Time to Diagnosis and Treatment for Ovarian Cancer and Associations with Outcomes: A Systematic Review.

Background: Ovarian cancer is commonly diagnosed symptomatically at an advanced stage. Better survival for early disease suggests improving diagnostic pathways may increase survival. This study examines literature assessing diagnostic intervals and their association with clinical and psychological outcomes. Methods: Medline, EMBASE, and EmCare databases were searched for studies including quantitative measures of at least one interval, published between January 1, 2000 and August 9, 2022. Interval measures and associations (interval, outcomes, analytic strategy) were synthesized. Risk of bias of association studies was assessed using the Aarhus Checklist and ROBINS-E tool. Results: In total, 65 papers (20 association studies) were included and 26 unique intervals were identified. Interval estimates varied widely and were impacted by summary statistic used (mean or median) and group focused on. Of Aarhus-defined intervals, patient (symptom to presentation, n = 23; range [median]: 7-168 days) and diagnostic (presentation to diagnosis, n = 22; range [median]: 7-270 days) were most common. Nineteen association studies examined survival or stage outcomes with most, including five low risk-of-bias studies, finding no association. Conclusions: Studies reporting intervals for ovarian cancer diagnosis are limited by inconsistent definitions and reporting. Greater utilization of the Aarhus statement to define intervals and appropriate analytic methods is needed to strengthen findings from future studies.

Biased effects of pre-diagnostic physical activity on breast cancer survival: Systematic review and meta-analysis.

BACKGROUND: Pre-diagnostic physical activity is reported to improve survival for women with breast cancer. However, studies of pre-diagnostic exposures and cancer survival are susceptible to bias, made clear when applying a target trial framework. We investigated the impact of selection bias, immortal time bias, confounding and bias due to inappropriate adjustment for post-exposure variables in a systematic review and meta-analysis of pre-diagnostic physical activity and survival after breast cancer. METHODS: Medline, Embase and Emcare were searched from inception to November 2021 for studies examining pre-diagnostic physical activity and overall or breast cancer-specific survival for women with breast cancer. Random-effects meta-analysis was used to estimate pooled hazard ratios (HRs) and 95% confidence intervals (CIs) comparing highest versus lowest pre-diagnostic physical activity. Subgroup meta-analyses were used to compare HRs of studies with and without different biases. ROBINS-E was used to assess risk of bias. RESULTS: We included 22 studies. Women with highest versus lowest pre-diagnostic physical activity had higher overall and breast cancer-specific survival across most analyses. The overall risk of bias was high. We observed marked differences in estimated HRs between studies that did and did not adjust for post-exposure variables or have immortal time bias. All studies were at risk of selection bias due to participants becoming eligible for study when they have survived to post-exposure events (e.g., breast cancer diagnosis). Insufficient studies were available to investigate confounding. CONCLUSION: Biases can substantially change effect estimates. Due to misalignment of treatment assignment (before diagnosis), eligibility (survival to post-exposure events) and start of follow-up, bias is difficult to avoid. It is difficult to lend a causal interpretation to effect estimates from studies of pre-diagnostic physical activity and survival after cancer. Biased effect estimates that are difficult to interpret may be less useful for clinical or public health policy applications.

Sex-steroid hormones and risk of postmenopausal estrogen receptor-positive breast cancer: a case-cohort analysis.

PURPOSE: Sex-steroid hormones are associated with postmenopausal breast cancer but potential confounding from other biological pathways is rarely considered. We estimated risk ratios for sex-steroid hormone biomarkers in relation to postmenopausal estrogen receptor (ER)-positive breast cancer, while accounting for biomarkers from insulin/insulin-like growth factor-signaling and inflammatory pathways. METHODS: This analysis included 1208 women from a case-cohort study of postmenopausal breast cancer within the Melbourne Collaborative Cohort Study. Weighted Poisson regression with a robust variance estimator was used to estimate risk ratios (RRs) and 95% confidence intervals (CIs) of postmenopausal ER-positive breast cancer, per doubling plasma concentration of progesterone, estrogens, androgens, and sex-hormone binding globulin (SHBG). Analyses included sociodemographic and lifestyle confounders, and other biomarkers identified as potential confounders. RESULTS: Increased risks of postmenopausal ER-positive breast cancer were observed per doubling plasma concentration of progesterone (RR: 1.22, 95% CI 1.03 to 1.44), androstenedione (RR 1.20, 95% CI 0.99 to 1.45), dehydroepiandrosterone (RR: 1.15, 95% CI 1.00 to 1.34), total testosterone (RR: 1.11, 95% CI 0.96 to 1.29), free testosterone (RR: 1.12, 95% CI 0.98 to 1.28), estrone (RR 1.21, 95% CI 0.99 to 1.48), total estradiol (RR 1.19, 95% CI 1.02 to 1.39) and free estradiol (RR 1.22, 95% CI 1.05 to 1.41). A possible decreased risk was observed for SHBG (RR 0.83, 95% CI 0.66 to 1.05). CONCLUSION: Progesterone, estrogens and androgens likely increase postmenopausal ER-positive breast cancer risk, whereas SHBG may decrease risk. These findings strengthen the causal evidence surrounding the sex-hormone-driven nature of postmenopausal breast cancer.

Sustained Hypothetical Interventions on Midlife Alcohol Consumption in Relation to All-Cause and Cancer Mortality: The Australian Longitudinal Study on Women's Health.

No randomized controlled trial has evaluated the effect of long-term alcohol interventions on mortality. Results reported in existing observational studies may be subject to selection bias and time-varying confounding. Using data from the Australian Longitudinal Study on Women's Health 1946-1951 birth cohort, collected regularly from 1996-2016, we estimated all-cause and cancer mortality had women been assigned various alcohol interventions (in categories ranging from 0 to >30 g/day ethanol, or reduced to ≤20 g/day if higher) at baseline, and had they maintained these levels of consumption. The cumulative risks for all-cause and cancer mortality were 5.6% (10,118 women followed for 20 years) and 2.9% (18 years), respectively. For all-cause and cancer mortality, baseline ethanol up to 30 g/day showed lower risk and >30 g/day showed higher risk relative to abstention. Had women sustainedly followed the interventions, a similar relationship was observed for all-cause mortality. However, the negative association observed for intakes ≤30 g/day and positive association for intakes >30 g/day was not evident for cancer mortality. Our findings suggest that all-cause mortality could have been lower than observed if this cohort of women had consumed some alcohol (no more than 30 g/day) rather than no consumption, but cancer mortality might not.

Do age at diagnosis, tumour thickness and tumour site explain sex differences in melanoma survival? A causal mediation analysis using cancer registry data.

Women diagnosed with melanoma have better survival than men, but little is known about potential intervention targets to reduce this survival gap by sex. We conducted a population-based study using Victorian Cancer Registry data including 5833 women and 6780 men aged 15 to 70 years when diagnosed with first primary melanoma between 2007 and 2015. Deaths to the end of 2020 were identified through linkage to the Victorian and national death registries. We estimated the effect of age at diagnosis, tumour thickness and tumour site on reducing the melanoma-specific survival gap by sex (ie, interventional indirect effects [IIEs]) on risk difference (RD) scale. Compared to women, there were 211 (95% CI: 145-278) additional deaths per 10 000 in men within 5 years following diagnosis. We estimated that 44% of this gap would be reduced by a hypothetical intervention shifting the distribution of melanoma thickness in men to be the same as that observed for women (IIEthickness RD 93 [95% CI: 75-118] per 10 000) and 20% by an intervention on tumour site (head and neck/trunk vs upper limb/lower limb; IIEsite RD 42 [95% CI: 15-72] per 10 000), while an intervention on age at diagnosis would have a negligible effect. Tumour thickness, tumour site and age at diagnosis mediated 65% of the effect of sex on 5-year melanoma survival in Victoria. Of these factors, tumour thickness had the most considerable mediating effect, suggesting that effective promotion of earlier detection of melanoma in men could potentially nearly halve the gap in melanoma-specific survival by sex.

National Health and Medical Research Council statement on electronic cigarettes: 2022 update.

INTRODUCTION: Electronic cigarette (e-cigarette) use in Australia has rapidly increased since the 2017 National Health and Medical Research Council (NHMRC) Chief Executive Officer (CEO) statement on e-cigarettes. The type of products available and the demographic characteristics of people using these products have changed. New evidence has been published and there is growing concern among public health professionals about the increased use, particularly among young people who do not currently smoke combustible cigarettes. The combination of these issues led NHMRC to review the current evidence and provide an updated statement on e-cigarettes. In this article, we describe the comprehensive process used to review the evidence and develop the 2022 NHMRC CEO statement on electronic cigarettes. MAIN RECOMMENDATIONS: E-cigarettes can be harmful; all e-cigarette users are exposed to chemicals and toxins that have the potential to cause adverse health effects. There are no health benefits of using e-cigarettes if you do not currently smoke tobacco cigarettes. Adolescents are more likely to try e-cigarettes if they are exposed to e-cigarettes on social media. Short term e-cigarette use may help some smokers to quit who have been previously unsuccessful with other smoking cessation aids. There are other proven safe and effective options available to help smokers to quit. CHANGES IN MANAGEMENT AS A RESULT OF THIS STATEMENT: The evidence base for the harms of e-cigarette use has strengthened since the previous NHMRC statement. Significant gaps in the evidence base remain, especially about the longer term health harms of using e-cigarettes and the toxicity of many chemicals in e-cigarettes inhaled as an aerosol.

Sunlight, vitamin D, vitamin D receptor polymorphisms, and risk of multiple myeloma: A systematic review.

This systematic review examines the relationship with multiple myeloma (MM) risk for sunlight and vitamin D related exposures, including vitamin D supplementation, circulating 25-hydroxyvitamin D concentration, personal ultraviolet B radiation exposure, ambient solar irradiance and vitamin D receptor (VDR) gene polymorphisms We conducted a search for terms related to multiple myeloma, vitamin D, vitamin D receptor, ultraviolet radiation, sunlight, and single nucleotide polymorphism (SNP) using Ovid MEDLINE, Ovid EMBASE, Web of Science and Cochrane CENTRAL. Studies were assessed for risk of bias and quality using the RoB 2.0, ROBINS-E or Q-Genie tools. We identified 13 eligible studies: one randomised controlled trial, two cohort studies, and ten case-control studies, including one nested case-control study and one meta-analysis of genome-wide association studies. We conducted a qualitative synthesis; quantitative synthesis was not appropriate due to study heterogeneity and the small number of studies identified. There was insufficient evidence to support an effect of any sunlight or vitamin D related exposure on MM risk. No polymorphisms in VDR were found to be strongly related to risk for people of European ancestry. Of the identified studies, many had high risk of bias or were of lower quality. Few studies have investigated the association between sunlight and vitamin D related exposures and multiple myeloma risk. The scarcity of high-quality studies makes it difficult to evaluate potential effects of these exposures on MM risk. Further research is necessary to investigate the influence of vitamin D related exposures on risk of multiple myeloma..

Sex-steroid hormones and risk of postmenopausal estrogen receptor-positive breast cancer: a case-cohort analysis.

Purpose: Sex-steroid hormones are associated with postmenopausal breast cancer but potential confounding from other biological pathways is rarely considered. We estimated risk ratios for sex-steroid hormone biomarkers in relation to postmenopausal estrogen receptor (ER)-positive breast cancer, while accounting for biomarkers from insulin/insulin-like growth factor-signaling and inflammatory pathways. Methods: This analysis included 1,208 women from a case-cohort study of postmenopausal breast cancer within the Melbourne Collaborative Cohort Study. Weighted Poisson regression with a robust variance estimator was used to estimate risk ratios (RRs) and 95% confidence intervals (CIs) of postmenopausal ER-positive breast cancer, per doubling plasma concentration of progesterone, estrogens, androgens, and sex hormone binding globulin (SHBG). Analyses included sociodemographic and lifestyle confounders, and other biomarkers identified as potential confounders. Results: Increased risks of postmenopausal ER-positive breast cancer were observed per doubling plasma concentration of progesterone (RR: 1.22, 95% CI: 1.03 to 1.44), androstenedione (RR: 1.20, 95% CI: 0.99 to 1.45), dehydroepiandrosterone (RR: 1.15, 95% CI: 1.00 to 1.34), total testosterone (RR: 1.11, 95% CI: 0.96 to 1.29), free testosterone (RR: 1.12, 95% CI: 0.98 to 1.28), estrone (RR: 1.21, 95% CI: 0.99 to 1.48), total estradiol (RR: 1.19, 95% CI: 1.02 to 1.39) and free estradiol (RR: 1.22, 95% CI: 1.05 to 1.41). A possible decreased risk was observed for SHBG (RR: 0.83, 95% CI: 0.66 to 1.05). Conclusion: Progesterone, estrogens and androgens likely increase postmenopausal ER-positive breast cancer risk, whereas SHBG may decrease risk. These findings strengthen the causal evidence surrounding the sex hormone-driven nature of postmenopausal breast cancer.

Modifiable lifestyle risk factors and survival after diagnosis with multiple myeloma.

BACKGROUND: While remaining incurable, median overall survival for MM now exceeds 5 years. Yet few studies have investigated how modifiable lifestyle factors influence survival. We investigate whether adiposity, diet, alcohol, or smoking are associated with MM-related fatality. RESEARCH DESIGN AND METHODS: We recruited 760 incident cases of MM via cancer registries in two Australian states during 2010-2016. Participants returned questionnaires on health and lifestyle. Follow-up ended in 2020. Flexible parametric survival models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for lifestyle exposures and risk of all-cause and MM-specific fatality. RESULTS: Higher pre-diagnosis Alternative Healthy Eating Index (AHEI) scores were associated with reduced MM-specific fatality (per 10-unit score, HR = 0.84, 95%CI = 0.70-0.99). Pre-diagnosis alcohol consumption was inversely associated with MM-specific fatality, compared with nondrinkers (0.1-20 g per day, HR = 0.59, 95%CI = 0.39-0.90; >20 g per day, HR = 0.67, 95%CI = 0.40-1.13). Tobacco smoking was associated with increased all-cause fatality compared with never smoking (former smokers: HR = 1.44, 95%CI = 1.10-1.88; current smokers: HR = 1.30, 95%CI = 0.80-2.10). There was no association between pre-enrollment body mass index (BMI) and MM-specific or all-cause fatality. CONCLUSIONS: Our findings support established recommendations for healthy diets and against smoking. Higher quality diet, as measured by the AHEI, may improve survival post diagnosis with MM.

Benefits and harms of breast cancer screening: Cohort study of breast cancer mortality and overdiagnosis.

BACKGROUND: Quantifying the benefits and harms of breast cancer screening accurately is important for planning and evaluating screening programs and for enabling women to make informed decisions about participation. However, few cohort studies have attempted to estimate benefit and harm simultaneously. AIMS: We aimed to quantify the impact of mammographic screening on breast cancer mortality and overdiagnosis using a cohort of women invited to attend Australia's national screening program, BreastScreen. METHODS: In a cohort of 41,330 women without prior breast cancer diagnosis, screening, or diagnostic procedures invited to attend BreastScreen Western Australia in 1994-1995, we estimated the cumulative risk of breast cancer mortality and breast cancer incidence (invasive and ductal carcinoma in situ) from age 50 to 85 years for attenders and non-attenders. Data were obtained by linking population-based state and national health registries. Breast cancer mortality risks were estimated from a survival analysis that accounted for competing risk of death from other causes. Breast cancer risk for unscreened women was estimated by survival analysis, while accounting for competing causes of death. For screened women, breast cancer risk was the sum of risk of being diagnosed at first screen, estimated using logistic regression, and risk of diagnosis following a negative first screen estimated from a survival analysis. RESULTS: For every 1,000 women 50 years old at first invitation to attend BreastScreen, there were 20 (95% CI 12-30) fewer breast cancer deaths and 25 (95% CI 15-35) more breast cancers diagnosed for women who attended than for non-attendees by age 85. Of the breast cancers diagnosed in screened women, 21% (95% CI 13%-27%) could be attributed to screening. DISCUSSION: The estimated ratio of benefit to harm was consistent with, but slightly less favourable to screening than most other estimates from cohort studies. CONCLUSION: Women who participate in organised screening for breast cancer in Australia have substantially lower breast cancer mortality, while some screen-detected cancers may be overdiagnosed.

Vitamin D supplementation and major cardiovascular events: D-Health randomised controlled trial.

OBJECTIVE: To investigate whether supplementing older adults with monthly doses of vitamin D alters the incidence of major cardiovascular events. DESIGN: Randomised, double blind, placebo controlled trial of monthly vitamin D (the D-Health Trial). Computer generated permuted block randomisation was used to allocate treatments. SETTING: Australia from 2014 to 2020. PARTICIPANTS: 21 315 participants aged 60-84 years at enrolment. Exclusion criteria were self-reported hypercalcaemia, hyperparathyroidism, kidney stones, osteomalacia, sarcoidosis, taking >500 IU/day supplemental vitamin D, or unable to give consent because of language or cognitive impairment. INTERVENTION: 60 000 IU/month vitamin D3 (n=10 662) or placebo (n=10 653) taken orally for up to five years. 16 882 participants completed the intervention period: placebo 8270 (77.6%); vitamin D 8552 (80.2%). MAIN OUTCOME MEASURES: The main outcome for this analysis was the occurrence of a major cardiovascular event, including myocardial infarction, stroke, and coronary revascularisation, determined through linkage with administrative datasets. Each event was analysed separately as secondary outcomes. Flexible parametric survival models were used to estimate hazard ratios and 95% confidence intervals. RESULTS: 21 302 people were included in the analysis. The median intervention period was five years. 1336 participants experienced a major cardiovascular event (placebo 699 (6.6%); vitamin D 637 (6.0%)). The rate of major cardiovascular events was lower in the vitamin D group than in the placebo group (hazard ratio 0.91, 95% confidence interval 0.81 to 1.01), especially among those who were taking cardiovascular drugs at baseline (0.84, 0.74 to 0.97; P for interaction=0.12), although the P value for interaction was not significant (<0.05). Overall, the difference in standardised cause specific cumulative incidence at five years was -5.8 events per 1000 participants (95% confidence interval -12.2 to 0.5 per 1000 participants), resulting in a number needed to treat to avoid one major cardiovascular event of 172. The rate of myocardial infarction (hazard ratio 0.81, 95% confidence interval 0.67 to 0.98) and coronary revascularisation (0.89, 0.78 to 1.01) was lower in the vitamin D group, but there was no difference in the rate of stroke (0.99, 0.80 to 1.23). CONCLUSIONS: Vitamin D supplementation might reduce the incidence of major cardiovascular events, although the absolute risk difference was small and the confidence interval was consistent with a null finding. These findings could prompt further evaluation of the role of vitamin D supplementation, particularly in people taking drugs for prevention or treatment of cardiovascular disease. TRIAL REGISTRATION: ACTRN12613000743763.

Linking Physical Activity to Breast Cancer Risk via Inflammation, Part 1: The Effect of Physical Activity on Inflammation.

The protective effect of physical activity on breast cancer incidence may partially be mediated by inflammation. Systematic searches of Medline, EMBASE, and SPORTDiscus were performed to identify intervention studies, Mendelian randomization studies, and prospective cohort studies that examined the effects of physical activity on circulating inflammatory biomarkers in adult women. Meta-analyses were performed to generate effect estimates. Risk of bias was assessed, and the Grading of Recommendations Assessment, Development, and Evaluation system was used to determine the overall quality of the evidence. Thirty-five intervention studies and one observational study met the criteria for inclusion. Meta-analyses of randomized controlled trials (RCT) indicated that, compared with control groups, exercise interventions reduced levels of C-reactive protein (CRP) [standardized mean difference (SMD) = -0.27, 95% confidence interval (CI) = -0.62 to 0.08), tumor necrosis factor alpha (TNFα, SMD = -0.63, 95% CI = -1.04 to -0.22), interleukin-6 (IL6, SMD = -0.55, 95% CI = -0.97 to -0.13) and leptin (SMD = -0.50, 95% CI = -1.10 to 0.09). Owing to heterogeneity in effect estimates and imprecision, evidence strength was graded as low (CRP, leptin) or moderate (TNFα and IL6). High-quality evidence indicated that exercise did not change adiponectin levels (SMD = 0.01, 95% CI = -0.14 to 0.17). These findings provide support for the biological plausibility of the first part of the physical activity-inflammation-breast cancer pathway.

Linking Physical Activity to Breast Cancer via Inflammation, Part 2: The Effect of Inflammation on Breast Cancer Risk.

This review synthesized and appraised the evidence for an effect of inflammation on breast cancer risk. Systematic searches identified prospective cohort and Mendelian randomization studies relevant to this review. Meta-analysis of 13 biomarkers of inflammation were conducted to appraise the evidence for an effect breast cancer risk; we examined the dose-response of these associations. Risk of bias was evaluated using the ROBINS-E tool and the quality of evidence was appraised with Grading of Recommendations Assessment, Development, and Evaluation. Thirty-four observational studies and three Mendelian randomization studies were included. Meta-analysis suggested that women with the highest levels of C-reactive protein (CRP) had a higher risk of developing breast cancer [risk ratio (RR) = 1.13; 95% confidence interval (CI), 1.01-1.26] compared with women with the lowest levels. Women with highest levels of adipokines, particularly adiponectin (RR = 0.76; 95% CI, 0.61-0.91) had a reduced breast cancer risk, although this finding was not supported by Mendelian randomization analysis. There was little evidence of an effect of cytokines, including TNFα and IL6, on breast cancer risk. The quality of evidence for each biomarker ranged from very low to moderate. Beyond CRP, the published data do not clearly support the role of inflammation in the development of breast cancer.

Methylation scores for smoking, alcohol consumption and body mass index and risk of seven types of cancer.

Methylation marks of exposure to health risk factors may be useful markers of cancer risk as they might better capture current and past exposures than questionnaires, and reflect different individual responses to exposure. We used data from seven case-control studies nested within the Melbourne Collaborative Cohort Study of blood DNA methylation and risk of colorectal, gastric, kidney, lung, prostate and urothelial cancer, and B-cell lymphoma (N cases = 3123). Methylation scores (MS) for smoking, body mass index (BMI), and alcohol consumption were calculated based on published data as weighted averages of methylation values. Rate ratios (RR) and 95% confidence intervals for association with cancer risk were estimated using conditional logistic regression and expressed per SD increase of the MS, with and without adjustment for health-related confounders. The contribution of MS to discriminate cases from controls was evaluated using the area under the curve (AUC). After confounder adjustment, we observed: large associations (RR = 1.5-1.7) with lung cancer risk for smoking MS; moderate associations (RR = 1.2-1.3) with urothelial cancer risk for smoking MS and with mature B-cell neoplasm risk for BMI and alcohol MS; moderate to small associations (RR = 1.1-1.2) for BMI and alcohol MS with several cancer types and cancer overall. Generally small AUC increases were observed after inclusion of several MS in the same model (colorectal, gastric, kidney, urothelial cancers: +3%; lung cancer: +7%; B-cell neoplasms: +8%). Methylation scores for smoking, BMI and alcohol consumption show independent associations with cancer risk, and may provide some improvements in risk prediction.

Dietary Inflammatory Index, Alternative Healthy Eating Index-2010, Mediterranean Diet Score and the risk of pancreatic cancer.

BACKGROUND: Previous studies of dietary patterns and pancreatic cancer risk have been inconclusive; we aimed to investigate the association of Mediterranean Diet Score (MDS), Alternative Healthy Eating Index-2010 (AHEI-2010), and Dietary Inflammatory Index (DII®) with risk of pancreatic cancer. METHODS: We used data from the Melbourne Collaborative Cohort Study including 33,690 men and women aged 40-69 years at recruitment in 1990-1994. A total of 258 incident cases of pancreatic cancer was identified over an average of 23.7 years of follow-up. Hazard ratios (HR) were estimated using Cox regression, with age as the underlying time metric, adjusting for potential confounders including sex, height, country of birth, education, socio-economic position, physical activity, energy intake, smoking status, pack-years smoking, years since quitting smoking, and alcohol intake. RESULTS: A healthier diet as assessed by the AHEI-2010 was associated with a lower risk of pancreatic cancer [HRQuartile4 vs Quartile1 = 0.58; 95%CI 0.40 - 0.85; p for trend 0.003]. Weaker but consistent evidence was observed for the other indexes [DII® HRQuartile4 vs Quartile1 = 1.30; 95%CI 0.82 - 2.06; p for trend 0.1], [MDS HRCategory3 vs Category1 = 0.79; 95%CI 0.49 - 1.26; p for trend 0.06]. CONCLUSION: Adherence to a healthier diet, as assessed by the AHEI-2010, may reduce the risk of pancreatic cancer.

Vitamin D Supplementation and the Incidence of Cataract Surgery in Older Australian Adults.

PURPOSE: Observational studies suggest that higher serum 25-hydroxy vitamin D (25(OH)D) concentration may be associated with lower risk of cataract. However, no randomized controlled trials have assessed the effect of vitamin D supplementation on the incidence of cataract. We aimed to assess whether vitamin D supplementation reduces the incidence of cataract surgery. DESIGN: We conducted an ancillary study of the D-Health Trial, a randomized, double-masked, placebo-controlled trial of monthly vitamin D conducted from 2014 through 2020 within the Australian general population. PARTICIPANTS: We invited 421 207 men and women 60 to 84 years of age to participate; including an additional 1896 volunteers, 40 824 expressed interest. Those with hypercalcemia, hyperparathyroidism, kidney stones, osteomalacia, or sarcoidosis or those who were taking more than 500 international units (IU) supplemental vitamin D per day were excluded. A total of 21 315 were randomized, and 1390 participants did not fulfil the eligibility criteria for this analysis (linked data available, no cataract within first 6 months), leaving 19 925 included. The median follow-up was 5 years. METHODS: Participants took 60 000 IU of vitamin D3 (n = 10 662) or placebo (n = 10 653) orally once per month for a maximum of 5 years. MAIN OUTCOME MEASURES: The primary outcome for this analysis was the first surgical treatment for cataract, ascertained through linkage to universal health insurance records and hospital data. RESULTS: Among 19 925 participants eligible for this analysis (mean age, 69.3 years; 46% women) 3668 participants (18.4%) underwent cataract surgery during follow-up (vitamin D: n = 1841 [18.5%]; placebo: n = 1827 [18.3%] ). The incidence of cataract surgery was similar between the two groups (incidence rate, 41.6 and 41.1 per 1000 person-years in the vitamin D and placebo groups, respectively; hazard ratio, 1.02; 95% confidence interval, 0.95-1.09). In prespecified subgroup analyses, the effect of vitamin D supplementation on the incidence of cataract surgery was not modified by age, sex, body mass index, predicted serum 25(OH)D concentration, or ambient ultraviolet radiation. CONCLUSIONS: Routinely supplementing older adults who live in an area with a low prevalence of vitamin D deficiency with high-dose vitamin D is unlikely to reduce the need for cataract surgery. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Linking Physical Activity to Breast Cancer Risk via the Insulin/Insulin-like Growth Factor Signaling System, Part 2: The Effect of Insulin/Insulin-like Growth Factor Signaling on Breast Cancer Risk.

Perturbation of the insulin/insulin-like growth factor (IGF) signaling system is often cited as a mechanism driving breast cancer risk. A systematic review identified prospective cohort studies and Mendelian randomization studies that examined the effects of insulin/IGF signaling (IGF, their binding proteins (IGFBP), and markers of insulin resistance] on breast cancer risk. Meta-analyses generated effect estimates; risk of bias was assessed and the Grading of Recommendations Assessment, Development and Evaluation system applied to evaluate the overall quality of the evidence. Four Mendelian randomization and 19 prospective cohort studies met our inclusion criteria. Meta-analysis of cohort studies confirmed that higher IGF-1 increased risk of breast cancer; this finding was supported by the Mendelian randomization studies. IGFBP-3 did not affect breast cancer. Meta analyses for connecting-peptide and fasting insulin showed small risk increases, but confidence intervals were wide and crossed the null. The quality of evidence obtained ranged from 'very low' to 'moderate'. There were insufficient studies to examine other markers of insulin/IGF signaling. These findings do not strongly support the biological plausibility of the second part of the physical activity-insulin/IGF signaling system-breast cancer pathway. Robust conclusions cannot be drawn due to the dearth of high quality studies. See related article by Swain et al., p. 2106.

Linking Physical Activity to Breast Cancer Risk via Insulin/Insulin-Like Growth Factor Signaling System, Part 1: The Effect of Physical Activity on the Insulin/Insulin-Like Growth Factor Signaling System.

Physical activity may reduce the risk of developing breast cancer via its effect on the insulin/insulin-like growth factor (IGF) signaling system. A systematic review searched for randomized controlled trials (RCT), Mendelian randomization and prospective cohort studies that examined the effects of physical activity on insulin/IGF signaling [IGFs, their binding proteins (IGFBP), and markers of insulin resistance] in adult women. Meta-analyses were performed to generate effect estimates. Risk of bias was assessed, and the Grading of Recommendations Assessment, Development, and Evaluation system used to determine the overall quality of the evidence. Fifty-eight RCTs met our inclusion criteria, no observational or Mendelian randomization studies met the criteria for inclusion. Meta-analyses indicated that physical activity interventions (vs. control) reduced fasting insulin, the Homeostatic Model Assessment for Insulin Resistance and fasting glucose. Physical activity increased IGF-1, but there was no clear effect on IGFBP-3 or the ratio of IGF-1:IGFBP-3. Strong evidence was only established for fasting insulin and insulin resistance. Further research is needed to examine the effect of physical activity on C-peptide and HBA1c in women. Reductions in fasting insulin and insulin resistance following exercise suggest some biological plausibility of the first part of the physical activity-insulin/IGF signaling-breast cancer pathway. See related article by Drummond et al., p. 2116.