Publications by authors named "Richard M Martin"

336 Publications

Response to Comment on Delphi Analysis of Relevant Comparators in a Cost-Effectiveness Model of Prostate Cancer Screening.

Pharmacoeconomics 2021 Jul 17. Epub 2021 Jul 17.

Health Economics Bristol (HEB), Population Health Sciences, Bristol Medical School, University of Bristol, 1-5 Whiteladies Road, Bristol, BS8 1NU, UK.

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http://dx.doi.org/10.1007/s40273-021-01062-1DOI Listing
July 2021

Workplace interventions that aim to improve employee health and well-being in male-dominated industries: a systematic review.

Occup Environ Med 2021 May 25. Epub 2021 May 25.

Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.

The published evidence on whether workplace health and well-being interventions are as effective in male-dominated industries compared with mixed-gender environments has not been synthesised. We performed a systematic review of workplace interventions aimed at improving employee health and well-being in male-dominated industries. We searched Web of Knowledge, PubMed, Medline, Cochrane Database and Web of Science for articles describing workplace interventions in male-dominated industries that address employee health and well-being. The primary outcome was to determine the effectiveness of the intervention and the process evaluation (intervention delivery and adherence). To assess the quality of evidence, Cochrane Collaboration's Risk of Bias Tool was used. Due to the heterogeneity of reported outcomes, meta-analysis was performed for only some outcomes and a narrative synthesis with albatross plots was presented. After full-text screening, 35 studies met the eligibility criteria. Thirty-two studies delivered the intervention face-to-face, while two were delivered via internet and one using postal mail. Intervention adherence ranged from 50% to 97%, dependent on mode of delivery and industry. 17 studies were considered low risk of bias. Albatross plots indicated some evidence of positive associations, particularly for interventions focusing on musculoskeletal disorders. There was little evidence of intervention effect on body mass index and systolic or diastolic blood pressure. Limited to moderate evidence of beneficial effects was found for workplace health and well-being interventions conducted within male-dominated industries. Such interventions in the workplace can be effective, despite a different culture in male-dominated compared with mixed industries, but are dependent on delivery, industry and outcome. CRD42019161283.
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http://dx.doi.org/10.1136/oemed-2020-107314DOI Listing
May 2021

Using genetic variants to evaluate the causal effect of cholesterol lowering on head and neck cancer risk: A Mendelian randomization study.

PLoS Genet 2021 Apr 22;17(4):e1009525. Epub 2021 Apr 22.

MRC Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom.

Head and neck squamous cell carcinoma (HNSCC), which includes cancers of the oral cavity and oropharynx, is a cause of substantial global morbidity and mortality. Strategies to reduce disease burden include discovery of novel therapies and repurposing of existing drugs. Statins are commonly prescribed for lowering circulating cholesterol by inhibiting HMG-CoA reductase (HMGCR). Results from some observational studies suggest that statin use may reduce HNSCC risk. We appraised the relationship of genetically-proxied cholesterol-lowering drug targets and other circulating lipid traits with oral (OC) and oropharyngeal (OPC) cancer risk using two-sample Mendelian randomization (MR). For the primary analysis, germline genetic variants in HMGCR, NPC1L1, CETP, PCSK9 and LDLR were used to proxy the effect of low-density lipoprotein cholesterol (LDL-C) lowering therapies. In secondary analyses, variants were used to proxy circulating levels of other lipid traits in a genome-wide association study (GWAS) meta-analysis of 188,578 individuals. Both primary and secondary analyses aimed to estimate the downstream causal effect of cholesterol lowering therapies on OC and OPC risk. The second sample for MR was taken from a GWAS of 6,034 OC and OPC cases and 6,585 controls (GAME-ON). Analyses were replicated in UK Biobank, using 839 OC and OPC cases and 372,016 controls and the results of the GAME-ON and UK Biobank analyses combined in a fixed-effects meta-analysis. We found limited evidence of a causal effect of genetically-proxied LDL-C lowering using HMGCR, NPC1L1, CETP or other circulating lipid traits on either OC or OPC risk. Genetically-proxied PCSK9 inhibition equivalent to a 1 mmol/L (38.7 mg/dL) reduction in LDL-C was associated with an increased risk of OC and OPC combined (OR 1.8 95%CI 1.2, 2.8, p = 9.31 x10-05), with good concordance between GAME-ON and UK Biobank (I2 = 22%). Effects for PCSK9 appeared stronger in relation to OPC (OR 2.6 95%CI 1.4, 4.9) than OC (OR 1.4 95%CI 0.8, 2.4). LDLR variants, resulting in genetically-proxied reduction in LDL-C equivalent to a 1 mmol/L (38.7 mg/dL), reduced the risk of OC and OPC combined (OR 0.7, 95%CI 0.5, 1.0, p = 0.006). A series of pleiotropy-robust and outlier detection methods showed that pleiotropy did not bias our findings. We found limited evidence for a role of cholesterol-lowering in OC and OPC risk, suggesting previous observational results may have been confounded. There was some evidence that genetically-proxied inhibition of PCSK9 increased risk, while lipid-lowering variants in LDLR, reduced risk of combined OC and OPC. This result suggests that the mechanisms of action of PCSK9 on OC and OPC risk may be independent of its cholesterol lowering effects; however, this was not supported uniformly across all sensitivity analyses and further replication of this finding is required.
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http://dx.doi.org/10.1371/journal.pgen.1009525DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8096036PMC
April 2021

Circulating Levels of Testosterone, Sex Hormone Binding Globulin and Colorectal Cancer Risk: Observational and Mendelian Randomization Analyses.

Cancer Epidemiol Biomarkers Prev 2021 Jul 20;30(7):1336-1348. Epub 2021 Apr 20.

Section of Nutrition and Metabolism, International Agency for Research on Cancer, Lyon, France.

Background: Epidemiologic studies evaluating associations between sex steroid hormones and colorectal cancer risk have yielded inconsistent results. To elucidate the role of circulating levels of testosterone, and sex hormone-binding globulin (SHBG) in colorectal cancer risk, we conducted observational and Mendelian randomization (MR) analyses.

Methods: The observational analyses included 333,530 participants enrolled in the UK Biobank with testosterone and SHBG measured. HRs and 95% confidence intervals (CI) were estimated using multivariable Cox proportional hazards models. For MR analyses, genetic variants robustly associated with hormone levels were identified and their association with colorectal cancer (42,866 cases/42,752 controls) was examined using two-sample MR.

Results: In the observational analysis, there was little evidence that circulating levels of total testosterone were associated with colorectal cancer risk; the MR analyses showed a greater risk for women (OR per 1-SD = 1.09; 95% CI, 1.01-1.17), although pleiotropy may have biased this result. Higher SHBG concentrations were associated with greater colorectal cancer risk for women (HR per 1-SD = 1.16; 95% CI, 1.05-1.29), but was unsupported by the MR analysis. There was little evidence of associations between free testosterone and colorectal cancer in observational and MR analyses.

Conclusions: Circulating concentrations of sex hormones are unlikely to be causally associated with colorectal cancer. Additional experimental studies are required to better understand the possible role of androgens in colorectal cancer development.

Impact: Our results from large-scale analyses provide little evidence for sex hormone pathways playing a causal role in colorectal cancer development..
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http://dx.doi.org/10.1158/1055-9965.EPI-20-1690DOI Listing
July 2021

Young adult cancer risk behaviours originate in adolescence: a longitudinal analysis using ALSPAC, a UK birth cohort study.

BMC Cancer 2021 Apr 7;21(1):365. Epub 2021 Apr 7.

Department of Population Health Sciences, Population Health Sciences, Bristol Medical School, University of Bristol, BF4, Barley House, Oakfield Grove, Bristol, BS8 2BN, UK.

Background: An estimated 40% of cancer cases in the UK in 2015 were attributable to cancer risk behaviours. Tobacco smoking, alcohol consumption, obesity, and unprotected sexual intercourse are known causes of cancer and there is strong evidence that physical inactivity is associated with cancer. These cancer risk behaviours co-occur however little is known about how they pattern longitudinally across adolescence and early adulthood. Using data from ALSPAC, a prospective population-based UK birth cohort study, we explored patterns of adolescent cancer risk behaviours and their associations with cancer risk behaviours in early adulthood.

Methods: Six thousand three hundred fifty-one people (46.0% of ALSPAC participants) provided data on all cancer risk behaviours at one time during adolescence, 1951 provided data on all cancer risk behaviours at all time points. Our exposure measure was quartiles of a continuous score summarising cumulative exposure to cancer risk behaviours and longitudinal latent classes summarising distinct categories of adolescents exhibiting similar patterns of behaviours, between age 11 and 18 years. Using both exposure measures, odds of harmful drinking (Alcohol Use Disorders Identification Test-C ≥ 8),daily tobacco smoking, nicotine dependence (Fagerström test ≥4), obesity (BMI ≥30), high waist circumference (females: ≥80 cm and males: ≥94 cm, and high waist-hip ratio (females: ≥0.85 and males: ≥1.00) at age 24 were estimated using logistic regression analysis.

Results: We found distinct groups of adolescents characterised by consistently high and consistently low engagement in cancer risk behaviours. After adjustment, adolescents in the top quartile had greater odds of all outcomes in early adulthood: nicotine dependency (odds ratio, OR = 5.37, 95% confidence interval, CI = 3.64-7.93); daily smoking (OR = 5.10, 95% CI =3.19-8.17); obesity (OR = 4.84, 95% CI = 3.33-7.03); high waist circumference (OR = 2.48, 95% CI = 1.94-3.16); harmful drinking (OR = 2.04, 95% CI = 1.57-2.65); and high waist-hip ratio (OR = 1.88, 95% CI = 1.30-2.71), compared to the bottom quartile. In latent class analysis, adolescents characterised by consistently high-risk behaviours throughout adolescence were at higher risk of all cancer risk behaviours at age 24, except harmful drinking.

Conclusions: Exposure to adolescent cancer risk behaviours greatly increased the odds of cancer risk behaviours in early adulthood. Interventions to reduce these behaviours should target multiple rather than single risk behaviours and should focus on adolescence.
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http://dx.doi.org/10.1186/s12885-021-08098-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8028717PMC
April 2021

Using a Modified Delphi Approach to Gain Consensus on Relevant Comparators in a Cost-Effectiveness Model: Application to Prostate Cancer Screening.

Pharmacoeconomics 2021 May 2;39(5):589-600. Epub 2021 Apr 2.

Health Economics Bristol (HEB), Population Health Sciences, Bristol Medical School, University of Bristol, 1-5 Whiteladies Road, Bristol, BS8 1NU, UK.

Objective: Challenges can exist when framing the decision question in a cost-effectiveness analysis, particularly when there is disagreement among experts on relevant comparators. Using prostate cancer screening and recent developments in risk stratification, early-detection biomarkers, and diagnostic technologies as a case study, we report a modified Delphi approach to handle decision-question uncertainty.

Methods: The study involved two rounds of anonymous online questionnaires to identify the prostate cancer screening strategies that international researchers, clinicians and decision makers felt important to consider in a cost-effectiveness model. Both purposive and snowball sampling were used to recruit experts. The questionnaire was based on a review of the literature and was piloted for language, comprehension and ease of use prior to dissemination. In Round 1, respondents indicated their preferred screening strategy (including no screening) through a series of multiple-choice questions. The responses informed a set of 13 consensus statements, which respondents ranked their agreement with on a 9-point Likert scale (Round 2). Consensus was considered reached if > 70% of participants indicated agreement and < 15% indicated disagreement.

Results: Twenty participants completed Round 1 and 17 completed Round 2. Consensus was shown towards comparing no formal screening, age-based, and risk-based strategies. The risk-based approaches included screening only higher-risk men, using shorter screening intervals for higher-risk men, screening higher-risk men at an earlier age, and tailoring screening intervals based on prostate-specific antigen (PSA) level at a previous test. There was agreement that inclusion of MRI in the pathway should be considered, but disagreement on the inclusion of new biomarkers.

Conclusion: In disease areas where technologies are rapidly evolving, a modified Delphi approach provides a useful tool to identify relevant comparators in an economic evaluation.
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http://dx.doi.org/10.1007/s40273-021-01009-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8079293PMC
May 2021

Genetically predicted circulating concentrations of micronutrients and risk of colorectal cancer among individuals of European descent: a Mendelian randomization study.

Am J Clin Nutr 2021 06;113(6):1490-1502

Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.

Background: The literature on associations of circulating concentrations of minerals and vitamins with risk of colorectal cancer is limited and inconsistent. Evidence from randomized controlled trials (RCTs) to support the efficacy of dietary modification or nutrient supplementation for colorectal cancer prevention is also limited.

Objectives: To complement observational and RCT findings, we investigated associations of genetically predicted concentrations of 11 micronutrients (β-carotene, calcium, copper, folate, iron, magnesium, phosphorus, selenium, vitamin B-6, vitamin B-12, and zinc) with colorectal cancer risk using Mendelian randomization (MR).

Methods: Two-sample MR was conducted using 58,221 individuals with colorectal cancer and 67,694 controls from the Genetics and Epidemiology of Colorectal Cancer Consortium, Colorectal Cancer Transdisciplinary Study, and Colon Cancer Family Registry. Inverse variance-weighted MR analyses were performed with sensitivity analyses to assess the impact of potential violations of MR assumptions.

Results: Nominally significant associations were noted for genetically predicted iron concentration and higher risk of colon cancer [ORs per SD (ORSD): 1.08; 95% CI: 1.00, 1.17; P value = 0.05] and similarly for proximal colon cancer, and for vitamin B-12 concentration and higher risk of colorectal cancer (ORSD: 1.12; 95% CI: 1.03, 1.21; P value = 0.01) and similarly for colon cancer. A nominally significant association was also noted for genetically predicted selenium concentration and lower risk of colon cancer (ORSD: 0.98; 95% CI: 0.96, 1.00; P value = 0.05) and similarly for distal colon cancer. These associations were robust to sensitivity analyses. Nominally significant inverse associations were observed for zinc and risk of colorectal and distal colon cancers, but sensitivity analyses could not be performed. None of these findings survived correction for multiple testing. Genetically predicted concentrations of β-carotene, calcium, copper, folate, magnesium, phosphorus, and vitamin B-6 were not associated with disease risk.

Conclusions: These results suggest possible causal associations of circulating iron and vitamin B-12 (positively) and selenium (inversely) with risk of colon cancer.
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http://dx.doi.org/10.1093/ajcn/nqab003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168352PMC
June 2021

The Use of Primary Care Big Data in Understanding the Pharmacoepidemiology of COVID-19: A Consensus Statement From the COVID-19 Primary Care Database Consortium.

Ann Fam Med 2021 Mar-Apr;19(2):135-140

The use of big data containing millions of primary care medical records provides an opportunity for rapid research to help inform patient care and policy decisions during the first and subsequent waves of the coronavirus disease 2019 (COVID-19) pandemic. Routinely collected primary care data have previously been used for national pandemic surveillance, quantifying associations between exposures and outcomes, identifying high risk populations, and examining the effects of interventions at scale, but there is no consensus on how to effectively conduct or report these data for COVID-19 research. A COVID-19 primary care database consortium was established in April 2020 and its researchers have ongoing COVID-19 projects in overlapping data sets with over 40 million primary care records in the United Kingdom that are variously linked to public health, secondary care, and vital status records. This consensus agreement is aimed at facilitating transparency and rigor in methodological approaches, and consistency in defining and reporting cases, exposures, confounders, stratification variables, and outcomes in relation to the pharmacoepidemiology of COVID-19. This will facilitate comparison, validation, and meta-analyses of research during and after the pandemic.
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http://dx.doi.org/10.1370/afm.2658DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7939714PMC
March 2021

Alteration of Metabolic Conditions Impacts the Regulation of IGF-II/H19 Imprinting Status in Prostate Cancer.

Cancers (Basel) 2021 Feb 16;13(4). Epub 2021 Feb 16.

IGF & Metabolic Endocrinology Group, Translational Health Sciences, Bristol Medical School, Learning & Research Building, Southmead Hospital, Bristol BS10 5NB, UK.

Prostate cancer is the second major cause of male cancer deaths. Obesity, type 2 diabetes, and cancer risk are linked. Insulin-like growth factor II (IGF-II) is involved in numerous cellular events, including proliferation and survival. The IGF-II gene shares its locus with the lncRNA, H19. IGF-II/H19 was the first gene to be identified as being "imprinted"-where the paternal copy is not transcribed-a silencing phenomenon lost in many cancer types. We disrupted imprinting behaviour in vitro by altering metabolic conditions and quantified it using RFLP, qPCR and pyrosequencing; changes to peptide were measured using RIA. Prostate tissue samples were analysed using ddPCR, pyrosequencing and IHC. We compared with in silico data, provided by TGCA on the cBIO Portal. We observed disruption of imprinting behaviour, in vitro with a significant increase in IGF-II and a reciprocal decrease in H19 mRNA; the increased mRNA was not translated into peptides. In vivo, most specimens retained imprinting status apart from a small subset which showed reduced imprinting. A positive correlation was seen between IGF-II and H19 mRNA expression, which concurred with findings of larger Cancer Genome Atlas (TGCA) cohorts. This positive correlation did not affect IGF-II peptide. Our findings show that type 2 diabetes and/or obesity, can directly affect regulation growth factors involved in carcinogenesis, indirectly suggesting a modification of lifestyle habits may reduce cancer risk.
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http://dx.doi.org/10.3390/cancers13040825DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7920081PMC
February 2021

Delivery by caesarean section and offspring adiposity and cardio-metabolic health at ages 6.5, 11.5 and 16 years: results from the PROBIT cohort in Belarus.

Pediatr Obes 2021 Mar 3:e12783. Epub 2021 Mar 3.

Division of Chronic Disease Research Across the Lifecourse, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, Massachusetts, USA.

Background: Caesarean delivery has been associated with later adiposity, perhaps via early programming or perhaps because of residual confounding by maternal or birth characteristics.

Objectives: Examine associations of caesarean delivery with adiposity and cardio-metabolic biomarkers.

Methods: Observational analysis of 15 069 children in the PROBIT cohort in Belarus. We examined measures of child anthropometry and blood pressure at 6.5, 11.5 and 16 years and fasting blood (11.5 years).

Results: Caesarean-delivered children were slightly heavier at 6.5 (mean BMI 15.8 vs. 15.6 kg/m ), 11.5 (18.4 vs. 18.2) and 16 years (21.5 vs. 21.3). After adjustment for prenatal characteristics including maternal third trimester BMI, however, we observed no association of caesarean versus vaginal delivery with child BMI (β 0.05 kg/m ; 95%CI: -0.03, 0.14), sum of skinfolds (0.14 mm; -0.13, 0.42), waist circumference (-0.07 cm; -0.23, 0.10), obesity (OR 0.99; 0.76, 1.29), or systolic (-0.20 mmHg; -0.70, 0.30) or diastolic (-0.17 mmHg, -0.60, 0.26) blood pressure at 6.5 years; results were similar at 11.5 and 16 years. At 11.5 years, we observed a modest association of caesarean delivery with fasting insulin (0.33 mU/L; 0.00, 0.65).

Conclusions: Caesarean delivery had little or no association with adiposity or related cardio-metabolic biomarkers in childhood. Adjustment for maternal BMI attenuated all outcome effect estimates.
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http://dx.doi.org/10.1111/ijpo.12783DOI Listing
March 2021

Causal Effects of Lifetime Smoking on Breast and Colorectal Cancer Risk: Mendelian Randomization Study.

Cancer Epidemiol Biomarkers Prev 2021 May 2;30(5):953-964. Epub 2021 Mar 2.

Section of Nutrition and Metabolism, International Agency for Research on Cancer, Lyon, France.

Background: Observational evidence has shown that smoking is a risk factor for breast and colorectal cancer. We used Mendelian randomization (MR) to examine causal associations between smoking and risks of breast and colorectal cancer.

Methods: Genome-Wide Association Study summary data were used to identify genetic variants associated with lifetime amount of smoking ( = 126 variants) and ever having smoked regularly ( = 112 variants). Using two-sample MR, we examined these variants in relation to incident breast (122,977 cases/105,974 controls) and colorectal cancer (52,775 cases/45,940 controls).

Results: In inverse-variance weighted models, a genetic predisposition to higher lifetime amount of smoking was positively associated with breast cancer risk [OR per 1-SD increment: 1.13; 95% confidence interval (CI): 1.00-1.26; = 0.04]; although heterogeneity was observed. Similar associations were found for estrogen receptor-positive and estrogen receptor-negative tumors. Higher lifetime amount of smoking was positively associated with colorectal cancer (OR per 1-SD increment, 1.21; 95% CI, 1.04-1.40; = 0.01), colon cancer (OR, 1.31; 95% CI, 1.11-1.55; < 0.01), and rectal cancer (OR, 1.36; 95% CI, 1.07-1.73; = 0.01). Ever having smoked regularly was not associated with risks of breast (OR, 1.01; 95% CI, 0.90-1.14; = 0.85) or colorectal cancer (OR, 0.97; 95% CI, 0.86-1.10; = 0.68).

Conclusions: These findings are consistent with prior observational evidence and support a causal role of higher lifetime smoking amount in the development of breast and colorectal cancer.

Impact: The results from this comprehensive MR analysis indicate that lifetime smoking is a causal risk factor for these common malignancies.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-1218DOI Listing
May 2021

Polygenic hazard score is associated with prostate cancer in multi-ethnic populations.

Nat Commun 2021 02 23;12(1):1236. Epub 2021 Feb 23.

Division of Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, Radiotherapy Related Research, The Christie Hospital NHS Foundation Trust, Manchester, UK.

Genetic models for cancer have been evaluated using almost exclusively European data, which could exacerbate health disparities. A polygenic hazard score (PHS) is associated with age at prostate cancer diagnosis and improves screening accuracy in Europeans. Here, we evaluate performance of PHS (PHS, adapted for OncoArray) in a multi-ethnic dataset of 80,491 men (49,916 cases, 30,575 controls). PHS is associated with age at diagnosis of any and aggressive (Gleason score ≥ 7, stage T3-T4, PSA ≥ 10 ng/mL, or nodal/distant metastasis) cancer and prostate-cancer-specific death. Associations with cancer are significant within European (n = 71,856), Asian (n = 2,382), and African (n = 6,253) genetic ancestries (p < 10). Comparing the 80/20 PHS percentiles, hazard ratios for prostate cancer, aggressive cancer, and prostate-cancer-specific death are 5.32, 5.88, and 5.68, respectively. Within European, Asian, and African ancestries, hazard ratios for prostate cancer are: 5.54, 4.49, and 2.54, respectively. PHS risk-stratifies men for any, aggressive, and fatal prostate cancer in a multi-ethnic dataset.
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http://dx.doi.org/10.1038/s41467-021-21287-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902617PMC
February 2021

Statins as Potential Chemoprevention or Therapeutic Agents in Cancer: a Model for Evaluating Repurposed Drugs.

Curr Oncol Rep 2021 Feb 13;23(3):29. Epub 2021 Feb 13.

MRC Clinical Trials Unit at University College London, 90 High Holborn, London, WC1V 6LJ, UK.

Purpose Of Review: Repurposing established medicines for a new therapeutic indication potentially has important global and societal impact. The high costs and slow pace of new drug development have increased interest in more cost-effective repurposed drugs, particularly in the cancer arena. The conventional drug development pathway and evidence framework are not designed for drug repurposing and there is currently no consensus on establishing the evidence base before embarking on a large, resource intensive, potential practice changing phase III randomised controlled trial (RCT). Numerous observational studies have suggested a potential role for statins as a repurposed drug for cancer chemoprevention and therapy, and we review the strength of the cumulative evidence here.

Recent Findings: In the setting of cancer, a potential repurposed drug, like statins, typically goes through a cyclical history, with initial use for several years in another disease setting, prior to epidemiological research identifying a possible chemo-protective effect. However, further information is required, including review of RCT data in the initial disease setting with exploration of cancer outcomes. Additionally, more contemporary methods should be considered, such as Mendelian randomization and pharmaco-epidemiological research with "target" trial design emulation using electronic health records. Pre-clinical and traditional observational data potentially support the role of statins in the treatment of cancer; however, randomised trial evidence is not supportive. Evaluation of contemporary methods provides little added support for the use of statin therapy in cancer. We provide complementary evidence of alternative study designs to enable a robust critical appraisal from a number of sources of the go/no-go decision for a prospective phase III RCT of statins in the treatment of cancer.
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http://dx.doi.org/10.1007/s11912-021-01023-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7882549PMC
February 2021

Retrospective cohort study evaluating clinical, biochemical and pharmacological prognostic factors for prostate cancer progression using primary care data.

BMJ Open 2021 02 12;11(2):e044420. Epub 2021 Feb 12.

Bristol Medical School, Population Health Sciences, University of Bristol, Bristol, UK.

Objectives: To confirm the association of previously reported prognostic factors with future progression of localised prostate cancer using primary care data and identify new potential prognostic factors for further assessment in prognostic model development and validation.

Design: Retrospective cohort study, employing Cox proportional hazards regression controlling for age, prostate specific antigen (PSA), and Gleason score, was stratified by diagnostic stage.

Setting: Primary care in England.

Participants: Males with localised prostate cancer diagnosedbetween 01/01/1987 and 31/12/2016 within the Clinical Practice ResearchDatalink database, with linked data from the National Cancer Registration andAnalysis Service and Office for National Statistics.

Primary And Secondary Outcomes: Primary outcome measure was prostate cancer mortality. Secondary outcome measures were all-cause mortality and commencing systemic therapy. Up-staging after diagnosis was not used as a secondary outcome owing to significant missing data.

Results: 10 901 men (mean age 74.38±9.03 years) with localised prostate cancer were followed up for a mean of 14.12 (±6.36) years. 2331 (21.38%) men underwent systemic therapy and 3450 (31.65%) died, including 1250 (11.47%) from prostate cancer. Factors associated with an increased risk of prostate cancer mortality included age; high PSA; current or ex-smoker; ischaemic heart disease; high C reactive protein; high ferritin; low haemoglobin; high blood glucose and low albumin.

Conclusions: This study identified several new potential prognostic factors for prostate cancer progression, as well as confirming some known prognostic factors, in an independent primary care data set. Further research is needed to develop and validate a prognostic model for prostate cancer progression.
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http://dx.doi.org/10.1136/bmjopen-2020-044420DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7883851PMC
February 2021

Transcriptome-wide Mendelian randomization study prioritising novel tissue-dependent genes for glioma susceptibility.

Sci Rep 2021 Jan 27;11(1):2329. Epub 2021 Jan 27.

MRC Integrative Epidemiology Unit, University of Bristol, Bristol, BS8 2BN, UK.

Genome-wide association studies (GWAS) have discovered 27 loci associated with glioma risk. Whether these loci are causally implicated in glioma risk, and how risk differs across tissues, has yet to be systematically explored. We integrated multi-tissue expression quantitative trait loci (eQTLs) and glioma GWAS data using a combined Mendelian randomisation (MR) and colocalisation approach. We investigated how genetically predicted gene expression affects risk across tissue type (brain, estimated effective n = 1194 and whole blood, n = 31,684) and glioma subtype (all glioma (7400 cases, 8257 controls) glioblastoma (GBM, 3112 cases) and non-GBM gliomas (2411 cases)). We also leveraged tissue-specific eQTLs collected from 13 brain tissues (n = 114 to 209). The MR and colocalisation results suggested that genetically predicted increased gene expression of 12 genes were associated with glioma, GBM and/or non-GBM risk, three of which are novel glioma susceptibility genes (RETREG2/FAM134A, FAM178B and MVB12B/FAM125B). The effect of gene expression appears to be relatively consistent across glioma subtype diagnoses. Examining how risk differed across 13 brain tissues highlighted five candidate tissues (cerebellum, cortex, and the putamen, nucleus accumbens and caudate basal ganglia) and four previously implicated genes (JAK1, STMN3, PICK1 and EGFR). These analyses identified robust causal evidence for 12 genes and glioma risk, three of which are novel. The correlation of MR estimates in brain and blood are consistently low which suggested that tissue specificity needs to be carefully considered for glioma. Our results have implicated genes yet to be associated with glioma susceptibility and provided insight into putatively causal pathways for glioma risk.
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http://dx.doi.org/10.1038/s41598-021-82169-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7840943PMC
January 2021

Coffee consumption and risk of breast cancer: A Mendelian randomization study.

PLoS One 2021 19;16(1):e0236904. Epub 2021 Jan 19.

Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom.

Background: Observational studies have reported either null or weak protective associations for coffee consumption and risk of breast cancer.

Methods: We conducted a two-sample Mendelian randomization (MR) analysis to evaluate the relationship between coffee consumption and breast cancer risk using 33 single-nucleotide polymorphisms (SNPs) associated with coffee consumption from a genome-wide association (GWA) study on 212,119 female UK Biobank participants of White British ancestry. Risk estimates for breast cancer were retrieved from publicly available GWA summary statistics from the Breast Cancer Association Consortium (BCAC) on 122,977 cases (of which 69,501 were estrogen receptor (ER)-positive, 21,468 ER-negative) and 105,974 controls of European ancestry. Random-effects inverse variance weighted (IVW) MR analyses were performed along with several sensitivity analyses to assess the impact of potential MR assumption violations.

Results: One cup per day increase in genetically predicted coffee consumption in women was not associated with risk of total (IVW random-effects; odds ratio (OR): 0.91, 95% confidence intervals (CI): 0.80-1.02, P: 0.12, P for instrument heterogeneity: 7.17e-13), ER-positive (OR = 0.90, 95% CI: 0.79-1.02, P: 0.09) and ER-negative breast cancer (OR: 0.88, 95% CI: 0.75-1.03, P: 0.12). Null associations were also found in the sensitivity analyses using MR-Egger (total breast cancer; OR: 1.00, 95% CI: 0.80-1.25), weighted median (OR: 0.97, 95% CI: 0.89-1.05) and weighted mode (OR: 1.00, CI: 0.93-1.07).

Conclusions: The results of this large MR study do not support an association of genetically predicted coffee consumption on breast cancer risk, but we cannot rule out existence of a weak association.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0236904PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7815134PMC
April 2021

Circulating adiponectin and leptin and risk of overall and aggressive prostate cancer: a systematic review and meta-analysis.

Sci Rep 2021 01 11;11(1):320. Epub 2021 Jan 11.

Bristol Medical School, Population Health Sciences, University of Bristol, Bristol, UK.

Obesity is associated with an increased risk of advanced, recurrent and fatal prostate cancer. Adipokines may mediate this relationship. We conducted a systematic review and meta-analysis of associations of leptin and adiponectin with overall and aggressive prostate cancer. Bibliographic databases were systematically searched up to 1st April 2017. Log Odds Ratios (ORs) per 2.5 unit increase in adiponectin or leptin levels were derived and pooled. All analyses were stratified by study type (cross-sectional/prospective). 746 papers were retrieved, 34 eligible studies identified, 31 of these could be included in the meta-analysis. Leptin was not consistently associated with overall prostate cancer (pooled OR 1.00, 95%CI 0.98-1.02, per 2.5 ng/ml increase, prospective study OR 0.97, 95%CI 0.95-0.99, cross-sectional study OR 1.19, 95%CI 1.13-1.26) and there was weak evidence of a positive association with aggressive disease (OR 1.03, 95%CI 1.00-1.06). There was also weak evidence of a small inverse association of adiponectin with overall prostate cancer (OR 0.96, 95%CI 0.93-0.99, per 2.5 µg/ml increase), but less evidence of an association with aggressive disease (OR 0.98, 95%CI 0.94-1.01). The magnitude of any effects are small, therefore levels of circulating adiponectin or leptin alone are unlikely to be useful biomarkers of risk or prognosis.
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http://dx.doi.org/10.1038/s41598-020-79345-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7801499PMC
January 2021

Additional SNPs improve risk stratification of a polygenic hazard score for prostate cancer.

Prostate Cancer Prostatic Dis 2021 Jun 8;24(2):532-541. Epub 2021 Jan 8.

Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA, 02115, USA.

Background: Polygenic hazard scores (PHS) can identify individuals with increased risk of prostate cancer. We estimated the benefit of additional SNPs on performance of a previously validated PHS (PHS46).

Materials And Method: 180 SNPs, shown to be previously associated with prostate cancer, were used to develop a PHS model in men with European ancestry. A machine-learning approach, LASSO-regularized Cox regression, was used to select SNPs and to estimate their coefficients in the training set (75,596 men). Performance of the resulting model was evaluated in the testing/validation set (6,411 men) with two metrics: (1) hazard ratios (HRs) and (2) positive predictive value (PPV) of prostate-specific antigen (PSA) testing. HRs were estimated between individuals with PHS in the top 5% to those in the middle 40% (HR95/50), top 20% to bottom 20% (HR80/20), and bottom 20% to middle 40% (HR20/50). PPV was calculated for the top 20% (PPV80) and top 5% (PPV95) of PHS as the fraction of individuals with elevated PSA that were diagnosed with clinically significant prostate cancer on biopsy.

Results: 166 SNPs had non-zero coefficients in the Cox model (PHS166). All HR metrics showed significant improvements for PHS166 compared to PHS46: HR95/50 increased from 3.72 to 5.09, HR80/20 increased from 6.12 to 9.45, and HR20/50 decreased from 0.41 to 0.34. By contrast, no significant differences were observed in PPV of PSA testing for clinically significant prostate cancer.

Conclusions: Incorporating 120 additional SNPs (PHS166 vs PHS46) significantly improved HRs for prostate cancer, while PPV of PSA testing remained the same.
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http://dx.doi.org/10.1038/s41391-020-00311-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8157993PMC
June 2021

Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction.

Nat Genet 2021 01 4;53(1):65-75. Epub 2021 Jan 4.

Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia.

Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction.
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http://dx.doi.org/10.1038/s41588-020-00748-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8148035PMC
January 2021

Circulating insulin-like growth factor-I, total and free testosterone concentrations and prostate cancer risk in 200 000 men in UK Biobank.

Int J Cancer 2021 May 11;148(9):2274-2288. Epub 2020 Dec 11.

Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK.

Insulin-like growth factor-I (IGF-I) and testosterone have been implicated in prostate cancer aetiology. Using data from a large prospective full-cohort with standardised assays and repeat blood measurements, and genetic data from an international consortium, we investigated the associations of circulating IGF-I, sex hormone-binding globulin (SHBG), and total and calculated free testosterone concentrations with prostate cancer incidence and mortality. For prospective analyses, risk was estimated using multivariable-adjusted Cox regression in 199 698 male UK Biobank participants. Hazard ratios (HRs) were corrected for regression dilution bias using repeat hormone measurements from a subsample. Two-sample Mendelian randomisation (MR) analysis of IGF-I and risk used genetic instruments identified from UK Biobank men and genetic outcome data from the PRACTICAL consortium (79 148 cases and 61 106 controls). We used cis- and all (cis and trans) SNP MR approaches. A total of 5402 men were diagnosed with and 295 died from prostate cancer (mean follow-up 6.9 years). Higher circulating IGF-I was associated with elevated prostate cancer diagnosis (HR per 5 nmol/L increment = 1.09, 95% CI 1.05-1.12) and mortality (HR per 5 nmol/L increment = 1.15, 1.02-1.29). MR analyses also supported the role of IGF-I in prostate cancer diagnosis (cis-MR odds ratio per 5 nmol/L increment = 1.34, 1.07-1.68). In observational analyses, higher free testosterone was associated with a higher risk of prostate cancer (HR per 50 pmol/L increment = 1.10, 1.05-1.15). Higher SHBG was associated with a lower risk (HR per 10 nmol/L increment = 0.95, 0.94-0.97), neither was associated with prostate cancer mortality. Total testosterone was not associated with prostate cancer. These findings implicate IGF-I and free testosterone in prostate cancer development and/or progression.
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http://dx.doi.org/10.1002/ijc.33416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8048461PMC
May 2021

A multivariable Mendelian randomization analysis investigating smoking and alcohol consumption in oral and oropharyngeal cancer.

Nat Commun 2020 11 27;11(1):6071. Epub 2020 Nov 27.

MRC Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, BS8 1TL, UK.

The independent effects of smoking and alcohol in head and neck cancer are not clear, given the strong association between these risk factors. Their apparent synergistic effect reported in previous observational studies may also underestimate independent effects. Here we report multivariable Mendelian randomization performed in a two-sample approach using summary data on 6,034 oral/oropharyngeal cases and 6,585 controls from a recent genome-wide association study. Our results demonstrate strong evidence for an independent causal effect of smoking on oral/oropharyngeal cancer (IVW OR 2.6, 95% CI = 1.7, 3.9 per standard deviation increase in lifetime smoking behaviour) and an independent causal effect of alcohol consumption when controlling for smoking (IVW OR 2.1, 95% CI = 1.1, 3.8 per standard deviation increase in drinks consumed per week). This suggests the possibility that the causal effect of alcohol may have been underestimated. However, the extent to which alcohol is modified by smoking requires further investigation.
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http://dx.doi.org/10.1038/s41467-020-19822-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7695733PMC
November 2020

Cancer survivorship, excess body fatness and weight-loss intervention-where are we in 2020?

Br J Cancer 2021 Mar 25;124(6):1057-1065. Epub 2020 Nov 25.

Department of Sport, Exercise & Rehabilitation, Faculty of Health and Life Sciences, Northumbria University, Northumberland Building, Newcastle upon Tyne, NE1 8ST, UK.

Earlier diagnosis and more effective treatments mean that the estimated number of cancer survivors in the United Kingdom is expected to reach 4 million by 2030. However, there is an increasing realisation that excess body fatness (EBF) is likely to influence the quality of cancer survivorship and disease-free survival. For decades, the discussion of weight management in patients with cancer has been dominated by concerns about unintentional weight loss, low body weight and interventions to increase weight, often re-enforced by the existence of the obesity paradox, which indicates that high body weight is associated with survival benefits for some types of cancer. However, observational evidence provides strong grounds for testing the hypothesis that interventions for promoting intentional loss of body fat and maintaining skeletal muscle in overweight and obese cancer survivors would bring important health benefits in terms of survival outcomes and long-term impact on treatment-related side effects. In this paper, we outline the need for studies to improve our understanding of the health benefits of weight-loss interventions, such as hypocaloric healthy-eating plans combined with physical activity. In particular, complex intervention trials that are pragmatically designed are urgently needed to develop effective, clinically practical, evidence-based strategies for reducing EBF and optimising body composition in people living with and beyond common cancers.
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http://dx.doi.org/10.1038/s41416-020-01155-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7961062PMC
March 2021

Cancer prevention through weight control-where are we in 2020?

Br J Cancer 2021 Mar 25;124(6):1049-1056. Epub 2020 Nov 25.

MRC Integrative Epidemiology Unit, University of Bristol, Oakfield House, Bristol, BS8 2BN, UK.

Growing data from epidemiological studies highlight the association between excess body fat and cancer incidence, but good indicative evidence demonstrates that intentional weight loss, as well as increasing physical activity, offers much promise as a cost-effective approach for reducing the cancer burden. However, clear gaps remain in our understanding of how changes in body fat or levels of physical activity are mechanistically linked to cancer, and the magnitude of their impact on cancer risk. It is important to investigate the causal link between programmes that successfully achieve short-term modest weight loss followed by weight-loss maintenance and cancer incidence. The longer-term impact of weight loss and duration of overweight and obesity on risk reduction also need to be fully considered in trial design. These gaps in knowledge need to be urgently addressed to expedite the development and implementation of future cancer-control strategies. Comprehensive approaches to trial design, Mendelian randomisation studies and data-linkage opportunities offer real possibilities to tackle current research gaps. In this paper, we set out the case for why non-pharmacological weight-management trials are urgently needed to support cancer-risk reduction and help control the growing global burden of cancer.
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http://dx.doi.org/10.1038/s41416-020-01154-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7960959PMC
March 2021

Risk of neuropsychiatric and cardiovascular adverse events following treatment with varenicline and nicotine replacement therapy in the UK Clinical Practice Research Datalink: a case-cross-over study.

Addiction 2021 06 14;116(6):1532-1545. Epub 2020 Dec 14.

Department of Non-communicable Disease Epidemiology, Faculty of Epidemiology and Population Health, LSHTM, London, UK.

Background And Aims: Varenicline and nicotine replacement therapy (NRT) are the most commonly used medications to quit smoking. Given their widespread use, monitoring adverse risks remains important. This study aimed to estimate the neuropsychiatric and cardiovascular risks associated with varenicline and NRT as used in routine UK care.

Design: Case-cross-over study.

Setting: UK-based electronic primary care records in the Clinical Practice Research Datalink from 2006 to 2015 linked to hospital and mortality data sets.

Participants: Adult smokers (n =282,429) observed during periods when exposed and not exposed to either varenicline or NRT.

Measurements: Main outcomes included suicide, self-harm, myocardial infarction (MI), all-cause death and cause-specific death [MI, chronic obstructive pulmonary disease (COPD)]. In primary analyses, conditional logistic regression was used to compare the chance of varenicline or NRT exposure during the risk period (90 days prior to the event) with the chance of exposure during an earlier single reference period (91-180 days prior to the event) or multiple 90-day reference periods to increase statistical power.

Findings: In the primary analyses, findings were inconclusive for the associations between varenicline and the main outcomes using a single reference period, while NRT was associated with MI [odds ratio (OR) = 1.40, 95% confidence interval (CI) = 1.18-1.67]. Using multiple reference periods, varenicline was associated with an increased risk of self-harm (OR = 1.32, 95% CI = 1.12-1.56) and suicide (OR = 3.56, 95% CI = 1.32-9.60) but a reduction in all-cause death (OR = 0.75, 95% CI = 0.61-0.93). NRT was associated with MI (OR = 1.54, 95% CI = 1.36-1.74), self-harm (OR = 1.30, 95% CI = 1.18-1.44) and deaths from MI (OR = 1.53, 95% CI = 1.11-2.10), COPD (OR = 1.33, 95% CI = 1.14-1.56) and all causes (OR = 1.28, 95% CI = 1.18-1.40) when using multiple reference periods.

Conclusions: There appear to be positive associations between (1) nicotine replacement therapy (NRT) and myocardial infarction, death and risk of self-harm and (2) varenicline and increased risk of self-harm and suicide, as well as a negative association between varenicline and all-cause death. The associations may not be causal. They may reflect health changes at the time of smoking cessation (nicotine replacement therapy is prescribed for people with cardiac problems) or be associated with quit attempts (exposure to both medicines was associated with self-harm).
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http://dx.doi.org/10.1111/add.15338DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8246946PMC
June 2021

Examination of potential novel biochemical factors in relation to prostate cancer incidence and mortality in UK Biobank.

Br J Cancer 2020 12 23;123(12):1808-1817. Epub 2020 Sep 23.

Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK.

Background: Although prostate cancer is a leading cause of cancer death, its aetiology is not well understood. We aimed to identify novel biochemical factors for prostate cancer incidence and mortality in UK Biobank.

Methods: A range of cardiovascular, bone, joint, diabetes, renal and liver-related biomarkers were measured in baseline blood samples collected from up to 211,754 men at recruitment and in a subsample 5 years later. Participants were followed-up via linkage to health administrative datasets to identify prostate cancer cases. Hazard ratios (HRs) and 95% confidence intervals were calculated using multivariable-adjusted Cox regression corrected for regression dilution bias. Multiple testing was accounted for by using a false discovery rate controlling procedure.

Results: After an average follow-up of 6.9 years, 5763 prostate cancer cases and 331 prostate cancer deaths were ascertained. Prostate cancer incidence was positively associated with circulating vitamin D, urea and phosphate concentrations and inversely associated with glucose, total protein and aspartate aminotransferase. Phosphate and cystatin-C were the only biomarkers positively and inversely, respectively, associated with risk in analyses excluding the first 4 years of follow-up. There was little evidence of associations with prostate cancer death.

Conclusion: We found novel associations of several biomarkers with prostate cancer incidence. Future research will examine associations by tumour characteristics.
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http://dx.doi.org/10.1038/s41416-020-01081-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7722733PMC
December 2020

Ischemic Heart Disease Mortality and Occupational Radiation Exposure in a Nested Matched Case-Control Study of British Nuclear Fuel Cycle Workers: Investigation of Confounding by Lifestyle, Physiological Traits and Occupational Exposures.

Radiat Res 2020 10;194(4):431-444

Centre for Occupational and Environmental Health, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, M13 9PL, United Kingdom.

Epidemiological studies have suggested a link between low-level radiation exposure and an increased risk of cardiovascular disease, but the possibility of bias or confounding must be considered. We analyzed data from a matched case-control study nested in a cohort of British male industrial (i.e., blue-collar) nuclear fuel cycle workers using paired conditional logistic regression. The cases were comprised of workers from two nuclear sites who had died from ischemic heart disease (IHD) and were matched to controls on nuclear site, date of birth and first year of employment (1,220 pairs). Radiation doses from external sources and to the liver from internally deposited plutonium and uranium were obtained. Models were adjusted for age at start of employment at either site, decade of start, age at exit from study (death or censoring), process/other worker and socio-economic status. Included potential confounding factors of interest were occupational noise, shift work, pre-employment blood pressure, body mass index and tobacco smoking. Cumulative external doses ranged from 0-1,656 mSv and cumulative internal doses for those monitored for radioactive intakes ranged from 0.004-5,732 mSv. In a categorical analysis, additionally adjusted for whether or not a worker was monitored for internal exposure, IHD mortality risk was associated with cumulative external unlagged dose with a 42% excess risk (95% CI: 4%, 95%) at >103 mSv (highest quartile relative to lowest quartile), and 35% (95% CI: -1%, 84%) at >109 mSv 15-year lagged dose. The log-linear increase in risk per 100 mSv was 2% (95% CI: -4%, 8%) for unlagged external dose and 5% (95% CI: -2%, 11%) for 15-year lagged dose. Associations with external dose for workers monitored only for exposure to external radiation reflected those previously reported for the cohort from which the cases and controls were drawn. There was little evidence of excess risk associated with cumulative doses from internal sources, which had not been assessed in the cohort study. The impact of the included potential confounding variables was minimal, with the possible exception of occupational noise exposure. Subgroup analyses indicated evidence of heterogeneity between sites, occupational groups and employment duration, and an important factor was whether workers were monitored for the potential presence of internal emitters, which was not explained by other factors included in the study. In summary, we found evidence for an increased IHD mortality risk associated with external radiation dose, but little evidence of an association with internal dose. External dose associations were minimally affected by important confounders. However, the considerable heterogeneity in the associations with external doses observed between subgroups of workers is difficult to explain and requires further work.
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http://dx.doi.org/10.1667/RADE-19-00007.1DOI Listing
October 2020

Comparison of Antihypertensive Drug Classes for Dementia Prevention.

Epidemiology 2020 11;31(6):852-859

Dementia Research Group, Bristol Medical School, University of Bristol, Bristol, United Kingdom.

Background: Hypertension in midlife is associated with increased risk of Alzheimer disease and vascular dementia late in life. In addition, some antihypertensive drugs have been proposed to have cognitive benefits, independent of their effect on hypertension. Consequently, there is potential to repurpose antihypertensive drugs for the prevention of dementia. This study systematically compared seven antihypertensive drug classes for this purpose, using the Clinical Practice Research Datalink.

Methods: We assessed treatments for hypertension in an instrumental variable analysis to address potential confounding and reverse causation. We used physicians' prescribing preference as an ordinal instrument, defined by the physicians' last seven prescriptions. Participants considered were new antihypertensive users between 1996 and 2016, aged 40 and over.

Results: We analyzed 849,378 patients, with total follow up of 5,497,266 patient-years. We estimated that β-adrenoceptor blockers and vasodilator antihypertensives conferred small protective effects-for example, β-adrenoceptor blockers were associated with 13 (95% confidence interval = 6, 20) fewer cases of any dementia per 1000 treated compared with other antihypertensives.

Conclusions: We estimated small differences in the effects of antihypertensive drug classes on dementia outcomes. We also show that the magnitude of the differences between drug classes is smaller than that previously reported. Future research should look to implement other causal analysis methods to address biases in conventional observational research, with the ultimate aim of triangulating the evidence concerning this hypothesis.
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http://dx.doi.org/10.1097/EDE.0000000000001245DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7523578PMC
November 2020

Active monitoring, radical prostatectomy and radical radiotherapy in PSA-detected clinically localised prostate cancer: the ProtecT three-arm RCT.

Health Technol Assess 2020 08;24(37):1-176

Department of Urology, Leeds Teaching Hospitals NHS Trust, Leeds, UK.

Background: Prostate cancer is the most common cancer among men in the UK. Prostate-specific antigen testing followed by biopsy leads to overdetection, overtreatment as well as undertreatment of the disease. Evidence of treatment effectiveness has lacked because of the paucity of randomised controlled trials comparing conventional treatments.

Objectives: To evaluate the effectiveness of conventional treatments for localised prostate cancer (active monitoring, radical prostatectomy and radical radiotherapy) in men aged 50-69 years.

Design: A prospective, multicentre prostate-specific antigen testing programme followed by a randomised trial of treatment, with a comprehensive cohort follow-up.

Setting: Prostate-specific antigen testing in primary care and treatment in nine urology departments in the UK.

Participants: Between 2001 and 2009, 228,966 men aged 50-69 years received an invitation to attend an appointment for information about the Prostate testing for cancer and Treatment (ProtecT) study and a prostate-specific antigen test; 82,429 men were tested, 2664 were diagnosed with localised prostate cancer, 1643 agreed to randomisation to active monitoring ( = 545), radical prostatectomy ( = 553) or radical radiotherapy ( = 545) and 997 chose a treatment.

Interventions: The interventions were active monitoring, radical prostatectomy and radical radiotherapy.

Trial Primary Outcome Measure: Definite or probable disease-specific mortality at the 10-year median follow-up in randomised participants.

Secondary Outcome Measures: Overall mortality, metastases, disease progression, treatment complications, resource utilisation and patient-reported outcomes.

Results: There were no statistically significant differences between the groups for 17 prostate cancer-specific ( = 0.48) and 169 all-cause ( = 0.87) deaths. Eight men died of prostate cancer in the active monitoring group (1.5 per 1000 person-years, 95% confidence interval 0.7 to 3.0); five died of prostate cancer in the radical prostatectomy group (0.9 per 1000 person-years, 95% confidence interval 0.4 to 2.2 per 1000 person years) and four died of prostate cancer in the radical radiotherapy group (0.7 per 1000 person-years, 95% confidence interval 0.3 to 2.0 per 1000 person years). More men developed metastases in the active monitoring group than in the radical prostatectomy and radical radiotherapy groups: active monitoring,  = 33 (6.3 per 1000 person-years, 95% confidence interval 4.5 to 8.8); radical prostatectomy,  = 13 (2.4 per 1000 person-years, 95% confidence interval 1.4 to 4.2 per 1000 person years); and radical radiotherapy,  = 16 (3.0 per 1000 person-years, 95% confidence interval 1.9 to 4.9 per 1000 person-years;  = 0.004). There were higher rates of disease progression in the active monitoring group than in the radical prostatectomy and radical radiotherapy groups: active monitoring ( = 112; 22.9 per 1000 person-years, 95% confidence interval 19.0 to 27.5 per 1000 person years); radical prostatectomy ( = 46; 8.9 per 1000 person-years, 95% confidence interval 6.7 to 11.9 per 1000 person-years); and radical radiotherapy ( = 46; 9.0 per 1000 person-years, 95% confidence interval 6.7 to 12.0 per 1000 person years;  < 0.001). Radical prostatectomy had the greatest impact on sexual function/urinary continence and remained worse than radical radiotherapy and active monitoring. Radical radiotherapy's impact on sexual function was greatest at 6 months, but recovered somewhat in the majority of participants. Sexual and urinary function gradually declined in the active monitoring group. Bowel function was worse with radical radiotherapy at 6 months, but it recovered with the exception of bloody stools. Urinary voiding and nocturia worsened in the radical radiotherapy group at 6 months but recovered. Condition-specific quality-of-life effects mirrored functional changes. No differences in anxiety/depression or generic or cancer-related quality of life were found. At the National Institute for Health and Care Excellence threshold of £20,000 per quality-adjusted life-year, the probabilities that each arm was the most cost-effective option were 58% (radical radiotherapy), 32% (active monitoring) and 10% (radical prostatectomy).

Limitations: A single prostate-specific antigen test and transrectal ultrasound biopsies were used. There were very few non-white men in the trial. The majority of men had low- and intermediate-risk disease. Longer follow-up is needed.

Conclusions: At a median follow-up point of 10 years, prostate cancer-specific mortality was low, irrespective of the assigned treatment. Radical prostatectomy and radical radiotherapy reduced disease progression and metastases, but with side effects. Further work is needed to follow up participants at a median of 15 years.

Trial Registration: Current Controlled Trials ISRCTN20141297.

Funding: This project was funded by the National Institute for Health Research Health Technology Assessment programme and will be published in full in ; Vol. 24, No. 37. See the National Institute for Health Research Journals Library website for further project information.
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http://dx.doi.org/10.3310/hta24370DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7443739PMC
August 2020

Genetically predicted circulating concentrations of micronutrients and risk of breast cancer: A Mendelian randomization study.

Int J Cancer 2021 02 25;148(3):646-653. Epub 2020 Aug 25.

Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece.

The epidemiological literature reports inconsistent associations between consumption or circulating concentrations of micronutrients and breast cancer risk. We investigated associations between genetically predicted concentrations of 11 micronutrients (beta-carotene, calcium, copper, folate, iron, magnesium, phosphorus, selenium, vitamin B , vitamin B and zinc) and breast cancer risk using Mendelian randomization (MR). A two-sample MR study was conducted using 122 977 women with breast cancer and 105 974 controls from the Breast Cancer Association Consortium. MR analyses were conducted using the inverse variance-weighted approach, and sensitivity analyses were conducted to assess the impact of potential violations of MR assumptions. A value of 1 SD (SD: 0.08 mmol/L) higher genetically predicted concentration of magnesium was associated with a 17% (odds ratio [OR]: 1.17, 95% confidence interval [CI]: 1.10-1.25, P value = 9.1 × 10 ) and 20% (OR: 1.20, 95% CI: 1.08-1.34, P value = 3.2 × 10 ) higher risk of overall and ER breast cancer, respectively. An inverse association was observed for a SD (0.5 mg/dL) higher genetically predicted phosphorus concentration and ER breast cancer (OR: 0.84, 95% CI: 0.72-0.98, P value = .03). There was little evidence that any other nutrient was associated with breast cancer. The results for magnesium were robust under all sensitivity analyses and survived correction for multiple comparisons. Higher circulating concentrations of magnesium and potentially phosphorus may affect breast cancer risk. Further work is required to replicate these findings and investigate underlying mechanisms.
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http://dx.doi.org/10.1002/ijc.33246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8268064PMC
February 2021