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Abstract Background More specific diagnostic for prostate cancer is needed to decrease overdetection and number of diagnostic procedures. Objective To assess the performance of combining a blood-based biomarker panel and magnetic resonance imaging (MRI)-targeted biopsies for prostate cancer detection. Design, setting, and participants We used a prospective, multicenter, paired diagnostic study design. A total of 532 men aged 45–74 yr referred for prostate cancer workup were included during 2016–2017. Intervention Participants underwent blood sampling for analysis of the Stockholm3 test including protein biomarkers, genetic polymorphisms, and clinical variables; 1.5 T MRI; systematic prostate biopsies; and MRI-targeted biopsies to lesions with Prostate Imaging Reporting and Data System version 2 ≥3. Outcome measurements and statistical analysis The main outcome was numbers of detected prostate cancer characterized by grade group (GG) and the number of performed biopsies using relative sensitivity (RS). Results and limitations Median prostate-specific antigen was 6.3 ng/ml, and mean age was 63.9 yr. Targeted and systematic biopsies detected 170 and 162 GG ≥2 tumors, respectively (RS 1.05; 95% confidence interval [CI] 0.96–1.14). Compared with performing systematic biopsies on all men, performing targeted and systematic biopsies only on men with >10% risk of GG ≥2 cancer, as predicted by the Stockholm3 test, required 62% (95% CI 58–66) of the biopsy procedures and detected 58% (95% CI 48–70) of GG 1 disease, with increased sensitivity for GG ≥2 detection (RS 1.10; 95% CI 1.02–1.17). Performing only targeted biopsies in men with elevated Stockholm3 test altered these results only slightly. Compared with performing systematic and targeted biopsies on all men, performing this only for men with an elevated Stockholm3 test decreased detection of GG ≥2 cancer slightly (RS 0.92; 95% CI 0.88–0.95). Limitations include lacking knowledge of true disease prevalence. Conclusions These findings provide evidence that strategies combining the blood-based Stockholm3 test and MRI-targeted biopsies can be used to inform biopsy decision making. Patient summary In this study, 532 men coming for prostate cancer workup underwent blood sampling, and both traditional and magnetic resonance imaging/fusion-guided prostate biopsies. We report that performing targeted biopsies only in men with an elevated risk as assessed by the Stockholm3 test saved biopsies, decreased overdetection, and maintained the number of detected high-grade cancers. Take Home Message In this prospective, multicenter study, a strategy of performing magnetic resonance imaging/fusion biopsies in men with an elevated risk of prostate cancer, as assessed by the Stockholm3 test, saved biopsy procedures, decreased detection of low-grade tumors, and maintained sensitivity to detect high-grade cancer. [ABSTRACT FROM AUTHOR]

Background: Patients who have undergone radical cystectomy for urinary bladder cancer are not sufficiently physically active and therefore may suffer complications leading to readmissions. A physical rehabilitation programme early postoperatively might prevent or at least alleviate these potential complications and improve physical function. The main aim of the CanMoRe trial is to evaluate the impact of a standardised and individually adapted exercise intervention in primary health care to improve physical function (primary outcome) and habitual physical activity, health-related quality of life, fatigue, psychological wellbeing and readmissions due to complications in patients undergoing robotic-assisted radical cystectomy for urinary bladder cancer.Methods: In total, 120 patients will be included and assigned to either intervention or control arm of the study. All patients will receive preoperative information on the importance of early mobilisation and during the hospital stay they will follow a standard protocol for enhanced mobilisation. The intervention group will be given a referral to a physiotherapist in primary health care close to their home. Within the third week after discharge, the intervention group will begin 12 weeks of biweekly exercise. The exercise programme includes aerobic and strengthening exercises. The control group will receive oral and written information about a home-based exercise programme. Physical function will serve as the primary outcome and will be measured using the Six-minute walk test. Secondary outcomes are gait speed, handgrip strength, leg strength, habitual physical activity, health-related quality of life, fatigue, psychological wellbeing and readmissions due to complications. The measurements will be conducted at discharge (i.e. baseline), post-intervention and 1 year after surgery. To evaluate the effects of the intervention mixed or linear regression models according to the intention to treat procedure will be used.Discussion: This proposed randomised controlled trial has the potential to provide new knowledge within rehabilitation after radical cystectomy for urinary bladder cancer. The programme should be easy to apply to other patient groups undergoing abdominal surgery for cancer and has the potential to change the health care chain for these patients.Trial Registration: ClinicalTrials.gov. Clinical trial registration number NCT03998579 . First posted June 26, 2019. [ABSTRACT FROM AUTHOR]

Objective: An exercise programme in primary care soon after radical cystectomy for urinary bladder cancer was previously evaluated regarding its effects on physical function. A secondary aim, presented herein, was to evaluate the programme in terms of its effect on postoperative complications., Materials and Methods: Patients who were planned for robot-assisted radical cystectomy for urinary bladder cancer at Karolinska University Hospital between September 2019 and October 2022 were invited to participate. At discharge from hospital, they were randomised to intervention group including aerobic and resistance exercises with physiotherapist in primary care twice a week for 12 weeks and daily walks, or to unsupervised home-based exercise including daily walks. Readmission rates between 30 and 90 days after discharge, and complications according to Clavien Dindo were collected from the medical records and analysed., Results: Ninety patients were randomised, with a mean (SD) age of 72 (9) years. Readmission rates between 30 and 90 days showed no difference between the groups. For readmitted patients, the intervention group had significantly fewer complications reported as Clavien Dindo grade 2 compared to the control group.  Conclusion: An exercise programme in primary care soon after robot-assisted radical cystectomy appears to be safe for patients, as measured by hospital readmission rates.  Trial registration: Clinical Trials (NCT03998579).

Background: α1-Adrenergic receptor antagonists are commonly used to treat benign prostatic hyperplasia. Preclinical studies suggest that they induce cell death and inhibit tumor growth. This study evaluated the risk of prostate cancer death in men using α1-adrenergic receptor antagonists., Methods: A population-based cohort study in Stockholm, Sweden (January 1, 2007, to December 31, 2019) included 451 779 men with a prostate-specific antigen test result. Study entry was 1 year after the first prostate-specific antigen test. Men were considered exposed at their second filled prescription. The primary outcome was prostate cancer mortality. Secondary outcomes were all-cause mortality and prostate cancer incidence. Cox proportional hazards regression models were used to calculate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for all outcomes. Inverse-probability weighting with marginal structural models accounted for time-dependent confounders., Results: Of 351 297 men in the final cohort, 39 856 (11.3%) were exposed to α1-adrenergic receptor antagonists. Median (interquartile range) follow-up for prostate cancer mortality was 8.9 (5.1-10.9) years; median (interquartile range) exposure time to α1-adrenergic receptor antagonists was 4.4 (2.0-7.6) years. There was no evidence of an association between α1-adrenergic receptor antagonist use and prostate cancer mortality, all-cause mortality, or high-grade prostate cancer. α1-Adrenergic receptor antagonist use was associated with an increased risk of prostate cancer (HR = 1.11, 95% CI = 1.06 to 1.17) and low-grade prostate cancer (HR = 1.22, 95% CI = 1.11 to 1.33). Men whose prostate cancer was treated with α1-adrenergic receptor antagonists underwent more frequent prostate-specific antigen testing., Conclusions: Our findings show no significant association between α1-adrenergic receptor adrenoceptor antagonist exposure and prostate cancer mortality or high-grade prostate cancer. Although the preclinical evidence indicates a potential chemopreventive effect, this study's findings do not support it., (© The Author(s) 2024. Published by Oxford University Press.)

Background: Positive surgical margins (PSMs) are frequent in patients undergoing radical prostatectomy (RP). The impact of PSMs on cancer-specific (CSM) and overall (OM) mortality has not yet been proved definitively., Objective: To evaluate whether the presence and the features of PSMs were associated with CSM and OM in patients who underwent robotic-assisted RP., Design, Setting, and Participants: A cohort of 8141 patients underwent robotic-assisted RP with >10 yr of follow-up., Outcome Measurements and Statistical Analysis: Cox multivariable analyses assessed the impact of margin status (positive vs negative) and PSM features (negative vs <3 mm vs >3 mm vs multifocal) on the risk of CSM, OM, and biochemical recurrence (BCR) after adjusting for potential confounders. We repeated our analyses after stratifying patients according to clinical (Cancer of the Prostate Risk Assessment [CAPRA] categories) and pathological characteristics (adverse: pT 3-4 and/or grade group [GG] 4-5 and/or pN1 and/or prostate-specific antigen [PSA] persistence)., Results and Limitations: PSMs were found in 1348 patients (16%). Among these, 48 (3.6%) patients had multifocal PSMs. Overall, 1550 men experienced BCR and 898 men died, including 130 for prostate cancer. At Cox multivariable analyses, PSMs were associated with CSM in patients with adverse clinical (Intermediate risk: hazard ratio [HR]: 1.71, p = 0.048; high risk: HR: 2.20, p = 0.009) and pathological (HR: 1.79, p = 0.005) characteristics. Only multifocal PSMs were associated with CSM and OM in the whole population (HR for CSM: 4.68, p < 0.001; HR for OM: 1.82, p = 0.037) and in patients with adverse clinical (intermediate risk: HR for CSM: 7.26, p = 0.006; high risk: HR for CSM: 9.26, p < 0.001; HR for OM: 2.97, p = 0.006) and pathological (HR for CSM: 9.50, p < 0.001; HR for OM: 2.59, p = 0.001) characteristics. Potential limitations include a selection bias and a lack of information on the Gleason score at PSM location., Conclusions: We did not find an association between unifocal PSMs and mortality. Conversely, our results underscore the importance of avoiding multifocal PSMs in patients with adverse clinical (intermediate- and high-risk CAPRA score) and pathological (GG ≥4, pT ≥3, pN1, or PSA persistence) characteristics, to enhance overall survival and reduce CSM., Patient Summary: In this study, we evaluated whether the presence and the characteristics of positive surgical margins were associated with mortality in patients who underwent robotic-assisted radical prostatectomy. We found that the presence of positive surgical margins, particularly multifocal margins, was associated with mortality only in patients with adverse clinical and pathological characteristics., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objective: The aim of this study is to evaluate treatment patterns and long-term oncological outcomes of patients with locally advanced prostate cancer (LAPCa)., Patients and Methods: This is a population-based study including LAPC (cT3-4, M0) patients from the Stockholm region (Sweden). A sub-analysis was performed in men treated with primary cystoprostatectomy or total pelvic exenteration (TPE) for cT4 prostate cancer (PCa).Cox regression was used to identify predictors of overall mortality (OM) and cancer-specific mortality (CSM). Biochemical progression-free survival (BPFS) and 90 days complications were reported for the radical surgery subgroup., Results: We included 2921 patients with cT3( N  = 2713) or cT4( N  = 208), M0 PCa diagnosed between 2003 and 2019. Out of these, 249(9%), 1497(51%) and 1175(40%) underwent radical prostatectomy, RT + ADT and androgen deprivation therapy (ADT), respectively. Survival rates were 76% (IQR: 68, 83), 47% (IQR: 44, 50) and 23% (IQR: 20, 27), respectively at 10 years. Irrespective of treatment modalities, cT4 patients had worse survival compared to cT3 patients (OM: HR1.44, IQR:1.17,1.77; PCSM: HR1.39, IQR:1.06,1.82). Twenty-seven patients with cT4, N0-1, M0 were treated with cystoprostatectomy or TPE. Twenty-two patients (81.5%) received neoadjuvant ADT. The 5-year BPFS, CSS and OS rates were 39.6%, 68.8% and 63.8%, respectively. Nine patients (33.3%) had Clavien-Dindo grade III and 1 (3.7%) grade IV complication within 90 days after surgery., Conclusions: Pelvic surgery with radical intent as part of a multidisciplinary management may be an effective alternative for selected patients with locally advanced PCa leading to local tumour control and an acceptable morbidity., Competing Interests: None of the contributing authors have any conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript., (© 2024 The Author(s). BJUI Compass published by John Wiley & Sons Ltd on behalf of BJU International Company.)

Introduction: After radical cystectomy physical activity is important to reduce risk of complications, but patients with urinary bladder cancer have difficulties in achieving general recommendations on physical activity and exercise. The aim of this randomised controlled trial was therefore to evaluate the effects of a physical exercise programme in primary care, following discharge from hospital after robot-assisted radical cystectomy for urinary bladder cancer., Materials and Methods: Patients with urinary bladder cancer scheduled for robot-assisted radical cystectomy at Karolinska University Hospital, Sweden between September 2019 and October 2022 were invited to join the study. At discharge, they were randomised to intervention or active control group. The intervention group was planned to start exercise with physiotherapist in primary care during the third week; the programme included aerobic and strengthening exercises, twice a week for 12 weeks, and daily walks. The control group received unsupervised home-based exercise with daily walks and a sit-to-stand exercise. Assessments were conducted before surgery, at discharge and after four months regarding the primary outcome physical function (Six-minute walk test), and secondary outcomes physical activity, pain, health-related quality of life, fatigue, and psychological wellbeing., Results: Ninety patients were included, mean (sd) age 71.5 (8.5) years. An intention-to-treat analysis showed no intervention effect on the primary outcome physical function, or on pain or psychological wellbeing, but effect on physical activity with a difference from discharge to four months with a median (IQR) of 4790 (3000) and 2670 (4340) daily steps in the intervention and control group, respectively (p = 0.046), and for fatigue, and health-related quality of life, in favour of the intervention group., Conclusion: Both the intervention and control groups improved physical function, but the patients who exercised in primary care experienced additional positive effects on physical activity, fatigue, and health-related quality of life. Hence, exercise in primary care after discharge from hospital could be a promising method after radical cystectomy for urinary bladder cancer., Trial Registration: The study was registered in Clinical Trials with registration number NCT03998579, 20,190,607., (© 2024. The Author(s).)

Background: Risk assessment for ischemic stroke (IS) and myocardial infarction (MI) is done routinely before surgery, but the increase in risks associated with surgery is not known. The aim of this study is to assess the risk of arterial ischemic events during the first year after oncological surgery., Methods: We used Swedish healthcare databases to identify 443,300 patients who underwent cancer surgery between 1987 and 2016 and 4,127,761 matched comparison subjects. We estimated odds ratios (ORs) for myocardial infarction and ischemic stroke during the hospitalization with logistic regression and calculated 1-year cumulative incidences and hazard ratios (HRs) with 95% confidence intervals (CIs) for the outcomes after discharge., Results: The cumulative incidences of myocardial infarction and ischemic stroke during the first postoperative year were 1.33% and 1.25%, respectively. In the comparison cohort, the corresponding 1-year cumulative incidences were 1.04% and 1.00%. During the hospitalization, the OR for myocardial infarction was 8.81 (95% CI 8.24-9.42) and the OR for ischemic stroke was 6.71 (95% CI 6.22-7.23). After discharge, the average HR during follow-up for 365 days was 0.90 (95% CI 0.87-0.93) for myocardial infarction and 1.02 (95% CI 0.99-1.05) for ischemic stroke., Conclusions: We found an overall increased risk of IS and MI during the first year after cancer surgery that was attributable to events occurring during the hospitalization period. After discharge from the hospital, the overall risk of myocardial infarction was lower among the cancer surgery patients than among matched comparison subjects., (© 2023. The Author(s).)

Importance: The risks and benefits of thromboprophylaxis therapy after cancer surgery are debated. Studies that determine thrombosis risk after cancer surgery with high accuracy are needed., Objectives: To evaluate 1-year risk of venous thromboembolic events after major cancer surgery and how these events vary over time., Design, Setting, and Participants: This register-based retrospective observational matched cohort study included data on the full population of Sweden between 1998 and 2016. All patients who underwent major surgery for cancer of the bladder, breast, colon or rectum, gynecologic organs, kidney and upper urothelial tract, lung, prostate, or gastroesophageal tract were matched in a 1:10 ratio with cancer-free members of the general population on year of birth, sex, and county of residence. Data were analyzed from February 13 to December 5, 2023., Exposure: Major surgery for cancer., Main Outcomes and Measures: The main outcome was incidence of venous thromboembolic events within 1 year after the surgery. Crude absolute risks and risk differences of events within 1 year and adjusted time-dependent cause-specific hazard ratios (HRs) of postdischarge events were calculated., Results: A total of 432 218 patients with cancer (median age, 67 years [IQR, 58-75 years]; 68.7% women) and 4 009 343 cancer-free comparators (median age, 66 years [IQR, 57-74 years]; 69.3% women) were included in the study. The crude 1-year cumulative risk of pulmonary embolism was higher among the cancer surgery population for all cancers, with the following absolute risk differences: for bladder cancer, 2.69 percentage points (95% CI, 2.33-3.05 percentage points); for breast cancer, 0.59 percentage points (95% CI 0.55-0.63 percentage points); for colorectal cancer, 1.57 percentage points (95% CI, 1.50-1.65 percentage points); for gynecologic organ cancer, 1.32 percentage points (95% CI, 1.22-1.41 percentage points); for kidney and upper urinary tract cancer, 1.38 percentage points (95% CI, 1.21-1.55 percentage points); for lung cancer, 2.61 percentage points (95% CI, 2.34-2.89 percentage points); for gastroesophageal cancer, 2.13 percentage points (95% CI, 1.89-2.38 percentage points); and for prostate cancer, 0.57 percentage points (95% CI, 0.49-0.66 percentage points). The cause-specific HR of pulmonary embolism comparing patients who underwent cancer surgery with matched comparators peaked just after discharge and generally plateaued 60 to 90 days later. At 30 days after surgery, the HR was 10 to 30 times higher than in the comparison cohort for all cancers except breast cancer (colorectal cancer: HR, 9.18 [95% CI, 8.03-10.50]; lung cancer: HR, 25.66 [95% CI, 17.41-37.84]; breast cancer: HR, 5.18 [95% CI, 4.45-6.05]). The hazards subsided but never reached the level of the comparison cohort except for prostate cancer. Similar results were observed for deep vein thrombosis., Conclusions and Relevance: This cohort study found an increased rate of venous thromboembolism associated with cancer surgery. The risk persisted for about 2 to 4 months postoperatively but varied between cancer types. The increased rate is likely explained by the underlying cancer disease and adjuvant treatments. The results highlight the need for individualized venous thromboembolism risk evaluation and prophylaxis regimens for patients undergoing different surgery for different cancers.

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.)

Introduction: Postoperative complications and readmission to hospital after major cancer surgery are common. Early mobilisation in hospital is thought to reduce complications, and patients are recommended to mobilise for at least 2 h on the day of surgery, and thereafter at least 6 h per day. Evidence for early mobilisation is limited and therefore also how early mobilisation may influence the development of postoperative complications. The aim of this study was to evaluate the association between early mobilisation after abdominal cancer surgery and readmission to hospital due to postoperative complications., Material and Methods: Adult patients who had abdominal cancer surgery due to ovarian, colorectal, or urinary bladder cancer between January 2017 and May 2018 were included in the study. Exposure was set to the mean number of steps taken over the first three postoperative days, measured with an activity monitor. Primary outcome was readmission to hospital within 30 days after discharge, and secondary outcome was severity of complications. Data were obtained from medical records. Logistic regression was used to investigate the association between exposure and outcomes., Results: Of 133 patients included in the study, 25 were readmitted to the hospital within 30 days after discharge. The analysis showed no association between early mobilisation and readmission or severity of complications., Conclusion: Early mobilisation does not seem to increase the odds of readmission, nor the severity of complications. This study contributes to the limited research on the association between early mobilisation and postoperative complications after abdominal cancer surgery., Competing Interests: Declaration of competing interest No., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Pathological digital rectal examination (DRE) is suggestive of prostate cancer but has low sensitivity and specificity. DRE is incorporated in many clinical risk calculators, but there is less evidence on how DRE performs in the setting of blood biomarkers and polygenic risk prediction models other than prostate-specific antigen (PSA) associated with prostate cancer. The Stockholm3 test combines a blood test and clinical variables including DRE., Objective: To assess the predictive performance of DRE for finding clinically significant prostate cancer in systematic biopsy and evaluate its added value to the multivariable diagnostic test Stockholm3., Design Setting and Participants: This population-based study in the screening by invitation setting included 5543 men aged 50-69 yr with PSA ≥3 ng/ml who were referred for systematic prostate biopsy between 2012 and 2015. The STHLM3 study is registered with ISRCTN.com as ISRCTN84445406., Outcome Measurements and Statistical Analysis: Predictive performance was assessed via estimates of sensitivity and specificity and in logistic regression. Clinically significant cancer was defined as International Society of Urological Pathology grade group ≥2 (GG ≥2) cancer on systematic biopsy., Results and Limitations: We found that 11% of men with PSA ≥3 ng/ml had a suspicious DRE. A suspicious DRE was associated with a 3.16-fold higher risk (95% confidence interval [CI] 2.83-3.52) of GG ≥2 cancer and greater length of cancer on biopsy. The risk of nonsignificant cancer was similar regardless of the DRE finding. The risk of GG ≥2 cancer was 46.2% (95% CI 42.2-50.3%) for men with a suspicious DRE versus 14.6% (95% CI 13.7-15.7%) for men with a negative DRE. The elevated risk of GG ≥2 cancer persisted after adjusting for the other Stockholm3 test parameters (odds ratio 2.88, 95% CI 2.32-3.57). For detection of GG ≥2 cancer among men with PSA ≥3 ng/ml, DRE had sensitivity of 27.8% (95% CI 25.1-30.7%) and specificity of 92.8% (95% CI 92.1-93.6%)., Conclusions: In this screening-by-invitation setting we found that for men with PSA ≥3 ng/ml, a suspicious DRE indicates more than threefold higher risk of harboring significant prostate cancer. DRE as a variable adds significant precision to the Stockholm3 prediction model. Men with a suspicious DRE should be referred for further diagnostic workup, including biopsy., Patient Summary: We investigated the ability of digital rectal examination to predict if a patient has clinically significant prostate cancer. We found that digital rectal examination provides valuable information and can help doctors in making an informed decision on whether to recommend prostate biopsy., (© 2022 The Authors.)

Background: Little is known about disease trajectories for men with castration-resistant prostate cancer (CRPC)., Objective: To create a state transition model that estimates time spent in the CRPC state and its outcomes., Design Setting and Participants: The model was generated using population-based prostate-specific antigen data from 40% of the Swedish male population, which were linked to nationwide population-based databases. We compared the observed and predicted cumulative incidence of transitions to and from the CRPC state., Outcome Measurements and Statistical Analysis: We measured time spent in the CRPC state and the proportion of men who died of prostate cancer during follow-up by CRPC risk category., Results and Limitations: Time spent in the CRPC state varied from 1.1 yr for the highest risk category to 3.9 yr for the lowest risk category. The proportion of men who died from prostate cancer within 10 yr ranged from 93% for the highest risk category to 54% for the lowest. There was good agreement between the model estimates and observed data., Conclusions: There is large variation in the time spent in the CRPC state, varying from 1 yr to 4 yr according to risk category., Patient Summary: It is possible to accurately estimate the disease trajectory and duration for men with castration-resistant prostate cancer., (© 2022 The Authors.)

Background: In men aged above 50 yr, lower urinary tract symptoms (LUTS), benign prostate hyperplasia, and prostate cancer are common urological conditions. Current guidelines for general practitioners frequently recommend prostate-specific antigen (PSA) testing in patients with LUTS for the detection of prostate cancer., Objective: To assess the performance of PSA, PSA density, and the Stockholm3 blood test for identification of prostate cancer among men with LUTS., Design Setting and Participants: In this post hoc analysis of a population-based diagnostic trial (STHLM3, n  = 58 588), 4588 men aged 50-69 yr, without previous prostate cancer, with International Prostate Symptom Score (IPSS) data, and having PSA ≥ 3 ng/mL were identified. Men with at least moderate LUTS, defined as an IPSS score of ≥8, were included. PSA density and Stockholm3 scores were calculated., Intervention: Participants underwent 10-12-core systematic prostate biopsies., Outcome Measurements and Statistical Analysis: The primary outcome was significant prostate cancer (sPCa) defined as International Society of Urological Pathology (ISUP) grade ≥2. Logistic regression analysis adjusted for age and previous biopsy status was performed. The area under the receiver operating characteristic curve (AUC) was calculated, and decision curve analysis was performed., Results and Limitations: Out of 4588 men, 1544 (34%) reported at least moderate LUTS. The median age was 64 yr, and 11% had undergone a previous prostate biopsy. The Stockholm3 test showed superior discrimination for sPCa to PSA density, which in turn showed superior discrimination to PSA (AUC 0.77 vs 0.70 vs 0.61, p  <  0.02). Calibration of the Stockholm3 test was adequate. Performing biopsy only in men with PSA ≥5 ng/mL saved 64% of biopsies, but resulted in missing 52% of detectable sPCa. Recommending biopsy for men with PSA density ≥0.07 resulted in sparing 26% of biopsy procedures and delaying the diagnosis of 12% of sPCa cases, with a 6.1% risk of sPCa among unbiopsied men. Recommending men with Stockholm3 ≥ 0.11 for biopsy resulted in sparing 53% of biopsy procedures and delaying the diagnosis of 20% of sPCa cases, with a 5.1% risk of finding sPCa in unbiopsied men., Conclusions: PSA density and the Stockholm3 blood test were superior to PSA for the identification of prostate cancer among men with LUTS., Patient Summary: In this analysis of a large Swedish study, we find that the use of prostate-specific antigen (PSA) density or the Stockholm3 blood test instead of only PSA might improve the detection of prostate cancer among men with lower urinary tract symptoms., (© 2020 The Author(s).)

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.

We determined the effect of sample size on performance of polygenic hazard score (PHS) models in prostate cancer. Age and genotypes were obtained for 40,861 men from the PRACTICAL consortium. The dataset included 201,590 SNPs per subject, and was split into training and testing sets. Established-SNP models considered 65 SNPs that had been previously associated with prostate cancer. Discovery-SNP models used stepwise selection to identify new SNPs. The performance of each PHS model was calculated for random sizes of the training set. The performance of a representative Established-SNP model was estimated for random sizes of the testing set. Mean HR 98/50 (hazard ratio of top 2% to average in test set) of the Established-SNP model increased from 1.73 [95% CI: 1.69-1.77] to 2.41 [2.40-2.43] when the number of training samples was increased from 1 thousand to 30 thousand. Corresponding HR 98/50 of the Discovery-SNP model increased from 1.05 [0.93-1.18] to 2.19 [2.16-2.23]. HR 98/50 of a representative Established-SNP model using testing set sample sizes of 0.6 thousand and 6 thousand observations were 1.78 [1.70-1.85] and 1.73 [1.71-1.76], respectively. We estimate that a study population of 20 thousand men is required to develop Discovery-SNP PHS models while 10 thousand men should be sufficient for Established-SNP models.

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.)

Background: Although prostate-specific antigen (PSA) testing is common, little is known about the pattern of retesting by either PSA values or subsequent prostate biopsies. Poor follow-up of high PSA values may lead to delayed diagnosis., Objective: To estimate the probabilities of follow-up (including retesting, prostate biopsies, diagnosis, and cause-specific death) for men undergoing prostate cancer testing at a population level., Design, Setting, and Participants: Cohort study design for men living in Stockholm with no previous diagnosis of prostate cancer between 2003 and 2015. Men were linked to the national health and population registries in Sweden. We report follow-up for men aged 50-79 yr at 2003 or at their index PSA test., Outcome Measurements and Statistical Analysis: State probabilities with 95% confidence intervals (CIs) were calculated using multistate Markov models., Results and Limitations: Among men not previously diagnosed with prostate cancer with an initial PSA value of ≥10ng/ml, the proportions at 1 yr with no subsequent testing or only elevated PSA test values >3ng/ml were 21.7% (95% CI: 19.5, 23.9), 25.2% (95% CI: 23.9, 26.6), and 47.7% (95% CI: 46.2, 49.1) for those aged 50-59, 60-69, and 70-79 yr, respectively. No significant changes were noticed when stratifying by comorbidities. Limitations include the lack of detail from patient medical charts. This detail would have allowed for more accurate assessment of appropriate clinical follow-up., Conclusions: Regardless of medical history, a large proportion of men with PSA≥10ng/ml were not followed appropriately at 1 yr after the index PSA test. This may partially explain why opportunistic testing is not as effective as screening within trials to reduce prostate cancer mortality., Patient Summary: For men aged 50-69 yr, who undertake a prostate-specific antigen (PSA) test, a PSA level of >10ng/ml should prompt further investigation. However, we found that one out of 10 of these men did not receive repeat testing within 1 yr of the initial test. This may partially explain why opportunistic prostate cancer testing is less effective than screening trials., (Copyright © 2018 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Context: Until recently, there has been a lack of evidence-based treatment alternatives in men with nonmetastatic castrate-resistant prostate cancer (NM-CRPC). However, new evidence-based treatment alternatives are emerging., Objective: We aimed to describe time-to-event outcomes in NM-CRPC patients based on evidence from both prospective and retrospective studies. Second, we aimed to describe predictors of these outcomes in the same patient population., Evidence Acquisition: A systematic review was conducted to identify clinical studies (both prospective and retrospective) in NM-CRPC patients. All published Kaplan-Meier curves were digitized, and individual participant data were extracted using a published and validated R code. The following outcomes were considered: overall survival (OS), bone metastasis-free survival (BMFS), time to bone metastasis (TTBM), metastasis-free survival, time to metastasis, time to progression (TTP), progression-free survival, and time to prostate-specific antigen (PSA) progression. Second, we described all predictor/outcome relationships., Evidence Synthesis: Median survival times, in months, for OS, BMFS, TTBM, and TTP in placebo arms of randomized clinical trials are 45.3 (95% confidence interval [CI]: 43.5-46.8), 31.5 (95% CI: 28-33.4), 28.8 (95% CI: 25.2-31.6), and 22.2 (95% CI: 19.3-24.8), respectively. In general, reported outcomes in retrospective studies seemed to be longer than those reported in clinical trials. Baseline PSA nadir levels, PSA doubling time, PSA velocity, and alkaline phosphatase velocity are reliable predictors of time-to-event outcomes in NM-CRPC patients, whereas Gleason score is not., Conclusions: NM-CRPC is a long-standing condition where effective treatments to slow down disease progression historically have been lacking. Compared with prospective studies, retrospective studies have had limited ability to correctly identify NM-CRPC patients and estimate time to different outcomes in NM-CRPC patients., Patient Summary: For patients with nonmetastatic castration-resistant prostate cancer (NM-CRPC), currently no effective treatments resulting in longer survival compared with watchful waiting are available. On average, without additional treatment, half of these patients survive <45 mo after NM-CRPC diagnosis., (Copyright © 2018 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: It is unclear whether preoperative staging using Magnetic Resonance Imaging (MRI) reduces the risk of positive margins in prostate cancer. We aimed to assess the effect on surgical margins and degree of nerve sparing of a pelvic MRI presented at a preoperative MRI conference., Methods: Single institution, observational cohort study including 1037 men that underwent robot assisted radical prostatectomy between October 2013 and June 2015. Of these, 557 underwent a preoperative MRI combined with a preoperative MRI conference and 410 did not. With whole-mount prostate specimen histopathology as gold standard we assessed the ability of MRI in finding the index tumor and the sensitivity and specificity for extra prostatic extension. We calculated relative risks for positive surgical margins and non-nerve sparing procedure, adjusting for preoperative risk factors using stabilized inverse-probability weighting., Results: MRI detected the index tumor in 80% of the cases. Non-organ confined disease (pT3) at histology was present in the MRI and the non-MRI group in 42% and 24%, respectively. Rate of positive surgical margins comparing the MRI and non-MRI groups was 26.7% and 33.7%, respectively, relative risk 0.79 [95% CI 0.65-0.96], weighted relative risk (wRR) 0.69 [95% CI 0.55-0.86]. The wRR of extensive positive surgical margins was 0.45 [95% CI 0.31-0.67]. Undergoing MRI was also associated with an increased risk of being operated with a non-nerve sparing technique (wRR, 1.84 [95% CI 1.11-3.03])., Conclusions: Our study suggests that preoperative prostate MRI in combination with a preoperative MRI conference affects the degree of nerve-sparing surgery and reduces positive surgical margins.

Background: Risk prediction models and magnetic resonance imaging (MRI) of the prostate can reduce unnecessary biopsies and overdiagnosis of low-risk prostate cancer. However, it is unclear how these tools should be used in concert., Objective: To develop a unified risk prediction model (S3M-MRI) that combines the Stockholm3 score (based on protein and genetic markers and clinical variables) and Prostate Imaging-Reporting and Data System v.2 scores modified for MRI without contrast (modPI-RADS)., Design, Setting, and Participants: We used data for 532 men from the prospective multicentre STHLM3-MRI diagnostic study to construct S3M-MRI. We compared S3M-MRI to Stockholm3 and modPI-RADS alone with respect to model discrimination, calibration, and net benefit. We also compared clinical outcomes for five diagnostic strategies according to the use of combinations of the three models., Results and Limitations: The area under the receiver operating characteristic curve (AUC) was 0.88 (95% confidence interval [CI] 0.85-0.91) for S3M-MRI, which was significantly higher (p=0.04) than for Stockholm3 (0.86, 95% CI 0.83-0.89) and modPI-RADS (0.83, 95% CI 0.79-0.87). S3M-MRI had a higher net benefit on decision curve analysis for clinically relevant probability thresholds for biopsy recommendation in comparison to Stockholm3 and modPI-RADS. However, for different diagnostic strategies, sequential use of Stockholm3 followed by MRI only for Stockholm3-positive men resulted in a similar number of unnecessary biopsies (64 vs 69) and diagnosed International Society of Urological Pathology (ISUP) grade group 1 cancers (56 vs 51) at similar sensitivity for ISUP grade group ≥2 cancers, while avoiding 38% of MRI scans. Limitations include the ethnically homogeneous study population., Conclusions: The unified S3M-MRI model was superior to the Stockholm3 model and modPI-RADS alone. However, the S3M-MRI improvement was marginal compared to sequential use of Stockholm3 followed by MRI, and resulted in 60% more MRI scans., Patient Summary: A new risk prediction model combining clinical variables, genetic and protein biomarkers, and results from prostate magnetic resonance imaging improved the clinical outcome performance of prostate cancer diagnostics., (Copyright © 2018 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Several blood-based tests have been suggested to improve prostate cancer testing. The Stockholm3 test has been shown to reduce the number of prostate biopsies, to decrease detection of low-grade cancer and to maintain the detection rate of ISUP Gleason Group (GG) ≥ 2 cancer in a screening-by-invitation setting. We aimed to validate the performance of the Stockholm3 test in an independent, clinical practice cohort., Methods: The study-population consisted of 533 men in ages 45-75 without previous diagnosis of prostate cancer scheduled for prostate biopsy at any of three centers in Norway and Sweden. Blood samples for Stockholm3 analysis were drawn prior to systematic prostate biopsies. Clinically significant prostate cancer was defined as any finding of ISUP Grade Group (GG) 2 or higher. We calculated area under the curve (AUC) for predicting prostate cancer at biopsy and calculated. Models including PSA and PSA-density (PSA/prostate volume) were compared to a model including also clinical information, protein levels and single nucleotide polymorphisms (SNP)., Results: 263 of 533 (49%) participants were diagnosed with prostate cancer. 162 men had prostate cancer with GG ≥ 2. The Stockholm3 test discriminated better for GG ≥ 2 prostate cancer than PSA in combination with PSA-density AUC 8.9 (95% CI 82.7-89.2) and AUC 74.8 (95% CI 70.3-79.3). Using a Stockholm3 cut-off of 10% risk of GG ≥ 2 cancer, 38% of the biopsy procedures were saved, however delaying diagnosis for 6% (n = 10) of men with GG ≥ 2 cancer. Using PSA-density 0.1 as cut-off for biopsy saved 35% of biopsies, delaying diagnosis for 16% (n = 26) of men with GG ≥ 2 cancer., Conclusion: A prediction model including clinical information, protein levels and SNPs was independently validated in a clinical practice cohort and reduces the number of un-necessary biopsies while delaying diagnosis for a limited number of men.

Genome-wide association studies (GWAS) and fine-mapping efforts to date have identified more than 100 prostate cancer (PrCa)-susceptibility loci. We meta-analyzed genotype data from a custom high-density array of 46,939 PrCa cases and 27,910 controls of European ancestry with previously genotyped data of 32,255 PrCa cases and 33,202 controls of European ancestry. Our analysis identified 62 novel loci associated (P < 5.0 × 10 -8 ) with PrCa and one locus significantly associated with early-onset PrCa (≤55 years). Our findings include missense variants rs1800057 (odds ratio (OR) = 1.16; P = 8.2 × 10 -9 ; G>C, p.Pro1054Arg) in ATM and rs2066827 (OR = 1.06; P = 2.3 × 10 -9 ; T>G, p.Val109Gly) in CDKN1B. The combination of all loci captured 28.4% of the PrCa familial relative risk, and a polygenic risk score conferred an elevated PrCa risk for men in the ninetieth to ninety-ninth percentiles (relative risk = 2.69; 95% confidence interval (CI): 2.55-2.82) and first percentile (relative risk = 5.71; 95% CI: 5.04-6.48) risk stratum compared with the population average. These findings improve risk prediction, enhance fine-mapping, and provide insight into the underlying biology of PrCa 1 .

Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling.

Background: Screening for prostate cancer using prostate-specific antigen (PSA) alone leads to un-necessary biopsying and overdiagnosis. PSA density is easily accessible, but early evidence on its use for biopsy decisions was conflicting and use of PSA density is not commonly recommended in guidelines., Methods: We analyzed biopsy outcomes in 5291 men in the population-based STHLM3 study with PSA ≥ 3 ng/ml and ultrasound-guided prostate volume measurements by using percentages and regression models. PSA density was calculated as total PSA (ng/ml) divided by prostate volume (ml). Main endpoint was clinically significant cancer (csPCa) defined as Gleason Score ≥ 7., Results: The median PSA-density was 0.10 ng/ml 2 (IQR 0.075-0.14). PSA-density was associated with the risk of finding csPCa both with and without adjusting for the additional clinical information age, family history, previous biopsies, total PSA and free/total PSA (OR 1.06; 95% CI:1.05-1.07 and OR 1.07, 95% CI 1.06-1.08). Discrimination for csPCa was better when PSA density was added to a model with additional clinical information (AUC 0.75 vs. 0.73, P < 0.05). The proportion of men with Gleason Score 6 (ISUP 1) was similar across stratas of PSA-density. Omitting prostate biopsy for men with PSA-density ≤0.07 ng/ml 2 would save 19.7% of biopsy procedures, while missing 6.9% of csPCa. PSA-density cutoffs of 0.10 ng/ml 2 and 0.15 ng/ml 2 resulted in detection of 77% (729/947) and 49% (461/947) of Gleason Score ≥7 tumors., Conclusions: PSA-density might inform biopsy decisions, and spare some men from the morbidity associated with a prostate biopsy and diagnosis of low-grade prostate cancer.

Unlabelled: Breast, ovarian, and prostate cancers are hormone-related and may have a shared genetic basis, but this has not been investigated systematically by genome-wide association (GWA) studies. Meta-analyses combining the largest GWA meta-analysis data sets for these cancers totaling 112,349 cases and 116,421 controls of European ancestry, all together and in pairs, identified at P < 10(-8) seven new cross-cancer loci: three associated with susceptibility to all three cancers (rs17041869/2q13/BCL2L11; rs7937840/11q12/INCENP; rs1469713/19p13/GATAD2A), two breast and ovarian cancer risk loci (rs200182588/9q31/SMC2; rs8037137/15q26/RCCD1), and two breast and prostate cancer risk loci (rs5013329/1p34/NSUN4; rs9375701/6q23/L3MBTL3). Index variants in five additional regions previously associated with only one cancer also showed clear association with a second cancer type. Cell-type-specific expression quantitative trait locus and enhancer-gene interaction annotations suggested target genes with potential cross-cancer roles at the new loci. Pathway analysis revealed significant enrichment of death receptor signaling genes near loci with P < 10(-5) in the three-cancer meta-analysis., Significance: We demonstrate that combining large-scale GWA meta-analysis findings across cancer types can identify completely new risk loci common to breast, ovarian, and prostate cancers. We show that the identification of such cross-cancer risk loci has the potential to shed new light on the shared biology underlying these hormone-related cancers. Cancer Discov; 6(9); 1052-67. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 932., Competing Interests: The authors disclose no potential conflicts of interest., (©2016 American Association for Cancer Research.)

Although genome-wide association studies have identified over 100 risk loci that explain ∼33% of familial risk for prostate cancer (PrCa), their functional effects on risk remain largely unknown. Here we use genotype data from 59,089 men of European and African American ancestries combined with cell-type-specific epigenetic data to build a genomic atlas of single-nucleotide polymorphism (SNP) heritability in PrCa. We find significant differences in heritability between variants in prostate-relevant epigenetic marks defined in normal versus tumour tissue as well as between tissue and cell lines. The majority of SNP heritability lies in regions marked by H3k27 acetylation in prostate adenoc7arcinoma cell line (LNCaP) or by DNaseI hypersensitive sites in cancer cell lines. We find a high degree of similarity between European and African American ancestries suggesting a similar genetic architecture from common variation underlying PrCa risk. Our findings showcase the power of integrating functional annotation with genetic data to understand the genetic basis of PrCa.

Background: Unnecessary intervention and overtreatment of indolent disease are common challenges in clinical management of prostate cancer. Improved tools to distinguish lethal from indolent disease are critical., Methods: We performed a genome-wide survival analysis of cause-specific death in 24,023 prostate cancer patients (3,513 disease-specific deaths) from the PRACTICAL and BPC3 consortia. Top findings were assessed for replication in a Norwegian cohort (CONOR)., Results: We observed no significant association between genetic variants and prostate cancer survival., Conclusions: Common genetic variants with large impact on prostate cancer survival were not observed in this study., Impact: Future studies should be designed for identification of rare variants with large effect sizes or common variants with small effect sizes., (©2015 American Association for Cancer Research.)

Prostate cancer is the most frequently diagnosed cancer in males in developed countries. To identify common prostate cancer susceptibility alleles, we genotyped 211,155 SNPs on a custom Illumina array (iCOGS) in blood DNA from 25,074 prostate cancer cases and 24,272 controls from the international PRACTICAL Consortium. Twenty-three new prostate cancer susceptibility loci were identified at genome-wide significance (P < 5 × 10(-8)). More than 70 prostate cancer susceptibility loci, explaining ∼30% of the familial risk for this disease, have now been identified. On the basis of combined risks conferred by the new and previously known risk loci, the top 1% of the risk distribution has a 4.7-fold higher risk than the average of the population being profiled. These results will facilitate population risk stratification for clinical studies.

Prostate cancer (PrCa) is the most frequently diagnosed male cancer in developed countries. We conducted a multi-stage genome-wide association study for PrCa and previously reported the results of the first two stages, which identified 16 PrCa susceptibility loci. We report here the results of stage 3, in which we evaluated 1,536 SNPs in 4,574 individuals with prostate cancer (cases) and 4,164 controls. We followed up ten new association signals through genotyping in 51,311 samples in 30 studies from the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium. In addition to replicating previously reported loci, we identified seven new prostate cancer susceptibility loci on chromosomes 2p11, 3q23, 3q26, 5p12, 6p21, 12q13 and Xq12 (P = 4.0 × 10(-8) to P = 2.7 × 10(-24)). We also identified a SNP in TERT more strongly associated with PrCa than that previously reported. More than 40 PrCa susceptibility loci, explaining ∼25% of the familial risk in this disease, have now been identified.