Publications by authors named "Teuvo L J Tammela"

270 Publications

Atorvastatin induces adrenal androgen downshift in men with prostate cancer: A post Hoc analysis of a pilot adaptive Randomised clinical trial.

EBioMedicine 2021 Jun 16;68:103432. Epub 2021 Jun 16.

Faculty of Medicine and Health Technology, Tampere University, and Tays Cancer Center, Tampere University Hospital, Finland. Electronic address:

Background: Prostate cancer (PCa) progression depends on androgen receptor activity. Cholesterol is required for biosynthesis of all steroid hormones, including androgens. Impact of cholesterol-lowering statins on androgens is unknown. We explored atorvastatin influence on serum and prostatic tissue steroidomic profiles (SP) to expose novel pathways for limiting androgen concentration in men with PCa.

Methods: This is a pre-planned post hoc analysis of ESTO-1 pilot randomised, double-blinded, clinical trial. Statin naïve men, scheduled for radical prostatectomy due to localised PCa, were randomised 1:1 to use daily 80 mg of atorvastatin or placebo before the surgery for a median of 28 days. Participants were recruited and treated at the Pirkanmaa Hospital District, Tampere, Finland. 108 of the 158 recruited men were included in the analysis based on sample availability for hormone profiling. Serum and prostatic tissue steroid profiles were determined using liquid chromatography mass spectrometry. Wilcoxon rank sum test and bootstrap confidence intervals (CI) were used to analyse the difference between placebo and atorvastatin arms.

Findings: Most serum and prostatic steroids, including testosterone and dihydrotestosterone, were not associated with atorvastatin use. However, atorvastatin use induced serum SP changes in 11-ketoandrostenedione (placebo 960pM, atorvastatin 617.5pM, p-value <0.0001, median difference -342.5; 95% CI -505.23 - -188.98). In the prostatic tissue, atorvastatin was associated with plausible downshift in 11- ketodihydrotestosterone (placebo 25.0pM in 100 mg tissue/1 mL saline, atorvastatin 18.5pM in 100 mg tissue/1 mL saline, p-value 0.027, median difference -6.53; 95% CI -12.8 - -0.29); however, this association diminished after adjusting for multiple testing. No serious harms were reported.

Interpretation: Atorvastatin was associated with adrenal androgen downshift in the serum and possibly in the prostate. The finding warrants further investigation whether atorvastatin could improve androgen deprivation therapy efficacy.

Funding: Funded by grants from the Finnish Cultural Foundation, Finnish Cancer Society, Academy of Finland, and the Expert Responsibility Area of the Tampere University Hospital. CLINICALTRIALS.

Gov Identifier: NCT01821404.
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http://dx.doi.org/10.1016/j.ebiom.2021.103432DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8219992PMC
June 2021

Novel prostate cancer susceptibility gene SP6 predisposes patients to aggressive disease.

Prostate Cancer Prostatic Dis 2021 May 19. Epub 2021 May 19.

Institute of Biomedicine and FICAN West Cancer Centre, University of Turku and Turku University Hospital, Turku, Finland.

Prostate cancer (PrCa) is one of the most common cancers in men, but little is known about factors affecting its clinical outcomes. Genome-wide association studies have identified more than 170 germline susceptibility loci, but most of them are not associated with aggressive disease. We performed a genome-wide analysis of 185,478 SNPs in Finnish samples (2738 cases, 2400 controls) from the international Collaborative Oncological Gene-Environment Study (iCOGS) to find underlying PrCa risk variants. We identified a total of 21 common, low-penetrance susceptibility loci, including 10 novel variants independently associated with PrCa risk. Novel risk loci were located in the 8q24 (CASC8 rs16902147, OR 1.86, p = 3.53 × 10 and rs58809953, OR 1.71, p = 4.00 × 10; intergenic rs79012498, OR 1.81, p = 4.26 × 10), 17q21 (SP6 rs2074187, OR 1.66, p = 3.75 × 10), 11q13 (rs12795301, OR 1.42, p = 2.89 × 10) and 8p21 (rs995432, OR 1.38, p = 3.00 × 10) regions. Here, we describe SP6, a transcription factor gene, as a new, potentially high-risk gene for PrCa. The intronic variant rs2074187 in SP6 was associated not only with overall susceptibility to PrCa (OR 1.66) but also with a higher odds ratio for aggressive PrCa (OR 1.89) and lower odds for non-aggressive PrCa (OR 1.43). Furthermore, the new intergenic variant rs79012498 at 8q24 conferred risk for aggressive PrCa. Our findings highlighted the power of a population-stratified approach to identify novel, clinically actionable germline PrCa risk loci and strongly suggested SP6 as a new PrCa candidate gene that may be involved in the pathogenesis of PrCa.
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http://dx.doi.org/10.1038/s41391-021-00378-5DOI Listing
May 2021

Expression and ERG regulation of PIM kinases in prostate cancer.

Cancer Med 2021 05 1;10(10):3427-3436. Epub 2021 May 1.

Faculty of Medicine and Health Technology, Tampere University and Tays Cancer Center, Tampere University Hospital, Tampere, Finland.

The three oncogenic PIM family kinases have been implicated in the development of prostate cancer (PCa). The aim of this study was to examine the mRNA and protein expression levels of PIM1, PIM2, and PIM3 in PCa and their associations with the MYC and ERG oncogenes. We utilized prostate tissue specimens of normal, benign prostatic hyperplasia (BPH), prostatic intraepithelial neoplasia (PIN), untreated PCa, and castration-resistant prostate cancer (CRPC) for immunohistochemical (IHC) analysis. In addition, we analyzed data from publicly available mRNA expression and chromatin immunoprecipitation sequencing (ChIP-Seq) datasets. Our data demonstrated that PIM expression levels are significantly elevated in PCa compared to benign samples. Strikingly, the expression of both PIM1 and PIM2 was further increased in CRPC compared to PCa. We also demonstrated a significant association between upregulated PIM family members and both the ERG and MYC oncoproteins. Interestingly, ERG directly binds to the regulatory regions of all PIM genes and upregulates their expression. Furthermore, ERG suppression with siRNA reduced the expression of PIM in PCa cells. These results provide evidence for cooperation of PIM and the MYC and ERG oncoproteins in PCa development and progression and may help to stratify suitable patients for PIM-targeted therapies.
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http://dx.doi.org/10.1002/cam4.3893DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8124112PMC
May 2021

Antidiabetic Drugs and Prostate Cancer Prognosis in a Finnish Population-Based Cohort.

Cancer Epidemiol Biomarkers Prev 2021 May 2;30(5):982-989. Epub 2021 Mar 2.

Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.

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.
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http://dx.doi.org/10.1158/1055-9965.EPI-19-0580DOI Listing
May 2021

Antiepileptic drugs and prostate cancer risk in the Finnish Randomized Study of Screening for Prostate Cancer.

Int J Cancer 2021 Jul 19;149(2):307-315. Epub 2021 Mar 19.

Faculty of Medicine and Health Technology, University of Tampere, Tampere, Finland.

Antiepileptic drugs (AEDs) 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 PCa among users of AEDs. Study population was linked to the Finnish national prescription database to obtain information on individual medication reimbursements in 1996 to 2015. Cox regression with antiepileptic medication use as a time-dependent variable was used to analyze PCa risk overall, and low, medium and high-risk PCa separately. The analysis was adjusted for age, screening trial arm, and other drugs in use, including statins, antidiabetic drugs, antihypertensive drugs, aspirin, and nonsteroidal anti-inflammatory drugs. Compared to the nonusers of AEDs, overall PCa risk was decreased among AED users (hazard ratio [HR] = 0.86, 95% confidence interval [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 nonusers. The risk associations were similar for HDAC inhibitors as for AEDs in general.
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http://dx.doi.org/10.1002/ijc.33535DOI Listing
July 2021

Prognostic Index for Predicting Prostate Cancer Survival in a Randomized Screening Trial: Development and Validation.

Cancers (Basel) 2021 Jan 24;13(3). Epub 2021 Jan 24.

Unit of Health Sciences, Faculty of Social Sciences, Tampere University, FI-33014 Tampere, Finland.

We developed and validated a prognostic index to predict survival from prostate cancer (PCa) based on the Finnish randomized screening trial (FinRSPC). Men diagnosed with localized PCa ( = 7042) were included. European Association of Urology risk groups were defined. The follow-up was divided into three periods (0-3, 3-9 and 9-20 years) for development and two corresponding validation periods (3-6 and 9-15 years). A multivariable complementary log-log regression model was used to calculate the full prognostic index. Predicted cause-specific survival at 10 years from diagnosis was calculated for the control arm using a simplified risk score at diagnosis. The full prognostic index discriminates well men with PCa with different survival. The area under the curve (AUC) was 0.83 for both the 3-6 year and 9-15 year validation periods. In the simplified risk score, patients with a low risk score at diagnosis had the most favorable survival, while the outcome was poorest for the patients with high risk scores. The prognostic index was able to distinguish well between men with higher and lower survival, and the simplified risk score can be used as a basis for decision making.
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http://dx.doi.org/10.3390/cancers13030435DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7865328PMC
January 2021

Rare Germline Variants in ATM Predispose to Prostate Cancer: A PRACTICAL Consortium Study.

Eur Urol Oncol 2021 Jan 9. Epub 2021 Jan 9.

Institute of Biomedicine, University of Turku, Turku, Finland.

Background: Germline ATM mutations are suggested to contribute to predisposition to prostate cancer (PrCa). Previous studies have had inadequate power to estimate variant effect sizes.

Objective: To precisely estimate the contribution of germline ATM mutations to PrCa risk.

Design, Setting, And Participants: We analysed next-generation sequencing data from 13 PRACTICAL study groups comprising 5560 cases and 3353 controls of European ancestry.

Outcome Measurements And Statistical Analysis: Variant Call Format files were harmonised, annotated for rare ATM variants, and classified as tier 1 (likely pathogenic) or tier 2 (potentially deleterious). Associations with overall PrCa risk and clinical subtypes were estimated.

Results And Limitations: PrCa risk was higher in carriers of a tier 1 germline ATM variant, with an overall odds ratio (OR) of 4.4 (95% confidence interval [CI]: 2.0-9.5). There was also evidence that PrCa cases with younger age at diagnosis (<65 yr) had elevated tier 1 variant frequencies (p = 0.04). Tier 2 variants were also associated with PrCa risk, with an OR of 1.4 (95% CI: 1.1-1.7).

Conclusions: Carriers of pathogenic ATM variants have an elevated risk of developing PrCa and are at an increased risk for earlier-onset disease presentation. These results provide information for counselling of men and their families.

Patient Summary: In this study, we estimated that men who inherit a likely pathogenic mutation in the ATM gene had an approximately a fourfold risk of developing prostate cancer. In addition, they are likely to develop the disease earlier.
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http://dx.doi.org/10.1016/j.euo.2020.12.001DOI Listing
January 2021

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

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

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

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

Prostate cancer risk prediction using a polygenic risk score.

Sci Rep 2020 10 13;10(1):17075. Epub 2020 Oct 13.

Institute of Biomedicine, University of Turku, Kiinamyllynkatu 10, 20520, Turku, Finland.

Hereditary factors have a strong influence on prostate cancer (PC) risk and poorer outcomes, thus stratification by genetic factors addresses a critical need for targeted PC screening and risk-adapted follow-up. In this Finnish population-based retrospective study 2283 clinically diagnosed and 455 screen-detected patients from the Finnish Randomised Study of Screening for Prostate Cancer (FinRSPC), 2400 healthy individuals have been involved. Individual genetic risk through establishment of a polygenic risk score based on 55 PC risk SNPs identified through the Finnish subset of the Collaborative Oncological Gene-Environment Study was assessed. Men with PC had significantly higher median polygenic risk score compared to the controls (6.59 vs. 3.83, P < 0.0001). The polygenic risk score above the control median was a significant predictor of PC (OR 2.13, 95% CI 1.90-2.39). The polygenic risk score predicted the risk of PC with an AUC of 0.618 (95% CI 0.60-0.63). Men in the highest polygenic risk score quartile were 2.8-fold (95% CI 2.4-3.30) more likely to develop PC compared with men in the lowest quartile. In the FinRSPC cohort, a significantly higher percentage of men had a PSA level of ≥ 4 ng/mL in polygenic risk score quartile four compared to quartile one (18.7% vs 8.3%, P < 0.00001). Adding the PRS to a PSA-only model contributed additional information in predicting PC in the FinRSPC model. Results strongly suggest that use of the polygenic risk score would facilitate the identification of men at increased risk for PC.
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http://dx.doi.org/10.1038/s41598-020-74172-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7553910PMC
October 2020

Number of screening rounds attended and incidence of high-risk prostate cancer in the Finnish Randomized Study of Screening for Prostate Cancer (FinRSPC).

Cancer 2021 Jan 13;127(2):188-192. Epub 2020 Oct 13.

Unit of Health Sciences, Faculty of Social Sciences, Tampere University, Tampere, Finland.

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.
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http://dx.doi.org/10.1002/cncr.33254DOI Listing
January 2021

Expected impact of MRI-related interreader variability on ProScreen prostate cancer screening trial: a pre-trial validation study.

Cancer Imaging 2020 Oct 9;20(1):72. Epub 2020 Oct 9.

Department of Urology, University of Helsinki and Helsinki University Hospital, PL900, 00029 HUS, Helsinki, Finland.

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.
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http://dx.doi.org/10.1186/s40644-020-00351-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7547469PMC
October 2020

Seasonal changes in occurrence and severity of lower urinary tract symptoms-Tampere Aging Male Urologic Study (TAMUS).

Low Urin Tract Symptoms 2021 Apr 8;13(2):216-223. Epub 2020 Oct 8.

Faculty of Social Sciences, Tampere University, Tampere, Finland.

Objectives: To determine if lower urinary tract symptoms (LUTS) involve seasonal variation and how this affects the severity of LUTS.

Methods: A total of 3163 men aged 50 to 70 years were mailed a questionnaire on urinary symptoms. The overall response rate was 65.3% (2064 out of 3163 men). The men were asked whether their urinary symptoms showed variation in degree of difficulty according to time of year and if yes, when LUTS were the worst and the mildest. Ten different LUTS were evaluated with four response options for the severity of symptoms. Mean symptom scores and the proportions of symptomatic men were evaluated according to the presence of seasonal changes in different symptoms.

Results: Overall, 17.1% of men reported seasonal variation in severity of LUTS, older men more frequently than younger men. Worse LUTS during winter were reported by 81% of the men reporting seasonal variation, and 93% reported that LUTS were relieved in summer. More seasonal variation was reported by men with comorbidities (stroke, neurological disease) and those with medical treatment for LUTS or operative treatment for benign prostatic hyperplasia. Men with more severe LUTS were more likely to report seasonal changes.

Conclusions: One out of six men reported seasonal changes in LUTS, with winter worsening and summer relieving the symptoms. Men with seasonal variation in LUTS had more severe LUTS in all 10 symptom groups that were investigated.
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http://dx.doi.org/10.1111/luts.12353DOI Listing
April 2021

Antihypertensive drug use and prostate cancer-specific mortality in Finnish men.

PLoS One 2020 29;15(6):e0234269. Epub 2020 Jun 29.

School of Health Sciences, Tampere University, Tampere, Finland.

The aim of this study was to investigate pre- and post-diagnostic use of antihypertensive drugs on prostate cancer (PCa)-specific survival and the initiation of androgen deprivation therapy (ADT). The cohort investigated 8,253 PCa patients with 837 PCa-specific deaths during the median follow-up of 7.6 years after diagnosis. Information on drug use, cancer incidence, clinical features of PCa, and causes of death was collected from Finnish registries. Hazard ratios with 95% confidence intervals were calculated using Cox regression with antihypertensive drug use as a time-dependent variable. Separate analyses were performed on PCa survival related to pre- and post-diagnostic use of drugs and on the initiation of ADT. Antihypertensive drug use overall was associated with an increased risk of PCa-specific death (Pre-PCa: 1.21 (1.04-1.4), Post-PCa: 1.2 (1.02-1.41)). With respect to the separate drug groups, angiotensin II type 1 receptor (ATr) blockers, were associated with improved survival (Post-PCa: 0.81 (0.67-0.99)) and diuretics with an increased risk (Post-PCa: 1.25 (1.05-1.49)). The risk of ADT initiation was slightly higher among antihypertensive drug users as compared to non-users. In conclusion, this study supports anti-cancer effect of ATr blockers on PCa prognosis and this should be investigated further in controlled clinical trials.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0234269PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7323967PMC
August 2020

AR and ERG drive the expression of prostate cancer specific long noncoding RNAs.

Oncogene 2020 07 17;39(30):5241-5251. Epub 2020 Jun 17.

Faculty of Medicine and Health Technology, Tampere University and Tays Cancer Center, Tampere University Hospital, Tampere, Finland.

Long noncoding RNAs (lncRNAs) play pivotal roles in cancer development and progression, and some function in a highly cancer-specific manner. However, whether the cause of their expression is an outcome of a specific regulatory mechanism or nonspecific transcription induced by genome reorganization in cancer remains largely unknown. Here, we investigated a group of lncRNAs that we previously identified to be aberrantly expressed in prostate cancer (PC), called TPCATs. Our high-throughput real-time PCR experiments were integrated with publicly available RNA-seq and ChIP-seq data and revealed that the expression of a subset of TPCATs is driven by PC-specific transcription factors (TFs), especially androgen receptor (AR) and ETS-related gene (ERG). Our in vitro validations confirmed that AR and ERG regulated a subset of TPCATs, most notably for EPCART. Knockout of EPCART was found to reduce migration and proliferation of the PC cells in vitro. The high expression of EPCART and two other TPCATs (TPCAT-3-174133 and TPCAT-18-31849) were also associated with the biochemical recurrence of PC in prostatectomy patients and were independent prognostic markers. Our findings suggest that the expression of numerous PC-associated lncRNAs is driven by PC-specific mechanisms and not by random cellular events that occur during cancer development. Furthermore, we report three prospective prognostic markers for the early detection of advanced PC and show EPCART to be a functionally relevant lncRNA in PC.
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http://dx.doi.org/10.1038/s41388-020-1365-6DOI Listing
July 2020

The effect of sample size on polygenic hazard models for prostate cancer.

Eur J Hum Genet 2020 10 8;28(10):1467-1475. Epub 2020 Jun 8.

Humangenetik Tuebingen, Paul-Ehrlich-Str 23, D-72076, Tuebingen, Germany.

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 (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 of the Discovery-SNP model increased from 1.05 [0.93-1.18] to 2.19 [2.16-2.23]. HR 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.
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http://dx.doi.org/10.1038/s41431-020-0664-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608255PMC
October 2020

Long-term health-related quality of life among men with prostate cancer in the Finnish randomized study of screening for prostate cancer.

Cancer Med 2020 08 4;9(15):5643-5654. Epub 2020 Jun 4.

Faculty of Social Sciences/Health Sciences, Tampere University, Tampere, Finland.

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.
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http://dx.doi.org/10.1002/cam4.3181DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7402814PMC
August 2020

Cost-effectiveness analysis of PSA-based mass screening: Evidence from a randomised controlled trial combined with register data.

PLoS One 2019 5;14(11):e0224479. Epub 2019 Nov 5.

Faculty of Social Sciences (Health Sciences), Tampere University, Tampere, Finland.

In contrast to earlier studies which have used modelling to perform cost-effectiveness analysis, this study links data from a randomised controlled trial with register data from nationwide registries to reveal new evidence on costs, effectiveness, and cost-effectiveness of organised mass prostate-cancer screening based on prostate-specific antigen (PSA) testing. Cost-effectiveness analyses were conducted with individual-level data on health-care costs from comprehensive registers and register data on real-world effectiveness from the two arms of the Finnish Randomised Study of Screening for Prostate Cancer (FinRSPC), following 80,149 men from 1996 through 2015. The study examines cost-effectiveness in terms of overall mortality and, in addition, in terms of diagnosed men's mortality from prostate cancer and mortality with but not from prostate cancer. Neither arm of the FinRSPC was clearly more cost-effective in analysis in terms of overall mortality. Organised screening in the FinRSPC could be considered cost-effective in terms of deaths from prostate cancer: averting just over one death per 1000 men screened. However, even with an estimated incremental cost-effectiveness ratio of below 20,000€ per death avoided, this result should not be considered in isolation. This is because mass screening in this trial also resulted in increases in death with, but not from, prostate cancer: with over five additional deaths per 1000 men screened. Analysis of real-world data from the FinRSPC reveals new evidence of the comparative effectiveness of PSA-based screening after 20 years of follow-up, suggesting the possibility of higher mortality, as well as higher healthcare costs, for screening-arm men who have been diagnosed with prostate cancer but who do not die from it. These findings should be corroborated or contradicted by similar analyses using data from other trials, in order to reveal if more diagnosed men have also died in the screening arms of other trials of mass screening for prostate cancer.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0224479PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6830755PMC
April 2020

Risk of urothelial cancer death among people using antihypertensive drugs-a cohort study from Finland.

Scand J Urol 2019 Aug 28;53(4):185-192. Epub 2019 Jun 28.

Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.

To analyse the association between antihypertensive (anti-HT) drug use and risk of urothelial cancer (UC) death. UC occurs as bladder cancer (BCa) and upper tract urothelial carcinomas (UTUCs). Hypertension is a suggested risk factor for BCa and may impair disease prognosis. However, it's unclear if use of anti-HT drugs could improve the prognosis of UC. This study evaluated the association between use of anti-HT drugs and UC survival among 14,065 participants diagnosed with BCa and 1080 with UTUC during 1995-2012 in Finland. It analyzed data using the multivariable adjusted conditional Cox regression model. Angiotensin-receptor (ATR) blocker use before BCa diagnosis was associated with slightly decreased risk of BCa death (HR = .81, CI = .71-0.93). The association was dose-dependent and it decreased in association with elevated intensity of ATR-blocker use. Post-diagnostic use of ATR-blockers was similarly associated with better survival compared to non-users (HR = .81, CI = .71-0.92. Interestingly, use of calcium-channel blockers also associated with better survival and the risk of BCa death decreased with increasing intensity of use (HR = .67, CI = .52-0.86 for highest intensity). This large population-based cohort suggests decreased risk of BCa death among ATR-blocker and calcium-channel blocker users. The risk association among ATR-blockers and calcium-channel blockers was dose-dependent suggesting a causal explanation. Similar risk associations are not observed for other anti-HT drug users, which may suggest a direct effect of ATR blocker or calcium-channel blocker use. Further studies are needed to elucidate the potential anticancer mechanism.
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http://dx.doi.org/10.1080/21681805.2019.1634147DOI Listing
August 2019

Could Differences in Treatment Between Trial Arms Explain the Reduction in Prostate Cancer Mortality in the European Randomized Study of Screening for Prostate Cancer?

Eur Urol 2019 06 28;75(6):1015-1022. Epub 2019 Mar 28.

Department of Urology, Institute of Clinical Sciences, Sahlgrenska Academy at University of Gothenburg, Sweden; Region Västra Götaland, Sahlgrenska University Hospital, Department of Urology, Gothenborg, Sweden. Electronic address:

Background: Differential treatment between trial arms has been suggested to bias prostate cancer (PC) mortality in the European Randomized Study of Screening for Prostate Cancer (ERSPC).

Objective: To quantify the contribution of treatment differences to the observed PC mortality reduction between the screening arm (SA) and the control arm (CA).

Design, Setting, And Participants: A total of 14 136 men with PC (SA: 7310; CA: 6826) in the core age group (55-69yr) at 16yr of follow-up.

Outcome Measurements And Statistical Analysis: The outcomes measurements were observed and estimated numbers of PC deaths by treatment allocation in the SA and CA, respectively. Primary treatment allocation was modeled using multinomial logistic regression adjusting for center, age, year, prostate-specific antigen, grade group, and tumor-node-metastasis stage. For each treatment, logistic regression models were fitted for risk of PC death, separately for the SA and CA, and using the same covariates as for the treatment allocation model. Treatment probabilities were multiplied by estimated PC death risks for each treatment based on one arm, and then summed and compared with the observed number of deaths.

Results And Limitations: The difference between the observed and estimated treatment distributions (hormonal therapy, radical prostatectomy, radiotherapy, and active surveillance/watchful waiting) in the two arms ranged from -3.3% to 3.3%. These figures, which represent the part of the treatment differences between arms that cannot be explained by clinicopathological differences, are small compared with the observed differences between arms that ranged between 7.2% and 10.1%. The difference between the observed and estimated numbers of PC deaths among men with PC was 0.05% (95% confidence interval [CI] -0.1%, 0.2%) when applying the CA model to the SA, had the two groups received identical primary treatment, given their clinical characteristics. When instead applying the SA model to the CA, the difference was, as expected, very similar-0.01% (95% CI -0.3%, 0.2%). Consistency of the results of the models demonstrates the robustness of the modeling approach. As the observed difference between trial arms was 4.2%, our findings suggest that differential treatment explains only a trivial proportion of the main findings of ERSPC. A limitation of the study is that only data on primary treatment were available.

Conclusions: Use of prostate-specific antigen remains the predominant explanation for the reduction in PC mortality seen in the ERSPC trial and is not attributable to differential treatment between trial arms.

Patient Summary: This study shows that prostate cancer deaths in the European screening trial (European Randomized Study of Screening for Prostate Cancer) were prevented because men were diagnosed and treated earlier through prostate-specific antigen screening, and not because of different, or better, treatment in the screening arm compared with the control arm.
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http://dx.doi.org/10.1016/j.eururo.2019.03.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7526685PMC
June 2019

A 16-yr Follow-up of the European Randomized study of Screening for Prostate Cancer.

Eur Urol 2019 07 26;76(1):43-51. Epub 2019 Feb 26.

Erasmus Medical Centre, Rotterdam, The Netherlands.

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 16yr 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 182160 men, followed up until 2014 (maximum of 16yr), with a predefined core age group of 162389 men (55-69yr), 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<0.001) at 16yr. The difference in absolute PCa mortality increased from 0.14% at 13yr to 0.18% at 16yr. The number of men needed to be invited for screening to prevent one PCa death was 570 at 16yr compared with 742 at 13yr. The number needed to diagnose was reduced to 18 from 26 at 13yr. Men with PCa detected during the first round had a higher prevalence of PSA >20ng/ml (9.9% compared with 4.1% in the second round, p<0.001) and higher PCa mortality (hazard ratio=1.86, p<0.001) than those detected subsequently.

Conclusions: Findings corroborate earlier results that PSA screening significantly reduces PCa mortality, showing larger absolute benefit with longer follow-up and a reduction in excess incidence. Repeated screening may be important to reduce PCa mortality on a population level.

Patient Summary: In this report, we looked at the outcomes from prostate cancer in a large European population. We found that repeated screening reduces the risk of dying from prostate cancer.
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http://dx.doi.org/10.1016/j.eururo.2019.02.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7513694PMC
July 2019

Antihypertensive drugs and prostate cancer risk in a Finnish population-based cohort.

Scand J Urol 2018 Oct - Dec;52(5-6):321-327. Epub 2019 Jan 30.

g Faculty of Social Sciences , University of Tampere , Tampere , Finland.

Background: The etiology of prostate cancer (PCa) involves environmental and genetic factors. Understanding the role of medication use on PCa risk may clarify the pathophysiological changes and mechanisms in development of cancer.

Methods: This study investigated PCa risk in relation to overall use of anti-hypertensive drugs and those with specific mechanisms of action. The study cohort (78,615 men) was linked to the prescription database to obtain information on medication use during 20-year follow-up. Information was obtained on PCa diagnoses, causes of deaths, and for a sub-set on B.M.I. and use of non-prescription drugs. Time-dependent drug use variables hazard ratios (HR) with 95% confidence intervals (CI) were calculated using Cox regression analyses.

Results: Use of antihypertensive drugs slightly increased PCa risk (HR = 1.16, 95% CI = 1.11-1.22). The risk increase was clearest for metastatic PCa (HR = 1.36, 95% CI = 1.14-1.62). ACE inhibitors, beta-blockers, and diuretics were all separately associated with a small excess risk (HR = 1.10, 95% CI = 1.01-1.19, HR = 1.14, 95% CI = 1.06-1.21, and HR = 1.16, 95% CI = 1.07-1.27, respectively). None of the other groups showed a clear association with PCa risk.

Conclusions: The use of antihypertensive drugs was associated with increased prostate cancer risk. Similar risk association for multiple drug groups suggests that the findings may not reflect a direct medication effect, but may be due to underlying hypertension.
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http://dx.doi.org/10.1080/21681805.2018.1559882DOI Listing
August 2019

Allopurinol and the risk of prostate cancer in a Finnish population-based cohort.

Prostate Cancer Prostatic Dis 2019 09 29;22(3):483-490. Epub 2019 Jan 29.

University of Tampere, Faculty of Medicine and Life Sciences, Tampere, Finland.

Background: Allopurinol reduces oxidative stress and may thus have an anti-inflammatory effect. Previous studies suggest that allopurinol use might decrease the risk of prostate cancer (PCa) among gout patients. We studied the association between allopurinol use and PCa incidence.

Methods: The cohort consists of 76,874 men without prevalent PCa, originally identified for the Finnish Randomized Study of Screening for Prostate Cancer (FinRSPC). The follow-up started at entry to the trial. We excluded men using allopurinol in the year before entry (wash-out). PCa cases detected during 1996-2015 were identified from the Finnish Cancer Registry. Information on tumor Gleason score and TNM stage were obtained from medical files. Information on PSA level was obtained from screening samples for men in the FinRSPC screening arm and from laboratory databases for men in the control arm. Information on BMI was based on a questionnaire sent to men in the FinRSPC screening arm in 2004-2008. Drug purchase information were obtained from the national prescription database. We used Cox regression (adjusted for age, FinRSPC trial arm, PCa family history and use of other medication) to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) of PCa risk by allopurinol use. We analyzed medication as a time-dependent variable to minimize immortal time bias.

Results: There were 9062 new PCa diagnoses in the cohort. Follow-up time did not differ by allopurinol use (median 17 yr; IQR 11-19 vs median 17 yr; IQR 12.33-19). The risk of PCa did not differ by allopurinol use (multivariable adjusted HR 1.03; 95% CI 0.92-1.16). Allopurinol use did not associate with the risk of high-grade or metastatic cancer. Cumulative duration or average yearly dose of allopurinol use showed no association with PCa risk. No delayed risk associations were observed in the lag-time analyses.

Conclusions: We observed no difference in the PCa risk by allopurinol use.
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http://dx.doi.org/10.1038/s41391-019-0129-2DOI Listing
September 2019

Blood glucose, glucose balance, and disease-specific survival after prostate cancer diagnosis in the Finnish Randomized Study of Screening for Prostate Cancer.

Prostate Cancer Prostatic Dis 2019 09 24;22(3):453-460. Epub 2019 Jan 24.

Faculty of Social Sciences, Tampere University, Tampere, Finland.

Introduction: Diabetes mellitus has been linked with adverse prostate cancer (PCa) outcomes. However, role of hyperglycemia in PCa progression is unclear. We evaluated the link between hyperglycemia and PCa survival among Finnish PCa patients.

Methods: The study cohort included 1770 men with data on fasting glucose and diagnosed with PCa within the Finnish Randomized Study of Screening for PCa in 1995-2009. Additionally, 1398 men had data on glycated hemoglobin (HbA1c). Information on fasting glucose and HbA1c measurements was obtained from the regional laboratory database. Antidiabetic medication use was obtained from the prescription database of the Social Insurance Institution (SII). Time-dependent Cox regression analysis was used to estimate hazard ratios (HRs) and 95% confidence intervals for PCa death among diabetic, impaired glucose tolerant, and normoglycemic men.

Results: During median follow-up of 9.9 years after the diagnosis, 182 men died from PCa. After adjustment for tumor stage, Gleason grade, and PSA level at diagnosis, diabetic fasting glucose level after PCa diagnosis was associated with elevated risk of PCa death compared to normoglycemic men (HR 1.67 95% CI 1.18-2.36). The risk association was strongest among participants with localized cancer at diagnosis; HR 2.39, 95% CI 1.45-3.93. The risk elevation was observed for glucose measurements taken up to 5 years earlier. Diabetic glucose levels measured before the diagnosis were not associated with PCa death.

Conclusion: Our study cohort suggests an increased risk of PCa death in men with diabetic fasting blood glucose levels, supporting the role of hyperglycemia as a risk factor for PCa progression.
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http://dx.doi.org/10.1038/s41391-018-0123-0DOI Listing
September 2019

Author Correction: Association analyses of more than 140,000 men identify 63 new prostate cancer susceptibility loci.

Nat Genet 2019 02;51(2):363

Dame Roma Mitchell Cancer Research Centre, University of Adelaide, Adelaide, South Australia, Australia.

In the version of this article initially published, the name of author Manuela Gago-Dominguez was misspelled as Manuela Gago Dominguez. The error has been corrected in the HTML and PDF version of the article.
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http://dx.doi.org/10.1038/s41588-018-0330-6DOI Listing
February 2019

Impact of lower urinary tract symptoms on mortality: a 21-year follow-up among middle-aged and elderly Finnish men.

Prostate Cancer Prostatic Dis 2019 05 8;22(2):317-323. Epub 2018 Nov 8.

Faculty of Social Sciences, University of Tampere, Tampere, Finland.

Background: The usefulness of lower urinary tract symptoms (LUTS) as mortality risk factors remains unclear. Repeated assessments are required to take into account symptom fluctuation and de novo symptom appearance. The study objective was to evaluate mortality in relation to three urinary storage symptoms-urgency, daytime frequency, and nocturia-in middle-aged and elderly men, considering also other time-varying factors during follow-up.

Methods: A mail survey of a population-based cohort of men initially aged 50, 60, and 70 years was conducted in Finland in 1994, 1999, 2004, and 2009. The questionnaire included assessments of LUTS based on the Danish Prostatic Symptom Score and comorbidities. The men were followed up for mortality through the population registry through 2014. LUTS-related hazard ratios (HR) were analyzed with time-dependent Cox regression adjusted for the year of birth and comorbidities using variable values updated every 5 years. Sensitivity analyses were conducted using values of all variables fixed to the baseline assessment of 1994.

Results: Of the 1332 eligible men with data on LUTS from each preceding survey, 514 (38.6%) died during the 21-year follow-up. In time-dependent analyses, daytime frequency, and nocturia were significantly associated with increased mortality: the adjusted HR was 1.42 (95% CI 1.11-1.83) for daytime frequency, 1.38 (1.07-1.79) for nocturia and 1.19 (0.94-1.50) for urgency. In sensitivity analyses with fixed baseline characteristics, only nocturia was suggestively associated with an increased risk of death: the adjusted HR was 1.09 (0.84-1.42) for daytime frequency, 1.41 (0.99-2.02) for nocturia and 0.94 (0.52-1.68) for urgency.

Conclusions: Among aging men, LUTS are more accurate predictors of short-term than longer-term mortality risk. Repeated assessments are needed to detect clinically relevant and persistent symptoms, often associated with ill health. Accordingly, men with daytime frequency or nocturia exhibit a 1.4-fold risk of death and therefore, should be evaluated for underlying comorbidity.
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http://dx.doi.org/10.1038/s41391-018-0108-zDOI Listing
May 2019

Severity and bother of lower urinary tract symptoms among men aged 30-80 years: Tampere Ageing Male Urological Study (TAMUS).

Scand J Urol 2018 Aug 1;52(4):296-301. Epub 2018 Nov 1.

d School of Health Sciences , University of Tampere , Tampere , Finland.

Objective: The aim of this study was to determine the severity and bother of lower urinary tract symptoms (LUTS) and evaluate the burden of each symptom in a male population.

Materials And Methods: Postal questionnaires were sent to 7470 men aged 30-80 years. The Danish Prostatic Symptom Score (DAN-PSS-1) was used to determine the severity, bother and total symptom score for each symptom. To assess the total burden of each symptom at the population level, the total symptom scores were weighted by the prevalence they represented.

Results: The overall response rate was 58.7% (4384/7470 men). Urgency caused the greatest burden to men aged 30-80, with a prevalence-weighted symptom score of 0.712. Urgency affected 66.2% of men and 5.1% experienced moderate symptoms with moderate bother. Post-micturition dribble caused the second greatest burden, with a prevalence-weighted score of 0.704, affecting 58.7% of men and with 31.1% reporting mild bother from it. Nocturia and feeling of incomplete emptying caused the third and fourth greatest burdens, respectively. In young men (aged 30 and 40 years), post-micturition dribble caused the greatest burden, as moderate symptoms were common and caused mild bother to 11.4%. Among retired (70 and 80 years) and middle-aged (50 and 60 years) men, urgency was the most burdensome symptom.

Conclusions: The most burdensome LUTS in men aged 30-80 years was urgency, followed by post-micturition dribble, nocturia and feeling of incomplete emptying. Urgency and nocturia were prominent in old men and post-micturition dribble was noted in young men.
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http://dx.doi.org/10.1080/21681805.2018.1505944DOI Listing
August 2018

Risk Prediction of Prostate Cancer with Single Nucleotide Polymorphisms and Prostate Specific Antigen.

J Urol 2019 03;201(3):486-495

Graduate Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University , Taipei.

Purpose: Combined information on single nucleotide polymorphisms and prostate specific antigen offers opportunities to improve the performance of screening by risk stratification. We aimed to predict the risk of prostate cancer based on prostate specific antigen together with single nucleotide polymorphism information.

Materials And Methods: We performed a prospective study of 20,575 men with prostate specific antigen testing and 4,967 with a polygenic risk score for prostate cancer based on 66 single nucleotide polymorphisms from the Finnish population based screening trial of prostate cancer and 5,269 samples of 7 single nucleotide polymorphisms from the Finnish prostate cancer DNA study. A Bayesian predictive model was built to estimate the risk of prostate cancer by sequentially combining genetic information with prostate specific antigen compared with prostate specific antigen alone in study subjects limited to those with prostate specific antigen 4 ng/ml or above.

Results: The posterior odds of prostate cancer based on 7 single nucleotide polymorphisms together with the prostate specific antigen level ranged from 3.7 at 4 ng/ml, 14.2 at 6 and 40.7 at 8 to 98.2 at 10 ng/ml. The ROC AUC was elevated to 88.8% (95% CI 88.6-89.1) for prostate specific antigen combined with the risk score based on 7 single nucleotide polymorphisms compared with 70.1% (95% CI 69.6-70.7) for prostate specific antigen alone. It was further escalated to 96.7% (95% CI 96.5-96.9) when all prostate cancer susceptibility polygenes were combined.

Conclusions: Expedient use of multiple genetic variants together with information on prostate specific antigen levels better predicts the risk of prostate cancer than prostate specific antigen alone and allows for higher prostate specific antigen cutoffs. Combined information also provides a basis for risk stratification which can be used to optimize the performance of prostate cancer screening.
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http://dx.doi.org/10.1016/j.juro.2018.10.015DOI Listing
March 2019

Blood cholesterol, tumor clinical characteristics and risk of prostate cancer progression after radical prostatectomy.

Scand J Urol 2018 Aug 26;52(4):269-276. Epub 2018 Oct 26.

a Faculty of Medicine and Life Sciences , University of Tampere , Tampere , Finland.

Objective: The effects of blood cholesterol levels on prostate cancer (PCa) prognosis are unclear. This study explored the associations between blood cholesterol levels and PCa clinical characteristics, including Gleason score and tumor, node, metastasis stage, as well as risk of PCa recurrence and death after radical prostatectomy. The association between statin-induced cholesterol decline and PCa prognosis was also studied.

Materials And Methods: The study cohort consisted of 1314 PCa patients who underwent radical prostatectomy as primary management at the Tampere University Hospital between 1995 and 2009. The follow-up continued until the end of 2016.

Results: No associations between cholesterol and PCa severity were found. High-density lipoprotein (HDL) > 1 mmol/l and low-density lipoprotein (LDL) > 3 mmol/l were associated with reduced risk of all-cause death in time-dependent analysis. However, the risk association was short term as neither HDL or LDL measured 3 years earlier had an effect on PCa prognosis. Modest statin-induced cholesterol decline lowered the risk of PCa recurrence. Hazard ratios (95% confidence intervals) by modest total cholesterol and LDL declines were 0.24 (0.09-0.60) and 0.31 (0.11-0.88), respectively.

Conclusions: The findings do not support cholesterol as a risk factor for PCa severity or prognosis after prostatectomy. Cholesterol decline by statin treatment was associated with improved recurrence-free survival compared to statin users whose cholesterol did not decline, which supports the importance of controlling for compliance with statin use when estimating the effects of statins in PCa.
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http://dx.doi.org/10.1080/21681805.2018.1492967DOI Listing
August 2018

The Number of Screening Cycles Needed to Reduce Prostate Cancer Mortality in the Finnish Section of the European Randomized Study of Prostate Cancer (ERSPC).

Clin Cancer Res 2019 01 15;25(2):839-843. Epub 2018 Oct 15.

University of Tampere, School of Health Sciences, Tampere, Finland.

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. 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.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-1807DOI Listing
January 2019
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