretics or calcium-blocking drugs, but combination therapy will usually be required to achieve goal.

Association of birth weight and current body size to blood pressure in female twins.

It has been proposed that low birth weight is associated with high levels of blood pressure in later life. The aim of this study was to assess the relationship of blood pressure to birth weight and current body size during growth and adulthood. A total of 711 female multiple births, with one group of 244 in their growth phase mean age 12.0 (2.3)(SD) years and the other of 467 adults (mean age 35.2 (12.6) years), had height, weight and both systolic (SBP) and diastolic (DBP) blood pressures measured, and self-reported their birth weight. Regression analyses were performed to assess the cross-sectional and within-pair associations of blood pressure to birth weight, with and without adjustments for current body size. Within-pair analysis was based on 296 twin pairs. Cross-sectionally, a reduction in birth weight of 1 kg was associated with 2 to 3 mm Hg higher age-adjusted SBP, which was of marginal significance and explained about 2% of the population variance. Adjustment for body mass index did not significantly change this association. Within-pair analyses found no association between birth weight and SBP or DBP,even after adjusting for current body size. After age, current body size was the strongest predictor of systolic BP. The weak association of blood pressure to birth weight cross-sectionally is of interest, but any within-pair effect of birth weight on blood pressure must be minimal compared with the effect of current body size.