189 results on '"Martin, Richard M"'
Search Results
2. The effect of SGLT2 inhibition on prostate cancer: Mendelian randomization and observational analysis using electronic healthcare and cohort data.
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Zheng J, Lu J, Qi J, Yang Q, Zhao H, Liu H, Chen Z, Huang L, Ye Y, Xu M, Xu Y, Wang T, Li M, Zhao Z, Zheng R, Wang S, Lin H, Hu C, Ling Chui CS, Au Yeung SL, Luo S, Dimopoulou O, Dixon P, Harrison S, Liu Y, Robinson J, Yarmolinsky J, Haycock P, Yuan J, Lewis S, Yuan Z, Gaunt TR, Smith GD, Ning G, Martin RM, Cui B, Wang W, and Bi Y
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- Humans, Male, Middle Aged, Diabetes Mellitus, Type 2 drug therapy, Diabetes Mellitus, Type 2 genetics, Cohort Studies, Aged, Glycated Hemoglobin metabolism, Sodium-Glucose Transporter 2 metabolism, Sodium-Glucose Transporter 2 genetics, Electronic Health Records, Prostatic Neoplasms genetics, Prostatic Neoplasms drug therapy, Mendelian Randomization Analysis, Sodium-Glucose Transporter 2 Inhibitors therapeutic use
- Abstract
We evaluated the effect of sodium-glucose cotransporter 2 (SGLT2) inhibition on prostate cancer by evidence triangulation. Using Mendelian randomization, we found that genetically proxied SGLT2 inhibition reduced the risk of overall (odds ratio = 0.56, 95% confidence interval [CI] = 0.38 to 0.82; 79,148 prostate cancer cases and 61,106 controls), advanced, and early-onset prostate cancer. Using electronic healthcare data (n
SGLT2i = 24,155; nDPP4i = 24,155), we found that the use of SGLT2 inhibitors was associated with a 23% reduced risk of prostate cancer (hazard ratio = 0.77, 95% CI = 0.61 to 0.99) in men with diabetes. Using data from two prospective cohorts (n4C = 57,779; nUK_Biobank = 165,430), we found little evidence to support the association of HbA1c with prostate cancer, implying a non-glycemic effect of SGLT2 inhibition on prostate cancer. In summary, this study provides multiple layers of evidence to support the beneficial effect of SGLT2 inhibition on reducing prostate cancer risk. Future trials are warranted to investigate whether SGLT2 inhibitors can be recommended for prostate cancer prevention., Competing Interests: Declaration of interests G.D.S. reports scientific advisory board membership for Relation Therapeutics and Insitro. UK Biobank has received ethical approval from the UK National Health Service’s National Research Ethics Service (ref. 11/NW/0382). All other studies contributing data to this analysis had the relevant institutional review board approval from each country and all participants provided informed consent., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2024
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3. Optimising the use of the prostate- specific antigen blood test in asymptomatic men for early prostate cancer detection in primary care: report from a UK clinical consensus.
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Harding TA, Martin RM, Merriel SW, Jones R, O'Sullivan JM, Kirby M, Olajide O, Norman A, Bhatt J, Hulson O, Martins T, Gnanapragasam VJ, Aning J, Burgess M, Rosario DJ, Pashayan N, Tesfai A, Norori N, Rylance A, and Seggie A
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- Humans, Male, United Kingdom, Middle Aged, Mass Screening methods, Practice Guidelines as Topic, Aged, Asymptomatic Diseases, Prostatic Neoplasms diagnosis, Prostatic Neoplasms blood, Prostate-Specific Antigen blood, Early Detection of Cancer, Primary Health Care, Consensus
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Background: Screening is not recommended for prostate cancer in the UK. Asymptomatic men aged ≥50 years can request a prostate-specific antigen (PSA) test following counselling on potential harms and benefits. There are areas of clinical uncertainty among GPs, resulting in the content and quality of counselling varying., Aim: To produce a consensus that can influence guidelines for UK primary care on the optimal use of the PSA test in asymptomatic men for early prostate cancer detection., Design and Setting: Prostate Cancer UK facilitated a RAND/UCLA consensus., Method: Statements covering five topics were developed with a subgroup of experts. A panel of 15 experts in prostate cancer scored (round one) statements on a scale of one (strongly disagree) to nine (strongly agree). Panellists met to discuss statements before rescoring (round two). A lived experience panel of seven men scored a subset of statements with outcomes fed into the main panel., Results: Of the initial 94 statements reviewed by the expert panel, a final 48/85 (56%) achieved consensus. In the absence of screening, there was consensus on proactive approaches to initiate discussions about the PSA test with men who were at higher-than-average risk., Conclusion: Improvements in the prostate cancer diagnostic pathway may have reduced some of the harms associated with PSA testing; however, several areas of uncertainty remain in relation to screening, including optimal PSA thresholds for referral and intervals for retesting. There is consensus on proactive approaches to testing in higher-than-average risk groups. This should prompt a review of current guidelines., (© The Authors.)
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- 2024
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4. Identifying proteomic risk factors for overall, aggressive, and early onset prostate cancer using Mendelian Randomisation and tumour spatial transcriptomics.
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Desai TA, Hedman ÅK, Dimitriou M, Koprulu M, Figiel S, Yin W, Johansson M, Watts EL, Atkins JR, Sokolov AV, Schiöth HB, Gunter MJ, Tsilidis KK, Martin RM, Pietzner M, Langenberg C, Mills IG, Lamb AD, Mälarstig A, Key TJ, Travis RC, and Smith-Byrne K
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- Humans, Male, Risk Factors, Genome-Wide Association Study, Biomarkers, Tumor genetics, Transcriptome, Genetic Predisposition to Disease, Gene Expression Profiling, Polymorphism, Single Nucleotide, Odds Ratio, Proteome, Age of Onset, Prostatic Neoplasms genetics, Prostatic Neoplasms pathology, Prostatic Neoplasms metabolism, Mendelian Randomization Analysis, Proteomics methods
- Abstract
Background: Understanding the role of circulating proteins in prostate cancer risk can reveal key biological pathways and identify novel targets for cancer prevention., Methods: We investigated the association of 2002 genetically predicted circulating protein levels with risk of prostate cancer overall, and of aggressive and early onset disease, using cis-pQTL Mendelian randomisation (MR) and colocalisation. Findings for proteins with support from both MR, after correction for multiple-testing, and colocalisation were replicated using two independent cancer GWAS, one of European and one of African ancestry. Proteins with evidence of prostate-specific tissue expression were additionally investigated using spatial transcriptomic data in prostate tumour tissue to assess their role in tumour aggressiveness. Finally, we mapped risk proteins to drug and ongoing clinical trials targets., Findings: We identified 20 proteins genetically linked to prostate cancer risk (14 for overall [8 specific], 7 for aggressive [3 specific], and 8 for early onset disease [2 specific]), of which the majority replicated where data were available. Among these were proteins associated with aggressive disease, such as PPA2 [Odds Ratio (OR) per 1 SD increment = 2.13, 95% CI: 1.54-2.93], PYY [OR = 1.87, 95% CI: 1.43-2.44] and PRSS3 [OR = 0.80, 95% CI: 0.73-0.89], and those associated with early onset disease, including EHPB1 [OR = 2.89, 95% CI: 1.99-4.21], POGLUT3 [OR = 0.76, 95% CI: 0.67-0.86] and TPM3 [OR = 0.47, 95% CI: 0.34-0.64]. We confirmed an inverse association of MSMB with prostate cancer overall [OR = 0.81, 95% CI: 0.80-0.82], and also found an inverse association with both aggressive [OR = 0.84, 95% CI: 0.82-0.86] and early onset disease [OR = 0.71, 95% CI: 0.68-0.74]. Using spatial transcriptomics data, we identified MSMB as the genome-wide top-most predictive gene to distinguish benign regions from high grade cancer regions that comparatively had five-fold lower MSMB expression. Additionally, ten proteins that were associated with prostate cancer risk also mapped to existing therapeutic interventions., Interpretation: Our findings emphasise the importance of proteomics for improving our understanding of prostate cancer aetiology and of opportunities for novel therapeutic interventions. Additionally, we demonstrate the added benefit of in-depth functional analyses to triangulate the role of risk proteins in the clinical aggressiveness of prostate tumours. Using these integrated methods, we identify a subset of risk proteins associated with aggressive and early onset disease as priorities for investigation for the future prevention and treatment of prostate cancer., Funding: This work was supported by Cancer Research UK (grant no. C8221/A29017)., Competing Interests: Declaration of interests This work was supported by Cancer Research UK (grant no. C8221/A29017). Anders Mälarstig, Åsa Hedman, and Marios Dimitriou are employees of Pfizer Inc. Anders Mälarstig declares stock options for Pfizer Inc. Alastair D. Lamb is Section Editor for Prostate Cancer and Web, British Journal of Urology International., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)
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- 2024
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5. Prostate-Specific Antigen Screening and 15-Year Prostate Cancer Mortality: A Secondary Analysis of the CAP Randomized Clinical Trial.
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Martin RM, Turner EL, Young GJ, Metcalfe C, Walsh EI, Lane JA, Sterne JAC, Noble S, Holding P, Ben-Shlomo Y, Williams NJ, Pashayan N, Bui MN, Albertsen PC, Seibert TM, Zietman AL, Oxley J, Adolfsson J, Mason MD, Davey Smith G, Neal DE, Hamdy FC, and Donovan JL
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- Aged, Humans, Male, Middle Aged, England epidemiology, Follow-Up Studies, Mass Screening methods, Mass Screening statistics & numerical data, Neoplasm Grading, Wales epidemiology, Ultrasonography, Image-Guided Biopsy, Early Detection of Cancer methods, Early Detection of Cancer statistics & numerical data, Prostate-Specific Antigen blood, Prostatic Neoplasms diagnosis, Prostatic Neoplasms epidemiology, Prostatic Neoplasms mortality, Prostatic Neoplasms therapy
- Abstract
Importance: The Cluster Randomized Trial of PSA Testing for Prostate Cancer (CAP) reported no effect of prostate-specific antigen (PSA) screening on prostate cancer mortality at a median 10-year follow-up (primary outcome), but the long-term effects of PSA screening on prostate cancer mortality remain unclear., Objective: To evaluate the effect of a single invitation for PSA screening on prostate cancer-specific mortality at a median 15-year follow-up compared with no invitation for screening., Design, Setting, and Participants: This secondary analysis of the CAP randomized clinical trial included men aged 50 to 69 years identified at 573 primary care practices in England and Wales. Primary care practices were randomized between September 25, 2001, and August 24, 2007, and men were enrolled between January 8, 2002, and January 20, 2009. Follow-up was completed on March 31, 2021., Intervention: Men received a single invitation for a PSA screening test with subsequent diagnostic tests if the PSA level was 3.0 ng/mL or higher. The control group received standard practice (no invitation)., Main Outcomes and Measures: The primary outcome was reported previously. Of 8 prespecified secondary outcomes, results of 4 were reported previously. The 4 remaining prespecified secondary outcomes at 15-year follow-up were prostate cancer-specific mortality, all-cause mortality, and prostate cancer stage and Gleason grade at diagnosis., Results: Of 415 357 eligible men (mean [SD] age, 59.0 [5.6] years), 98% were included in these analyses. Overall, 12 013 and 12 958 men with a prostate cancer diagnosis were in the intervention and control groups, respectively (15-year cumulative risk, 7.08% [95% CI, 6.95%-7.21%] and 6.94% [95% CI, 6.82%-7.06%], respectively). At a median 15-year follow-up, 1199 men in the intervention group (0.69% [95% CI, 0.65%-0.73%]) and 1451 men in the control group (0.78% [95% CI, 0.73%-0.82%]) died of prostate cancer (rate ratio [RR], 0.92 [95% CI, 0.85-0.99]; P = .03). Compared with the control, the PSA screening intervention increased detection of low-grade (Gleason score [GS] ≤6: 2.2% vs 1.6%; P < .001) and localized (T1/T2: 3.6% vs 3.1%; P < .001) disease but not intermediate (GS of 7), high-grade (GS ≥8), locally advanced (T3), or distally advanced (T4/N1/M1) tumors. There were 45 084 all-cause deaths in the intervention group (23.2% [95% CI, 23.0%-23.4%]) and 50 336 deaths in the control group (23.3% [95% CI, 23.1%-23.5%]) (RR, 0.97 [95% CI, 0.94-1.01]; P = .11). Eight of the prostate cancer deaths in the intervention group (0.7%) and 7 deaths in the control group (0.5%) were related to a diagnostic biopsy or prostate cancer treatment., Conclusions and Relevance: In this secondary analysis of a randomized clinical trial, a single invitation for PSA screening compared with standard practice without routine screening reduced prostate cancer deaths at a median follow-up of 15 years. However, the absolute reduction in deaths was small., Trial Registration: isrctn.org Identifier: ISRCTN92187251.
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- 2024
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6. Causal Estimation of Long-term Intervention Cost-effectiveness Using Genetic Instrumental Variables: An Application to Cancer.
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Dixon P, Martin RM, and Harrison S
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- Male, Humans, Cost-Benefit Analysis, Sodium-Glucose Transporter 2, Hypoglycemic Agents, Quality-Adjusted Life Years, Prostatic Neoplasms genetics, Breast Neoplasms genetics
- Abstract
Background: This article demonstrates a means of assessing long-term intervention cost-effectiveness in the absence of data from randomized controlled trials and without recourse to Markov simulation or similar types of cohort simulation., Methods: Using a Mendelian randomization study design, we developed causal estimates of the genetically predicted effect of bladder, breast, colorectal, lung, multiple myeloma, ovarian, prostate, and thyroid cancers on health care costs and quality-adjusted life-years (QALYs) using outcome data drawn from the UK Biobank cohort. We then used these estimates in a simulation model to estimate the cost-effectiveness of a hypothetical population-wide preventative intervention based on a repurposed class of antidiabetic drugs known as sodium-glucose cotransporter-2 (SGLT2) inhibitors very recently shown to reduce the odds of incident prostate cancer., Results: Genetic liability to prostate cancer and breast cancer had material causal impacts on either or both health care costs and QALYs. Mendelian randomization results for the less common cancers were associated with considerable uncertainty. SGLT2 inhibition was unlikely to be a cost-effective preventative intervention for prostate cancer, although this conclusion depended on the price at which these drugs would be offered for a novel anticancer indication., Implications: Our new causal estimates of cancer exposures on health economic outcomes may be used as inputs into decision-analytic models of cancer interventions such as screening programs or simulations of longer-term outcomes associated with therapies investigated in randomized controlled trials with short follow-ups. Our method allowed us to rapidly and efficiently estimate the cost-effectiveness of a hypothetical population-scale anticancer intervention to inform and complement other means of assessing long-term intervention value., Highlights: The article demonstrates a novel method of assessing long-term intervention cost-effectiveness without relying on randomized controlled trials or cohort simulations.Mendelian randomization was used to estimate the causal effects of certain cancers on health care costs and quality-adjusted life-years (QALYs) using data from the UK Biobank cohort.Given causal data on the association of different cancer exposures on costs and QALYs, it was possible to simulate the cost-effectiveness of an anticancer intervention.Genetic liability to prostate cancer and breast cancer significantly affected health care costs and QALYs, but the hypothetical intervention using SGLT2 inhibitors for prostate cancer may not be cost-effective, depending on the drug's price for the new anticancer indication. The methods we propose and implement can be used to efficiently estimate intervention cost-effectiveness and to inform decision making in all manner of preventative and therapeutic contexts.
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- 2024
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7. Leisure time television watching, computer use and risks of breast, colorectal and prostate cancer: A Mendelian randomisation analysis.
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Papadimitriou N, Kazmi N, Dimou N, Tsilidis KK, Martin RM, Lewis SJ, Lynch BM, Hoffmeister M, Kweon SS, Li L, Milne RL, Sakoda LC, Schoen RE, Phipps AI, Figueiredo JC, Peters U, Dixon-Suen SC, Gunter MJ, and Murphy N
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- Humans, Male, Female, Computers statistics & numerical data, Genome-Wide Association Study, Leisure Activities, Risk Factors, Prostatic Neoplasms genetics, Prostatic Neoplasms epidemiology, Prostatic Neoplasms etiology, Television statistics & numerical data, Breast Neoplasms genetics, Breast Neoplasms epidemiology, Breast Neoplasms etiology, Colorectal Neoplasms genetics, Colorectal Neoplasms epidemiology, Colorectal Neoplasms etiology, Mendelian Randomization Analysis, Sedentary Behavior
- Abstract
Background: Sedentary behaviours have been associated with increased risks of some common cancers in epidemiological studies; however, it is unclear if these associations are causal., Methods: We used univariable and multivariable two-sample Mendelian randomisation (MR) to examine potential causal relationships between sedentary behaviours and risks of breast, colorectal and prostate cancer. Genetic variants associated with self-reported leisure television watching and computer use were identified from a recent genome-wide association study (GWAS). Data related to cancer risk were obtained from cancer GWAS consortia. A series of sensitivity analyses were applied to examine the robustness of the results to the presence of confounding., Results: A 1-standard deviation (SD: 1.5 h/day) increment in hours of television watching increased risk of breast cancer (OR per 1-SD: 1.15, 95% confidence interval [CI]: 1.05-1.26) and colorectal cancer (OR per 1-SD: 1.32, 95% CI: 1.16-1.49) while there was little evidence of an association for prostate cancer risk (OR per 1-SD: 0.94, 95% CI: 0.84-1.06). After adjusting for years of education, the effect estimates for television watching were attenuated (breast cancer, OR per 1-SD: 1.08, 95% CI: 0.92-1.27; colorectal cancer, OR per 1-SD: 1.08, 95% CI: 0.90-1.31). Post hoc analyses showed that years of education might have a possible confounding and mediating role in the association between television watching with breast and colorectal cancer. Consistent results were observed for each cancer site according to sex (colorectal cancer), anatomical subsites and cancer subtypes. There was little evidence of associations between genetically predicted computer use and cancer risk., Conclusions: Our univariable analysis identified some positive associations between hours of television watching and risks of breast and colorectal cancer. However, further adjustment for additional lifestyle factors especially years of education attenuated these results. Future studies using objective measures of exposure can provide new insights into the possible role of sedentary behaviour in cancer development., (© 2023 World Health Organization; licensed by John Wiley & Sons Ltd. Cancer Medicine published by John Wiley & Sons Ltd.)
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- 2024
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8. Characterizing prostate cancer risk through multi-ancestry genome-wide discovery of 187 novel risk variants.
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Wang A, Shen J, Rodriguez AA, Saunders EJ, Chen F, Janivara R, Darst BF, Sheng X, Xu Y, Chou AJ, Benlloch S, Dadaev T, Brook MN, Plym A, Sahimi A, Hoffman TJ, Takahashi A, Matsuda K, Momozawa Y, Fujita M, Laisk T, Figuerêdo J, Muir K, Ito S, Liu X, Uchio Y, Kubo M, Kamatani Y, Lophatananon A, Wan P, Andrews C, Lori A, Choudhury PP, Schleutker J, Tammela TLJ, Sipeky C, Auvinen A, Giles GG, Southey MC, MacInnis RJ, Cybulski C, Wokolorczyk D, Lubinski J, Rentsch CT, Cho K, Mcmahon BH, Neal DE, Donovan JL, Hamdy FC, Martin RM, Nordestgaard BG, Nielsen SF, Weischer M, Bojesen SE, Røder A, Stroomberg HV, Batra J, Chambers S, Horvath L, Clements JA, Tilly W, Risbridger GP, Gronberg H, Aly M, Szulkin R, Eklund M, Nordstrom T, Pashayan N, Dunning AM, Ghoussaini M, Travis RC, Key TJ, Riboli E, Park JY, Sellers TA, Lin HY, Albanes D, Weinstein S, Cook MB, Mucci LA, Giovannucci E, Lindstrom S, Kraft P, Hunter DJ, Penney KL, Turman C, Tangen CM, Goodman PJ, Thompson IM Jr, Hamilton RJ, Fleshner NE, Finelli A, Parent MÉ, Stanford JL, Ostrander EA, Koutros S, Beane Freeman LE, Stampfer M, Wolk A, Håkansson N, Andriole GL, Hoover RN, Machiela MJ, Sørensen KD, Borre M, Blot WJ, Zheng W, Yeboah ED, Mensah JE, Lu YJ, Zhang HW, Feng N, Mao X, Wu Y, Zhao SC, Sun Z, Thibodeau SN, McDonnell SK, Schaid DJ, West CML, Barnett G, Maier C, Schnoeller T, Luedeke M, Kibel AS, Drake BF, Cussenot O, Cancel-Tassin G, Menegaux F, Truong T, Koudou YA, John EM, Grindedal EM, Maehle L, Khaw KT, Ingles SA, Stern MC, Vega A, Gómez-Caamaño A, Fachal L, Rosenstein BS, Kerns SL, Ostrer H, Teixeira MR, Paulo P, Brandão A, Watya S, Lubwama A, Bensen JT, Butler EN, Mohler JL, Taylor JA, Kogevinas M, Dierssen-Sotos T, Castaño-Vinyals G, Cannon-Albright L, Teerlink CC, Huff CD, Pilie P, Yu Y, Bohlender RJ, Gu J, Strom SS, Multigner L, Blanchet P, Brureau L, Kaneva R, Slavov C, Mitev V, Leach RJ, Brenner H, Chen X, Holleczek B, Schöttker B, Klein EA, Hsing AW, Kittles RA, Murphy AB, Logothetis CJ, Kim J, Neuhausen SL, Steele L, Ding YC, Isaacs WB, Nemesure B, Hennis AJM, Carpten J, Pandha H, Michael A, De Ruyck K, De Meerleer G, Ost P, Xu J, Razack A, Lim J, Teo SH, Newcomb LF, Lin DW, Fowke JH, Neslund-Dudas CM, Rybicki BA, Gamulin M, Lessel D, Kulis T, Usmani N, Abraham A, Singhal S, Parliament M, Claessens F, Joniau S, Van den Broeck T, Gago-Dominguez M, Castelao JE, Martinez ME, Larkin S, Townsend PA, Aukim-Hastie C, Bush WS, Aldrich MC, Crawford DC, Srivastava S, Cullen J, Petrovics G, Casey G, Wang Y, Tettey Y, Lachance J, Tang W, Biritwum RB, Adjei AA, Tay E, Truelove A, Niwa S, Yamoah K, Govindasami K, Chokkalingam AP, Keaton JM, Hellwege JN, Clark PE, Jalloh M, Gueye SM, Niang L, Ogunbiyi O, Shittu O, Amodu O, Adebiyi AO, Aisuodionoe-Shadrach OI, Ajibola HO, Jamda MA, Oluwole OP, Nwegbu M, Adusei B, Mante S, Darkwa-Abrahams A, Diop H, Gundell SM, Roobol MJ, Jenster G, van Schaik RHN, Hu JJ, Sanderson M, Kachuri L, Varma R, McKean-Cowdin R, Torres M, Preuss MH, Loos RJF, Zawistowski M, Zöllner S, Lu Z, Van Den Eeden SK, Easton DF, Ambs S, Edwards TL, Mägi R, Rebbeck TR, Fritsche L, Chanock SJ, Berndt SI, Wiklund F, Nakagawa H, Witte JS, Gaziano JM, Justice AC, Mancuso N, Terao C, Eeles RA, Kote-Jarai Z, Madduri RK, Conti DV, and Haiman CA
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- Humans, Male, Black People genetics, Genome-Wide Association Study, Hispanic or Latino genetics, Polymorphism, Single Nucleotide, Risk Factors, White People genetics, Asian People genetics, Genetic Predisposition to Disease, Prostatic Neoplasms genetics
- Abstract
The transferability and clinical value of genetic risk scores (GRSs) across populations remain limited due to an imbalance in genetic studies across ancestrally diverse populations. Here we conducted a multi-ancestry genome-wide association study of 156,319 prostate cancer cases and 788,443 controls of European, African, Asian and Hispanic men, reflecting a 57% increase in the number of non-European cases over previous prostate cancer genome-wide association studies. We identified 187 novel risk variants for prostate cancer, increasing the total number of risk variants to 451. An externally replicated multi-ancestry GRS was associated with risk that ranged from 1.8 (per standard deviation) in African ancestry men to 2.2 in European ancestry men. The GRS was associated with a greater risk of aggressive versus non-aggressive disease in men of African ancestry (P = 0.03). Our study presents novel prostate cancer susceptibility loci and a GRS with effective risk stratification across ancestry groups., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)
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- 2023
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9. Endemic statistical paradoxes in epidemiologic studies distort knowledge on prostate cancer: mitigation and caution of fallacies in prostate cancer causal epidemiological studies.
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Cussenot O, Fromont G, Cancel-Tassin G, Hamdy FC, and Martin RM
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- Male, Humans, Risk Factors, Epidemiologic Studies, Prostate-Specific Antigen, Prostatic Neoplasms diagnosis, Prostatic Neoplasms epidemiology, Prostatic Neoplasms prevention & control
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Purpose of Review: Many studies on epidemiology of prostate cancer (PCa) are based on a diagnosis of PCa using PSA (prostate-specific antigen) level. However, biases can distort the interpretation of the results, which in turn limits policy and decision making on public health prevention strategies or clinical guidelines. The main confusion is to interpret the posterior probability of the outcome following the exposure as a change in the prevalence of the disease outcome, whereas this change reflects only the predictive values of the PSA test induced by the exposure of interest., Recent Findings: Many studies report potential causal factors involved in PCa risk. However, the lack of integration of how physiological changes in PSA values are associated with the exposures being investigated, they explain in part contradictory and controversial results on PCa risk factors in the literature., Summary: A strategy to perform case--control studies based on PSA stratification is suggested to avoid misinterpretation related to PSA misclassification. Real data are analysed, and we show that we can exploit the mechanism of selection biases using different modalities of controls recruitment based on biomarker stratification to distinguish real from false causal factors., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)
- Published
- 2023
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10. Genetic predisposition to metabolically unfavourable adiposity and prostate cancer risk: A Mendelian randomization analysis.
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Perez-Cornago A, Smith-Byrne K, Hazelwood E, Watling CZ, Martin S, Frayling T, Lewis S, Martin RM, Yaghootkar H, Travis RC, and Key TJ
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- Male, Humans, Genetic Predisposition to Disease, Mendelian Randomization Analysis, Obesity complications, Obesity epidemiology, Obesity genetics, Body Mass Index, Genome-Wide Association Study, Polymorphism, Single Nucleotide, Adiposity genetics, Prostatic Neoplasms epidemiology, Prostatic Neoplasms genetics
- Abstract
Background: The associations of adiposity with aggressive prostate cancer risk are unclear. Using two-sample Mendelian randomization, we assessed the association of metabolically unfavourable adiposity (UFA), favourable adiposity (FA) and for comparison body mass index (BMI), with prostate cancer, including aggressive prostate cancer., Methods: We examined the association of these genetically predicted adiposity-related traits with risk of prostate cancer overall, aggressive and early onset disease using outcome summary statistics from the PRACTICAL consortium (including 15,167 aggressive cases)., Results: In inverse-variance weighted models, there was little evidence that genetically predicted one standard deviation higher UFA, FA and BMI were associated with aggressive prostate cancer [OR: 0.85 (95% CI:0.61-1.19), 0.80 (0.53-1.23) and 0.97 (0.88-1.08), respectively]; these associations were largely consistent in sensitivity analyses accounting for horizontal pleiotropy. There was no strong evidence that genetically determined UFA, FA or BMI were associated with overall prostate cancer or early age of onset prostate cancer., Conclusions: We did not find differences in the associations of UFA and FA with prostate cancer risk, which suggest that adiposity is unlikely to influence prostate cancer via the metabolic factors assessed; however, these did not cover some aspects related to metabolic health that may link obesity with aggressive prostate cancer, which should be explored in future studies., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)
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- 2023
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11. Genetically proxied glucose-lowering drug target perturbation and risk of cancer: a Mendelian randomisation analysis.
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Yarmolinsky J, Bouras E, Constantinescu A, Burrows K, Bull CJ, Vincent EE, Martin RM, Dimopoulou O, Lewis SJ, Moreno V, Vujkovic M, Chang KM, Voight BF, Tsao PS, Gunter MJ, Hampe J, Pellatt AJ, Pharoah PDP, Schoen RE, Gallinger S, Jenkins MA, Pai RK, Gill D, and Tsilidis KK
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- Male, Humans, Risk Factors, Glucose, Genome-Wide Association Study, PPAR gamma genetics, Mendelian Randomization Analysis, Polymorphism, Single Nucleotide genetics, Diabetes Mellitus, Type 2 drug therapy, Diabetes Mellitus, Type 2 genetics, Diabetes Mellitus, Type 2 complications, Breast Neoplasms genetics, Prostatic Neoplasms complications, Colorectal Neoplasms genetics
- Abstract
Aims/hypothesis: Epidemiological studies have generated conflicting findings on the relationship between glucose-lowering medication use and cancer risk. Naturally occurring variation in genes encoding glucose-lowering drug targets can be used to investigate the effect of their pharmacological perturbation on cancer risk., Methods: We developed genetic instruments for three glucose-lowering drug targets (peroxisome proliferator activated receptor γ [PPARG]; sulfonylurea receptor 1 [ATP binding cassette subfamily C member 8 (ABCC8)]; glucagon-like peptide 1 receptor [GLP1R]) using summary genetic association data from a genome-wide association study of type 2 diabetes in 148,726 cases and 965,732 controls in the Million Veteran Program. Genetic instruments were constructed using cis-acting genome-wide significant (p<5×10
-8 ) SNPs permitted to be in weak linkage disequilibrium (r2 <0.20). Summary genetic association estimates for these SNPs were obtained from genome-wide association study (GWAS) consortia for the following cancers: breast (122,977 cases, 105,974 controls); colorectal (58,221 cases, 67,694 controls); prostate (79,148 cases, 61,106 controls); and overall (i.e. site-combined) cancer (27,483 cases, 372,016 controls). Inverse-variance weighted random-effects models adjusting for linkage disequilibrium were employed to estimate causal associations between genetically proxied drug target perturbation and cancer risk. Co-localisation analysis was employed to examine robustness of findings to violations of Mendelian randomisation (MR) assumptions. A Bonferroni correction was employed as a heuristic to define associations from MR analyses as 'strong' and 'weak' evidence., Results: In MR analysis, genetically proxied PPARG perturbation was weakly associated with higher risk of prostate cancer (for PPARG perturbation equivalent to a 1 unit decrease in inverse rank normal transformed HbA1c : OR 1.75 [95% CI 1.07, 2.85], p=0.02). In histological subtype-stratified analyses, genetically proxied PPARG perturbation was weakly associated with lower risk of oestrogen receptor-positive breast cancer (OR 0.57 [95% CI 0.38, 0.85], p=6.45×10-3 ). In co-localisation analysis, however, there was little evidence of shared causal variants for type 2 diabetes liability and cancer endpoints in the PPARG locus, although these analyses were likely underpowered. There was little evidence to support associations between genetically proxied PPARG perturbation and colorectal or overall cancer risk or between genetically proxied ABCC8 or GLP1R perturbation with risk across cancer endpoints., Conclusions/interpretation: Our drug target MR analyses did not find consistent evidence to support an association of genetically proxied PPARG, ABCC8 or GLP1R perturbation with breast, colorectal, prostate or overall cancer risk. Further evaluation of these drug targets using alternative molecular epidemiological approaches may help to further corroborate the findings presented in this analysis., Data Availability: Summary genetic association data for select cancer endpoints were obtained from the public domain: breast cancer ( https://bcac.ccge.medschl.cam.ac.uk/bcacdata/ ); and overall prostate cancer ( http://practical.icr.ac.uk/blog/ ). Summary genetic association data for colorectal cancer can be accessed by contacting GECCO (kafdem at fredhutch.org). Summary genetic association data on advanced prostate cancer can be accessed by contacting PRACTICAL (practical at icr.ac.uk). Summary genetic association data on type 2 diabetes from Vujkovic et al (Nat Genet, 2020) can be accessed through dbGAP under accession number phs001672.v3.p1 (pha004945.1 refers to the European-specific summary statistics). UK Biobank data can be accessed by registering with UK Biobank and completing the registration form in the Access Management System (AMS) ( https://www.ukbiobank.ac.uk/enable-your-research/apply-for-access )., (© 2023. The Author(s).)- Published
- 2023
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12. Impact of PSA testing on secondary care costs in England and Wales: estimates from the Cluster randomised triAl of PSA testing for Prostate cancer (CAP).
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Thorn JC, Turner EL, Walsh EI, Donovan JL, Neal DE, Hamdy FC, Martin RM, and Noble SM
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- Male, Humans, Wales, Secondary Care, Mass Screening, England, Prostate-Specific Antigen, Prostatic Neoplasms diagnosis
- Abstract
Background: Screening men for prostate cancer using prostate-specific antigen (PSA) testing remains controversial. We aimed to estimate the likely budgetary impact on secondary care in England and Wales to inform screening decision makers., Methods: The Cluster randomised triAl of PSA testing for Prostate cancer study (CAP) compared a single invitation to men aged 50-69 for a PSA test with usual care (no screening). Routinely collected hospital care data were obtained for all men in CAP, and NHS reference costs were mapped to each event via Healthcare Resource Group (HRG) codes. Secondary-care costs per man per year were calculated, and cost differences (and population-level estimates) between arms were derived annually for the first five years following randomisation., Results: In the first year post-randomisation, secondary-care costs averaged across all men (irrespective of a prostate cancer diagnosis) in the intervention arm (n = 189279) were £44.80 (95% confidence interval: £18.30-£71.30) higher than for men in the control arm (n = 219357). Extrapolated to a population level, the introduction of a single PSA screening invitation could lead to additional secondary care costs of £314 million., Conclusions: Introducing a single PSA screening test for men aged 50-69 across England and Wales could lead to very high initial secondary-care costs., (© 2023. The Author(s).)
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- 2023
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13. Fifteen-Year Outcomes after Monitoring, Surgery, or Radiotherapy for Prostate Cancer.
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Hamdy FC, Donovan JL, Lane JA, Metcalfe C, Davis M, Turner EL, Martin RM, Young GJ, Walsh EI, Bryant RJ, Bollina P, Doble A, Doherty A, Gillatt D, Gnanapragasam V, Hughes O, Kockelbergh R, Kynaston H, Paul A, Paez E, Powell P, Rosario DJ, Rowe E, Mason M, Catto JWF, Peters TJ, Oxley J, Williams NJ, Staffurth J, and Neal DE
- Subjects
- Humans, Male, Androgen Antagonists therapeutic use, Androgens, Follow-Up Studies, Prostatectomy, Watchful Waiting, Middle Aged, Aged, Radiotherapy, Risk Assessment, Prostate-Specific Antigen blood, Prostatic Neoplasms blood, Prostatic Neoplasms diagnosis, Prostatic Neoplasms mortality, Prostatic Neoplasms therapy
- Abstract
Background: Between 1999 and 2009 in the United Kingdom, 82,429 men between 50 and 69 years of age received a prostate-specific antigen (PSA) test. Localized prostate cancer was diagnosed in 2664 men. Of these men, 1643 were enrolled in a trial to evaluate the effectiveness of treatments, with 545 randomly assigned to receive active monitoring, 553 to undergo prostatectomy, and 545 to undergo radiotherapy., Methods: At a median follow-up of 15 years (range, 11 to 21), we compared the results in this population with respect to death from prostate cancer (the primary outcome) and death from any cause, metastases, disease progression, and initiation of long-term androgen-deprivation therapy (secondary outcomes)., Results: Follow-up was complete for 1610 patients (98%). A risk-stratification analysis showed that more than one third of the men had intermediate or high-risk disease at diagnosis. Death from prostate cancer occurred in 45 men (2.7%): 17 (3.1%) in the active-monitoring group, 12 (2.2%) in the prostatectomy group, and 16 (2.9%) in the radiotherapy group (P = 0.53 for the overall comparison). Death from any cause occurred in 356 men (21.7%), with similar numbers in all three groups. Metastases developed in 51 men (9.4%) in the active-monitoring group, in 26 (4.7%) in the prostatectomy group, and in 27 (5.0%) in the radiotherapy group. Long-term androgen-deprivation therapy was initiated in 69 men (12.7%), 40 (7.2%), and 42 (7.7%), respectively; clinical progression occurred in 141 men (25.9%), 58 (10.5%), and 60 (11.0%), respectively. In the active-monitoring group, 133 men (24.4%) were alive without any prostate cancer treatment at the end of follow-up. No differential effects on cancer-specific mortality were noted in relation to the baseline PSA level, tumor stage or grade, or risk-stratification score. No treatment complications were reported after the 10-year analysis., Conclusions: After 15 years of follow-up, prostate cancer-specific mortality was low regardless of the treatment assigned. Thus, the choice of therapy involves weighing trade-offs between benefits and harms associated with treatments for localized prostate cancer. (Funded by the National Institute for Health and Care Research; ProtecT Current Controlled Trials number, ISRCTN20141297; ClinicalTrials.gov number, NCT02044172.)., (Copyright © 2023 Massachusetts Medical Society.)
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- 2023
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14. Patient-Reported Outcomes 12 Years after Localized Prostate Cancer Treatment.
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Donovan JL, Hamdy FC, Lane JA, Young GJ, Metcalfe C, Walsh EI, Davis M, Steuart-Feilding T, Blazeby JM, Avery KNL, Martin RM, Bollina P, Doble A, Doherty A, Gillatt D, Gnanapragasam V, Hughes O, Kockelbergh R, Kynaston H, Paul A, Paez E, Powell P, Rosario DJ, Rowe E, Mason M, Catto JWF, Peters TJ, Wade J, Turner EL, Williams NJ, Oxley J, Staffurth J, Bryant RJ, and Neal DE
- Subjects
- Male, Humans, Androgen Antagonists, Treatment Outcome, Quality of Life, Patient Reported Outcome Measures, Prostatic Neoplasms radiotherapy
- Abstract
BACKGROUND: Long-term patient-reported outcomes are needed to inform treatment decisions for localized prostate cancer. METHODS: Patient-reported outcomes of 1643 randomly assigned participants in the ProtecT (Prostate Testing for Cancer and Treatment) trial were evaluated to assess the functional and quality-of-life impacts of prostatectomy, radiotherapy with neoadjuvant androgen deprivation, and active monitoring. This article focuses on the outcomes of the randomly assigned participants from 7 to 12 years using mixed effects linear and logistic models. RESULTS: Response rates exceeded 80% for most measures. Among the randomized groups over 7 to 12 years, generic quality-of-life scores were similar. Among those in the prostatectomy group, urinary leakage requiring pads occurred in 18 to 24% of patients over 7 to 12 years, compared with 9 to 11% in the active monitoring group and 3 to 8% in the radiotherapy group. In the prostatectomy group, 18% reported erections sufficient for intercourse at 7 years, compared with 30% in the active monitoring and 27% in the radiotherapy groups; all converged to low levels of potency by year 12. Nocturia (voiding at least twice per night) occurred in 34% in the prostatectomy group compared with 48% in the radiotherapy group and 47% in the active monitoring group at 12 years. Fecal leakage affected 12% in the radiotherapy group compared with 6% in the other groups by year 12. The active monitoring group experienced gradual age-related declines in sexual and urinary function, avoiding radical treatment effects unless they changed management. CONCLUSIONS: ProtecT provides robust evidence about continued impacts of treatments in the long term. These data allow patients newly diagnosed with localized prostate cancer and their clinicians to assess the trade-offs between treatment harms and benefits and enable better informed and prudent treatment decisions. (Funded by the UK National Institute for Health and Care Research Health Technology Assessment Programme projects 96/20/06 and 96/20/99; ISRCTN number, ISRCTN20141297; ClinicalTrials.gov number, NCT02044172.)
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- 2023
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15. Associations of CTCF and FOXA1 with androgen and IGF pathways in men with localized prostate cancer.
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Barker R, Biernacka K, Kingshott G, Sewell A, Gwiti P, Martin RM, Lane JA, McGeagh L, Koupparis A, Rowe E, Oxley J, Perks CM, and Holly JMP
- Subjects
- Male, Humans, Androgens, Insulin-Like Growth Factor Binding Protein 2 genetics, CCCTC-Binding Factor genetics, Cell Line, Tumor, TOR Serine-Threonine Kinases metabolism, Insulin-Like Growth Factor I metabolism, Hepatocyte Nuclear Factor 3-alpha genetics, Hepatocyte Nuclear Factor 3-alpha metabolism, Prostatic Neoplasms genetics, Prostatic Neoplasms metabolism, Somatomedins genetics, Somatomedins metabolism
- Abstract
Aims: To examine associations between the transcription factors CCCTC-binding factor (CTCF) and forkhead box protein A1 (FOXA1) and the androgen receptor (AR) and their association with components of the insulin-like growth factor (IGF)-pathway in a cohort of men with localized prostate cancer., Methods: Using prostate tissue samples collected during the Prostate cancer: Evidence of Exercise and Nutrition Trial (PrEvENT) trial (N = 70 to 92, depending on section availability), we assessed the abundance of CTCF, FOXA1, AR, IGFIR, p-mTOR, PTEN and IGFBP-2 proteins using a modified version of the Allred scoring system. Validation studies were performed using large, publicly available datasets (TCGA) (N = 489)., Results: We identified a strong correlation between CTCF and AR staining with benign prostate tissue. CTCF also strongly associated with the IGFIR, with PTEN and with phospho-mTOR. FOXA1 was also correlated with staining for the IGF-IR, with IGFBP-2 and with staining for activated phosphor-mTOR. The staining for the IGF-IR was strongly correlated with the AR., Conclusion: Our findings emphasise the close and complex links between the endocrine controls, well known to play an important role in prostate cancer, and the transcription factors implicated by the recent genetic evidence., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)
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- 2023
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16. Circulating insulin-like growth factors and risks of overall, aggressive and early-onset prostate cancer: a collaborative analysis of 20 prospective studies and Mendelian randomization analysis.
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Watts EL, Perez-Cornago A, Fensom GK, Smith-Byrne K, Noor U, Andrews CD, Gunter MJ, Holmes MV, Martin RM, Tsilidis KK, Albanes D, Barricarte A, Bueno-de-Mesquita HB, Cohn BA, Deschasaux-Tanguy M, Dimou NL, Ferrucci L, Flicker L, Freedman ND, Giles GG, Giovannucci EL, Haiman CA, Hankey GJ, Holly JMP, Huang J, Huang WY, Hurwitz LM, Kaaks R, Kubo T, Le Marchand L, MacInnis RJ, Männistö S, Metter EJ, Mikami K, Mucci LA, Olsen AW, Ozasa K, Palli D, Penney KL, Platz EA, Pollak MN, Roobol MJ, Schaefer CA, Schenk JM, Stattin P, Tamakoshi A, Thysell E, Tsai CJ, Touvier M, Van Den Eeden SK, Weiderpass E, Weinstein SJ, Wilkens LR, Yeap BB, Allen NE, Key TJ, and Travis RC
- Subjects
- Male, Humans, Insulin-Like Growth Factor II genetics, Insulin-Like Growth Factor II metabolism, Insulin-Like Growth Factor Binding Protein 3 genetics, Insulin-Like Growth Factor Binding Protein 3 metabolism, Insulin-Like Growth Factor Binding Protein 1 genetics, Prospective Studies, Mendelian Randomization Analysis, Risk Factors, Case-Control Studies, Insulin-Like Growth Factor I genetics, Prostatic Neoplasms epidemiology, Prostatic Neoplasms genetics
- Abstract
Background: Previous studies had limited power to assess the associations of circulating insulin-like growth factors (IGFs) and IGF-binding proteins (IGFBPs) with clinically relevant prostate cancer as a primary endpoint, and the association of genetically predicted IGF-I with aggressive prostate cancer is not known. We aimed to investigate the associations of IGF-I, IGF-II, IGFBP-1, IGFBP-2 and IGFBP-3 concentrations with overall, aggressive and early-onset prostate cancer., Methods: Prospective analysis of biomarkers using the Endogenous Hormones, Nutritional Biomarkers and Prostate Cancer Collaborative Group dataset (up to 20 studies, 17 009 prostate cancer cases, including 2332 aggressive cases). Odds ratios (OR) and 95% confidence intervals (CI) for prostate cancer were estimated using conditional logistic regression. For IGF-I, two-sample Mendelian randomization (MR) analysis was undertaken using instruments identified using UK Biobank (158 444 men) and outcome data from PRACTICAL (up to 85 554 cases, including 15 167 aggressive cases). Additionally, we used colocalization to rule out confounding by linkage disequilibrium., Results: In observational analyses, IGF-I was positively associated with risks of overall (OR per 1 SD = 1.09: 95% CI 1.07, 1.11), aggressive (1.09: 1.03, 1.16) and possibly early-onset disease (1.11: 1.00, 1.24); associations were similar in MR analyses (OR per 1 SD = 1.07: 1.00, 1.15; 1.10: 1.01, 1.20; and 1.13; 0.98, 1.30, respectively). Colocalization also indicated a shared signal for IGF-I and prostate cancer (PP4: 99%). Men with higher IGF-II (1.06: 1.02, 1.11) and IGFBP-3 (1.08: 1.04, 1.11) had higher risks of overall prostate cancer, whereas higher IGFBP-1 was associated with a lower risk (0.95: 0.91, 0.99); these associations were attenuated following adjustment for IGF-I., Conclusions: These findings support the role of IGF-I in the development of prostate cancer, including for aggressive disease., (© The Author(s) 2022. Published by Oxford University Press on behalf of the International Epidemiological Association.)
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- 2023
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17. Cost-Effectiveness Analysis of Prostate Cancer Screening in the UK: A Decision Model Analysis Based on the CAP Trial.
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Keeney E, Sanghera S, Martin RM, Gulati R, Wiklund F, Walsh EI, Donovan JL, Hamdy F, Neal DE, Lane JA, Turner EL, Thom H, and Clements MS
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- Humans, Male, Middle Aged, Adult, Cost-Benefit Analysis, Early Detection of Cancer, State Medicine, Quality-Adjusted Life Years, Mass Screening methods, United Kingdom, Prostate-Specific Antigen, Prostatic Neoplasms diagnosis, Prostatic Neoplasms pathology
- Abstract
Background and Objective: Most guidelines in the UK, Europe and North America do not recommend organised population-wide screening for prostate cancer. Prostate-specific antigen-based screening can reduce prostate cancer-specific mortality, but there are concerns about overdiagnosis, overtreatment and economic value. The aim was therefore to assess the cost effectiveness of eight potential screening strategies in the UK., Methods: We used a cost-utility analysis with an individual-based simulation model. The model was calibrated to data from the 10-year follow-up of the Cluster Randomised Trial of PSA Testing for Prostate Cancer (CAP). Treatment effects were modelled using data from the Prostate Testing for Cancer and Treatment (ProtecT) trial. The participants were a hypothetical population of 10 million men in the UK followed from age 30 years to death. The strategies were: no screening; five age-based screening strategies; adaptive screening, where men with an initial prostate-specific antigen level of < 1.5 ng/mL are screened every 6 years and those above this level are screened every 4 years; and two polygenic risk-stratified screening strategies. We assumed the use of pre-biopsy multi-parametric magnetic resonance imaging for men with prostate-specific antigen ≥ 3 ng/mL and combined transrectal ultrasound-guided and targeted biopsies. The main outcome measures were projected lifetime costs and quality-adjusted life-years from a National Health Service perspective., Results: All screening strategies increased costs compared with no screening, with the majority also increasing quality-adjusted life-years. At willingness-to-pay thresholds of £20,000 or £30,000 per quality-adjusted life-year gained, a once-off screening at age 50 years was optimal, although this was sensitive to the utility estimates used. Although the polygenic risk-stratified screening strategies were not on the cost-effectiveness frontier, there was evidence to suggest that they were less cost ineffective than the alternative age-based strategies., Conclusions: Of the prostate-specific antigen-based strategies compared, only a once-off screening at age 50 years was potentially cost effective at current UK willingness-to-pay thresholds. An additional follow-up of CAP to 15 years may reduce uncertainty about the cost effectiveness of the screening strategies., (© 2022. The Author(s).)
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- 2022
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18. Screening asymptomatic men for prostate cancer: A comparison of international guidelines on prostate-specific antigen testing.
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Jackson SD, de la Rue MR, Greenslade TP, John AM, Wahid S, Martin RM, Williams NJ, and Turner EL
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- Adult, Early Detection of Cancer, Humans, Male, Mass Screening, Prostate-Specific Antigen, Prostatic Neoplasms diagnosis
- Abstract
Objective: To summarise and compare the key recommendations on prostate-specific antigen (PSA)-based screening for prostate cancer, and so highlight where more evidence is required to facilitate consistent recommendations., Methods: The Medline database and websites of 18 national screening organisations and professional associations were searched between January 2010 and November 2020 to identify screening guidelines published in English, considering recent clinical trials., Results: Population-based PSA testing of asymptomatic men is not widely recommended. Guidelines emphasize shared patient-clinician decision making. For 'average-risk' men choosing to be screened, the recommended age varies from 50-55 to 70 years, alongside consideration of life expectancy (ranging from 7-15 years). Screening intervals, when specified, are biennial (most common), annual, or determined from baseline PSA. The earliest age for screening high-risk men (frequently defined as of African descent or with a family history of prostate cancer) is 40 years, but recommendations often defer to clinical judgement., Conclusions: Population screening of asymptomatic men is not widely recommended. Instead, balancing the potential harms and benefits of PSA testing is endorsed. Variation between guidelines stems from differing interpretations of key trials and could lead to clinician-dependent screening views. The development of clinical decision aids and international consensus on guidelines may help reduce national and international variation on how men are counselled.
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- 2022
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19. Circulating free testosterone and risk of aggressive prostate cancer: Prospective and Mendelian randomisation analyses in international consortia.
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Watts EL, Perez-Cornago A, Fensom GK, Smith-Byrne K, Noor U, Andrews CD, Gunter MJ, Holmes MV, Martin RM, Tsilidis KK, Albanes D, Barricarte A, Bueno-de-Mesquita B, Chen C, Cohn BA, Dimou NL, Ferrucci L, Flicker L, Freedman ND, Giles GG, Giovannucci EL, Goodman GE, Haiman CA, Hankey GJ, Huang J, Huang WY, Hurwitz LM, Kaaks R, Knekt P, Kubo T, Langseth H, Laughlin G, Le Marchand L, Luostarinen T, MacInnis RJ, Mäenpää HO, Männistö S, Metter EJ, Mikami K, Mucci LA, Olsen AW, Ozasa K, Palli D, Penney KL, Platz EA, Rissanen H, Sawada N, Schenk JM, Stattin P, Tamakoshi A, Thysell E, Tsai CJ, Tsugane S, Vatten L, Weiderpass E, Weinstein SJ, Wilkens LR, Yeap BB, Allen NE, Key TJ, and Travis RC
- Subjects
- Biomarkers, Humans, Male, Mendelian Randomization Analysis, Prostate, Risk Factors, Testosterone, Prostatic Neoplasms epidemiology, Prostatic Neoplasms genetics, Sex Hormone-Binding Globulin analysis
- Abstract
Previous studies had limited power to assess the associations of testosterone with aggressive disease as a primary endpoint. Further, the association of genetically predicted testosterone with aggressive disease is not known. We investigated the associations of calculated free and measured total testosterone and sex hormone-binding globulin (SHBG) with aggressive, overall and early-onset prostate cancer. In blood-based analyses, odds ratios (OR) and 95% confidence intervals (CI) for prostate cancer were estimated using conditional logistic regression from prospective analysis of biomarker concentrations in the Endogenous Hormones, Nutritional Biomarkers and Prostate Cancer Collaborative Group (up to 25 studies, 14 944 cases and 36 752 controls, including 1870 aggressive prostate cancers). In Mendelian randomisation (MR) analyses, using instruments identified using UK Biobank (up to 194 453 men) and outcome data from PRACTICAL (up to 79 148 cases and 61 106 controls, including 15 167 aggressive cancers), ORs were estimated using the inverse-variance weighted method. Free testosterone was associated with aggressive disease in MR analyses (OR per 1 SD = 1.23, 95% CI = 1.08-1.40). In blood-based analyses there was no association with aggressive disease overall, but there was heterogeneity by age at blood collection (OR for men aged <60 years 1.14, CI = 1.02-1.28; P
het = .0003: inverse association for older ages). Associations for free testosterone were positive for overall prostate cancer (MR: 1.20, 1.08-1.34; blood-based: 1.03, 1.01-1.05) and early-onset prostate cancer (MR: 1.37, 1.09-1.73; blood-based: 1.08, 0.98-1.19). SHBG and total testosterone were inversely associated with overall prostate cancer in blood-based analyses, with null associations in MR analysis. Our results support free testosterone, rather than total testosterone, in the development of prostate cancer, including aggressive subgroups., (© 2022 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)- Published
- 2022
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20. Functional and quality of life outcomes of localised prostate cancer treatments (Prostate Testing for Cancer and Treatment [ProtecT] study).
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Lane JA, Donovan JL, Young GJ, Davis M, Walsh EI, Avery KNL, Blazeby JM, Mason MD, Martin RM, Peters TJ, Turner EL, Wade J, Bollina P, Catto JWF, Doherty A, Gillatt D, Gnanapragasam V, Hughes O, Kockelbergh R, Kynaston H, Oxley J, Paul A, Paez E, Rosario DJ, Rowe E, Staffurth J, Neal DE, Hamdy FC, and Metcalfe C
- Subjects
- Aged, Androgen Antagonists, Humans, Male, Middle Aged, Prostate pathology, Prostatectomy, Quality of Life, Treatment Outcome, Brachytherapy, Erectile Dysfunction, Prostatic Neoplasms pathology
- Abstract
Objective: To investigate the functional and quality of life (QoL) outcomes of treatments for localised prostate cancer and inform treatment decision-making., Patients and Methods: Men aged 50-69 years diagnosed with localised prostate cancer by prostate-specific antigen testing and biopsies at nine UK centres in the Prostate Testing for Cancer and Treatment (ProtecT) trial were randomised to, or chose one of, three treatments. Of 2565 participants, 1135 men received active monitoring (AM), 750 a radical prostatectomy (RP), 603 external-beam radiotherapy (EBRT) with concurrent androgen-deprivation therapy (ADT) and 77 low-dose-rate brachytherapy (BT, not a randomised treatment). Patient-reported outcome measures (PROMs) completed annually for 6 years were analysed by initial treatment and censored for subsequent treatments. Mixed effects models were adjusted for baseline characteristics using propensity scores., Results: Treatment-received analyses revealed different impacts of treatments over 6 years. Men remaining on AM experienced gradual declines in sexual and urinary function with age (e.g., increases in erectile dysfunction from 35% of men at baseline to 53% at 6 years and nocturia similarly from 20% to 38%). Radical treatment impacts were immediate and continued over 6 years. After RP, 95% of men reported erectile dysfunction persisting for 85% at 6 years, and after EBRT this was reported by 69% and 74%, respectively (P < 0.001 compared with AM). After RP, 36% of men reported urinary leakage requiring at least 1 pad/day, persisting for 20% at 6 years, compared with no change in men receiving EBRT or AM (P < 0.001). Worse bowel function and bother (e.g., bloody stools 6% at 6 years and faecal incontinence 10%) was experienced by men after EBRT than after RP or AM (P < 0.001) with lesser effects after BT. No treatment affected mental or physical QoL., Conclusion: Treatment decision-making for localised prostate cancer can be informed by these 6-year functional and QoL outcomes., (© 2022 The Authors. BJU International published by John Wiley & Sons Ltd on behalf of BJU International.)
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- 2022
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21. Does testosterone mediate the relationship between vitamin D and prostate cancer progression? A systematic review and meta-analysis.
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Robles LA, Harrison S, Tan VY, Beynon R, McAleenan A, Higgins JP, Martin RM, and Lewis SJ
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- Humans, Male, Prostate pathology, Testosterone, Vitamins, Prostatic Neoplasms pathology, Vitamin D
- Abstract
Purpose: Observational studies and randomized controlled trials (RCTs) have shown an association between vitamin D levels and prostate cancer progression. However, evidence of direct causality is sparse and studies have not examined biological mechanisms, which can provide information on plausibility and strengthen the evidence for causality., Methods: We used the World Cancer Research Fund International/University of Bristol two-stage framework for mechanistic systematic reviews. In stage one, both text mining of published literature and expert opinion identified testosterone as a plausible biological mechanism. In stage two, we performed a systematic review and meta-analysis to assess the evidence from both human and animal studies examining the effect of vitamin D on testosterone, and testosterone on advanced prostate cancer (diagnostic Gleason score of ≥ 8, development of metastasis) or prostate cancer-specific mortality., Results: A meta-analysis of ten human RCTs showed evidence of an effect of vitamin D on total testosterone (standardised mean difference (SMD) = 0.133, 95% CI = - 0.003-0.269, I
2 = 0.0%, p = 0.056). Five human RCTs showed evidence of an effect of vitamin D on free testosterone (SMD = 0.173, 95% CI = - 0.104-0.450, I2 = 52.4%, p = 0.220). Three human cohort studies of testosterone on advanced prostate cancer or prostate cancer-specific mortality provided inconsistent results. In one study, higher levels of calculated free testosterone were positively associated with advanced prostate cancer or prostate cancer-specific mortality. In contrast, higher levels of dihydrotestosterone were associated with lowering prostate cancer-specific mortality in another study. No animal studies met the study eligibility criteria., Conclusion: There is some evidence that vitamin D increases levels of total and free testosterone, although the effect of testosterone levels within the normal range on prostate cancer progression is unclear. The role of testosterone as a mechanism between vitamin D and prostate cancer progression remains inconclusive., (© 2022. The Author(s).)- Published
- 2022
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22. Attitudes and adherence to changes in nutrition and physical activity following surgery for prostate cancer: a qualitative study.
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Robles LA, Shingler E, McGeagh L, Rowe E, Koupparis A, Bahl A, Shiridzinomwa C, Persad R, Martin RM, and Lane JA
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- Exercise, Humans, Male, Nutritional Status, Qualitative Research, Prostatectomy, Prostatic Neoplasms diagnosis
- Abstract
Objectives: Interventions designed to improve men's diet and physical activity (PA) have been recommended as methods of cancer prevention. However, little is known about specific factors that support men's adherence to these health behaviour changes, which could inform theory-led diet and PA interventions. We aimed to explore these factors in men following prostatectomy for prostate cancer (PCa)., Design, Setting and Participants: A qualitative study using semistructured interviews with men, who made changes to their diet and/or PA as part of a factorial randomised controlled trial conducted at a single hospital in South West England. Participants were 17 men aged 66 years, diagnosed with localised PCa and underwent prostatectomy. Interview transcripts underwent thematic analysis., Results: Men were ambivalent about the relationship of nutrition and PA with PCa risk. They believed their diet and level of PA were reasonable before being randomised to their interventions. Men identified several barriers and facilitators to performing these new behaviours. Barriers included tolerance to dietary changes, PA limitations and external obstacles. Facilitators included partner involvement in diet, habit formation and brisk walking as an individual activity. Men discussed positive effects associated with brisk walking, such as feeling healthier, but not with nutrition interventions., Conclusions: The facilitators to behaviour change suggest that adherence to trial interventions can be supported using well-established behaviour change models. Future studies may benefit from theory-based interventions to support adherence to diet and PA behaviour changes in men diagnosed with PCa., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)
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- 2022
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23. Contribution of the Cluster randomised triAl of PSA testing for Prostate cancer (CAP) to the ongoing debate on the value of prostate cancer screening.
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Martin RM, Dixon P, Turner E, and Keeney E
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- Early Detection of Cancer, Humans, Longitudinal Studies, Male, Mass Screening, Randomized Controlled Trials as Topic, Prostate-Specific Antigen, Prostatic Neoplasms diagnosis, Prostatic Neoplasms prevention & control
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- 2022
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24. Do sex hormones confound or mediate the effect of chronotype on breast and prostate cancer? A Mendelian randomization study.
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Hayes BL, Robinson T, Kar S, Ruth KS, Tsilidis KK, Frayling T, Murray A, Martin RM, Lawlor DA, and Richmond RC
- Subjects
- Chronobiology Phenomena, Databases, Genetic, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Risk Factors, Breast Neoplasms genetics, Gonadal Steroid Hormones metabolism, Mendelian Randomization Analysis methods, Polymorphism, Single Nucleotide, Prostatic Neoplasms genetics
- Abstract
Morning-preference chronotype has been found to be protective against breast and prostate cancer. Sex hormones have been implicated in relation to chronotype and the development of both cancers. This study aimed to assess whether sex hormones confound or mediate the effect of chronotype on breast and prostate cancer using a Mendelian Randomization (MR) framework. Genetic variants associated with chronotype and sex hormones (total testosterone, bioavailable testosterone, sex hormone binding globulin, and oestradiol) (p<5×10-8) were obtained from published genome-wide association studies (n≤244,207 females and n≤205,527 males). These variants were used to investigate causal relationships with breast (nCases/nControls = 133,384/113,789) and prostate (nCases/nControls = 79,148/61,106) cancer using univariable, bidirectional and multivariable MR. In females, we found evidence for: I) Reduced risk of breast cancer per category increase in morning-preference (OR = 0.93, 95% CI:0. 88, 1.00); II) Increased risk of breast cancer per SD increase in bioavailable testosterone (OR = 1.10, 95% CI: 1.01, 1.19) and total testosterone (OR = 1.15, 95% CI:1.07, 1.23); III) Bidirectional effects between morning-preference and both bioavailable and total testosterone (e.g. mean SD difference in bioavailable testosterone = -0.08, 95% CI:-0.12, -0.05 per category increase in morning-preference vs difference in morning-preference category = -0.04, 95% CI: -0.08, 0.00 per SD increase in bioavailable testosterone). In males, we found evidence for: I) Reduced risk of prostate cancer per category increase in morning-preference (OR = 0.90, 95% CI: 0.83, 0.97) and II) Increased risk of prostate cancer per SD increase in bioavailable testosterone (OR = 1.22, 95% CI: 1.08, 1.37). No bidirectional effects were found between morning-preference and testosterone in males. While testosterone levels were causally implicated with both chronotype and cancer, there was inconsistent evidence for testosterone as a mediator of the relationship. The protective effect of morning-preference on both breast and prostate cancer is clinically interesting, although it may be difficult to effectively modify chronotype. Further studies are needed to investigate other potentially modifiable intermediates., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: DAL has received support from Roche Diagnostics and Medtronic Ltd for research unrelated to that presented here. TR has received grants from Daiichi-Sankyo and Amgen to attend educational workshops. All other authors have no competing interests to declare.
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- 2022
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25. Systematic Review of Cost-Effectiveness Models in Prostate Cancer: Exploring New Developments in Testing and Diagnosis.
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Keeney E, Thom H, Turner E, Martin RM, Morley J, and Sanghera S
- Subjects
- Adult, Aged, Biomarkers, Biopsy economics, Cost-Benefit Analysis, Humans, Male, Mass Screening economics, Middle Aged, Prostatic Neoplasms diagnosis, Quality-Adjusted Life Years, Prostatic Neoplasms economics
- Abstract
Objectives: Recent innovations in prostate cancer diagnosis include new biomarkers and more accurate biopsy methods. This study assesses the evidence base on cost-effectiveness of these developments (eg, Prostate Health Index and magnetic resonance imaging [MRI]-guided biopsy) and identifies areas of improvement for future cost-effectiveness models., Methods: A systematic review using the National Health Service Economic Evaluation Database, MEDLINE, Embase, Health Technology Assessment databases, National Institute for Health and Care Excellence guidelines, and United Kingdom National Screening Committee guidance was performed, between 2009 and 2021. Relevant data were extracted on study type, model inputs, modeling methods and cost-effectiveness conclusions, and results narratively synthesized., Results: A total of 22 model-based economic evaluations were included. A total of 11 compared the cost-effectiveness of new biomarkers to prostate-specific antigen testing alone and all found biomarkers to be cost saving. A total of 8 compared MRI-guided biopsy methods to transrectal ultrasound-guided methods and found MRI-guided methods to be most cost-effective. Newer detection methods showed a reduction in unnecessary biopsies and overtreatment. The most cost-effective follow-up strategy in men with a negative initial biopsy was uncertain. Many studies did not model for stage or grade of cancer, cancer progression, or the entire testing and treatment pathway. Few fully accounted for uncertainty., Conclusions: This review brings together the cost-effectiveness literature for novel diagnostic methods in prostate cancer, showing that most studies have found new methods to be more cost-effective than standard of care. Several limitations of the models were identified, however, limiting the reliability of the results. Areas for further development include accurately modeling the impact of early diagnostic tests on long-term outcomes of prostate cancer and fully accounting for uncertainty., (Copyright © 2021 International Society for Pharmacoeconomics and Outcomes Research, Inc. Published by Elsevier Inc. Published by Elsevier Inc. All rights reserved.)
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- 2022
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26. Response to Comment on Delphi Analysis of Relevant Comparators in a Cost-Effectiveness Model of Prostate Cancer Screening.
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Keeney E, Thom H, Turner E, Martin RM, and Sanghera S
- Subjects
- Cost-Benefit Analysis, Humans, Male, Prostate-Specific Antigen, Quality-Adjusted Life Years, Early Detection of Cancer, Prostatic Neoplasms diagnosis
- Published
- 2021
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27. Additional SNPs improve risk stratification of a polygenic hazard score for prostate cancer.
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Karunamuni RA, Huynh-Le MP, Fan CC, Thompson W, Eeles RA, Kote-Jarai Z, Muir K, Lophatananon A, Schleutker J, Pashayan N, Batra J, Grönberg H, Walsh EI, Turner EL, Lane A, Martin RM, Neal DE, Donovan JL, Hamdy FC, Nordestgaard BG, Tangen CM, MacInnis RJ, Wolk A, Albanes D, Haiman CA, Travis RC, Stanford JL, Mucci LA, West CML, Nielsen SF, Kibel AS, Wiklund F, Cussenot O, Berndt SI, Koutros S, Sørensen KD, Cybulski C, Grindedal EM, Park JY, Ingles SA, Maier C, Hamilton RJ, Rosenstein BS, Vega A, Kogevinas M, Penney KL, Teixeira MR, Brenner H, John EM, Kaneva R, Logothetis CJ, Neuhausen SL, Razack A, Newcomb LF, Gamulin M, Usmani N, Claessens F, Gago-Dominguez M, Townsend PA, Roobol MJ, Zheng W, Mills IG, Andreassen OA, Dale AM, and Seibert TM
- Subjects
- Adult, Aged, Follow-Up Studies, Humans, Male, Middle Aged, Predictive Value of Tests, Prognosis, Prostatic Neoplasms epidemiology, Prostatic Neoplasms genetics, Risk Factors, Biomarkers, Tumor genetics, Models, Statistical, Polymorphism, Single Nucleotide, Prostatic Neoplasms pathology, Risk Assessment methods
- Abstract
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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- 2021
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28. Using a Modified Delphi Approach to Gain Consensus on Relevant Comparators in a Cost-Effectiveness Model: Application to Prostate Cancer Screening.
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Keeney E, Thom H, Turner E, Martin RM, and Sanghera S
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- Consensus, Cost-Benefit Analysis, Delphi Technique, Humans, Male, Early Detection of Cancer, Prostate-Specific Antigen, Prostatic Neoplasms diagnosis
- Abstract
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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- 2021
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29. Circulating insulin-like growth factor-I, total and free testosterone concentrations and prostate cancer risk in 200 000 men in UK Biobank.
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Watts EL, Fensom GK, Smith Byrne K, Perez-Cornago A, Allen NE, Knuppel A, Gunter MJ, Holmes MV, Martin RM, Murphy N, Tsilidis KK, Yeap BB, Key TJ, and Travis RC
- Subjects
- Adult, Aged, Biological Specimen Banks, Humans, Male, Middle Aged, Prospective Studies, United Kingdom, Insulin-Like Growth Factor I metabolism, Mendelian Randomization Analysis methods, Prostatic Neoplasms blood, Testosterone blood
- Abstract
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., (© 2020 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)
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- 2021
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30. Polygenic hazard score is associated with prostate cancer in multi-ethnic populations.
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Huynh-Le MP, Fan CC, Karunamuni R, Thompson WK, Martinez ME, Eeles RA, Kote-Jarai Z, Muir K, Schleutker J, Pashayan N, Batra J, Grönberg H, Neal DE, Donovan JL, Hamdy FC, Martin RM, Nielsen SF, Nordestgaard BG, Wiklund F, Tangen CM, Giles GG, Wolk A, Albanes D, Travis RC, Blot WJ, Zheng W, Sanderson M, Stanford JL, Mucci LA, West CML, Kibel AS, Cussenot O, Berndt SI, Koutros S, Sørensen KD, Cybulski C, Grindedal EM, Menegaux F, Khaw KT, Park JY, Ingles SA, Maier C, Hamilton RJ, Thibodeau SN, Rosenstein BS, Lu YJ, Watya S, Vega A, Kogevinas M, Penney KL, Huff C, Teixeira MR, Multigner L, Leach RJ, Cannon-Albright L, Brenner H, John EM, Kaneva R, Logothetis CJ, Neuhausen SL, De Ruyck K, Pandha H, Razack A, Newcomb LF, Fowke JH, Gamulin M, Usmani N, Claessens F, Gago-Dominguez M, Townsend PA, Bush WS, Roobol MJ, Parent MÉ, Hu JJ, Mills IG, Andreassen OA, Dale AM, and Seibert TM
- Subjects
- Aged, Humans, Male, Middle Aged, Multivariate Analysis, Neoplasm Invasiveness, Self Report, Ethnicity genetics, Multifactorial Inheritance genetics, Prostatic Neoplasms genetics
- Abstract
Genetic models for cancer have been evaluated using almost exclusively European data, which could exacerbate health disparities. A polygenic hazard score (PHS
1 ) is associated with age at prostate cancer diagnosis and improves screening accuracy in Europeans. Here, we evaluate performance of PHS2 (PHS1 , adapted for OncoArray) in a multi-ethnic dataset of 80,491 men (49,916 cases, 30,575 controls). PHS2 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 < 10-180 ). Comparing the 80th /20th PHS2 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. PHS2 risk-stratifies men for any, aggressive, and fatal prostate cancer in a multi-ethnic dataset.- Published
- 2021
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31. Retrospective cohort study evaluating clinical, biochemical and pharmacological prognostic factors for prostate cancer progression using primary care data.
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Merriel SWD, Ingle SM, May MT, and Martin RM
- Subjects
- Aged, Aged, 80 and over, England epidemiology, Humans, Male, Neoplasm Staging, Primary Health Care, Prognosis, Proportional Hazards Models, Prostate-Specific Antigen, Retrospective Studies, Prostatic Neoplasms diagnosis, Prostatic Neoplasms pathology
- Abstract
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., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)
- Published
- 2021
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32. Circulating adiponectin and leptin and risk of overall and aggressive prostate cancer: a systematic review and meta-analysis.
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Burton AJ, Gilbert R, Tilling K, Langdon R, Donovan JL, Holly JMP, and Martin RM
- Subjects
- Humans, Male, Risk, Adiponectin blood, Leptin blood, Prostatic Neoplasms blood, Prostatic Neoplasms pathology
- Abstract
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.
- Published
- 2021
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33. Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction.
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Conti DV, Darst BF, Moss LC, Saunders EJ, Sheng X, Chou A, Schumacher FR, Olama AAA, Benlloch S, Dadaev T, Brook MN, Sahimi A, Hoffmann TJ, Takahashi A, Matsuda K, Momozawa Y, Fujita M, Muir K, Lophatananon A, Wan P, Le Marchand L, Wilkens LR, Stevens VL, Gapstur SM, Carter BD, Schleutker J, Tammela TLJ, Sipeky C, Auvinen A, Giles GG, Southey MC, MacInnis RJ, Cybulski C, Wokołorczyk D, Lubiński J, Neal DE, Donovan JL, Hamdy FC, Martin RM, Nordestgaard BG, Nielsen SF, Weischer M, Bojesen SE, Røder MA, Iversen P, Batra J, Chambers S, Moya L, Horvath L, Clements JA, Tilley W, Risbridger GP, Gronberg H, Aly M, Szulkin R, Eklund M, Nordström T, Pashayan N, Dunning AM, Ghoussaini M, Travis RC, Key TJ, Riboli E, Park JY, Sellers TA, Lin HY, Albanes D, Weinstein SJ, Mucci LA, Giovannucci E, Lindstrom S, Kraft P, Hunter DJ, Penney KL, Turman C, Tangen CM, Goodman PJ, Thompson IM Jr, Hamilton RJ, Fleshner NE, Finelli A, Parent MÉ, Stanford JL, Ostrander EA, Geybels MS, Koutros S, Freeman LEB, Stampfer M, Wolk A, Håkansson N, Andriole GL, Hoover RN, Machiela MJ, Sørensen KD, Borre M, Blot WJ, Zheng W, Yeboah ED, Mensah JE, Lu YJ, Zhang HW, Feng N, Mao X, Wu Y, Zhao SC, Sun Z, Thibodeau SN, McDonnell SK, Schaid DJ, West CML, Burnet N, Barnett G, Maier C, Schnoeller T, Luedeke M, Kibel AS, Drake BF, Cussenot O, Cancel-Tassin G, Menegaux F, Truong T, Koudou YA, John EM, Grindedal EM, Maehle L, Khaw KT, Ingles SA, Stern MC, Vega A, Gómez-Caamaño A, Fachal L, Rosenstein BS, Kerns SL, Ostrer H, Teixeira MR, Paulo P, Brandão A, Watya S, Lubwama A, Bensen JT, Fontham ETH, Mohler J, Taylor JA, Kogevinas M, Llorca J, Castaño-Vinyals G, Cannon-Albright L, Teerlink CC, Huff CD, Strom SS, Multigner L, Blanchet P, Brureau L, Kaneva R, Slavov C, Mitev V, Leach RJ, Weaver B, Brenner H, Cuk K, Holleczek B, Saum KU, Klein EA, Hsing AW, Kittles RA, Murphy AB, Logothetis CJ, Kim J, Neuhausen SL, Steele L, Ding YC, Isaacs WB, Nemesure B, Hennis AJM, Carpten J, Pandha H, Michael A, De Ruyck K, De Meerleer G, Ost P, Xu J, Razack A, Lim J, Teo SH, Newcomb LF, Lin DW, Fowke JH, Neslund-Dudas C, Rybicki BA, Gamulin M, Lessel D, Kulis T, Usmani N, Singhal S, Parliament M, Claessens F, Joniau S, Van den Broeck T, Gago-Dominguez M, Castelao JE, Martinez ME, Larkin S, Townsend PA, Aukim-Hastie C, Bush WS, Aldrich MC, Crawford DC, Srivastava S, Cullen JC, Petrovics G, Casey G, Roobol MJ, Jenster G, van Schaik RHN, Hu JJ, Sanderson M, Varma R, McKean-Cowdin R, Torres M, Mancuso N, Berndt SI, Van Den Eeden SK, Easton DF, Chanock SJ, Cook MB, Wiklund F, Nakagawa H, Witte JS, Eeles RA, Kote-Jarai Z, and Haiman CA
- Subjects
- Humans, Male, Middle Aged, Molecular Sequence Annotation, Neoplasm Invasiveness, Odds Ratio, Prostatic Neoplasms diagnosis, Risk Factors, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Prostatic Neoplasms genetics, Racial Groups genetics
- Abstract
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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- 2021
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34. Examination of potential novel biochemical factors in relation to prostate cancer incidence and mortality in UK Biobank.
- Author
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Perez-Cornago A, Fensom GK, Andrews C, Watts EL, Allen NE, Martin RM, Van Hemelrijck M, Key TJ, and Travis RC
- Subjects
- Adult, Aged, Aspartate Aminotransferases blood, Aspartate Aminotransferases urine, Blood Glucose analysis, Blood Proteins analysis, Blood Proteins urine, Cardiovascular Diseases blood, Cardiovascular Diseases urine, Cystatin C blood, Follow-Up Studies, Glycosuria, Humans, Incidence, Male, Middle Aged, Phosphates blood, Phosphates urine, Prospective Studies, Prostatic Neoplasms blood, Prostatic Neoplasms mortality, Prostatic Neoplasms urine, Time Factors, United Kingdom epidemiology, Urea blood, Urea urine, Vitamin D blood, Vitamin D urine, Biomarkers, Tumor blood, Biomarkers, Tumor urine, Prostatic Neoplasms epidemiology
- Abstract
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.
- Published
- 2020
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35. The ProtecT randomised trial cost-effectiveness analysis comparing active monitoring, surgery, or radiotherapy for prostate cancer.
- Author
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Noble SM, Garfield K, Lane JA, Metcalfe C, Davis M, Walsh EI, Martin RM, Turner EL, Peters TJ, Thorn JC, Mason M, Bollina P, Catto JWF, Doherty A, Gnanapragasam V, Hughes O, Kockelbergh R, Kynaston H, Paul A, Paez E, Rosario DJ, Rowe E, Oxley J, Staffurth J, Neal DE, Hamdy FC, and Donovan JL
- Subjects
- Adult, Aged, Cost-Benefit Analysis, Health Care Costs, Humans, Male, Middle Aged, Quality-Adjusted Life Years, Prostatic Neoplasms therapy
- Abstract
Background: There is limited evidence relating to the cost-effectiveness of treatments for localised prostate cancer., Methods: The cost-effectiveness of active monitoring, surgery, and radiotherapy was evaluated within the Prostate Testing for Cancer and Treatment (ProtecT) randomised controlled trial from a UK NHS perspective at 10 years' median follow-up. Prostate cancer resource-use collected from hospital records and trial participants was valued using UK reference-costs. QALYs (quality-adjusted-life-years) were calculated from patient-reported EQ-5D-3L measurements. Adjusted mean costs, QALYs, and incremental cost-effectiveness ratios were calculated; cost-effectiveness acceptability curves and sensitivity analyses addressed uncertainty; subgroup analyses considered age and disease-risk., Results: Adjusted mean QALYs were similar between groups: 6.89 (active monitoring), 7.09 (radiotherapy), and 6.91 (surgery). Active monitoring had lower adjusted mean costs (£5913) than radiotherapy (£7361) and surgery (£7519). Radiotherapy was the most likely (58% probability) cost-effective option at the UK NICE willingness-to-pay threshold (£20,000 per QALY). Subgroup analyses confirmed radiotherapy was cost-effective for older men and intermediate/high-risk disease groups; active monitoring was more likely to be the cost-effective option for younger men and low-risk groups., Conclusions: Longer follow-up and modelling are required to determine the most cost-effective treatment for localised prostate cancer over a man's lifetime., Trial Registration: Current Controlled Trials number, ISRCTN20141297: http://isrctn.org (14/10/2002); ClinicalTrials.gov number, NCT02044172: http://www.clinicaltrials.gov (23/01/2014).
- Published
- 2020
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36. A Genetic Risk Score to Personalize Prostate Cancer Screening, Applied to Population Data.
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Huynh-Le MP, Fan CC, Karunamuni R, Walsh EI, Turner EL, Lane JA, Martin RM, Neal DE, Donovan JL, Hamdy FC, Parsons JK, Eeles RA, Easton DF, Kote-Jarai Z, Amin Al Olama A, Benlloch Garcia S, Muir K, Grönberg H, Wiklund F, Aly M, Schleutker J, Sipeky C, Tammela TL, Nordestgaard BG, Key TJ, Travis RC, Pharoah PDP, Pashayan N, Khaw KT, Thibodeau SN, McDonnell SK, Schaid DJ, Maier C, Vogel W, Luedeke M, Herkommer K, Kibel AS, Cybulski C, Wokolorczyk D, Kluzniak W, Cannon-Albright LA, Brenner H, Schöttker B, Holleczek B, Park JY, Sellers TA, Lin HY, Slavov CK, Kaneva RP, Mitev VI, Batra J, Clements JA, Spurdle AB, Teixeira MR, Paulo P, Maia S, Pandha H, Michael A, Mills IG, Andreassen OA, Dale AM, and Seibert TM
- Subjects
- Aged, Early Detection of Cancer, Humans, Male, Middle Aged, Neoplasm Grading, Population Control, Prostatic Neoplasms genetics
- Abstract
Background: A polygenic hazard score (PHS), the weighted sum of 54 SNP genotypes, was previously validated for association with clinically significant prostate cancer and for improved prostate cancer screening accuracy. Here, we assess the potential impact of PHS-informed screening., Methods: United Kingdom population incidence data (Cancer Research United Kingdom) and data from the Cluster Randomized Trial of PSA Testing for Prostate Cancer were combined to estimate age-specific clinically significant prostate cancer incidence (Gleason score ≥7, stage T3-T4, PSA ≥10, or nodal/distant metastases). Using HRs estimated from the ProtecT prostate cancer trial, age-specific incidence rates were calculated for various PHS risk percentiles. Risk-equivalent age, when someone with a given PHS percentile has prostate cancer risk equivalent to an average 50-year-old man (50-year-standard risk), was derived from PHS and incidence data. Positive predictive value (PPV) of PSA testing for clinically significant prostate cancer was calculated using PHS-adjusted age groups., Results: The expected age at diagnosis of clinically significant prostate cancer differs by 19 years between the 1st and 99th PHS percentiles: men with PHS in the 1st and 99th percentiles reach the 50-year-standard risk level at ages 60 and 41, respectively. PPV of PSA was higher for men with higher PHS-adjusted age., Conclusions: PHS provides individualized estimates of risk-equivalent age for clinically significant prostate cancer. Screening initiation could be adjusted by a man's PHS., Impact: Personalized genetic risk assessments could inform prostate cancer screening decisions., (©2020 American Association for Cancer Research.)
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- 2020
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37. Active monitoring, radical prostatectomy and radical radiotherapy in PSA-detected clinically localised prostate cancer: the ProtecT three-arm RCT.
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Hamdy FC, Donovan JL, Lane JA, Mason M, Metcalfe C, Holding P, Wade J, Noble S, Garfield K, Young G, Davis M, Peters TJ, Turner EL, Martin RM, Oxley J, Robinson M, Staffurth J, Walsh E, Blazeby J, Bryant R, Bollina P, Catto J, Doble A, Doherty A, Gillatt D, Gnanapragasam V, Hughes O, Kockelbergh R, Kynaston H, Paul A, Paez E, Powell P, Prescott S, Rosario D, Rowe E, and Neal D
- Subjects
- Aged, Humans, Male, Middle Aged, Prospective Studies, Prostate-Specific Antigen blood, Prostatic Neoplasms mortality, Prostatic Neoplasms pathology, Quality of Life, Disease-Free Survival, Patient Reported Outcome Measures, Prostatectomy mortality, Prostatic Neoplasms radiotherapy, Prostatic Neoplasms therapy, Watchful Waiting
- Abstract
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 ( n = 545), radical prostatectomy ( n = 553) or radical radiotherapy ( n = 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 ( p = 0.48) and 169 all-cause ( p = 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, n = 33 (6.3 per 1000 person-years, 95% confidence interval 4.5 to 8.8); radical prostatectomy, n = 13 (2.4 per 1000 person-years, 95% confidence interval 1.4 to 4.2 per 1000 person years); and radical radiotherapy, n = 16 (3.0 per 1000 person-years, 95% confidence interval 1.9 to 4.9 per 1000 person-years; p = 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 ( n = 112; 22.9 per 1000 person-years, 95% confidence interval 19.0 to 27.5 per 1000 person years); radical prostatectomy ( n = 46; 8.9 per 1000 person-years, 95% confidence interval 6.7 to 11.9 per 1000 person-years); and radical radiotherapy ( n = 46; 9.0 per 1000 person-years, 95% confidence interval 6.7 to 12.0 per 1000 person years; p < 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 Health Technology Assessment ; Vol. 24, No. 37. See the National Institute for Health Research Journals Library website for further project information., Competing Interests: Malcolm Mason reports personal fees from Sanofi (Paris, France), Bayer (Leverkusen, Germany) and Janssen Pharmaceutica (Beerse, Belgium) outside the submitted work. Derek Rosario reports grants from Bayer and personal fees from Ferring Pharmaceuticals (Saint-Prex, Switzerland) outside the submitted work. Jane Blazeby was a member of the following during the project: National Institute for Health Research (NIHR) Health Technology Assessment (HTA) Clinical Trials and Evaluation Committee (2009–2013), HTA NIHR Obesity (2010–2012), Commissioning Board for HTA Surgery Themed Call Board and the NIHR Clinical Trials Unit (CTU) Standing Advisory Committee (2015–2019). Jenny Donovan was a member of the following during the project: HTA Commissioning Board (2006–12), Rapid Trials and Add-on Studies Board (2012), NIHR Senior Investigator panel (2009–12) and NIHR Health Services and Delivery Research board (Deputy Chairperson) (2010–11). Freddie C Hamdy was a member of the following during the project: HTA Commissioning Board (2007–12) and HTA Surgery Themed Call Board (2012–13). J Athene Lane was a member of the following during the project: CTUs funded by NIHR (2017 to present). Chris Metcalfe was a member of the following during the project: CTUs funded by NIHR (2010 to present). Tim Peters was a member of the following during the project: HTA Medicines for Children Themed Call (2005–6) and NIHR CTU Standing Advisory Committee (2008–14). John Staffurth reports support for travel to conferences and attendance on an advisory board from Bayer. Emma L Turner reports grants from Cancer Research UK (London, UK) during the conduct of the study.
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- 2020
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38. Systematic review and meta-analysis of the associations between body mass index, prostate cancer, advanced prostate cancer, and prostate-specific antigen.
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Harrison S, Tilling K, Turner EL, Martin RM, Lennon R, Lane JA, Donovan JL, Hamdy FC, Neal DE, Bosch JLHR, and Jones HE
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- Body Mass Index, Early Detection of Cancer methods, Humans, Male, Obesity epidemiology, Overweight epidemiology, Kallikreins metabolism, Prostate-Specific Antigen metabolism, Prostatic Neoplasms diagnosis
- Abstract
Purpose: The relationship between body mass index (BMI) and prostate cancer remains unclear. However, there is an inverse association between BMI and prostate-specific antigen (PSA), used for prostate cancer screening. We conducted this review to estimate the associations between BMI and (1) prostate cancer, (2) advanced prostate cancer, and (3) PSA., Methods: We searched PubMed and Embase for studies until 02 October 2017 and obtained individual participant data from four studies. In total, 78 studies were identified for the association between BMI and prostate cancer, 21 for BMI and advanced prostate cancer, and 35 for BMI and PSA. We performed random-effects meta-analysis of linear associations of log-PSA and prostate cancer with BMI and, to examine potential non-linearity, of associations between categories of BMI and each outcome., Results: In the meta-analyses with continuous BMI, a 5 kg/m
2 increase in BMI was associated with a percentage change in PSA of - 5.88% (95% CI - 6.87 to - 4.87). Using BMI categories, compared to normal weight men the PSA levels of overweight men were 3.43% lower (95% CI - 5.57 to - 1.23), and obese men were 12.9% lower (95% CI - 15.2 to - 10.7). Prostate cancer and advanced prostate cancer analyses showed little or no evidence associations., Conclusion: There is little or no evidence of an association between BMI and risk of prostate cancer or advanced prostate cancer, and strong evidence of an inverse and non-linear association between BMI and PSA. The association between BMI and prostate cancer is likely biased if missed diagnoses are not considered.- Published
- 2020
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39. Appraising causal relationships of dietary, nutritional and physical-activity exposures with overall and aggressive prostate cancer: two-sample Mendelian-randomization study based on 79 148 prostate-cancer cases and 61 106 controls.
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Kazmi N, Haycock P, Tsilidis K, Lynch BM, Truong T, Martin RM, and Lewis SJ
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- Case-Control Studies, Causality, Genome-Wide Association Study, Humans, Male, Mendelian Randomization Analysis, Risk Factors, Diet, Exercise, Nutrition Assessment, Prostatic Neoplasms epidemiology, Prostatic Neoplasms pathology
- Abstract
Background: Prostate cancer is the second most common male cancer worldwide, but there is substantial geographical variation, suggesting a potential role for modifiable risk factors in prostate carcinogenesis., Methods: We identified previously reported prostate cancer risk factors from the World Cancer Research Fund (WCRF)'s systematic appraisal of the global evidence (2018). We assessed whether each identified risk factor was causally associated with risk of overall (79 148 cases and 61 106 controls) or aggressive (15 167 cases and 58 308 controls) prostate cancer using Mendelian randomization (MR) based on genome-wide association-study summary statistics from the PRACTICAL and GAME-ON/ELLIPSE consortia. We assessed evidence for replication in UK Biobank (7844 prostate-cancer cases and 204 001 controls)., Results: WCRF identified 57 potential risk factors, of which 22 could be instrumented for MR analyses using single nucleotide polymorphisms. For overall prostate cancer, we identified evidence compatible with causality for the following risk factors (odds ratio [OR] per standard deviation increase; 95% confidence interval): accelerometer-measured physical activity, OR = 0.49 (0.33-0.72; P = 0.0003); serum iron, OR = 0.92 (0.86-0.98; P = 0.007); body mass index (BMI), OR = 0.90 (0.84-0.97; P = 0.003); and monounsaturated fat, OR = 1.11 (1.02-1.20; P = 0.02). Findings in our replication analyses in UK Biobank were compatible with our main analyses (albeit with wide confidence intervals). In MR analysis, height was positively associated with aggressive-prostate-cancer risk: OR = 1.07 (1.01-1.15; P = 0.03)., Conclusions: The results for physical activity, serum iron, BMI, monounsaturated fat and height are compatible with causality for prostate cancer. The results suggest that interventions aimed at increasing physical activity may reduce prostate-cancer risk, although interventions to change other risk factors may have negative consequences on other diseases., (© The Author(s) 2019; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.)
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- 2020
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40. The ProtecT trial: analysis of the patient cohort, baseline risk stratification and disease progression.
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Bryant RJ, Oxley J, Young GJ, Lane JA, Metcalfe C, Davis M, Turner EL, Martin RM, Goepel JR, Varma M, Griffiths DF, Grigor K, Mayer N, Warren AY, Bhattarai S, Dormer J, Mason M, Staffurth J, Walsh E, Rosario DJ, Catto JWF, Neal DE, Donovan JL, and Hamdy FC
- Subjects
- Aged, Cohort Studies, Disease Progression, Follow-Up Studies, Humans, Kallikreins blood, Male, Middle Aged, Neoplasm Staging, Prostate-Specific Antigen blood, Prostatic Neoplasms blood, Risk Assessment, Time Factors, Prostatic Neoplasms pathology
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Objective: To test the hypothesis that the baseline clinico-pathological features of the men with localized prostate cancer (PCa) included in the ProtecT (Prostate Testing for Cancer and Treatment) trial who progressed (n = 198) at a 10-year median follow-up were different from those of men with stable disease (n = 1409)., Patients and Methods: We stratified the study participants at baseline according to risk of progression using clinical disease stage, pathological grade and PSA level, using Cox proportional hazard models., Results: The findings showed that 34% of participants (n = 505) had intermediate- or high-risk PCa, and 66% (n = 973) had low-risk PCa. Of 198 participants who progressed, 101 (51%) had baseline International Society of Urological Pathology Grade Group 1, 59 (30%) Grade Group 2, and 38 (19%) Grade Group 3 PCa, compared with 79%, 17% and 5%, respectively, for 1409 participants without progression (P < 0.001). In participants with progression, 38% and 62% had baseline low- and intermediate-/high-risk disease, compared with 69% and 31% of participants with stable disease (P < 0.001). Treatment received, age (65-69 vs 50-64 years), PSA level, Grade Group, clinical stage, risk group, number of positive cores, tumour length and perineural invasion were associated with time to progression (P ≤ 0.005). Men progressing after surgery (n = 19) were more likely to have a higher Grade Group and pathological stage at surgery, larger tumours, lymph node involvement and positive margins., Conclusions: We demonstrate that one-third of the ProtecT cohort consists of people with intermediate-/high-risk disease, and the outcomes data at an average of 10 years' follow-up are generalizable beyond men with low-risk PCa., (© 2020 Crown copyright. BJU International published by John Wiley & Sons Ltd on behalf of BJU International.)
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- 2020
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41. Allergy, asthma, and the risk of breast and prostate cancer: a Mendelian randomization study.
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Jiang X, Dimou NL, Zhu Z, Bonilla C, Lewis SJ, Lindström S, Kraft P, Tsilidis KK, and Martin RM
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- Asthma genetics, Breast Neoplasms genetics, Case-Control Studies, Disease Susceptibility, Female, Genome-Wide Association Study, Humans, Male, Mendelian Randomization Analysis, Odds Ratio, Polymorphism, Single Nucleotide, Prostatic Neoplasms genetics, Asthma complications, Breast Neoplasms immunology, Prostatic Neoplasms immunology
- Abstract
Purpose: The relationship of allergic diseases, such as asthma, hay fever, and eczema, with cancer is under debate. Observational studies have reported conflicting findings, but such studies are susceptible to confounding and reverse causation. Understanding the potential role of allergy in carcinogenesis may shed new light on the biological mechanisms underpinning intrinsic immunity and cancer., Methods: We conducted a Mendelian randomization study, using germline genetic variants as instrumental variables, to determine the causal relevance of allergic disease and on two most common malignancies: breast cancer and prostate cancer. We used the summary statistics from the largest ever genome-wide association studies conducted on allergic disease (n
case = 180,129), asthma (ncase = 14,085), breast (ncase = 122,977), and prostate cancer (ncase = 79,148) and calculated odds ratios (ORs) and 95% confidence intervals (CIs) of cancer for allergic disease., Results: We did not observe any evidence to support a causal association between allergic disease and risk of breast cancer overall [OR 1.00 (95% CI 0.96-1.04), p = 0.95] or by subtype (estrogen receptor (ER)+ [0.99 (0.95-1.04), p = 0.71], ER- [1.05 (0.99-1.10), p = 0.11]). We also did not find any evidence for an association with prostate cancer [1.00 (0.94-1.05), p = 0.93] or advanced subtype [0.97 (0.90-1.05), p = 0.46]. Sensitivity analyses did not reveal directional pleiotropy., Conclusion: Our study does not support a causal effect of allergic disease on the risk of breast or prostate cancer. Future studies may be conducted to focus on understanding the causal role of allergic disease in cancer prognosis or drug responses (e.g., immunotherapy).- Published
- 2020
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42. Ten-year Mortality, Disease Progression, and Treatment-related Side Effects in Men with Localised Prostate Cancer from the ProtecT Randomised Controlled Trial According to Treatment Received.
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Neal DE, Metcalfe C, Donovan JL, Lane JA, Davis M, Young GJ, Dutton SJ, Walsh EI, Martin RM, Peters TJ, Turner EL, Mason M, Bryant R, Bollina P, Catto J, Doherty A, Gillatt D, Gnanapragasam V, Holding P, Hughes O, Kockelbergh R, Kynaston H, Oxley J, Paul A, Paez E, Rosario DJ, Rowe E, Staffurth J, Altman DG, and Hamdy FC
- Subjects
- Aged, Disease Progression, Humans, Male, Middle Aged, Prostatectomy adverse effects, Prostatic Neoplasms pathology, Radiotherapy adverse effects, Radiotherapy methods, Time Factors, Treatment Outcome, Watchful Waiting, Prostatic Neoplasms mortality, Prostatic Neoplasms therapy
- Abstract
Background: The ProtecT trial reported intention-to-treat analysis of men with localised prostate cancer (PCa) randomly allocated to active monitoring (AM), radical prostatectomy, and external beam radiotherapy., Objective: To determine report outcomes according to treatment received in men in randomised and treatment choice cohorts., Design, Setting, and Participants: This study focuses on secondary care. Men with clinically localised prostate cancer at one of nine UK centres were invited to participate in the treatment trial comparing AM, radical prostatectomy, and radiotherapy., Intervention: Two cohorts included 1643 men who agreed to be randomised; 997 declined randomisation and chose treatment., Outcome Measurements and Statistical Analysis: Health-related quality of life impacts on urinary, bowel, and sexual function were assessed using patient-reported outcome measures. Analysis was carried out based on treatment received for each cohort and on pooled estimates using meta-analysis. Differences were estimated with adjustment for known prognostic factors using propensity scores., Results and Limitations: According to treatment received, more men receiving AM died of PCa (AM 1.85%, surgery 0.67%, radiotherapy 0.73%), whilst this difference remained consistent with chance in the randomised cohort (p=0.08); stronger evidence was found in the exploratory analyses (randomised plus choice cohort) when AM was compared with the combined radical treatment group (p=0.003). There was also strong evidence that metastasis (AM 5.6%, surgery 2.4%, radiotherapy 2.7%) and disease progression (AM 20.35%, surgery 5.87%, radiotherapy 6.62%) were more common in the AM group. Compared with AM, there were higher risks of sexual dysfunction (95% at 6mo) and urinary incontinence (55% at 6mo) after surgery, and of sexual dysfunction (88% at 6mo) and bowel dysfunction (5% at 6mo) after radiotherapy. The key limitations are the potential for bias when comparing groups defined by treatment received and outdating of the interventions being evaluated during the lengthy follow-up required in trials of screen-detected PCa., Conclusions: Analyses according to treatment received showed increased rates of disease-related events and lower rates of patient-reported harms in men managed by AM compared with men managed by radical treatment, and stronger evidence of greater PCa mortality in the AM group., Patient Summary: More than 90 out of every 100 men with localised prostate cancer do not die of prostate cancer within 10yr, irrespective of whether treatment is by means of monitoring, surgery, or radiotherapy. Side effects on sexual and bladder function are much better after active monitoring, but the risks of spreading of prostate cancer are more common., (Copyright © 2019 The Author(s). Published by Elsevier B.V. All rights reserved.)
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- 2020
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43. Phase II randomised control feasibility trial of a nutrition and physical activity intervention after radical prostatectomy for prostate cancer.
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Hackshaw-McGeagh LE, Penfold C, Shingler E, Robles LA, Perks CM, Holly JMP, Rowe E, Koupparis A, Bahl A, Persad R, Shiridzinomwa C, Johnson L, Biernacka KM, Frankow A, Woodside JV, Gilchrist S, Oxley J, Abrams P, Lane JA, and Martin RM
- Subjects
- Diet, England, Feasibility Studies, Fruit, Humans, Male, Middle Aged, Nutritional Status, Prostatic Neoplasms surgery, Vegetables, Diet, Healthy methods, Exercise, Exercise Therapy methods, Prostatectomy rehabilitation, Prostatic Neoplasms rehabilitation
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Objective: Dietary factors and physical activity may alter prostate cancer progression. We explored the feasibility of lifestyle interventions following radical prostatectomy for localised prostate cancer., Design: Patients were recruited into a presurgical observational cohort; following radical prostatectomy, they were offered randomisation into a 2×3 factorial randomised controlled trial (RCT)., Setting: A single National Health Service trust in the South West of England, UK., Participants: Those with localised prostate cancer and listed for radical prostatectomy were invited to participate., Randomisation: Random allocation was performed by the Bristol Randomised Trial Collaboration via an online system., Interventions: Men were randomised into both a modified nutrition group (either increased vegetable and fruit, and reduced dairy milk; or lycopene supplementation; or control) and a physical activity group (brisk walking or control) for 6 months., Blinding: Only the trial statistician was blind to allocations., Primary Outcome Measures: Primary outcomes were measures of feasibility: randomisation rates and intervention adherence at 6 months. Collected at trial baseline, three and six months, with daily adherence reported throughout. Our intended adherence rate was 75% or above, the threshold for acceptable adherence was 90%., Results: 108 men entered the presurgical cohort, and 81 were randomised into the postsurgical RCT (randomisation rate: 93.1%) and 75 completed the trial. Of 25 men in the nutrition intervention, 10 (40.0%; 95% CI 23.4% to 59.3%) adhered to the fruit and vegetable recommendations and 18 (72.0%; 95% CI 52.4% to 85.7%) to reduced dairy intake. Adherence to lycopene (n=28), was 78.6% (95% CI 60.5% to 89.8%), while 21/39 adhered to the walking intervention (53.8%; 95% CI 38.6% to 68.4%). Most men were followed up at 6 months (75/81; 92.6%). Three 'possibly related' adverse events were indigestion, abdominal bloating and knee pain., Conclusions: Interventions were deemed feasible, with high randomisation rates and generally good adherence. A definitive RCT is proposed., Trial Registration Number: ISRCTN 99048944., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ.)
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- 2019
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44. Effect of green tea and lycopene on the insulin-like growth factor system: the ProDiet randomized controlled trial.
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Biernacka KM, Holly JMP, Martin RM, Frankow A, Bull CJ, Hamdy FC, Donovan JL, Neal DE, Metcalfe C, and Lane A
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- Aged, Dietary Supplements, Follow-Up Studies, Humans, Lycopene administration & dosage, Male, Middle Aged, Pilot Projects, Gene Expression Regulation drug effects, Insulin-Like Growth Factor Binding Protein 3 metabolism, Insulin-Like Growth Factor I metabolism, Insulin-Like Growth Factor II metabolism, Lycopene pharmacology, Prostatic Neoplasms diet therapy, Tea chemistry
- Abstract
Whether prostate cancer (PCa) may be preventable by dietary interventions can be assessed in randomized trials using intermediate biomarkers of cancer risk or progression. We investigated whether lycopene or green tea modify circulating insulin-like growth factor (IGF) peptides in men at increased risk of PCa. Participants (aged 50-69 years) in one centre in the UK wide PCa testing and treatment trial (ProtecT) with prostate specific antigen between 2.0 and 2.95 ng/ml or negative biopsies, were randomized to daily lycopene (n = 44 assigned 15 mg capsules/day; 44 assigned a lycopene-rich diet; 45 assigned placebo) and green tea (n = 45 assigned 600 mg/day epigallocatechin gallate; 45 assigned green tea drink; 43 assigned placebo) for 6 months. The interventions significantly elevated the primary outcomes, serum epigallocatechin gallate and lycopene at 6 months of follow-up. We report here an exploratory analysis in which serum IGF-I, IGF-II, IGF binding protein (BP)-2 and IGFBP-3 were measured at baseline and 6 months of postintervention. A total of 133 men were randomized (34% of eligible men approached) and 130 had follow-up IGF peptides (98%). In intention-to-treat analyses, there was only weak evidence that lycopene or green tea influenced some aspects of serum IGF-I, IGF-II, IGFBP-2 or IGFBP-3. In men randomized to lycopene supplements, IGFBP-2 was nonsignificantly (50.9 ng/ml; 95% confidence interval: -51.2-152.9, P = 0.3) higher in comparison to placebo, whereas in men randomized to green tea supplements, IGFBP-3 was nonsignificantly (205.2 ng/ml; 95% confidence interval: -583.3-172.9, P = 0.3) lower than with placebo. In this small, pilot randomized controlled trial, there was little evidence that lycopene or green tea interventions influenced serum levels of IGF-I, IGF-II, IGFBBP-3 and IGFBP-2. However, the effects were imprecisely estimates and some observed trends may justify larger trials.
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- 2019
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45. Circulating vitamin D concentrations and risk of breast and prostate cancer: a Mendelian randomization study.
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Jiang X, Dimou NL, Al-Dabhani K, Lewis SJ, Martin RM, Haycock PC, Gunter MJ, Key TJ, Eeles RA, Muir K, Neal D, Giles GG, Giovannucci EL, Stampfer M, Pierce BL, Schildkraut JM, Warren Andersen S, Thompson D, Zheng W, Kraft P, and Tsilidis KK
- Subjects
- Aged, Breast Neoplasms genetics, Causality, Female, Genome-Wide Association Study, Humans, Male, Mendelian Randomization Analysis, Middle Aged, Polymorphism, Single Nucleotide, Prostatic Neoplasms genetics, Receptors, Estrogen biosynthesis, Risk Factors, Breast Neoplasms epidemiology, Prostatic Neoplasms epidemiology, Vitamin D blood
- Abstract
Background: Observational studies have suggested an association between circulating vitamin D concentrations [25(OH)D] and risk of breast and prostate cancer, which was not supported by a recent Mendelian randomization (MR) analysis comprising 15 748 breast and 22 898 prostate-cancer cases. Demonstrating causality has proven challenging and one common limitation of MR studies is insufficient power., Methods: We aimed to determine whether circulating concentrations of vitamin D are causally associated with the risk of breast and prostate cancer, by using summary-level data from the largest ever genome-wide association studies conducted on vitamin D (N = 73 699), breast cancer (Ncase = 122 977) and prostate cancer (Ncase = 79 148). We constructed a stronger instrument using six common genetic variants (compared with the previous four variants) and applied several two-sample MR methods., Results: We found no evidence to support a causal association between 25(OH)D and risk of breast cancer [OR per 25 nmol/L increase, 1.02 (95% confidence interval: 0.97-1.08), P = 0.47], oestrogen receptor (ER)+ [1.00 (0.94-1.07), P = 0.99] or ER- [1.02 (0.90-1.16), P = 0.75] subsets, prostate cancer [1.00 (0.93-1.07), P = 0.99] or the advanced subtype [1.02 (0.90-1.16), P = 0.72] using the inverse-variance-weighted method. Sensitivity analyses did not reveal any sign of directional pleiotropy., Conclusions: Despite its almost five-fold augmented sample size and substantially improved statistical power, our MR analysis does not support a causal effect of circulating 25(OH)D concentrations on breast- or prostate-cancer risk. However, we can still not exclude a modest or non-linear effect of vitamin D. Future studies may be designed to understand the effect of vitamin D in subpopulations with a profound deficiency., (© The Author(s) 2018; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.)
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- 2019
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46. Factors associated with trial recruitment, preferences, and treatments received were elucidated in a comprehensive cohort study.
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Donovan JL, Opmeer B, Young GJ, Mills N, Martin RM, Lane JA, Metcalfe C, Peters TJ, Davis M, Turner EL, Walsh E, Neal DE, and Hamdy FC
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- Aged, Cohort Studies, Humans, Male, Middle Aged, Early Detection of Cancer, Patient Preference statistics & numerical data, Patient Selection, Prostatic Neoplasms diagnosis, Prostatic Neoplasms therapy, Randomized Controlled Trials as Topic standards, Randomized Controlled Trials as Topic statistics & numerical data
- Abstract
Objectives: Recruitment to pragmatic trials is often difficult, and little is known about factors associated with key participation and treatment decisions. These were explored in the Prostate cancer testing and Treatment (ProtecT) study., Study Design and Setting: Baseline sociodemographic, patient-reported outcome, clinical history, and prostate cancer biopsy data were collected for all patients eligible to take part in the ProtecT trial, in a comprehensive cohort design. Men who rejected randomization specified a preferred option and were followed up identically to the randomized cohort. Factors associated with participation decisions, patient preferences, and reasons for changing treatment were explored., Results: Of 2,664 men with clinically localized prostate cancer, 997 (37%) rejected randomization. Their treatment preferences and subsequent treatment choices/changes in both randomized and treatment choice cohorts were strongly associated with prostate cancer risk features: toward active monitoring for low-risk disease and toward radical options with higher risk prostate cancer. Among many factors measured, only a small number of weak associations were found for occupation groups and some patient symptoms. Similar percentages changed from the random allocation and initially stated preference., Conclusion: The comprehensive cohort design provided new insights into trial recruitment and participation decisions. Opportunities to improve recruitment by supporting recruiters with equipoise and patient preferences were identified., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2019
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47. Investigating the effects of lycopene and green tea on the metabolome of men at risk of prostate cancer: The ProDiet randomised controlled trial.
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Beynon RA, Richmond RC, Santos Ferreira DL, Ness AR, May M, Smith GD, Vincent EE, Adams C, Ala-Korpela M, Würtz P, Soidinsalo S, Metcalfe C, Donovan JL, Lane AJ, and Martin RM
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- Aged, Humans, Magnetic Resonance Spectroscopy methods, Male, Metabolomics methods, Middle Aged, Prostate-Specific Antigen blood, Prostatic Neoplasms blood, Prostatic Neoplasms diet therapy, Pyruvic Acid blood, Feeding Behavior physiology, Lycopene, Metabolome physiology, Prostatic Neoplasms metabolism, Tea
- Abstract
Lycopene and green tea consumption have been observationally associated with reduced prostate cancer risk, but the underlying mechanisms have not been fully elucidated. We investigated the effect of factorial randomisation to a 6-month lycopene and green tea dietary advice or supplementation intervention on 159 serum metabolite measures in 128 men with raised PSA levels (but prostate cancer-free), analysed by intention-to-treat. The causal effects of metabolites modified by the intervention on prostate cancer risk were then assessed by Mendelian randomisation, using summary statistics from 44,825 prostate cancer cases and 27,904 controls. The systemic effects of lycopene and green tea supplementation on serum metabolic profile were comparable to the effects of the respective dietary advice interventions (R
2 = 0.65 and 0.76 for lycopene and green tea respectively). Metabolites which were altered in response to lycopene supplementation were acetate [β (standard deviation difference vs. placebo): 0.69; 95% CI = 0.24, 1.15; p = 0.003], valine (β: -0.62; -1.03, -0.02; p = 0.004), pyruvate (β: -0.56; -0.95, -0.16; p = 0.006) and docosahexaenoic acid (β: -0.50; -085, -0.14; p = 0.006). Valine and diacylglycerol were lower in the lycopene dietary advice group (β: -0.65; -1.04, -0.26; p = 0.001 and β: -0.59; -1.01, -0.18; p = 0.006). A genetically instrumented SD increase in pyruvate increased the odds of prostate cancer by 1.29 (1.03, 1.62; p = 0.027). An intervention to increase lycopene intake altered the serum metabolome of men at risk of prostate cancer. Lycopene lowered levels of pyruvate, which our Mendelian randomisation analysis suggests may be causally related to reduced prostate cancer risk., (© 2018 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)- Published
- 2019
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48. Does testosterone mediate the relationship between vitamin D and prostate cancer? A systematic review and meta-analysis protocol.
- Author
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Robles LA, Dawe K, Martin RM, Higgins JPT, and Lewis SJ
- Subjects
- Animals, Disease Progression, Drug Interactions physiology, Humans, Male, Observational Studies as Topic, Meta-Analysis as Topic, Prostatic Neoplasms metabolism, Systematic Reviews as Topic, Testosterone physiology, Vitamin D physiology
- Abstract
Background: Evidence from studies on prostate cancer progression have identified vitamin D to be a potentially important nutrient. However, the World Cancer Research Fund and American Institute for Cancer Research have reported the quality of this evidence to be limited and warrant further investigation. We plan to use the recently developed WCRF International/University of Bristol mechanistic systematic review framework to determine whether the observed association between vitamin D and prostate cancer exists through a plausible biological pathway., Methods: This protocol sets out how we will perform a systematic review of the literature in human and animal studies. We will search the electronic databases MEDLINE, EMBASE, PubMed, and BIOSIS Citation Index without restrictions on year of publication or language. We will extract data from observational and experimental studies examining two inter-linked pathways in the relationship between vitamin D and prostate cancer progression: (1) vitamin D and testosterone, and (2) testosterone and prostate cancer progression. We focus on testosterone as its actions form a potentially novel intermediate mechanism that was identified via our online literature mining tools. The outcomes of interest include incidence or prevalence of prostate cancer, measures of prostate cancer progression (including biochemical recurrence, local, or distal metastases), and prostate cancer-specific mortality. We will assess study quality and the level of certainty of the evidence. We will analyse data where possible, using meta-analysis with forest plots or albatross plots; otherwise, a narrative synthesis will be performed., Discussion: To our knowledge, this will be the first systematic synthesis of the evidence underpinning the vitamin D-testosterone-prostate cancer mechanistic pathway. The results of the review may inform future research, intervention trials, and public health messages.
- Published
- 2019
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49. A Collaborative Analysis of Individual Participant Data from 19 Prospective Studies Assesses Circulating Vitamin D and Prostate Cancer Risk.
- Author
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Travis RC, Perez-Cornago A, Appleby PN, Albanes D, Joshu CE, Lutsey PL, Mondul AM, Platz EA, Weinstein SJ, Layne TM, Helzlsouer KJ, Visvanathan K, Palli D, Peeters PH, Bueno-de-Mesquita B, Trichopoulou A, Gunter MJ, Tsilidis KK, Sánchez MJ, Olsen A, Brenner H, Schöttker B, Perna L, Holleczek B, Knekt P, Rissanen H, Yeap BB, Flicker L, Almeida OP, Wong YYE, Chan JM, Giovannucci EL, Stampfer MJ, Ursin G, Gislefoss RE, Bjørge T, Meyer HE, Blomhoff R, Tsugane S, Sawada N, English DR, Eyles DW, Heath AK, Williamson EJ, Manjer J, Malm J, Almquist M, Marchand LL, Haiman CA, Wilkens LR, Schenk JM, Tangen CM, Black A, Cook MB, Huang WY, Ziegler RG, Martin RM, Hamdy FC, Donovan JL, Neal DE, Touvier M, Hercberg S, Galan P, Deschasaux M, Key TJ, and Allen NE
- Subjects
- Aged, Case-Control Studies, Cross-Sectional Studies, Humans, Male, Middle Aged, Odds Ratio, Prospective Studies, Risk Factors, Vitamin D blood, Prostatic Neoplasms blood, Prostatic Neoplasms etiology, Risk Assessment methods, Vitamin D analogs & derivatives
- Abstract
Previous prospective studies assessing the relationship between circulating concentrations of vitamin D and prostate cancer risk have shown inconclusive results, particularly for risk of aggressive disease. In this study, we examine the association between prediagnostic concentrations of 25-hydroxyvitamin D [25(OH)D] and 1,25-dihydroxyvitamin D [1,25(OH)
2 D] and the risk of prostate cancer overall and by tumor characteristics. Principal investigators of 19 prospective studies provided individual participant data on circulating 25(OH)D and 1,25(OH)2 D for up to 13,462 men with incident prostate cancer and 20,261 control participants. ORs for prostate cancer by study-specific fifths of season-standardized vitamin D concentration were estimated using multivariable-adjusted conditional logistic regression. 25(OH)D concentration was positively associated with risk for total prostate cancer (multivariable-adjusted OR comparing highest vs. lowest study-specific fifth was 1.22; 95% confidence interval, 1.13-1.31; P trend < 0.001). However, this association varied by disease aggressiveness ( Pheterogeneity = 0.014); higher circulating 25(OH)D was associated with a higher risk of nonaggressive disease (OR per 80 percentile increase = 1.24, 1.13-1.36) but not with aggressive disease (defined as stage 4, metastases, or prostate cancer death, 0.95, 0.78-1.15). 1,25(OH)2 D concentration was not associated with risk for prostate cancer overall or by tumor characteristics. The absence of an association of vitamin D with aggressive disease does not support the hypothesis that vitamin D deficiency increases prostate cancer risk. Rather, the association of high circulating 25(OH)D concentration with a higher risk of nonaggressive prostate cancer may be influenced by detection bias. SIGNIFICANCE: This international collaboration comprises the largest prospective study on blood vitamin D and prostate cancer risk and shows no association with aggressive disease but some evidence of a higher risk of nonaggressive disease., (©2018 American Association for Cancer Research.)- Published
- 2019
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50. Circulating Metabolic Biomarkers of Screen-Detected Prostate Cancer in the ProtecT Study.
- Author
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Adams CD, Richmond R, Ferreira DLS, Spiller W, Tan V, Zheng J, Würtz P, Donovan J, Hamdy F, Neal D, Lane JA, Smith GD, Relton C, Eeles RA, Haiman CA, Kote-Jarai Z, Schumacher FR, Olama AAA, Benlloch S, Muir K, Berndt SI, Conti DV, Wiklund F, Chanock SJ, Gapstur S, Stevens VL, Tangen CM, Batra J, Clements JA, Gronberg H, Pashayan N, Schleutker J, Albanes D, Wolk A, West CML, Mucci LA, Cancel-Tassin G, Koutros S, Sorensen KD, Maehle L, Travis RC, Hamilton RJ, Ingles SA, Rosenstein BS, Lu YJ, Giles GG, Kibel AS, Vega A, Kogevinas M, Penney KL, Park JY, Stanford JL, Cybulski C, Nordestgaard BG, Brenner H, Maier C, Kim J, John EM, Teixeira MR, Neuhausen SL, De Ruyck K, Razack A, Newcomb LF, Lessel D, Kaneva RP, Usmani N, Claessens F, Townsend PA, Dominguez MG, Roobol MJ, Menegaux F, Khaw KT, Cannon-Albright LA, Pandha H, Thibodeau SN, and Martin RM
- Subjects
- Aged, Case-Control Studies, Cholesterol blood, Genome-Wide Association Study, Humans, Male, Mendelian Randomization Analysis, Middle Aged, Phospholipids blood, Prostate-Specific Antigen blood, Triglycerides blood, United Kingdom, Biomarkers, Tumor blood, Metabolome, Prostatic Neoplasms blood
- 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)., Methods: The case-control portion of the study was conducted in nine UK centers with men ages 50-69 years who underwent prostate-specific antigen 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., (©2018 American Association for Cancer Research.)
- Published
- 2019
- Full Text
- View/download PDF
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