Benefits and harms of prostate specific antigen testing according to Australian guidelines.

Guidelines for prostate specific antigen (PSA) testing in Australia recommend that men at average risk of prostate cancer who have been informed of the benefits and harms, and who decide to undergo regular testing, should be offered testing every 2 years from 50 to 69 years. This study aimed to estimate the benefits and harms of regular testing in this context. We constructed Policy1-Prostate, a discrete event microsimulation platform of the natural history of prostate cancer and prostate cancer survival, and PSA testing patterns and subsequent management in Australia. The model was calibrated to pre-PSA (before 1985) prostate cancer incidence and mortality and validated against incidence and mortality trends from 1985 to 2011 and international trials. The model predictions were concordant with trials and Australian observed incidence and mortality data from 1985 to 2011. Out of 1000 men who choose to test according to the guidelines, 36 [21-41] men will die from prostate cancer and 126 [119-133] men will be diagnosed with prostate cancer, compared with 50 [47-54] and 94 [90-98] men who do not test, respectively. During the 20 years of active PSA testing, 32.3% [25.6%-38.8%] of all PSA-test detected cancers are overdiagnosed cases that is, 30 [21-42] out of 94 [83-107] PSA-test detected cancers. Australian men choosing to test with PSA every two years from 50 to 69 will reduce their risk of ever dying from prostate cancer and incur a risk of overdiagnosis: for every man who avoids dying from prostate cancer, two will be overdiagnosed with prostate cancer between 50 and 69 years of age. Australian men, with health professionals, can use these results to inform decision-making about PSA testing.

Cutaneous melanoma, prostate-specific antigen testing and the subsequent risk of prostate cancer diagnosis: a prospective analysis of the 45 and Up Study.

BACKGROUND: The association between cutaneous melanoma and subsequent risk of prostate cancer (PC) was examined in a large population-based cohort study. METHODS: Male participants in the Sax Institute's 45 and Up Study (Australia) were recruited between 2006 and 2009. Questionnaire data and linked administrative health data from the Centre for Health Record Linkage and Services Australia identified melanomas diagnosed between 1/1/1994 and 12 months before Study recruitment (i.e., between 2005 and 2008), incident PCs, primary healthcare utilisation and prostate-specific antigen (PSA) tests. Men were excluded from the current analyses if they had a recorded PC or other cancer diagnosis other than melanoma and non-melanoma skin cancer prior to recruitment. Multivariable Cox regression was used to estimate hazard ratios (HRs) adjusting for PSA-testing frequency before PC diagnosis. RESULTS: Of 96,548 eligible men, 1899 were diagnosed with melanoma during the melanoma diagnosis period and 3677 incident PC diagnosed during follow-up (latest date 31/12/2013). Men with melanoma diagnosis had increased risk of a subsequent PC diagnoses (vs. no melanoma; fully adjusted HR = 1.32; 95% CI: 1.09-1.60). There was weak evidence of higher risks of a subsequent PC diagnosis for men diagnosed with more than one melanoma compared to men diagnosed with only one melanoma (p = 0.077), and if first melanoma diagnosis was 10 to 15 years before Study recruitment (fully adjusted HR = 2.05; 95% CI [1.35, 3.12]). CONCLUSION: Melanoma diagnosis was associated with increased risk of subsequent PC diagnosis, after adjusting for PSA testing and primary healthcare utilisation. While our ability to adjust for PC screening reduced risk of detection bias, we acknowledge that residual confounding from increased medical surveillance after melanoma diagnoses cannot be entirely ruled out.

Family history, obesity, urological factors and diabetic medications and their associations with risk of prostate cancer diagnosis in a large prospective study.

BACKGROUND: Prostate cancer (PC) aetiology is unclear. PC risk was examined in relation to several factors in a large population-based prospective study. METHODS: Male participants were from Sax Institute's 45 and Up Study (Australia) recruited between 2006 and 2009. Questionnaire and linked administrative health data from the Centre for Health Record Linkage and Services Australia were used to identify incident PC, healthcare utilisations, Prostate Specific Antigen (PSA) testing reimbursements and dispensing of metformin and benign prostatic hyperplasia (BPH) prescriptions. Multivariable Cox and Joint Cox regression analyses were used to examine associations by cancer spread, adjusting for various confounders. RESULTS: Of 107,706 eligible men, 4257 developed incident PC up to end 2013. Risk of PC diagnosis increased with: PC family history (versus no family history of cancer; HRadjusted = 1.36; 95% CI:1.21-1.52); father and brother(s) diagnosed with PC (versus cancer-free family history; HRadjusted = 2.20; 95% CI:1.61-2.99); severe lower-urinary-tract symptoms (versus mild; HRadjusted = 1.77; 95% CI:1.53-2.04) and vasectomy (versus none; HRadjusted = 1.08; 95% CI:1.00-1.16). PC risk decreased with dispensed prescriptions (versus none) for BPH (HRadjusted = 0.76; 95% CI:0.69-0.85) and metformin (HRadjusted = 0.57; 95% CI:0.48-0.68). Advanced PC risk increased with vasectomy (HRadjusted = 1.28; 95% CI:1.06-1.55) and being obese (versus normal weight; HRadjusted = 1.31; 95% CI:1.01-1.69). CONCLUSION: Vasectomy and obesity are associated with an increased risk of advanced PC. The reduced risk of localised and advanced PC associated with BPH, and diabetes prescriptions warrants investigation.

Physical activity, obesity and sedentary behaviour and the risks of colon and rectal cancers in the 45 and up study.

BACKGROUND: Obesity and physical activity (PA) are predictors of colon (CC) and rectal (RC) cancers. Prolonged sitting is also emerging as a potential predictor for these cancers. Little knowledge exists about the interactive effects of obesity, PA and prolonged sitting on cancer risk. This analysis assessed independent and interactive effects of PA, body mass index (BMI) and sitting time on CC and RC risks. METHODS: This analysis used data from a prospective study of 226,584 participants aged 45 years and over in New South Wales (NSW), Australia, who joined the 45 and Up study between 2006 and 2009. Baseline data were linked with data relating to mortality, cancer registration, hospital admission and Department of Human Services to December 2010. Multivariable Cox regression was used to estimate adjusted hazard ratios (referred to as relative risks, RRs) and 95% confidence intervals (Cis). Statistical significance was defined as p < 0.05. RESULTS: There were 846 and 369 ascertained cases of CC and RC. BMI was positively associated with CC risk (p = 0.003, P-trend = 0.0006) but not with RC. CC risk was increased in participants in the highest BMI quartile (≥29.4-≤50 kg/m2) compared to the lowest (15- < 23.6 kg/m2), (RR = 1.32, 95% CI:1.08-1.63). PA was associated with CC risk (p = 0.02) but not with RC. Specifically, CC risk was lower in individuals partaking in any amount of vigorous activity (time/week) compared to participants with no engagement (RR = 0.78, 95% CI:0.65-0.93). Sitting time was not associated with CC or RC. We found no evidence of interactive effects of PA, BMI and prolonged sitting on cancer risk. CONCLUSION: This evidence suggests that a healthy weight and vigorous activity are essential to reduce CC risk since these factors may be independent of each other.

Adult body size, sexual history and adolescent sexual development, may predict risk of developing prostate cancer: Results from the New South Wales Lifestyle and Evaluation of Risk Study (CLEAR).

Prostate cancer (PC) is the most common non-cutaneous cancer in men worldwide. The relationships between PC and possible risk factors for PC cases (n = 1,181) and male controls (n = 875) from the New South Wales (NSW) Cancer, Lifestyle and Evaluation of Risk Study (CLEAR) were examined in this study. The associations between PC risk and paternal history of PC, body mass index (BMI), medical conditions, sexual behaviour, balding pattern and puberty, after adjusting for age, income, region of birth, place of residence, and PSA testing, were examined. Adjusted risk of PC was higher for men with a paternal history of PC (OR = 2.31; 95%CI: 1.70-3.14), personal history of prostatitis (OR = 2.30; 95%CI: 1.44-3.70), benign prostatic hyperplasia (OR = 2.29; 95%CI: 1.79-2.93), being overweight (vs. normal; OR = 1.24; 95%CI: 0.99-1.55) or obese (vs. normal; OR = 1.44; 95%CI: 1.09-1.89), having reported more than seven sexual partners in a lifetime (vs. < 3 partners; OR = 2.00; 95%CI: 1.49-2.68), and having reported more than 5 orgasms a month prior to PC diagnosis (vs. ≤3 orgasms; OR = 1.59; 95%CI: 1.18-2.15). PC risk was lower for men whose timing of puberty was later than their peers (vs. same as peers; OR = 0.75; 95%CI: 0.59-0.97), and a smaller risk reduction of was observed in men whose timing of puberty was earlier than their peers (vs. same as peers; OR = 0.85; 95%CI: 0.61-1.17). No associations were found between PC risk and vertex balding, erectile function, acne, circumcision, vasectomy, asthma or diabetes. These results support a role for adult body size, sexual activity, and adolescent sexual development in PC development.

The relationship between solar UV exposure, serum vitamin D levels and serum prostate-specific antigen levels, in men from New South Wales, Australia: the CHAMP study.

PURPOSE: We aim to determine the relationship between season, personal solar UV exposure, serum 25(OH)D and 1,25(OH)2D and serum prostate-specific antigen (PSA) levels. METHODS: Questionnaire data and blood samples were collected at baseline from participants of the Concord Health and Ageing in Men Project (n = 1,705), aged 70 and above. They were grouped as men 'free of prostate disease' for those with no record of having prostate cancer, benign prostatic hyperplasia, or prostatitis and with serum PSA levels below 20 ng/mL, and 'with prostate disease' for those with a record of either of these diseases or with serum PSA levels 20 ng/mL or above. Personal solar UV exposure (sUV) was estimated from recalled hours of outdoor exposure and weighted against ambient solar UV radiation. Sera were analysed to determine levels of PSA, 25(OH)D and 1,25(OH)2D, and analysed using multiple regression, adjusting for age, BMI and region of birth. RESULTS: The association between sUV and serum PSA levels was conditional upon season (p interaction = 0.04). There was no direct association between serum PSA and 25(OH)D in both groups of men. There was a positive association between serum PSA and 1,25(OH)2D in men with prostate disease (mean = 110.6 pmol/L; p heterogeneity = 0.03), but there was no such association in men free of prostate disease (mean = 109.3 pmol/L; p heterogeneity = 0.8). CONCLUSION: The association between PSA and sUV may only be evident at low solar UV irradiance, and this effect may be independent of serum vitamin D levels.

Descriptive analysis of prostate cancer pathology data from diagnosis and surgery in men from the 45 and Up Study.

Information available from the New South Wales Cancer Registry (NSWCR) about the aggressiveness of prostate cancer is limited to the summary stage variable 'degree of spread', which contains a high proportion of cases defined as 'unknown'. In this study we demonstrate the feasibility of obtaining and analysing prostate cancer pathology data from stored pathology records. Pathology data were extracted from stored pathology records of incident prostate cancer cases in men participating in the 45 and Up Study, a large Australian prospective cohort study, who were diagnosed between January 2006 and December 2013. Baseline questionnaires from the 45 and Up Study were linked to the NSWCR. Demographic and pathology items were tabulated and associations described. We evaluated the completeness of pathological characteristics by degree of spread of cancer at diagnosis. Among the 123,921 men enrolled in the 45 and Up Study, 5,091 had incident prostate cancer and 5,085 were linked to a pathology record. The most complete variables included grade group of diagnostic (85.8%) and surgical (99.8%) specimens, margin status (98.1%), extraprostatic extension (95.1%) and seminal vesicle invasion (96.8%). Most diagnostic specimens were grade group 1 (26.6%) or 2 (23.5%). Of the 5,085 cases, 30.8% were classified by the NSWCR with unknown degree of spread; a pathology record could be extracted for 99.4% of these. The unknown degree of spread cases had similar levels of completeness and distribution of diagnostic and surgical pathology features to those with a localised degree of spread. This study demonstrated the feasibility of obtaining and analysing data derived from pathology reports from centralised state-based cancer registry notifications. Supplementing degree of spread information with pathology data from diagnosis and surgery will improve both the quality of research and policy aimed at improving the lives of men with prostate cancer.

The association of ultraviolet radiation-B (305 nm), season of diagnosis, and latitude on the survival outcome of prostate cancer in the high UV environment of Australia.

BACKGROUND: Positive associations between sun exposure and cancer survival have been observed in regions of high latitudes, where ambient solar ultraviolet (SUV) radiation is generally low. PURPOSE: We examined the effects of ambient ultraviolet-B radiation (UVB) at time of diagnosis, season of diagnosis and latitude of residence on survival outcome from prostate cancer. METHOD: Regression models for relative survival were used to estimate relative excess risks (RER) of death after diagnosis of prostate cancer from cancer registries in Eastern Australia (Queensland, New South Wales, Victoria and Tasmania). RESULTS: Relative excess risks was increased with diagnosis in summer (RER = 1.20; 95 % CI 1.14-1.26) relative to winter, high ambient UVB at the time of diagnosis (>60 mW/m(2); RER = 1.10; 95 % CI 1.05-1.15) relative to low SUV (<30 mW/m(2)), and with residence in high latitudes (35°S-43°S; RER = 1.20; 95 % CI 1.14-1.26) relative to low latitudes (9°S-29.9°S). RER was highest for summer diagnosis in all three latitude bands, after adjusting for age, follow-up period, and socioeconomic status. CONCLUSION: The contradictory outcome from season and latitude suggests that their use as surrogates for UV warrants validation. Our data suggest that high ambient solar ultraviolet radiation at the time of diagnosis of prostate cancer increases the risk of dying from this cancer.

Alcohol consumption and socioeconomic status associated with the risk of kidney cancer in a large Australian cohort study.

PURPOSE: Studies have shown an inverse association between alcohol consumption and kidney cancer risk. We postulate that this inverse association may be further influenced by other risk factors. METHODS: We used an Australian cohort, the 45 and Up Study, recruited between 2005 and 2009 to investigate the association between alcohol consumption, and other potential risk factors and kidney cancer incidence. The median follow-up was 5.4 years. RESULTS: Of the 267,357 participants aged ≤45 years living in New South Wales, 497 were diagnosed with kidney cancer. There was a significant inverse association between alcohol consumption and risk of kidney cancer (P = .027), and a significant inverse dose-response relationship (P = .011). There was a significant interaction between alcohol consumption and socioeconomic status (P interaction = .001). Participants residing in higher socioeconomic areas (the two most advantaged quintiles) who consumed 8-10 drinks or greater than 10 drinks per week, respectively, had a lower risk of kidney cancer compared to the group who consumed 1-4 drinks per week (hazard ratio (HR) 0.34, 95% confidence interval (CI) 0.15-0.76, HR 0.51, 95% CI 0.31-0.83) with a dose-response trend of HR 0.62 (95% CI 0.42-0.93) per 7 drink increase in weekly alcohol consumption. CONCLUSIONS: There could be an inverse association between alcohol consumption and risk in those residents in higher socioeconomic areas.

Sun exposure may increase risk of prostate cancer in the high UV environment of New South Wales, Australia: a case-control study.

Ultraviolet (UV) radiation in sunlight may influence risk of prostate cancer. In New South Wales (NSW), Australia, we examined the relationship between sun exposure at 30 and 50 years of age and risk of prostate cancer in a case-control study combining the NSW prostate cancer care and outcome study (cases) and the NSW non-Hodgkin's lymphoma study (controls). Prostate cancer risk increased with increasing estimated sun exposure (adjusted OR for highest vs. lowest quartiles of average weekly sun exposure in the warmer months 2.07 95% CI: 1.36-3.15) and this increase was most evident with weekend sun exposure (adjusted OR=5.55, 95% CI: 2.94-10.48). High sun sensitivity was also positively associated with risk for prostate cancer (adjusted OR=1.63, 95% CI: 1.09-2.44). The apparent effects of weekly sun exposure did not vary by disease aggressiveness. Our results suggest that increasing sun exposure in mid-adult years increases prostate cancer risk in a high ambient solar UV environment. Given that previous studies, conducted mainly in low solar UV environments, have generally found evidence of a negative association, our findings suggest there may be a U-shaped relationship between solar UV exposure and prostate cancer. Further studies are needed to test the hypothesis that high solar UV exposure is a risk factor for prostate cancer and to explore possible mechanisms for such an association.

Sunlight and vitamin D affect DNA damage, cell division and cell death in human lymphocytes: a cross-sectional study in South Australia.

The ultraviolet (UV)-B spectrum in solar UV radiation is essential for stimulating the epidermal production of vitamin D but also damages DNA and causes cancer in exposed cells. We examined the role of solar UV in inducing DNA damage in blood lymphocytes and the possible modulation of this damage by serum 25-hydroxy vitamin D (25(OH)D) in 207 male and female participants from South Australia. Personal solar UV exposure was estimated from hours of outdoor exposure recalled at the time of blood collection for analysis of DNA damage in lymphocytes, using the cytokinesis-block micronucleus cytome (CBMN-cyt) assay and of serum 25(OH)D. We examined the association between solar UV exposure, serum 25(OH)D and DNA damage using multiple linear regression, with age, sex, body mass index and alcohol consumption as covariates. The frequency of cells with micronuclei (a biomarker of chromosome breakage or loss) increased with increasing sun exposure [% increase = 5.24; 95% confidence interval (CI): 0.35 to 10.37 P-value = 0.04] but cells with nucleoplasmic bridges (a biomarker of misrepair of DNA strand breaks or telomere end fusions) decreased (% increase = -8.38; 95% CI: -14.32 to -2.03 P-value = 0.01). There was also a fall in the nuclear division index (NDI) (% increase = -1.01; 95% CI: -2.00 to 0.00 P-value = 0.05), suggesting diminished mitogenic response and, possibly, immune suppression. There was no overall relationship between 25(OH)D and DNA damage. There were, however, weak modulating effects of 25(OH)D on the associations of solar UV exposure with micronucleus formation and with NDI (P-interaction = 0.03 and 0.05, respectively), where the increase in micronuclei and fall in NDI with increasing solar UV were greater at serum 25(OH)D levels <50 nmol/l. Thus, the influence of solar UV exposure in causing DNA damage or immune suppression in internal tissues may be stronger when vitamin D levels are low.

Does vitamin D protect against DNA damage?

Vitamin D is a secosteroid best known for its role in maintaining bone and muscle health. Adequate levels of vitamin D may also be beneficial in maintaining DNA integrity. This role of vitamin D can be divided into a primary function that prevents damage from DNA and a secondary function that regulates the growth rate of cells. The potential for vitamin D to reduce oxidative damage to DNA in a human has been suggested by clinical trial where vitamin D supplementation reduced 8-hydroxy-2'-deoxyguanosine, a marker of oxidative damage, in colorectal epithelial crypt cells. Studies in animal models and in different cell types have also shown marked reduction in oxidative stress damage and chromosomal aberrations, prevention of telomere shortening and inhibition of telomerase activity following treatment with vitamin D. The secondary function of vitamin D in preventing DNA damage includes regulation of the poly-ADP-ribose polymerase activity in the DNA damage response pathway involved in the detection of DNA lesions. It is also able to regulate the cell cycle to prevent the propagation of damaged DNA, and to regulate apoptosis to promote cell death. Vitamin D may contribute to prevention of human colorectal cancer, though there is little evidence to suggest that prevention of DNA damage mediates this effect, if real. Very limited human data mean that the intake of vitamin D required to minimise DNA damage remains uncertain.

Socioeconomic differences in prostate cancer treatment: A systematic review and meta-analysis.

BACKGROUND: Since the 1990s, most nations have had a reduction or stabilisation in prostate cancer mortality. However, socioeconomic differences in disease specific mortality and survival have persisted. This has been partially attributed to differences in treatment choices. The aim of this systematic review and meta-analysis was to describe and quantify socioeconomic differences in use of prostate cancer treatment in the literature. METHODS: MEDLINE, CINAHL and Embase were searched from 01 January 2000-01 April 2021 to identify articles that reported use of prostate cancer treatment by socioeconomic status. Random effects meta-analysis was used to analyse socioeconomic differences in treatment where there was more than one study for treatment type. A modified version of the Newcastle-Ottawa Scale was used to assess risk of bias. RESULTS: Out of 7267 articles identified, eight met the inclusion criteria and six were analysed using meta-analysis. Meta-analysis could only be completed for non-active treatment (watchful waiting/active surveillance). Lower education was associated with non-active treatment (OR=0.90, [95% CI 0.83-0.98], p=0.02, I2=67%), however, level of income was not (OR=0.87, [CI 0.75-1.02], p=0.08, I2=94%). Sensitivity analysis of studies where active surveillance was the outcome (n=3), indicated no associations with level of income (OR=0.91, [95% CI 0.82-1.01], p=0.08, I2=52%) or education (OR=0.88, [95% CI 0.70-1.10], p=0.25, I2=79%). All studies were assessed as high-risk of bias. DISCUSSION: The relationship between socioeconomic status and prostate cancer treatment depended on the socioeconomic variable being used, the treatment type and how it was defined in research. Considerable methodological limitations were identified. Further research should improve on previous findings and address current gaps.

Large-scale systematic analysis of exposure to multiple cancer risk factors and the associations between exposure patterns and cancer incidence.

Exposures to cancer risk factors such as smoking and alcohol are not mutually independent. We aimed to identify risk factor exposure patterns and their associations with sociodemographic characteristics and cancer incidence. We considered 120,771 female and, separately, 100,891 male participants of the Australian prospective cohort 45 and Up Study. Factor analysis grouped 36 self-reported variables into 8 combined factors each for females (largely representing 'smoking', 'alcohol', 'vigorous exercise', 'age at childbirth', 'Menopausal Hormone Therapy', 'parity and breastfeeding', 'standing/sitting', 'fruit and vegetables') and males (largely representing 'smoking', 'alcohol', 'vigorous exercise', 'urology and health', 'moderate exercise', 'standing/sitting', 'fruit and vegetables', 'meat and BMI'). Associations with cancer incidence were investigated using multivariable logistic regression (4-8 years follow-up: 6193 females, 8749 males diagnosed with cancer). After multiple-testing correction, we identified 10 associations between combined factors and cancer incidence for females and 6 for males, of which 14 represent well-known relationships (e.g. bowel cancer: females 'smoking' factor Odds Ratio (OR) 1.16 (95% Confidence Interval (CI) 1.08-1.25), males 'smoking' factor OR 1.15 (95% CI 1.07-1.23)), providing evidence for the validity of this approach. The catalogue of associations between exposure patterns, sociodemographic characteristics, and cancer incidence can help inform design of future studies and targeted prevention programmes.

Characteristics Associated with the Use of Diagnostic Prostate Biopsy and Biopsy Outcomes in Australian Men.

BACKGROUND: Population characteristics associated with the use of prostate biopsy are poorly understood. We described the use of diagnostic prostate biopsy and subsequent biopsy outcomes in a population-based Australian cohort. METHODS: A total of 91,764 men from the Sax Institute's 45 and Up Study (New South Wales, Australia) recruited during 2006 to 2009 were included. Self-completed baseline questionnaires and linked administrative health data were used. Study period was from the date of recruitment to December 2013. Cox regression and logistic regression identified factors associated with receipt of biopsy and subsequent prostate cancer diagnosis. RESULTS: During the study period, 5,089 participants had a diagnostic prostate biopsy, and 2,805 men (55.1% of those biopsied) received a cancer diagnosis. Men with a family history of prostate cancer (HR 1.55; 95% confidence interval (CI), 1.43-1.68), severe lower urinary tract symptoms (HR 1.62; 95% CI, 1.41-1.86), or a record of medication for benign prostatic hyperplasia (HR 1.34; 95% CI, 1.23-1.47) had increased risks of receiving a biopsy. Men with a family history of prostate cancer had increased odds of a positive biopsy (OR 1.21; 95% CI, 1.01-1.43). High alcohol consumption (≥21 drinks per week compared with 1-6 drinks per week) was associated with decreased risk of biopsy (HR 0.88; 95% CI, 0.80-0.96) but increased odds of a positive biopsy (OR 1.63; 95% CI, 1.32-2.02). CONCLUSIONS: Certain characteristics are associated with both undertaking diagnostic prostate biopsy and positive biopsy outcomes. IMPACT: This highlights the need to improve management of specific groups of men, especially those with clinical symptoms that overlap with prostate cancer, in their investigation for prostate cancer.

High-dose vitamin D supplementation to prevent prostate cancer progression in localised cases with low-to-intermediate risk of progression on active surveillance (ProsD): protocol of a phase II randomised controlled trial.

INTRODUCTION: Active surveillance (AS) for patients with prostate cancer (PC) with low risk of PC death is an alternative to radical treatment. A major drawback of AS is the uncertainty whether a patient truly has low risk PC based on biopsy alone. Multiparametric MRI scan together with biopsy, appears useful in separating patients who need curative therapy from those for whom AS may be safe. Two small clinical trials have shown short-term high-dose vitamin D supplementation may prevent PC progression. There is no substantial evidence for its long-term safety and efficacy, hence its use in the care of men with PC on AS needs assessment. This protocol describes the ProsD clinical trial which aims to determine if oral high-dose vitamin D supplementation taken monthly for 2 years can prevent PC progression in cases with low-to-intermediate risk of progression. METHOD AND ANALYSIS: This is an Australian national multicentre, 2:1 double-blinded placebo-controlled phase II randomised controlled trial of monthly oral high-dose vitamin D supplementation (50 000 IU cholecalciferol), in men diagnosed with localised PC who have low-to-intermediate risk of disease progression and are being managed by AS. This trial will assess the feasibility, efficacy and safety of supplementing men with an initial oral loading dose of 500 000 IU cholecalciferol, followed by a monthly oral dose of 50 000 IU during the 24 months of AS. The primary trial outcome is the commencement of active therapy for clinical or non-clinical reason, within 2 years of AS. ETHICS AND DISSEMINATION: This trial is approved by Bellberry Ethics Committee (2016-06-459). All results will be reported in peer-reviewed journals. TRIAL REGISTRATION NUMBER: ACTRN12616001707459.

Post-treatment levels of plasma 25- and 1,25-dihydroxy vitamin D and mortality in men with aggressive prostate cancer.

Vitamin D may reduce mortality from prostate cancer (PC). We examined the associations of post-treatment plasma 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D concentrations with PC mortality. Participants were PC cases from the New South Wales Prostate Cancer Care. All contactable and consenting participants, at 4.9 to 8.6 years after diagnosis, were interviewed and had plasma 25-hydroxyvitamin D (25(OH)D) and 1,25-dihydroxyvitamin D (1,25(OH)2D) measured in blood specimens. Cox regression allowing for left-truncation was used to calculate adjusted mortality hazards ratios (HR) and 95% confidence intervals (95% CI) for all-cause and PC-specific mortality in relation to vitamin D levels and other potentially-predictive variables. Of the participants (n = 111; 75·9% response rate), there were 198 deaths from any cause and 41 from PC in the study period. Plasma 25(OH)D was not associated with all-cause or PC-specific mortality (p-values > 0·10). Plasma 1,25(OH)2D was inversely associated with all-cause mortality (HR for highest relative to lowest quartile = 0·45; 95% CI: 0·29-0·69), and PC-specific mortality (HR = 0·40; 95% CI: 0·14-1·19). These associations were apparent only in men with aggressive PC: all-cause mortality HR = 0·28 (95% CI·0·15-0·52; p-interaction = 0·07) and PC-specific mortality HR = 0·26 (95% CI: 0·07-1.00). Time spent outdoors was also associated with lower all-cause (HR for 4th relative to 1st exposure quartile = 0·42; 95% CI: 0·24-0·75) and PC-specific (HR = 0·48; 95% CI: 0·14-1·64) mortality, although the 95% CI for the latter was wide. The inverse association between post-treatment plasma 1,25(OH)2D levels and all-cause and PC-specific mortality in men with aggressive PC, suggest a possible beneficial effect of vitamin D supplementation in these men.

Sorting of a nonmuscle tropomyosin to a novel cytoskeletal compartment in skeletal muscle results in muscular dystrophy.

Tropomyosin (Tm) is a key component of the actin cytoskeleton and >40 isoforms have been described in mammals. In addition to the isoforms in the sarcomere, we now report the existence of two nonsarcomeric (NS) isoforms in skeletal muscle. These isoforms are excluded from the thin filament of the sarcomere and are localized to a novel Z-line adjacent structure. Immunostained cross sections indicate that one Tm defines a Z-line adjacent structure common to all myofibers, whereas the second Tm defines a spatially distinct structure unique to muscles that undergo chronic or repetitive contractions. When a Tm (Tm3) that is normally absent from muscle was expressed in mice it became associated with the Z-line adjacent structure. These mice display a muscular dystrophy and ragged-red fiber phenotype, suggestive of disruption of the membrane-associated cytoskeletal network. Our findings raise the possibility that mutations in these tropomyosin and these structures may underpin these types of myopathies.

Risk of Second Primary Cancer in Survivors of In Situ Melanoma.

Survivors of invasive melanoma have an increased risk of developing second primary cancers; however, similar risks associated with in situ melanoma have not been established. We evaluated 39,872 survivors of first primary in situ melanoma diagnosed from 1982 through 2012 in Queensland, Australia. Relative risk of second nonmelanoma primary cancers was estimated from standardized incidence ratios with 95% confidence intervals. A total of 4,823 (12%) in situ melanoma survivors developed a second primary cancer. A small increased risk (6%) compared with the general population was found. In those younger than 50 years, risk was increased by 14% for all cancers combined. In situ melanoma survivors had significantly increased risks of developing lip, thyroid, pancreatic, and brain cancers and decreased risks of head and neck, and lung cancers. Male in situ melanoma survivors had a significantly increased risk of prostate cancer; female survivors had an increased risk of thyroid cancer and lymphoid leukemia. Findings indicate that in situ melanoma may predict the diagnosis of certain second primary cancers. This altered risk may be due to biological, behavioral, or genetic factors or increased medical surveillance, and it requires further investigation, particularly among people younger than 50 years.