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Purpose:The European Randomized Study of Screening for Prostate Cancer (ERSPC) has shown a 21% reduction in prostate cancer mortality by PSA-based screening. The aim of the study is to evaluate screening effect on prostate cancer incidence and mortality in relation to number of screening rounds attended.Experimental Design: The participants in the screening arm of the Finnish trial (31,867 men) were classified according to screening attendance in a time-dependent fashion. Initially, all men in the screening arm were regarded as nonattenders until the first screening attendance, then remained among the once-screened until the second screen and similarly for the possible third round. The control arm was the reference. Follow-up started at randomization and ended at death, emigration, or end of 2013. Prostate cancer incidence and mortality, as well lung cancer and overall mortality were evaluated.Results:Prostate cancer incidence was increased among screened men, but was not directly related to the number of screening rounds. Prostate cancer mortality was decreased in men screened twice or three times, but did not materially differ in those who did not attend the screening, and in men screened once compared with the control arm. The largest mortality reduction was in men screened three times [HR 0.17; 95% confidence interval (CI), 0.09–0.33]. However, a reduction was also seen in lung cancer (HR 0.59; 95% CI, 0.47–0.73) and overall mortality (HR 0.56; 95% CI, 0.52–0.60).Conclusions:Assuming a similar relative reduction being due to selection bias and screening in prostate cancer as other causes of death (40% reduction), approximately half of the observed prostate cancer mortality reduction by repeated screening is likely to be noncausal and a real screening effect may account for up to 40% reduction in men screened three times. Prostate cancer mortality reduction can only be achieved by repeated screening cycles.

Results of the case-control study

Prostate-specific antigen (PSA)-based screening for prostate cancer (PCa) can reduce PCa mortality, but also involves over-detection of low-risk disease with potential adverse effects. We evaluated PCa incidence among men with PSA below 3 ng/mL and no PCa diagnosis at the first screening round of the Finnish Randomized Study of Screening for PCa. Follow-up started at the first screening attendance and ended at PCa diagnosis, emigration, death, or the common closing date (December 2016), whichever came first. Cox regression analysis was used to estimate hazard ratios and their confidence intervals (CI). Among men with PSA

Although platelets and thrombosis play a role in cancer progression, anticoagulant drug warfarin has not been independently associated with prostate cancer (PCa) survival. SNPs altering warfarin metabolism may in theory affect the association. We investigated the risk associations by warfarin use stratified by the SNP-profile of CYP2C9 and VKORC1 enzymes known to affect warfarin metabolism. A total of 3,241 men participating in the FinRSPC and 1,436 men with PCa and treated at Tampere University Hospital were genotyped for CYP2C9 SNP rs1057910 and VKORC1 SNP rs9923231 known to affect warfarin metabolism. Cox regression method was used to calculate hazard ratios (HRs) and 95% confidence intervals for the risk of death overall, cancer death and PCa death after PCa diagnosis. Data on warfaring purchases was obtained from national registry. The SNPs did not modify the risk association between warfarin use and cancer death (HR 1.02, 95% CI 0.77-1.35), PCa progression, clinical features of PCa or the risk of PCa death. Overall risk of death was non-statistically elevated among warfarin users compared to non-users independent of SNP carrier status. SNPs in CYP2C9 and VKORC1 do not modify the association between warfarin use and PCa risk or outcomes among men with PCa. However, use of warfarin is associated with higher overall risk of death independent of metabolic genotype. Our results confirm the previously demonstrated association between anticoagulant use and increased cancer mortality, and suggests the association is not directly caused by warfarin as it is not modified by warfarin metabolism.

Diabetes has been associated with an increased risk of benign prostatic hyperplasia (BPH). However, the role of antidiabetic drugs as a BPH risk factor is unclear. The objective of our study was to examine the risk of BPH by antidiabetic drug use and glycemic control in a large population-based cohort of Finnish men.A total of 74,754 men in the Finnish Randomized Study of Screening for Prostate Cancer (FinRSPC) free of BPH at baseline in 1996-1999 were linked to the national medication reimbursement database for information on physician-prescribed antidiabetic drug purchases. Information on recorded BPH procedures and diagnoses was obtained from the National Care Register for Health Care, and for a subgroup of 17,739 men, information on blood glucose levels (BGLs) from the Fimlab Laboratories database. Cox regression with antidiabetic drug use and BGL as time-dependent variables was used to analyze the risks for starting BPH medication, recorded BPH diagnosis, and undergoing BPH surgery. The analysis was adjusted for age, use of statins, antihypertensive medication, and nonsteroidal anti-inflammatory drugs.Of the subjects, 14,012 men (18.7%) used antidiabetic medication. Of the subgroup with fasting blood glucose data available, 7487 (42.2%) had diabetic level. The risks for BPH diagnosis (HR: 1.08, 95% CI: 1.03-1.13) and surgery (HR: 1.16, 95% CI: 1.09-1.24) were slightly elevated among antidiabetic drug users compared to nonusers. The association was strongest for insulin use. Similarly, risk of BPH surgery was increased in men with diabetic blood glucose compared to normoglycemic men. The risk association was attenuated by use of antidiabetic drugs.Diabetic BGL and antidiabetic medication use, especially insulin, are associated with an elevated risk of BPH surgery compared to nondiabetic men. These findings support the roles of insulin use and untreated hyperglycemia as possible BPH risk factors.

Background Allopurinol is gout medication that inhibits uric acid formation. Its possible anti-carcinogenic properties have been under research in past years. Studies based on Taiwanese registries showed that long term allopurinol use might reduce prostate cancer (PCa) incidence. However, our studies based on Finnish registries did not support those findings. In this study, we evaluate whether allopurinol use is associated with prostate cancer-specific survival (CSS) or overall survival (OS) in a Finnish population-based cohort. Methods The study cohort was originally enrolled for the Finnish Randomized Study of Screening for Prostate Cancer (FinRSPC). We included all newly diagnosed PCa cases during 1996–2015, 9252 men in total. Information on allopurinol purchases was from the national prescription registry of the Social Insurance Institution of Finland. Information about deaths, treatments, and use of other medications was obtained from registries, and tumor stage and PSA at diagnosis from medical records. Follow-up started at diagnosis, and we analysed separately two endpoints: PCa-specific death and overall death. We used an extended Cox regression with adjustment for age at diagnosis, Charlson comorbidity index, FinRSPC trial arm, use of other drugs and EAU PCa risk group. Results During a median follow-up of 9.86 years, 2942 deaths occurred, including 883 from PCa. There was no difference in CSS between allopurinol user and non-users, but allopurinol users had lower OS (multivariable-adjusted hazard ratio 1.77; 95% CI: 1.57–2.00). However, this decrease in OS was mitigated along with increasing intensity of allopurinol use. Conclusions We found no marked difference in CSS by allopurinol use. Allopurinol users had lower OS but there were no significant differences by duration or intensity of allopurinol use. Allopurinol use may not have anticancer effects against prostate cancer; instead, it may be a surrogate for metabolic problems causing shorter OS among men with PCa.

Purpose: Screening for prostate cancer may have limited impact on decreasing prostate cancer-related mortality. A major disadvantage is overdiagnosis, whereby lesions are identified that would not have become evident during the man’s lifetime if screening had not taken place. The present study aims to estimate the rate of overdiagnosis using Finnish data from the European randomized trial of prostate screening. Methods: We used data from 80,149 men randomized to a screening or a control group, distinguishing four birth cohorts. We used the “catch-up method” to identify when the difference in the cumulative incidence of prostate cancer between the screening and control groups had stabilised, implying that the screening has no further effect. We define the overdiagnosis rate to be the relative excess cumulative incidence in the screened group at that point. As an independent method, we also examined the diagnosis rates of T1c tumours as an indicator of early tumors detected by PSA. Results: The estimates of overdiagnosis rates from the catch-up method using the full period of available follow-up ranged between cohorts from 2.3% to 15.4%, and the T1c analysis gave very similar results. Conclusions: Some overdiagnosis has occurred, but there is uncertainty about its extent. A long follow-up is required to demonstrate the full impact of screening. We evaluated the overdiagnosis rates at a population level, associated with being offered screening, taking account of contamination (screening among the controls). The overall evaluation of screening should incorporate mortality benefit, cost-effectiveness and quality of life.

Statins have been associated with a decreased cancer mortality. However, cholesterol level as such may modify the risk of cancer death. To clarify the complex interplay between statins, cholesterol level, and cancer mortality, we conducted a comprehensive analysis to separate the effects of cholesterol level and statin medication on cancer mortality. Our study population consisted of 16,924 men participating in the Finnish Randomized Study of Screening for Prostate Cancer with at least one cholesterol measurement during follow-up (1996-2017). Cox proportional regression was used to estimate hazard ratios. In total, 1699 cancer deaths were observed during the median follow-up of 19 years. When statins' association with the risk of cancer death was estimated without adjustment for cholesterol level, statin use was associated with a lowered cancer mortality (HR 0.87; 95% CI 0.79-0.97) compared to non-users. However, with further adjustment for total cholesterol level, statin use was no longer associated with a lower cancer mortality (HR 1.08; 95% CI 0.97-1.20). Upon stratified analysis, statin use was associated with a decreased cancer mortality only if the total cholesterol level decreased after the initiation of statin use (HR 0.66; 95% CI 0.58-0.76). The inverse association between statin use and cancer mortality is limited to men with a reduction in total cholesterol level after the commencement of statins, i.e., statin use is associated with a lowered cancer mortality only if the total cholesterol level decreases. This suggests that the effect of statin use on cancer mortality relates to the decreased total cholesterol level. publishedVersion

Contains fulltext : 237261.pdf (Publisher’s version ) (Closed access) Adherence to national and international clinical practice guidelines is suboptimal throughout Europe. The European Association of Urology Guidelines Office project "IMAGINE" (IMpact Assessment of Guidelines Implementation and Education) has been developed to measure baseline adherence to urological guideline recommendations across Europe and to identify issues that drive nonadherence.

BACKGROUND The European Randomized Study of Screening for Prostate Cancer has shown a 20% reduction in prostate cancer (PC) mortality by prostate-specific antigen-based screening. In addition, screening has been shown to reduce the risk of advanced PC. The objective of the current study was to analyze the impact of screening participation on the incidence of PC by risk group. METHODS The participants in the screening arm of the Finnish trial (31,867 men) were classified according to screening attendance in a time-dependent fashion. Initially, all men in the screening arm were regarded as nonattenders until the first screening attendance; they then remained in the once-screened group until the second screen and similarly for the possible third round. The control arm formed the reference group. Follow-up started at randomization and ended at the time of diagnosis of PC, emigration, or the end of 2015. PC cases were divided into risk groups according to European Association of Urology definitions. RESULTS The incidence of low-risk PC increased with the number of screens, whereas no clear relation with participation was noted in the intermediate-risk and high-risk cases. For patients with advanced PC, attending screening at least twice was associated with a lower risk. CONCLUSIONS Screening reduces the risk of advanced PC after only 2 screening cycles. A single screen demonstrated no benefit in terms of PC incidence. Repeated screening is necessary to achieve screening advantages.

Tumour associated trypsin inhibitor (TATI) is a peptide that is a marker for several tumours. TATI may also behave as an acute phase reactant in severe inflammatory disease. Overexpression of TATI predicts an unfavourable outcome for many cancers. This study aimed to evaluate the prognostic value of pre- and postoperative concentration of TATI in serum (S-TATI) of patients with renal cell carcinoma (RCC).S-TATI was determined by time resolved immunofluorometric assay in preoperative and postoperative samples that were collected from 132 RCC patients, who underwent partial or complete nephrectomy in Helsinki University Hospital from May 2005 to July 2010.Preoperative S-TATI was significantly associated with tumour stage, lymph-node involvement, metastatic stage, Chronic Kidney Disease Stage (CKD grade), and preoperative C-reactive protein level (Our data suggest that elevated postoperative S-TATI may be associated with adverse prognosis in RCC patients.

Background In prostate cancer (PCa), lower education level is associated with less screening, more advanced stage at diagnosis and worse survival. The aim of this study was to estimate the association between education level and treatment modality and subsequently survival. Methods The 9255 men diagnosed with PCa in the Finnish Randomized Study of Screening for Prostate Cancer were included. Cancer stage, comorbidity, education level and primary treatment modality were extracted from the patient records, the Finnish Cancer Registry, Statistics Finland and the National Institute of Health and Welfare, and these covariates were used in logistic regression (treatment selection) and Cox regression (survival analysis). Results In high-risk cancers, men with tertiary education were more likely to be treated with radical prostatectomy (odds ratio [OR] = 1.76; 95% confidence interval [CI] = 1.27–2.44) than men with primary education. Men with secondary (OR = 0.57; 95% CI = 0.38–0.84) or tertiary (OR = 0.42; 95% CI = 0.29–0.60) education were managed less frequently with mere hormonal therapy. In locally advanced cases, tertiary education was associated with more curatively aimed therapies and less hormonal therapy (OR for radical prostatectomy = 2.34; 95% CI = 1.49–3.66; OR for radiotherapy = 1.42; 95% CI = 1.09–1.85; OR for hormonal therapy = 0.45; 95% CI = 0.33–0.60). The hazard ratio for PCa death was lower in men with secondary (0.81; 95% CI = 0.69–0.95) and tertiary (0.75; 95% CI = 0.65–0.87) education than in the patients with primary education. Conclusions When controlled for the cancer risk group, comorbidity and patient's age, low education level is independently associated with less curatively aimed treatment in men with high-risk or locally advanced PCa and subsequently worse prognosis.

Objective: To analyze the health-related quality of life (HRQoL) and survival of real-world prostate cancer (PC) patients and to calculate quality-adjusted life-years (QALYs) experienced under different treatment strategies. Materials and Methods: PC patients undergoing active surveillance (n = 226), radiation treatment (n = 280), surgery (n = 299), or hormonal treatment (n = 62) responded to the generic 15-dimensional (15D) HRQoL questionnaire at the time of the diagnosis and were followed up 3, 6, 12, and 24 months later. QALYs experienced during the follow-up were calculated for each treatment group, and variables associated with survival were analyzed using Cox proportional hazards models. Results: HRQoL was stable during the first 2 years after diagnosis in all other treatment groups, except in patients treated with hormonal therapy. The overall survival within 6.5-year follow-up time was 84.4%. The number of QALYs experienced during the 2-year follow-up was similar in patients in active surveillance (1.790), surgery (1.784), and radiation groups (1.767), but significantly lower in the hormonal therapy group (1.665). Conclusions: Patients receiving hormonal treatment had significantly impaired HRQoL and survival compared with other treatments. Although the number of QALYs experienced was similar in the 3 other treatment lines, there were marked differences between treatment lines on some 15D dimensions.

Importance: Prostate-specific antigen (PSA) screening for prostate cancer has resulted in a slight reduction in prostate cancer mortality but also a concomitant overdiagnosis of low-risk tumors. Prostate-specific antigen levels are affected by use of cholesterol-lowering statin drugs, but the association of statin use with PSA screening performance is unknown. Objective: To investigate whether statin use was associated with outcomes of a randomized PSA-based prostate cancer screening intervention. Design, setting, and participants: This post hoc subgroup analysis of a cohort from a population-based randomized clinical trial used data from the population-based Finnish Randomized Study of Prostate Cancer Screening, which randomized men to PSA screening or routine care from March 1, 1996, to December 31, 1999, with follow-up continuing until December 31, 2015. The population included all men aged 55 to 67 years at baseline and residing in the Tampere or Helsinki districts of Finland. Information on statin purchases from 1996 to 2009 was obtained from a national prescription registry. Eligible men were identified from the population registry of Finland. Prevalent prostate cancer cases at baseline were excluded. Data were analyzed from January 1, 2019 to March 31, 2021. Interventions: Three invitations for PSA screening at 4-year intervals from 1996 to 2007 vs routine care. Main outcomes and measures: Risk for prostate cancer overall, high-risk disease, and prostate cancer mortality in the screening group vs the control group as an intention-to-treat analysis. The analysis was stratified by statin use. Results: The study comprised 78 606 men (median age, 59 years [range, 55-67 years]) with statin purchase data available. Although PSA screening was associated with increased prostate cancer incidence among statin nonusers (screening vs control, 11.2 vs 8.6 per 1000 person-years); rate ratio [RR], 1.31; 95% CI, 1.24-1.38), no similar increase in incidence was observed among statin users (6.9 vs 5.9 per 1000 person-years; RR, 1.02; 95% CI, 0.95-1.10; P < .001 for interaction). Incidence of low-risk (Gleason score 6) and localized tumors was lower among statin users, whereas detection of tumors with a Gleason score of 8 to 10 was similar. Screening was associated with a lower incidence of metastatic tumors regardless of statin use. Conclusion and relevance: In this post hoc subgroup analysis of a cohort from a population-based randomized clinical trial, PSA screening among statin users was associated with a decreased incidence of advanced prostate cancer that was similar among statin nonusers, but with less increase in detection of low-grade localized tumors in statin users than in nonusers. These findings suggest that statin use does not materially compromise benefits of PSA-based screening. acceptedVersion

To evaluate the feasibility of a population-based screening trial using prostate-specific antigen (PSA), a kallikrein panel and multiparametric magnetic resonance imaging (MRI) aimed at minimizing overdiagnosis, while retaining mortality benefit.Feasibility of the screening algorithm was evaluated in terms of participation, screening test results and cancer detection. A random sample of 400 men aged 65 years was identified from the population registry and invited for screening with three stepwise tests (PSA, kallikrein panel and MRI). Men with PSA levels ≥3 ng/mL were further tested with the kallikrein panel, and those with positive findings (risk7.5%) were referred for prostate MRI. Men with positive MRI (Prostate Imaging Reporting and Data System [PI-RADS] score 3-5) had targeted biopsies only. Men with negative MRI, but PSA density ≥0.15 underwent systematic biopsies.Of the 399 men invited, 158 (40%) participated and 27 had PSA levels ≥3 ng/mL (7% of the invited and 17% of the participants). Of these, 22 had a positive kallikrein panel (6% of the invited and 81% of the PSA-positive men). Finally, 10 men (3% of the invited and 45% of 4Kscore [kallikrein panel]-positive) had a suspicious MRI finding (PI-RADS score ≥3) and five were diagnosed with a clinically significant prostate cancer (Gleason Grade Group [GG] ≥2) at fusion biopsy (3% of the participants), with two GG 1 cases (1%). Additional testing (kallikrein panel and MRI) after PSA reduced biopsies by 56%.The findings constitute proof of principle for our screening protocol, as we achieved a substantial detection rate for clinically significant cancer with few clinically insignificant cases. Participation, however, was suboptimal.

Purpose Statins’ cholesterol-lowering efficacy is well-known. Recent epidemiological studies have found that inhibition of cholesterol synthesis may have beneficial effects on prostate cancer (PCa) patients, especially patients treated with androgen deprivation therapy (ADT). We evaluated statins’ effect on prostate cancer prognosis among patients treated with ADT. Materials and methods Our study population consisted of 8253 PCa patients detected among the study population of the Finnish randomized study of screening for prostate cancer. These were limited to 4428 men who initiated ADT during the follow-up. Cox proportional regression model adjusted for tumor clinical characteristics and comorbidities was used to estimate hazard ratios for risk of PSA relapse after ADT initiation and prostate cancer death. Results During the median follow-up of 6.3 years after the ADT initiation, there were 834 PCa deaths and 1565 PSA relapses in a study cohort. Statin use after ADT was associated with a decreased risk of PSA relapse (HR 0.73, 95% CI 0.65–0.82) and prostate cancer death (HR 0.82; 95% CI 0.69–0.96). In contrast, statin use defined with a one-year lag (HR 0.89, 95% CI 0.76–1.04), statin use before ADT initiation (HR 1.12, 95% CI 0.96–1.31), and use in the first year on ADT (HR 1.02, 95% CI 0.85–1.24) were not associated with prostate cancer death, without dose dependency. Conclusion Statin use after initiation of ADT, but not before, was associated with improved prostate cancer prognosis.

OBJECTIVE: To evaluate digital rectal examination (DRE) as a predictor of prostate cancer (PC) at serum PSA level 3.0-3.9 ng/ml. We compared the PC incidence rates of men with different screening test results in this PSA range and analyzed DRE in comparison with free/total PSA ratio as an additional screening test. MATERIALS AND METHODS: Using data from the FinRSPC trial, PC incidence rate ratios (IRR) for groups defined by the secondary screening test results (DRE vs. free/total PSA) were calculated for 17-year follow-up, using adjustment for age, family history of PC and place of residence. Screening test performance was evaluated by calculating sensitivity, specificity, positive and negative predictive value, and likelihood ratio. RESULTS: The IRR for men with a positive DRE compared to those with a negative result was 1.40 (95% confidence interval (CI) 1.00-1.96), while the IRR for men with a positive free/total PSA result compared to those with a negative one was 1.62 (95% CI 1.08-2.43). The estimated sensitivity was 0.15 (95% CI 0.11-0.20, 40/270) for DRE and 0.32 (95% CI 0.23-0.41, 36/113) for free/total PSA, and the specificity 0.91 (95% CI 0.88-0.93, 419/461) for DRE and 0.85 (95% CI 0.78-0.90, 134/158) for free/total PSA. CONCLUSIONS: Our results do not support utility of DRE as a screening test for PC at serum PSA level 3.0-3.9 ng/ml, while the results regarding free/total PSA determination were more encouraging and reconfirm the decision to switch from DRE to free/total PSA. publishedVersion

Antiepileptic drugs (AED) with histone deacetylase (HDAC) inhibitor properties decrease prostate cancer (PCa) cell proliferation in vitro. A population-based cohort of 78 615 men was used to evaluate the risk of prostate cancer among users of AEDs. Study population was linked to the Finnish national prescription database to obtain information on individual medication reimbursements in 1996-2015. Cox regression with antiepileptic medication use as a time-dependent variable was used to analyze prostate cancer risk overall, and low, medium and high-risk prostate cancer separately. The analysis was adjusted for age, screening trial arm and other drugs in use, including statins, antidiabetic drugs, antihypertensive drugs, aspirin and NSAIDs. Compared to the non-users of antiepileptic drugs, overall PCa risk was decreased among antiepileptic drug users (HR 0.86, 95% CI 0.76-0.96). A similar PCa risk decrease was observed among users of HDACi AEDs (HR 0.87, 95% CI 0.76 - 1.01), but no risk difference was found when comparing HDACi AED users to users of other AEDs (HR 0.98, 95% CI 0.76 - 1.27). Our study showed a decrease in overall PCa risk among men using AEDs compared to non-users. The risk associations were similar for HDAC inhibitors as for antiepileptic drugs in general. publishedVersion

More information is needed about effects of prostate-specific antigen (PSA) screening for informed decision making. The objective of our study is to evaluate the effects of an implemented screening decision on the risk of prostate cancer (PC) diagnosis and PC death. In a randomized trial, 31,867 Finnish men aged 55-67 years were allocated to the screening arm and 48,282 to the control arm during 1996-1999. Two to three screening rounds were offered to the screening arm with a PSA cut-off of 4.0 ng/ml. A counterfactual exclusion method was used to adjust for the effects of screening noncompliance and PSA contamination on risk of PC death and PC incidence by prognostic group at 15 years of follow up. After correcting for noncompliance and contamination, PSA screening led to 32.4 (95% CI 26.4, 38.6) more PC diagnoses per 1,000 men after 15 years and 1.4 (95% CI 0.0, 2.8) fewer PC deaths compared to the control arm. The corresponding results of an intention-to-screen analysis were 16.5 (95% CI 12.3, 20.7) and 0.8 (95% CI 0.5, 2.0), respectively. These results can be used for patient counseling in informed decision making about PC screening. A limitation of the study was the lack of comprehensive data on contamination.

Background: The European Randomized study of Screening for Prostate Cancer (ERSPC) has previously demonstrated that prostate-specific antigen (PSA) screening decreases prostate cancer (PCa) mortality. Objective: To determine whether PSA screening decreases PCa mortality for up to 16 yr and to assess results following adjustment for nonparticipation and the number of screening rounds attended. Design, setting, and participants: This multicentre population-based randomised screening trial was conducted in eight European countries. Report includes 182 160 men, followed up until 2014 (maximum of 16 yr), with a predefined core age group of 162 389 men (55-69 yr), selected from population registry. Outcome measurements and statistical analysis: The outcome was PCa mortality, also assessed with adjustment for nonparticipation and the number of screening rounds attended. Results and limitations: The rate ratio of PCa mortality was 0.80 (95% confidence interval [CI] 0.72-0.89, p 20 ng/ml (9.9% compared with 4.1% in the second round, p

Background/Aim: This cross-sectional study estimated direct cancer-related health care, productivity and informal care costs for a six-month period for different states of breast cancer (BC). Patients and Methods: A total of 827 BC patients answered a questionnaire enquiring about informal care, work capacity, and demographic factors. Direct health care resource use and productivity costs were obtained from registries. Mutually exclusive groups were formed based on disease state and time from diagnosis: primary treatment (first six months after diagnosis), rehabilitation (>six months after diagnosis), remission (>1.5 years after diagnosis), and metastatic. Results: Mean total costs were: primary treatment (sic)22,876, rehabilitation (sic)3,456, remission (sic)1,728, and metastatic (sic)24,320. Mean direct health care costs were: primary treatment (sic)11,798, rehabilitation (sic)2,398, remission (sic)1,147, and metastatic (sic)13,923. Mean productivity costs varied between 18-39% and indirect costs (productivity and informal care costs) between 31-48% of the total costs. Conclusion: Direct medical costs were highest, but indirect costs constituted up to half of the total costs and are essential when estimating the total cost burden, as many patients are of working age.

Alexander Schultz needs little introduction to readers of Scandinavian Journal of Urology. One of the leading Scandinavian urologists of his generation, Alexander was a constant standard bearer for...

Background: Hyperinsulemia and glycemic control may play a role as prostate cancer prognostic factors, whereas use of certain antidiabetic drugs, that is metformin, could improve the prognosis. We examined the link between antidiabetic medication use and prostate cancer survival taking into account simultaneous use of multiple drugs. Methods: The study cohort composed of 6,537 men in The Finnish Randomized Study of Screening for Prostate Cancer with prostate cancer diagnosed 1996 to 2009. Use of medication was attained from the nationwide prescription database of the Social Insurance Institution of Finland. Median follow-up was 9.2 years postdiagnosis. A total of 1,603 (24,5%) men had used antidiabetic medication. A total of 771 men died of prostate cancer during the follow-up. We used multivariable-adjusted Cox regression to evaluate the risk of prostate cancer death and onset of androgen deprivation therapy (ADT) with adjustment for prostate cancer clinical characteristics, comorbidities and use of other drugs. Separate analyses were further adjusted for blood glucose. Results: Risk of prostate cancer death was higher among antidiabetic drug users overall (HR = 1.42; 95% CI, 1.18–1.70) compared with nonusers, separately among insulin and metformin users. Adjustment for blood glucose level abolished the risk increase. Risk of ADT initiation was increased among the medication users (HR = 1.26; 95% CI, 1.05–1.49). Conclusions: Men with prostate cancer using antidiabetic medication are generally at increased risk of dying from prostate cancer compared with nonusers. The risk association is driven by underlying diabetes, as adjustment for blood glucose level ameliorates the risk increase. Impact: Type 2 diabetes should be considered as a risk factor when considering prostate cancer prognosis.

Background Drugs with histone deacetylase inhibitory (HDACi) properties have shown to decrease prostate cancer (PCa) cell growth in vitro. Methods A cohort of 9261 PCa cases from the Finnish Randomized Study of Screening for Prostate Cancer (FinRSPC) was used to evaluate prostate cancer-specific mortality in men using anti-epileptic drugs (AEDs). A national subscription database was used to obtain information on medication use. Cox regression with AED use as a time-dependent variable was used to analyse prostate cancer mortality in men using AEDs compared to non-users, and in men using HDACi AEDs compared to users of other AEDs. The analysis was adjusted for age, screening trial arm, PCa risk group, primary treatment of PCa, Charlson co-morbidity score and concomitant use of other drugs. Results The use of AEDs, in general, was associated with an increased risk of PCa death. The use of HDACi AEDs was not significantly associated with decreased PCa mortality compared to use of other AEDs (HR 0.61, 95% CI 0.31–1.23). Conclusions AED usage is associated with elevated PCa mortality compared to non-users, likely reflecting the differences between men with epilepsy and those without. No benefit was observed from HDACi drugs compared to other AEDs.

Background The aim of this study is to investigate the potential impact of prostate magnetic resonance imaging (MRI) -related interreader variability on a population-based randomized prostate cancer screening trial (ProScreen). Methods From January 2014 to January 2018, 100 men aged 50–63 years with clinical suspicion of prostate cancer (PCa) in Helsinki University Hospital underwent MRI. Nine radiologists individually reviewed the pseudonymized MRI scans of all 100 men in two ProScreen trial centers. All 100 men were biopsied according to a histological composite variable comprising radical prostatectomy histology (N = 38) or biopsy result within 1 year from the imaging (N = 62). Fleiss’ kappa (κ) was used to estimate the combined agreement between all individual radiologists. Sample data were subsequently extrapolated to 1000-men subgroups of the ProScreen cohort. Results Altogether 89% men of the 100-men sample were diagnosed with PCa within a median of 2.4 years of follow-up. Clinically significant PCa (csPCa) was identified in 76% men. For all PCa, mean sensitivity was 79% (SD ±10%, range 62–96%), and mean specificity 60% (SD ±22%, range 27–82%). For csPCa (Gleason Grade 2–5) MRI was equally sensitive (mean 82%, SD ±9%, range 67–97%) but less specific (mean 47%, SD ±20%, range 21–75%). Interreader agreement for any lesion was fair (κ 0.40) and for PI-RADS 4–5 lesions it was moderate (κ 0.60). Upon extrapolating these data, the average sensitivity and specificity to a screening positive subgroup of 1000 men from ProScreen with a 30% prevalence of csPCa, 639 would be biopsied. Of these, 244 men would be true positive, and 395 false positive. Moreover, 361 men would not be referred to biopsy and among these, 56 csPCas would be missed. The variation among the radiologists was broad as the least sensitive radiologist would have twice as many men biopsied and almost three times more men would undergo unnecessary biopsies. Although the most sensitive radiologist would miss only 2.6% of csPCa (false negatives), the least sensitive radiologist would miss every third. Conclusions Interreader agreement was fair to moderate. The role of MRI in the ongoing ProScreen trial is crucial and has a substantial impact on the screening process.

Background The long‐term health‐related quality of life (HRQOL) impacts of PCa screening have not been adequately evaluated. We aimed to compare the generic and disease‐specific health‐related quality of life (HRQOL) among men with prostate cancer in the screening arm with the control arm of the PSA‐based prostate cancer screening trial in up to 15 years of follow‐up. Materials and methods This study was conducted within population‐based Finnish Randomized Study of Screening for Prostate Cancer (FinRSPC). During 1996‐1999 80,458 men were randomized to the serum prostate‐specific antigen (PSA) screening arm (SA, N = 32 000) and the control arm (CA, N = 48 458). Men in the screening arm were screened at 4‐year intervals until 2007. HRQOL questionnaires were delivered to newly diagnosed prostate cancer patients in the screening and control arm 1996‐2006 (N = 5128) at the time of diagnosis (baseline), at 3‐month, 12‐month and 5, 10, and 15‐year follow‐up. Validated UCLA Prostate Cancer Index (UCLA‐PCI) and RAND 36‐Item Health Survey were used for HRQOL assessment. The data were analyzed with a random effects model for repeated measures. Results At baseline, men with prostate cancer in the screening arm reported better Sexual Function, as well as less Sexual and Urinary Bother. Long‐term follow‐up revealed slightly higher HRQOL scores in the screening arm in prostate cancer specific measures at 10‐year post diagnosis, but the differences were statistically significant only in Urinary Bother (UCLA‐PCI score 77.9; 95% CI 75.2 to 80.5 vs. 70.9; 95% CI 66.8 to 74.9 P = .005). The generic HRQOL scores were comparable between the trial arms. The overall differences in disease‐specific or generic HRQOL scores by trial arm did not vary during the follow‐up. Conclusion No major differences were observed in HRQOL in men with prostate cancer between the prostate cancer screening and control arms during five to 15‐year follow‐up., Our study contributes to the evaluation of the benefits and harms of prostate cancer screening on long‐term quality of life. The results suggest that screening does not materially affect long‐term quality of life in men with prostate cancer. Model‐based mean scores (95% CIs) in Urinary Bother by arm of the FinRSPC.

Renal cell cancer (RCC) has become a prototype example of the extensive intratumor heterogeneity and clonal evolution of human cancers. However, there is little direct evidence on how the genetic heterogeneity impacts on drug response profiles of the cancer cells. Our goal was to determine how genomic clonal evolution impacts drug responses. Finding from our study could help to define the challenge that clonal evolution poses on cancer therapy. We established multiple patient-derived cells (PDCs) from different tumor regions of four RCC patients, verified their clonal relationship to each other and to the uncultured tumor tissue by genome sequencing. Furthermore, comprehensive drug-sensitivity testing with 460 oncological drugs was performed on all PDC clones. The PDCs retained many cancer-specific copy number alterations and mutations in driver genes such as VHL, PBRM1, PIK3C2A, KMD5C and TSC2 genes. The drug testing highlighted vulnerability in the PDCs toward approved RCC drugs, such as the mTOR-inhibitor temsirolimus, but also novel sensitivities were uncovered. The individual PDC clones from different tumor regions in a patient showed distinct drug-response profiles, suggesting that genomic heterogeneity contributes to the variability in drug responses. Studies of multiple PDCs from a patient with cancer are informative for elucidating cancer heterogeneity and for the determination on how the genomic evolution is manifested in cancer drug responsiveness. This approach could facilitate tailoring of drugs and drug combinations to individual patients.

Aim This study was conducted to evaluate the efficacy of surgical treatment for metastases accompanied by modern targeted therapies and to evaluate the performance of the Leuven-Udine (L.U.) prognostic groups model. Methods This retrospective analysis included 97 consecutive patients with metastatic renal cell carcinoma (mR.C.C.) who underwent surgery for metastases at Helsinki University Hospital between 2006 and 2017. The endpoints were overall survival (O.S.), cancer-specific survival (C.S.S.), recurrence-free survival (R.F.S.) and interval from diagnosis to oncological treatment. Results The median follow-up time was 46 months (interquartile range, I.Q.R. = 24-74). The estimated median O.S. was 67 months (I.Q.R. = 30-130). A radical surgical result at metastasectomy was achieved in 46 of 97 patients (47%). Of those 46 patients, 28 (61%) experienced recurrence after complete metastasectomy. Median R.F.S. after complete metastasectomy was 10 months (I.Q.R. = 3-37). Five-year O.S. was 59% for patients with complete metastasectomy and 44% for patients with non-complete metastasectomy (p = .035). The median interval from diagnosis to the initiation of targeted oncological treatment was 19 months for patients with non-complete metastasectomy and has hitherto not been reached for patients with complete metastasectomy (p = .006). A statistically significant validation of the prognostic value of the L.U. prognostic groups for predicting C.S.S. was not obtained (p = .420). Conclusions Metastasectomy is an option for selected patients with mR.C.C. Complete resection should be attempted when feasible. The data failed to support the prognostic significance of the L.U. model in patients with mR.C.C.

Hypercholesterolemia has been associated with advanced stage prostate cancer (PCa), but the role of lipid parameters such as HDL and triglycerides is unclear. We examined PCa risk by lipid parameters in a population nested within the Finnish Randomized Study of Screening for Prostate Cancer (FinRSPC). Cholesterol measurements were available on 17,696 men. During the 17-year median follow-up, 2404 PCa cases were diagnosed. Cox regression model was used to estimate hazard ratios (HR) and their 95% confidence intervals (95% CI) for overall PCa risk and stratified by Gleason grade and tumor stage. We compared normolipidemic and hyperlipidemic men on four cholesterol parameters total cholesterol (TC), HDL, LDL, and triglycerides (TG), analyzed as time-dependent variables. TC in the highest tertile (above 5.1 mmol/l) and LDL above 3 mmol/l were associated with increased risk of Gleason 8–10 cancer (HR 1.42, 95% CI 1.04–1.95 and HR 1.38, 95% CI 1.02–1.86, respectively). Further, overall PCa risk was elevated in the 3-year lag time analysis by TC in the highest two tertiles (HR 1.27, 95% CI 1.05–1.54 for TC above 4.4 mmol/l, and HR 1.26, 95% CI 1.05–1.51 for TC above 5.1 mmol/l) and HDL in the highest tertile (HR 1.33, 95% CI 1.08–1.64) and above 1 mmol/l (HR 1.29, 95% CI 1.01–1.65). In contrast, TC in the highest tertile was associated with a decreased risk of PCa with 20-year lag time. The risk associations for overall PCa grew stronger with added lag time but were observed only in the FinRSPC control arm. Statin use did not modify the risk association. Hypercholesterolemia may increase overall PCa risk in short-term, inverse risk association was observed with 20-years’ time lag. Similar risk increase of overall PCa was also observed for elevated HDL, conflicting with previous findings on the subject.

In-vitro studies have suggested that the antiarrhythmic drug digoxin might restrain the growth of cancer cells by inhibiting Na+/K+-ATPase. We evaluated the association between cancer mortality and digoxin, sotalol and general antiarrhythmic drug use in a retrospective cohort study. The study population consists of 78,615 men originally identified for the Finnish Randomized Study of Screening for Prostate Cancer. Information on antiarrhythmic drug purchases was collected from the national prescription database. We used the Cox regression method to analyze separately overall cancer mortality and mortality from the most common types of cancer. During the median follow-up of 17.0 years after the baseline 28,936 (36.8%) men died, of these 8,889 due to cancer. 9,023 men (11.5%) had used antiarrhythmic drugs. Overall cancer mortality was elevated among antiarrhythmic drug users compared to non-users (HR 1.43, 95% CI 1.34–1.53). Similar results were observed separately for digoxin and for sotalol. However, the risk associations disappeared in long-term use and were modified by background co-morbidities. All in all, cancer mortality was elevated among antiarrhythmic drug users. This association is probably non-causal as it was related to short-term use and disappeared in long-term use. Our results do not support the anticancer effects of digoxin or any other antiarrhythmic drug.

Objectives To identify the prognostic factors of prostate cancer death among patients enrolled in a Finnish prostate cancer screening trial. Methods Data on TNM stage, Gleason score, serum prostate-specific antigen at diagnosis, comorbidity and primary treatment were collected from medical records, as well as date and cause of death from Statistics Finland. Four prognostic risk groups were defined based on TNM stage, Gleason score and prostate-specific antigen at diagnosis. Hazard ratios and their 95% confidence intervals for prostate cancer death were calculated using Cox regression and competing-risk analysis with follow up from randomization. The differences in the effects of prognostic factors were assessed using interaction terms. Results The 15-year survival was significantly lower among cases in the control arm compared with the screening arm (0.90 vs 0.92). However, the survival advantage was limited to screen-detected cases (0.94 vs 0.91 in cases detected outside screening). The prognostic risk group was the strongest factor predicting survival in the control arm, but weaker in screen-detected cases. Advanced disease was associated with substantially poorer outcome in cases detected outside screening than in screen-detected disease. Primary treatment had a similar effect in all groups. Comorbidity had a small prognostic effect in the control arm only. Conclusions Prognostic factors had a different effect on the outcome of cases detected through screening as those diagnosed otherwise. A high diagnostic prostate-specific antigen and advanced disease carried a poor prognosis, especially among the cases detected outside screening, even when lead-time was eliminated. This shows that the screening resulted in earlier treatment among the cases in the screening arm.

Metabolic syndrome and obesity are linked with hyperuricemia, and it has also been proposed that oxidative stress associated with hyperuricemia may promote benign prostatic hyperplasia (BPH). However, it is currently unknown whether use of antihyperuricemic medication is associated with risk of developing BPH. We studied the association between BPH and use of antihyperuricemic allopurinol in a Finnish population-based cohort.The study cohort consisted of 74,754 men originally identified for the Finnish Randomized Study of Screening for Prostate Cancer (FinRSPC). Information on gout and BPH medication usage (5α-reductase inhibitors, 5ARIs) during 1996-2014 was obtained from the National medication reimbursement database. Information on BPH diagnoses from in- and outpatient hospital visits and BPH-related surgery was obtained from the National Health Care Registry. Men with a record of BPH at baseline was excluded. We used Cox regression to analyze risk of starting BPH medication, having a recorded diagnosis or undergoing BPH surgery by allopurinol use with adjustment for age and simultaneous use of statins, antidiabetic or antihypertensive drugs and aspirin or other NSAIDs. Medication use was analyzed as a time-dependent variable to minimize immortal time bias.Men using allopurinol had a decreased risk for all three BPH endpoints: BPH medication (HR 0.81; 95% CI 0.75-0.88), BPH diagnosis (HR 0.78; 95% CI 0.71-0.86) and BPH-related surgery (HR 0.67; 95% CI 0.58-0.76) after multivariable adjustment. The risk association did not change by cumulative use. The risk decrease disappeared after 1-2 years lag time. Only BMI modified the risk association; the risk decrease was observed only among men with BMI above the median (27.3 kg/mWe found that allopurinol use is associated with lowered risk of BPH medication, diagnosis and surgery. A possible explanation could be antioxidative effects of urate-lowering allopurinol.

Purpose: We investigated the tolerability, safety and antitumor effects of a novel intraprostatic depot formulation of antiandrogen 2-hydroxyflutamide (in Nano-Zolid (R)) in men with localized prostate cancer. Materials and Methods: Two clinical trials, LPC-002 and LPC-003, were performed in a total of 47 men. The formulation was injected transrectally into the prostate under ultrasound guidance. In LPC-002 the effects on prostate specific antigen and prostate volume were measured for 6 months in 24 patients. In LPC-003 antitumor effects were evaluated by histopathology and magnetic resonance imaging including spectroscopy during 6 or 8 weeks in 23 patients. In each study testosterone and 2-hydroxyflutamide in plasma were measured as well as quality of life parameters. Results: In LPC-002 (mean dose 690 mg) a reduction was observed in prostate specific antigen and prostate volume. Average nadir prostate specific antigen and prostate volume were 24.9% and 14.0% below baseline, respectively. When increasing the dose in LPC-003 to 920 and 1,740 mg, average prostate specific antigen decreased 16% and 23% after 6 and 8 weeks, respectively. Magnetic resonance imaging and magnetic resonance spectroscopy showed morphological changes and a global reduction in metabolite concentrations following treatment, indicating an antitumor response. Injections did not result in hormone related side effects. Three serious adverse events were reported and all resolved with oral antibiotic treatment. Conclusions: Intraprostatic injections of 2-hydroxyflutamide depot formulations showed antitumor effects, and proved to be safe and tolerable. However, for better anticancer effects higher doses and better dose distribution are suggested.

Background and Aims: To evaluate simple tumor characteristics (renal tumor diameter and parenchymal invasion depth) compared with more complex classifications, that is, Renal Tumor Invasion Index (RTII) and Preoperative Aspects and Dimensions Used for an Anatomical classification, in predicting the type of nephrectomy (radical vs partial) performed. Material and Methods: A total of 915 patients who had undergone either partial nephrectomy ( n = 388, 42%) or radical nephrectomy ( n = 527, 58%) were identified from the Helsinki University Hospital kidney tumor database between 1 January 2006 and 31 December 2014. Tumor maximum diameter and depth of invasion into the parenchyma were estimated from computed tomography or magnetic resonance imaging images and compared with Preoperative Aspects and Dimensions Used for an Anatomical and Renal Tumor Invasion Index. Logistic regression and receiver operating curves were used to compare the parameters at predicting the type of nephrectomy. Results and conclusion: All the anatomical variables of receiver operating curve/area under the curve analyses were significant predictors for the type of nephrectomy. Parenchymal invasion (area under the curve 0.91; 95% confidence interval, 0.89–0.93), RTII (area under the curve 0.91; 95% confidence interval, 0.89–0.93), and diameter (area under the curve 0.91; 95% confidence interval, 0.89–0.93) performed significantly better than Preoperative Aspects and Dimensions Used for an Anatomical classification (area under the curve 0.88; 95% confidence interval, 0.85–0.89). In multivariable analysis, invasion depth was the best predictor of nephrectomy type (percentage correct, 85.6%). Addition of one anatomic parameter into the model of non-anatomical cofactors improved the accuracy of the model significantly, but the addition of more parameters did not. Parenchymal invasion depth and tumor diameter are the most accurate anatomical features for predicting the nephrectomy type. All potential anatomical classification systems should be tested against these two simple characteristics.

The current evidence of PSA-based prostate cancer screening shows a reduction in cause-specific mortality, but with substantial overdiagnosis. Recently, new developments in detection of clinically relevant prostate cancer include multiple kallikreins as biomarkers besides PSA, and multiparametric magnetic resonance imaging (mpMRI) for biopsy decision. They offer opportunities for improving the outcomes in screening, particularly reduction in overdiagnosis and higher specificity for potentially lethal cancer. A population-based randomized screening trial will be started, with 67,000 men aged 55-67 years at entry. A quarter of the men will be allocated to the intervention arm, and invited to screening. The control arm will receive no intervention. All men in the screening arm will be offered a serum PSA determination. Those with PSA of 3 ng/ml or higher will have an additional multi-kallikrein panel and those with indications of increased risk of clinically relevant prostate cancer will undergo mpMRI. Men with a malignancy-suspect finding in MRI are referred to targeted biopsies. Screening interval is 6 years for men with baseline PSA 3. The main outcome of the trial is prostate cancer mortality, with analysis at 10 and 15 years. The statistical power is sufficient for detecting a 28% reduction at 10 years and 22% at 15 years. The proposed study has the potential to provide the evidence to justify screening as a public health policy if mortality benefit can be sustained with substantially reduced overdiagnosis.

Background Recent research has suggested that statins have an effect on prostate cancer prognosis. It is currently unclear how prostate cancer screening, tumor and patient characteristics, or treatment selection may affect this association. Objective To evaluate the risk of prostate cancer death among statin users. To determine how disease and treatment characteristics affect the association. Design, setting, and participants This is a population-based cohort study consisting of a general male population of Finland participating in the Finnish Randomized Study for Prostate Cancer Screening. The cohort of consisted of 6537 prostate cancer cases diagnosed in the Finnish Randomized Study of Screening for Prostate Cancer population during 1996–2012. The cohort was linked to the National Prescription Database for information on the use of statins and other drugs. Intervention Statin use before and after prostate cancer diagnosis compared with nonuse. Outcome measurements and statistical analysis Hazard ratios (HRs) for the risk of prostate cancer death by amount, duration, and intensity of statin use. Cox proportional hazards regression with postdiagnostic statin use as a time-dependent variable. Results During the median follow-up of 7.5 yr postdiagnosis 617 men died of prostate cancer. Statin use after diagnosis was associated with a decreased risk of prostate cancer death (HR 0.80; 95% confidence interval 0.65–0.98). A decreasing risk trend was observed by increasing intensity of usage (doses/year). The risk decrease was clearest in men managed with androgen deprivation therapy. Prediagnostic statin use was not associated with risk of prostate cancer death (HR 0.92; 95% confidence interval 0.75–1.12). Conclusions Decreased risk of prostate cancer death by statin use after diagnosis suggests that statins may delay or prevent prostate cancer progression. The risk decrease was significant only in men managed with androgen deprivation therapy, but statistical power was limited to estimate the association in men managed with surgery or radiotherapy. Patient summary Use of statins after prostate cancer diagnosis was associated with a decreased risk of prostate cancer death. The risk decrease was dose-dependent and observed especially among patients treated with hormone therapy.

Background: Although the prognosis of localised prostate cancer is good, the negative effects of prostate cancer treatment often impair patient quality of life. A growing number of men experience these negative effects over a longer time because of the increased incidence of and prolonged survival in prostate cancer, and the ageing of the population. Only a few studies have investigated the adverse effects of different prostate cancer treatments using large population-based samples. Methods: We conducted a nationwide survey (n=1239) to collect detailed information regarding the negative effects (i.e., the occurrence, perceived level and perceived bother since the beginning of the treatment) of prostate cancer treatments: radical prostatectomy, external beam radiotherapy, brachytherapy, hormone therapy and surveillance. Furthermore, we measured patient satisfaction with the outcome of the treatment and their psychological well-being (i.e., psychological symptoms and satisfaction with life) 5 years after diagnosis. The negative effects between the treatments were compared, and the determinants of satisfaction and psychological well-being were investigated. Results: The negative effects of all types of active prostate cancer treatments were common and persistent (33–48% reported symptoms at 5 years) and showed the known differences between the treatments. Prostatectomy and the radiotherapies caused urinary leakage; radiotherapy also caused symptoms of urinary irritation; and external radiation also caused bowel dysfunction. Most symptoms were considered highly bothersome. Most respondents (81−93%) reported that their treatment negatively affected their sex lives; 70–92% reported sexual dysfunction; and 20–58% reported that their sex lives with their spouses had ended. Urinary symptoms were especially associated with poorer psychological outcomes. The perception of symptom level and bother had a greater effect on patient satisfaction and well-being than the symptoms per se. Conclusion: Multiple and persistent negative effects follow active prostate cancer treatment, and these effects predict long-term patient satisfaction and psychological well-being. The harms and benefits associated with prostate cancer treatments should be considered when selecting whether and how to actively treat prostate cancer.

Background: Precise cause of death (CoD) ascertainment is crucial in any cancer screening trial to avoid bias from misclassification due to excessive recording of diagnosed cancer as a CoD in death certificates instead of non-cancer disease that actually caused death. We estimated whether there was bias in CoD determination between screening (SA) and control arms (CA) in a population-based prostate cancer (PCa) screening trial. Methods: Our trial is the largest component of the European Randomized Study of Screening for Prostate Cancer with more than 80,000 men. Randomly selected deaths in men with PCa (N = 442/2568 cases, 17.2%) were reviewed by an independent CoD committee. Median follow-up was 16.8 years in both arms. Results: Overdiagnosis of PCa was present in the SA as the risk ratio for PCa incidence was 1.19 (95% confidence interval (CI) 1.14-1.24). The hazard ratio (HR) for PCa mortality was 0.94 (95% CI 0.82-1.08) in favor of the SA. Agreement with official CoD registry was 94.6% (k = 0.88) in the SA and 95.4% (k = 0.91) in the CA. Altogether 14 PCa deaths were estimated as false-positive in both arms and exclusion of these resulted in HR 0.92 (95% CI 0.80-1.06). Conclusions: A small differential misclassification bias in ascertainment of CoD was present, most likely due to attribution bias (overdiagnosis in the SA). Maximum precision in CoD ascertainment can only be achieved with independent review of all deaths in the diseased population. However, this is cumbersome and expensive and may provide little benefit compared to random sampling. (C) 2016 Elsevier Ltd. All rights reserved.

PurposeAnticoagulants may reduce mortality of cancer patients, though the evidence remains controversial. We studied the association between different anticoagulants and cancer death.MethodsAll anticoagulant use during 1995-2015 was analyzed among 75,336 men in the Finnish Randomized Study of Screening for Prostate Cancer. Men with prevalent cancer were excluded. Multivariable Cox regression was performed to compare risk of death from any cancer and disease-specific death from 9 specific cancer types between (1) anticoagulant users overall and (2) warfarin users compared to anticoagulant non-users and (3) warfarin or (4) low-molecular-weight heparins (LMWH) compared to users of other anticoagulants. Medication use was analyzed as time-dependent variable to minimize immortal time bias. 1-, 2- and 3-year lag-time analyses were performed.ResultsDuring a median follow-up of 17.2years, a total of 27,233 men died of whom 8033 with cancer as the primary cause of death. In total, 32,628 men (43%) used anticoagulants. Any anticoagulant use was associated with an increased risk of cancer death (HR=2.50, 95% CI 2.37-2.64) compared to non-users. Risk was similar independent of the amount, duration, or intensity of use. The risk increase was observed both among warfarin and LMWH users, although not as strong in warfarin users. Additionally, cancer-specific risks of death were similar to overall cancer mortality in all anticoagulant categories.ConclusionOur study does not support reduced cancer mortality among anticoagulant users. Future studies on drug use and cancer mortality should be adjusted for anticoagulants as they are associated with significantly higher risk of cancer death.

Objectives: Financial difficulties experienced by cancer patients may affect their health-related quality of life (HRQoL). This study assessed the direct economic burden that out-of-pocket (OOP) payments cause and explored how they and financial difficulties are associated with HRQoL. Methods: This is a cross-sectional registry and survey study of 1978 cancer patients having either prostate (630), breast (840) or colorectal cancer (508) treated in Finland. The patients were divided into five groups according to the stage of their disease: primary treatment, rehabilitation, remission, metastatic disease and palliative care. The cost data and OOP payments were retrieved from primary and secondary healthcare registries, the Social Insurance Institution of Finland, and a patient questionnaire. HRQoL was measured by 15D, EQ-5D-3L and by EORTC-QLQ-C30. Financial difficulties were evaluated based on patients' self-assessment in the EORTC-QLQ-C30 four-level question about financial difficulties. A path analysis was used to explore the relationship between clinical and demographic factors, HRQoL, OOP payments and financial difficulties. Results: The highest OOP payments were caused by outpatient medication. Total costs and OOP payments were highest in the palliative care group in which the OOP payments consisted mostly of outpatient medication and public sector specialist care. Private sector health care was an important item of OOP payments in the early stages of cancer. Financial difficulties increased together with OOP payments. HRQoL deteriorated the more a person had financial difficulties. In the path analysis, financial difficulties had a major negative direct and total effect on the HRQoL. Factors that attenuated financial difficulties were age, cohabiting and higher education and factors that increased them were OOP payments, total costs of healthcare use, and unemployment. Conclusions: High OOP payments are related to financial difficulties, which have a negative effect on HRQoL. Outpatient medication was a major driver of OOP payments. Among palliative patients, the economic burden was highest and associated with impaired HRQoL.

Radical prostatectomy reduces mortality among men with clinically detected localized prostate cancer, but evidence from randomized trials with long-term follow-up is sparse.We randomly assigned 695 men with localized prostate cancer to watchful waiting or radical prostatectomy from October 1989 through February 1999 and collected follow-up data through 2017. Cumulative incidence and relative risks with 95% confidence intervals for death from any cause, death from prostate cancer, and metastasis were estimated in intention-to-treat and per-protocol analyses, and numbers of years of life gained were estimated. We evaluated the prognostic value of histopathological measures with a Cox proportional-hazards model.By December 31, 2017, a total of 261 of the 347 men in the radical-prostatectomy group and 292 of the 348 men in the watchful-waiting group had died; 71 deaths in the radical-prostatectomy group and 110 in the watchful-waiting group were due to prostate cancer (relative risk, 0.55; 95% confidence interval [CI], 0.41 to 0.74; P0.001; absolute difference in risk, 11.7 percentage points; 95% CI, 5.2 to 18.2). The number needed to treat to avert one death from any cause was 8.4. At 23 years, a mean of 2.9 extra years of life were gained with radical prostatectomy. Among the men who underwent radical prostatectomy, extracapsular extension was associated with a risk of death from prostate cancer that was 5 times as high as that among men without extracapsular extension, and a Gleason score higher than 7 was associated with a risk that was 10 times as high as that with a score of 6 or lower (scores range from 2 to 10, with higher scores indicating more aggressive cancer).Men with clinically detected, localized prostate cancer and a long life expectancy benefited from radical prostatectomy, with a mean of 2.9 years of life gained. A high Gleason score and the presence of extracapsular extension in the radical prostatectomy specimens were highly predictive of death from prostate cancer. (Funded by the Swedish Cancer Society and others.).

The aims of this study were to measure the real-life health-related quality of life (HRQoL) of newly diagnosed prostate cancer (PCa) patients, to compare it with that of the general male population and to explore factors affecting HRQoL.All newly diagnosed PCa patients in the Helsinki University Hospital were asked to fill in 15D and EORTC QLQ-C30 questionnaires. Clinical background information was collected retrospectively from patient charts. Patients were categorized into three mutually exclusive groups based on the disease stage: Local, Locally advanced and Metastatic groups. Multivariate linear regression analysis was conducted to explore which factors explained variance in 15D scores. A regression model was built to map the EORTC QLQ-C30 to 15D in a random sample of 50% of patients and the model was tested in the other half of the patients.In total, 1050 men with a mean age of 67 years responded to the questionnaires. The mean ± SD 15D score of patients was slightly lower than that of the age-standardized general male population: 0.905 ± 0.089 vs 0.915 ± 0.082 (p = .057). The mean ± SD 15D utility scores were 0.912 ± 0.084, 0.897 ± 0.102 and 0.855 ± 0.109 for Local, Locally advanced and Metastatic groups, respectively. The mapping model of EORTC QLQ-C30 to 15D was robust and fitted well (root mean square error = 0.042, adjusted R² = .79).The HRQoL of PCa patients entering treatment was similar to that of the general population. HRQoL was most impaired among patients with metastatic disease, whereas the difference between patients with localized PCa and the general population was minor. Mapping indicated that the 15D score aggregates quite accurately the information from the EORTC QLQ-C30.

Background: Protective effects have been suggested for digoxin against prostate cancer risk. However, few studies have evaluated the possible effects on prostate cancer-specific survival. We studied the association between use of digoxin or beta-blocker sotalol and prostate cancer-specific survival as compared with users of other antiarrhythmic drugs in a retrospective cohort study. Methods: Our study population consisted of 6537 prostate cancer cases from the Finnish Randomized Study of Screening for Prostate Cancer diagnosed during 1996–2009 (485 digoxin users). The median exposure for digoxin was 480 DDDs (interquartile range 100–1400 DDDs). During a median follow-up of 7.5 years after diagnosis, 617 men (48 digoxin users) died of prostate cancer. We collected information on antiarrhythmic drug purchases from the national prescription database. Both prediagnostic and postdiagnostic drug usages were analysed using the Cox regression method. Results: No association was found for prostate cancer death with digoxin usage before (HR 1.00, 95% CI 0.56–1.80) or after (HR 0.81, 95% CI 0.43–1.51) prostate cancer diagnosis. The results were also comparable for sotalol and antiarrhythmic drugs in general. Among men not receiving hormonal therapy, prediagnostic digoxin usage was associated with prolonged prostate cancer survival (HR 0.20, 95% CI 0.05–0.86). Conclusions: No general protective effects against prostate cancer were observed for digoxin or sotalol usage.

This study evaluated the clinical outcome of patients with renal cell carcinoma (RCC) with tumour thrombus (TT) after surgical management.In total, 142 consecutive RCC patients with TT who were operated on in Helsinki University Hospital between 2006 and 2014 were analysed. Eighty-eight (62%) of these patients had been operated on with radical intention and 54 (38%) with cytoreductive intention. A total of 73 patients (51%) received postoperative targeted therapy. The primary endpoint was cancer-specific survival (CSS).The 5 year CSS for level of involvement of TT in the renal vein, subdiaphragmatic vena cava and supradiaphragmatic vena cava was 60% (81 patients), 43% (52 patients) and 51% (nine patients), respectively (p = .42). The median CSS for lymph-node involvement was 63 months for patients with no lymph-node involvement but 10 months for patients with lymph-node involvement (p .01). The median CSS for metastasis status was 63 months for patients with no metastases compared with 18 months for patients with metastases (p .01). Among several factors examined, WHO performance status (p = .04), tumour necrosis (p = .05), presence of distant metastases (p = .04) and tumour histology (p = .05) were associated with CSS in the multivariate analysis.Operative treatment for RCC with TT is associated with good prognosis when there is no lymph-node involvement or distant metastases.