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Sökning: WFRF:(Lane J Athene)

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2.
  • Adams, Charleen, et al. (författare)
  • Circulating Metabolic Biomarkers of Screen-Detected Prostate Cancer in the ProtecT Study.
  • 2018
  • Ingår i: Cancer Epidemiology, Biomarkers and Prevention. - 1055-9965 .- 1538-7755.
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Whether associations between circulating metabolites and prostate cancer are causal is unknown. We report on the largest study of metabolites and prostate cancer (2,291 cases and 2,661 controls) and appraise causality for a subset of the prostate cancer-metabolite associations using two-sample Mendelian randomization (MR).MATERIALS AND METHODS: The case-control portion of the study was conducted in nine UK centres with men aged 50-69 years who underwent prostate-specific antigen (PSA) screening for prostate cancer within the Prostate testing for cancer and Treatment (ProtecT) trial. Two data sources were used to appraise causality: a genome-wide association study (GWAS) of metabolites in 24,925 participants and a GWAS of prostate cancer in 44,825 cases and 27,904 controls within the Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium.RESULTS: Thirty-five metabolites were strongly associated with prostate cancer (p <0.0014, multiple-testing threshold). These fell into four classes: i) lipids and lipoprotein subclass characteristics (total cholesterol and ratios, cholesterol esters and ratios, free cholesterol and ratios, phospholipids and ratios, and triglyceride ratios); ii) fatty acids and ratios; iii) amino acids; iv) and fluid balance. Fourteen top metabolites were proxied by genetic variables, but MR indicated these were not causal.CONCLUSIONS: We identified 35 circulating metabolites associated with prostate cancer presence, but found no evidence of causality for those 14 testable with MR. Thus, the 14 MR-tested metabolites are unlikely to be mechanistically important in prostate cancer risk.IMPACT: The metabolome provides a promising set of biomarkers that may aid prostate cancer classification.
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3.
  • Tilling, Kate, et al. (författare)
  • Development of a new method for monitoring prostate-specific antigen changes in men with localised prostate cancer : a comparison of observational cohorts
  • 2010
  • Ingår i: European Urology. - 0302-2838 .- 1873-7560. ; 57:3, s. 446-452
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Prostate-specific antigen (PSA) measurements are increasingly used to monitor men with localised prostate cancer (PCa), but there is little consensus about the method to use. OBJECTIVE: To apply age-specific predictions of PSA level (developed in men without cancer) to one cohort of men with clinically identified PCa and one cohort of men with PSA-detected PCa. We hypothesise that among men with clinically identified cancer, the annual increase in PSA level would be steeper than in men with PSA-detected cancer. DESIGN, SETTING, AND PARTICIPANTS: The Scandinavian Prostate Cancer Group 4 (SPCG-4) cohort consisted of 321 men assigned to the watchful waiting arm of the SPCG-4 trial. The UK cohort consisted of 320 men with PSA-detected PCa in the Prostate testing for cancer and Treatment (ProtecT) study who opted for monitoring. Multilevel models describing changes in PSA level were fitted to the two cohorts, and average PSA level at age 50, change in PSA level with age, and predicted PSA values were derived. MEASUREMENTS: PSA level. RESULTS AND LIMITATIONS: In the SPCG-4 cohort, mean PSA at age 50 was similar to the cancer-free cohort but with a steeper yearly increase in PSA level (16.4% vs 4.0%). In the UK cohort, mean PSA level was higher than that in the cancer-free cohort (due to a PSA biopsy threshold of 3.0 ng/ml) but with a similar yearly increase in PSA level (4.1%). Predictions were less accurate for the SPCG-4 cohort (median difference between observed and predicted PSA level: -2.0 ng/ml; interquartile range [IQR]: -7.6-0.7 ng/ml) than for the UK cohort (median difference between observed and predicted PSA level: -0.8 ng/ml; IQR: -2.1-0.1 ng/ml). CONCLUSIONS: In PSA-detected men, yearly change in PSA was similar to that in cancer-free men, whereas in men with symptomatic PCa, the yearly change in PSA level was considerably higher. Our method needs further evaluation but has promise for refining active monitoring protocols.
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4.
  • Watts, Eleanor L., et al. (författare)
  • The associations of anthropometric, behavioural and sociodemographic factors with circulating concentrations of IGF‐I, IGF‐II, IGFBP‐1, IGFBP‐2 and IGFBP‐3 in a pooled analysis of 16,024 men from 22 studies
  • 2019
  • Ingår i: International Journal of Cancer. - : John Wiley & Sons. - 0020-7136 .- 1097-0215. ; 145:12, s. 3244-3256
  • Tidskriftsartikel (refereegranskat)abstract
    • Insulin‐like growth factors (IGFs) and insulin‐like growth factor binding proteins (IGFBPs) have been implicated in the aetiology of several cancers. To better understand whether anthropometric, behavioural and sociodemographic factors may play a role in cancer risk via IGF signalling, we examined the cross‐sectional associations of these exposures with circulating concentrations of IGFs (IGF‐I and IGF‐II) and IGFBPs (IGFBP‐1, IGFBP‐2 and IGFBP‐3). The Endogenous Hormones, Nutritional Biomarkers and Prostate Cancer Collaborative Group dataset includes individual participant data from 16,024 male controls (i.e. without prostate cancer) aged 22–89 years from 22 prospective studies. Geometric means of protein concentrations were estimated using analysis of variance, adjusted for relevant covariates. Older age was associated with higher concentrations of IGFBP‐1 and IGFBP‐2 and lower concentrations of IGF‐I, IGF‐II and IGFBP‐3. Higher body mass index was associated with lower concentrations of IGFBP‐1 and IGFBP‐2. Taller height was associated with higher concentrations of IGF‐I and IGFBP‐3 and lower concentrations of IGFBP‐1. Smokers had higher concentrations of IGFBP‐1 and IGFBP‐2 and lower concentrations of IGFBP‐3 than nonsmokers. Higher alcohol consumption was associated with higher concentrations of IGF‐II and lower concentrations of IGF‐I and IGFBP‐2. African Americans had lower concentrations of IGF‐II, IGFBP‐1, IGFBP‐2 and IGFBP‐3 and Hispanics had lower IGF‐I, IGF‐II and IGFBP‐3 than non‐Hispanic whites. These findings indicate that a range of anthropometric, behavioural and sociodemographic factors are associated with circulating concentrations of IGFs and IGFBPs in men, which will lead to a greater understanding of the mechanisms through which these factors influence cancer risk.
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5.
  • Simpkin, Andrew J., et al. (författare)
  • Prostate-specific antigen patterns in US and European populations : comparison of six diverse cohorts
  • 2016
  • Ingår i: BJU International. - 1464-4096 .- 1464-410X. ; 118:6, s. 911-918
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVE: To determine whether there are differences in prostate-specific antigen (PSA) levels at diagnosis or changes in PSA levels between US and European populations of men with and without prostate cancer (PCa).SUBJECTS AND METHODS: We analysed repeated measures of PSA from six clinically and geographically diverse cohorts of men: two cohorts with PSA-detected PCa, two cohorts with clinically detected PCa and two cohorts without PCa. Using multilevel models, average PSA at diagnosis and PSA change over time were compared among study populations.RESULTS: The annual percentage PSA change of 4-5% was similar between men without cancer and men with PSA-detected cancer. PSA at diagnosis was 1.7 ng/mL lower in a US cohort of men with PSA-detected PCa (95% confidence interval 1.3-2.0 ng/mL), compared with a UK cohort of men with PSA-detected PCa, but there was no evidence of a different rate of PSA change between these populations.CONCLUSION: We found that PSA changes over time are similar in UK and US men diagnosed through PSA testing and even in men without PCa. Further development of PSA models to monitor men on active surveillance should be undertaken in order to take advantage of these similarities. We found no evidence that guidelines for using PSA to monitor men cannot be passed between US and European studies.
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6.
  • Simpkin, Andrew J, et al. (författare)
  • Development, validation and evaluation of an instrument for active monitoring of men with clinically localised prostate cancer : systematic review, cohort studies and qualitative study
  • 2015
  • Ingår i: Health Services and Delivery Research. ; 3:30
  • Tidskriftsartikel (refereegranskat)abstract
    • Background:Active surveillance [(AS), sometimes called active monitoring (AM)],is a National Institute for Health and Care Excellence-recommended management option for men with clinically localised prostate cancer (PCa). It aims to target radical treatment only to those who would benefit most. Little consensus exists nationally or internationally about safe and effective protocols for AM/AS or triggers that indicate if or when men should move to radical treatment.Objective:The aims of this project were to review how prostate-specific antigen (PSA) has been used in AM/AS programmes; to develop and test the validity of a new model for predicting future PSA levels; to develop an instrument, based on PSA, that would be acceptable and effective for men and clinicians to use in clinical practice; and to design a robust study to evaluate the cost-effectiveness of the instrument.Methods:A systematic review was conducted to investigate how PSA is currently used to monitor men in worldwide AM/AS studies. A model for PSA change with age was developed using Prostate testing for cancer and Treatment (ProtecT) data and validated using data from two PSA-era cohorts and two pre-PSA-era cohorts. The model was used to derive 95% PSA reference ranges (PSARRs) across ages. These reference ranges were used to predict the onset of metastases or death from PCa in one of the pre-PSA-era cohorts. PSARRs were incorporated into an active monitoring system (AMS) and demonstrated to 18 clinicians and 20 men with PCa from four NHS trusts. Qualitative interviews investigated patients’ and clinicians’ views about current AM/AS protocols and the acceptability of the AMS within current practice.Results:The systematic review found that the most commonly used triggers for clinical review of PCa were PSA doubling time (PSADT) < 3 years or PSA velocity (PSAv) > 1 ng/ml/year. The model for PSA change (developed using ProtecT study data) predicted PSA values in AM/AS cohorts within 2 ng/ml of observed PSA in up to 79% of men. Comparing the three PSA markers, there was no clear optimal approach to alerting men to worsening cancer. The PSARR and PSADT markers improved the model c-statistic for predicting death from PCa by 0.11 (21%) and 0.13 (25%), respectively, compared with using diagnostic information alone [PSA, age, tumour stage (T-stage)]. Interviews revealed variation in clinical practice regarding eligibility and follow-up protocols. Patients and clinicians perceive current AM/AS practice to be framed by uncertainty, ranging from uncertainty about selection of eligible AM/AS candidates to uncertainty about optimum follow-up protocols and thresholds for clinical review/radical treatment. Patients and clinicians generally responded positively to the AMS. The impact of the AMS on clinicians’ decision-making was limited by a lack of data linking AMS values to long-term outcomes and by current clinical practice, which viewed PSA measures as one of several tools guiding clinical decisions in AM/AS. Patients reported that they would look to clinicians, rather than to a tool, to direct decision-making.Limitations:The quantitative findings were severely hampered by a lack of clinical outcomes or events (such as metastases). The qualitative findings were limited through reliance on participants’ reports of practices and recollections of events rather than observations of actual interactions.Conclusions:Patients and clinicians found that the instrument provided additional, potentially helpful, information but were uncertain about the current usefulness of the risk model we developed for routine management. Comparison of the model with other monitoring strategies will require clinical outcomes from ongoing AM/AS studies.Funding:The National Institute for Health Research Health Services and Delivery Research programme.
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7.
  • Simpkin, Andrew J, et al. (författare)
  • Systematic Review and Meta-analysis of Factors Determining Change to Radical Treatment in Active Surveillance for Localized Prostate Cancer.
  • 2015
  • Ingår i: European Urology. - 0302-2838 .- 1873-7560. ; 67:6
  • Tidskriftsartikel (refereegranskat)abstract
    • CONTEXT: Many men with clinically localized prostate cancer are being monitored as part of active surveillance (AS) programs, but little is known about reasons for receiving radical treatment.OBJECTIVES: A systematic review of the evidence about AS was undertaken, with a meta-analysis to identify predictors of radical treatment.EVIDENCE ACQUISITION: A comprehensive search of the Embase, MEDLINE and Web of Knowledge databases to March 2014 was performed. Studies reporting on men with localized prostate cancer followed by AS or monitoring were included. AS was defined where objective eligibility criteria, management strategies, and triggers for clinical review or radical treatment were reported.EVIDENCE SYNTHESIS: The 26 AS cohorts included 7627 men, with a median follow-up of 3.5 yr (range of medians 1.5-7.5 yr). The cohorts had a wide range of inclusion criteria, monitoring protocols, and triggers for radical treatment. There were eight prostate cancer deaths and five cases of metastases in 24,981 person-years of follow-up. Each year, 8.8% of men (95% confidence interval 6.7-11.0%) received radical treatment, most commonly because of biopsy findings, prostate-specific antigen triggers, or patient choice driven by anxiety. Studies in which most men changed treatment were those including only low-risk Gleason score 6 disease and scheduled rebiopsies.CONCLUSIONS: The wide variety of AS protocols and lack of robust evidence make firm conclusions difficult. Currently, patients and clinicians have to make judgments about the balance of risks and benefits in AS protocols. The publication of robust evidence from randomized trials and longer-term follow-up of cohorts is urgently required.PATIENT SUMMARY: We reviewed 26 studies of men on active surveillance for prostate cancer. There was evidence that studies including men with the lowest risk disease and scheduled rebiopsy had higher rates of radical treatment.
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8.
  • Walsh, Eleanor I, et al. (författare)
  • Characteristics of men responding to an invitation to undergo testing for prostate cancer as part of a randomised trial.
  • 2016
  • Ingår i: Trials. - 1745-6215 .- 1745-6215. ; 17:1
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Sociodemographic characteristics are associated with participating in cancer screening and trials. We compared the characteristics of those responding with those not responding to a single invitation for prostate-specific antigen (PSA) testing for prostate cancer as part of the Cluster randomised triAl of PSA testing for Prostate cancer (CAP).METHODS: Age, rurality and deprivation among 197,763 men from 271 cluster-randomised primary care centres in the UK were compared between those responding (n = 90,300) and those not responding (n = 100,953) to a prostate cancer testing invitation.RESULTS: There was little difference in age between responders and nonresponders. Responders were slightly more likely to come from urban rather than rural areas and were slightly less deprived than those who did not respond.CONCLUSION: These data indicate similarities in age and only minor differences in deprivation and urban location between responders and nonresponders. These differences were smaller, but in the same direction as those observed in other screening trials.TRIAL REGISTRATION: ISRCTN92187251 . Registered on 29 November 2004.
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