Transdermal oestradiol and exercise in androgen deprivation therapy (ESTRACISE): protocol.

OBJECTIVE: To report the protocol of a study evaluating the efficacy of transdermal oestradiol (E2) gel in reducing the adverse effects of androgen deprivation therapy (ADT), specifically on sexual function, and to assess the utility of E2 in combination with supervised exercise. STUDY DESIGN AND METHODS: The primary endpoint of this open-label Phase IIA randomized controlled trial is the efficacy of transdermal E2 gel. Secondary endpoints include: (i) the occurrence of ADT-induced adverse effects; (ii) the safety and tolerability of E2; (iii) the impact of E2 with or without exercise on physical, physiological, muscle, and systemic biomarkers; and (iv) quality of life. The trial will recruit high-risk PCa patients (n = 310) undergoing external beam radiation therapy with adjuvant subcutaneous ADT. Participants will be stratified and randomized in a 1:1 ratio to either the E2 + ADT arm or the ADT-only control arm. Additionally, a subset of patients (n = 120) will be randomized into a supervised exercise programme. RESULTS: The primary outcome is assessed according to the efficacy of E2 in mitigating the deterioration of Expanded Prostate Cancer Index Composite sexual function domain scores. Secondary outcomes are assessed according to the occurrence of ADT-induced adverse effects, safety and tolerability of E2, impact of E2 with or without exercise on physical performance, body composition, bone mineral density, muscle size, systematic biomarkers, and quality of life. CONCLUSION: The ESTRACISE study's innovative design can offer novel insights about the benefits of E2 gel, and the substudy can reinforce the benefits resistance training and deliver valuable new novel insights into the synergistic benefits of E2 gel and exercise, which are currently unknown. TRIAL REGISTRATION: The protocol has been registered in euclinicaltrials.eu (2023-504704-28-00) and in clinicaltrials.gov (NCT06271551).

Protocol of a randomised, controlled trial comparing immediate curative therapy with conservative treatment in men aged ≥75 years with non-metastatic high-risk prostate cancer (SPCG 19/GRand-P).

BACKGROUND: Older men (aged ≥75 years) with high risk, non-metastatic prostate cancer (PCa) are increasingly treated with curative therapy (surgery or radiotherapy). However, it is unclear if curative therapy prolongs life and improves health-related quality of life (HRQoL) in this age group compared to conservative therapy, which has evolved considerably during the last decade. STUDY DESIGN: The Scandinavian Prostate Cancer Group (SPCG) 19/Norwegian Get-Randomized Research Group-Prostate (GRand-P) is a randomised, two-armed, controlled, multicentre, phase III trial carried out at study centres in Norway, Denmark, Finland, and Sweden. ENDPOINTS: The primary endpoints are overall survival and HRQoL (burden of disease scale, European Organisation for the Research and Treatment of Cancer [EORTC] Elderly Cancer patients). Secondary endpoints are PCa-specific survival, metastasis-free survival, role-functioning scale (EORTC quality of life questionnaire 30-item core), urinary irritative/obstructive scale (26-item Expanded Prostate Cancer Index Composite [EPIC-26]), bowel scale (EPIC-26), intervention-free survival, PCa morbidity, use of secondary and tertiary systemic therapies, mean quality-adjusted life-years (QALYs), and mean total healthcare costs. PATIENTS AND METHODS: A total of 980 men (aged ≥75 years) with non-metastatic, high-risk PCa will initially be screened with Geriatric 8 (G8) health status screening tool and Mini-COG© brief cognitive test. Participants identified by G8 as 'fit' or 'frail' will be randomised (ratio 1:1) to either immediate curative therapy (radiotherapy or prostatectomy) or conservative therapy (endocrine therapy or observation). Participants who are unable or unwilling to participate in randomisation will be enrolled in a separate observation group. Randomised patients will be followed for 10 years. TRIAL REGISTRATION: Ethics approval has been granted in Norway (457593), Denmark (H-22051998), Finland (R23043) and Sweden (Dnr 2023-05296-01). The trial is registered on Clinicaltrials.org (NCT05448547).

MiR26a reverses enzalutamide resistance in a bone-tumor targeted system with an enhanced effect on bone metastatic CRPC.

Resistance to androgen receptor (AR) inhibitors, including enzalutamide (Enz), as well as bone metastasis, are major challenges for castration-resistant prostate cancer (CRPC) treatment. In this study, we identified that miR26a can restore Enz sensitivity and inhibit bone metastatic CRPC. To achieve the highest combination effect of miR26a and Enz, we developed a cancer-targeted nano-system (Bm@PT/Enz-miR26a) using bone marrow mesenchymal stem cell (BMSC) membrane and T140 peptide to co-deliver Enz and miR26a. The in vitro/in vivo results demonstrated that miR26a can reverse Enz resistance and synergistically shrink tumor growth, invasion, and metastasis (especially secondary metastasis) in both subcutaneous and bone metastatic CRPC mouse models. We also found that the EZH2/SFRP1/WNT5A axis may be involved in this role. These findings open new avenues for treating bone metastatic and Enz-resistant CRPC.

Prostate cancer incidence in men with prostate-specific antigen below 3 ng/mL: The Finnish Randomized Study of Screening for Prostate Cancer.

Prostate-specific antigen (PSA)-based screening for prostate cancer (PCa) can reduce PCa mortality, but also involves overdetection 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 <3 ng/mL, cumulative PCa incidence was 9.1% after 17.6 years median follow-up. Cumulative incidence was 3.6% among men with baseline PSA 0 to 0.99 ng/mL, 11.5% in those with PSA 1.0 to 1.99 ng/mL and 25.7% among men with PSA 2 to 2.99 ng/mL (hazard ratio 9.0, 95% CI: 7.9-10.2 for the latter). The differences by PSA level were most striking for low-risk disease based on Gleason score and EAU risk group. PSA values <1 ng/mL indicate a very low 20-year risk, while at PSA 2 to 2.99 ng/mL risks are materially higher, with 4- to 5-fold risk for aggressive disease. Using risk-stratification and appropriate rescreening intervals will reduce screening intensity and overdetection. Using cumulative incidence of clinically significant PCa (csPCa) as the criterion, rescreening intervals could range from approximately 3 years for men with initial PSA 2 to 2.99 ng/mL, 6 years for men with PSA 1 to 1.99 ng/mL to 10 years for men with PSA <1 ng/mL.

Antidiabetic drugs, glycemic control and risk of benign prostatic hyperplasia.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Robot-assisted versus three-dimensional laparoscopic radical prostatectomy: 12-month outcomes of a randomised controlled trial.

OBJECTIVES: To compare functional and oncological outcomes of robot-assisted laparoscopic prostatectomy (RALP) to three-dimensional laparoscopic radical prostatectomy (3D-LRP) at 12 months after surgery. PATIENTS AND METHODS: Prospective randomised single-centre study of 145 consecutive men referred to radical prostatectomy in a tertiary referral centre in Finland. Patients were randomised 1:1 to the RALP (N = 75) and 3D-LRP (N = 70) groups. The primary outcome was urinary continence evaluated with the Expanded Prostate Cancer Index Composite 26-item version (EPIC-26) incontinence domain score at 12 months after surgery. Secondary outcomes included the use of protective pads at 12 months after surgery, EPIC-26 domain scores of irritative/obstructive, bowel, sexual and hormonal symptoms, positive surgical margin (PSM) rate, and biochemical recurrence (BCR). Complication frequency within the 3-month period after surgery was evaluated according to Clavien-Dindo classification. Statistical significance between groups was analysed using Mann-Whitney, chi-square and Fisher's exact tests. The trial was terminated after interim analysis based on no statistically significant difference in EPIC-26 urinary incontinence domain scores. Altogether 145 patients of the target accrual of 280 patients were recruited. RESULTS: Postoperative continence at 12 months after surgery according to the EPIC-26 incontinence domain was 79.25 in both groups (P = 0.4). Between group difference was -5.8 (95% confidence interval -15.2 to 3.6). There was no statistically significant difference in the rates of PSM or BCR between the two surgical modality groups. CONCLUSION: We were unable to demonstrate a difference between the RALP and 3D-LRP groups for functional and oncological outcomes at 12 months after surgery.

Testosterone replacement therapy is not associated with increased prostate cancer incidence, prostate cancer-specific, or cardiovascular disease-specific mortality in Finnish men.

BACKGROUND: Concerns have been expressed over the safety of testosterone replacement therapy (TRT) in men with late-onset hypogonadism (LOH). Previous studies have shown controversial results regarding the association of TRT with the risk of cardiovascular events or prostate cancer (PCa) incidence, aggressiveness, and mortality. This study explores the overall risk of PCa and risk by tumor grade and stage, as well as mortality from PCa and cardiovascular disease (CVD), among men treated with TRT compared to men without LOH and TRT use. MATERIALS AND METHODS: The study included 78,615 men of age 55-67 years at baseline from the Finnish Randomized Study of Screening for Prostate Cancer (FinRSPC). Follow-up started at randomization and ended at death, emigration, or a common closing date January 1st, 2017. Cox proportional hazards regression model with time-dependent variables and adjustment for age, trial arm, use of other medications, and Charlson comorbidity index was used. Comprehensive information on TRT purchases during 1995-2015 was obtained from the Finnish National Prescription Database. PCa cases were identified from the Finnish Cancer Registry and causes of death obtained from Statistics Finland. RESULTS: Over the course of 18 years of follow-up, 2919 men were on TRT, and 285 PCa cases were diagnosed among them. TRT users did not exhibit a higher incidence or mortality rate of PCa compared to non-users. On the contrary, men using TRT had lower PCa mortality than non-users (HR = 0.52; 95% CI 0.3-0.91). Additionally, TRT users had slightly lower CVD and all-cause mortality compared to non-users (HR = 0.87; 95% CI 0.75-1.01 and HR = 0.93; 95% CI 0.87-1.0, respectively). No time- or dose-dependency of TRT use was evident in any of the analyses. CONCLUSION: Men using TRT were not associated to increased risk for PCa and did not experience increased PCa- or CVD-specific mortality compared to non-users. Further studies considering blood testosterone levels are warranted.

Nationwide analysis of survival after radical cystectomy for bladder cancer in Finland.

BACKGROUND: Population-based survival results after radical cystectomy (RC) are limited. Our objective was to report short and long-term survival results after RC for bladder cancer from Finland in a population-based setting. MATERIALS AND METHODS: The Finnish National Cystectomy Database containing retrospectively collected essential RC data covering the years 2005-2017 was combined with the survival data from the Finnish Cancer Registry. Kaplan-Meier plots were used to estimate survival and the survival graphs were illustrated according to the final pathological staging. Centers were divided according to operational volume, and the results were then compared using Pearsons's Chi-squared test. RESULTS: A total of 2047 patients were included in the study. 30-, and 90-day mortality was 1.3%, and 3.8%, respectively. The OS of the entire RC population at 5- and 10 years was 66% and 55%, and CSS was 74% and 72%, respectively. Center volume did not significantly associate with surgical mortality or long-term survival. The 5- and 10-year OS according to pT-category was 87% and 74% for pT0, 85% and 69% for pTa-pTis-pT1, 70% and 58% for pT2, 50% and 42% for pT3 and 41% and 30% for pT4. The corresponding 5- and 10-year CSS rates were 96% and 93% for pT0, 91% and 90% for pTa-pTis-pT1, 78% and 75% for pT2, 56% and 55% for pT3 and 47% and 44% for pT4. The 5- and 10-year OS rates in patients with no lymph node metastases (pN-) were 74% and 62%, and CSS 82% and 80%, respectively. If lymph nodes were positive (pN+), the corresponding OS rates were 44% and 34% and CSS 49% and 48%, respectively. CONCLUSION: RC survival results have improved in contemporary series and are associated with the pTNM-status. The nationwide results from Finland demonstrate outcome comparable to high volume single-center series.

Anti-epileptic drugs and prostate cancer-specific mortality compared to non-users of anti-epileptic drugs in the Finnish Randomized Study of Screening for Prostate Cancer.

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.

Improved renal cancer prognosis among users of drugs targeting renin-angiotensin system.

PURPOSE: We explored renal cell cancer (RCC) survival among users of antihypertensive medication as hypertension is proposed to be a risk factor for RCC and ACE-inhibitors and angiotensin receptor blockers (ARBs) have been associated with improved prognosis of RCC. METHODS: Finnish cohort of 13,873 participants with RCC diagnosed between 1995-2012 was formed from three national databases. RCC cases were identified from Finnish Cancer Registry, medication usage from national prescription database and co-morbidities from Care Registry of Healthcare. Logistic regression was used to calculate odds ratios for metastatic tumor extent at the time of diagnosis. Risk of RCC specific death after diagnosis was analyzed using Cox regression adjusted for tumor clinical characteristics. RESULTS: A total of 5,179 participants died of RCC during the follow-up. No risk association was found for metastatic tumor extent for any drug group. ACE-inhibitors, but no other drug group were associated with decreased risk of RCC specific death overall (HR 0.88, 95% CI 0.82-0.95) compared to non-users. In time-dependent analysis high-dose use of ACE-inhibitors (392 Defined Daily Dose (DDD)/year), HR 0.54, 95% CI 0.45-0.66) and ARBs (786.1 DDD/year, HR 0.66, 95% CI 0.50-0.87) associated with improved RCC survival. No information of TNM-classification or tobacco smoking was available. CONCLUSION: ACE-inhibitors and ARBs in high dose associated with improved RCC specific survival. This may reflect overall benefit of treating hypertension with medication targeting renin-angiotensin system (RAS) system among RCC patients. Further studies are needed to explore the role of RAS in RCC.

Tumor margins that lead to reoperation in breast cancer: A retrospective register study of 4,489 patients.

BACKGROUND AND OBJECTIVES: Optimal margins for ductal carcinoma in situ (DCIS) remain controversial in breast-conserving surgery (BCS) and mastectomy. We examine the association of positive margins, reoperations, DCIS and age. METHODS: A retrospective study of histopathological reports (4489 patients). Margin positivity was defined as ink on tumor for invasive carcinoma. For DCIS, we applied 2 mm anterior and side margin thresholds, and ink on tumor in the posterior margin. RESULTS: The incidence of positive side margins was 20% in BCS and 5% in mastectomies (p < 0.001). Of these patients, 68% and 14% underwent a reoperation (p < 0.001). After a positive side margin in BCS, the reoperation rates according to age groups were 74% (<49), 69% (50-64), 68% (65-79), and 42% (80+) (p = 0.013). Of BCS patients with invasive carcinoma in the side margin, 73% were reoperated on. A reoperation was performed in 70% of patients with a close (≤1 mm) DCIS side margin, compared to 43% with a wider (1.1-2 mm) margin (p = 0.002). The reoperation rates were 55% in invasive carcinoma with close DCIS, 66% in close extensive intraductal component (EIC), and 83% in close pure DCIS (p < 0.001). CONCLUSIONS: Individual assessment as opposed to rigid adherence to guidelines was used in the decision on reoperation.

Use of α1-adrenoceptor antagonists tamsulosin and alfuzosin and the risk of Alzheimer's disease.

PURPOSE: Tamsulosin has been associated with dementia, but the results have been inconsistent. Concerns have been raised about using exposure assessment time too close to the outcome. We investigated the association between use of α1-adrenoceptor antagonists indicated for benign prostate hyperplasia and risk of Alzheimer's disease (AD) using different exposure windows. METHODS: The study (24 602 cases and 98 397 matched controls) included men from the Finnish nationwide nested case-control study on Medication and Alzheimer's disease (MEDALZ). Cases received clinically verified AD diagnosis during 2005-2011 and were community-dwelling at the time of diagnosis. Use of tamsulosin and alfuzosin in 1995-2011 was identified from the Prescription Register and categorized based on whether it had occurred within 3 years before AD diagnosis (lag time) or before that. Dose-response analysis using defined daily doses of drug (DDDs) was conducted. Associations were investigated with conditional logistic regression, adjusted for confounders and mediators. RESULTS: The use of α1-adrenoceptor antagonists before lag time associated with an increased risk of AD (OR 1.24 [1.20-1.27]). After adjustment for comorbidities and concomitant drug use throughout the assessment time (confounders) and healthcare contacts within the lag period (mediators), the association weakened (aOR 1.10 [1.06-1.14]). We found no evidence of dose-response-relationship when comparing the users of higher than median DDDs to the users of lower than median DDDs. CONCLUSION: Our findings, especially the lack of dose-response-relationship and attenuation after mediator adjustment, do not provide strong support for the previous hypothesis on α1-adrenoceptor antagonists as a risk factor for dementia.

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

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.

Preservation of Endopelvic Fascia: Effects on Postoperative Incontinence and Sexual Function - A Randomized Clinical Trial.

BACKGROUND: Urinary incontinence and sexual dysfunction are common after robot-assisted radical prostatectomy (RALP). New surgical techniques to improve these functions after the operation are under evaluation for example, preservation of endopelvic fascia during RALP. However, the benefits of this technique have not been critically scrutinized in a randomized setting. AIM: In this study, we compared endopelvic fascia preserving operation with the standard surgical procedure in a randomized trial at the Tampere University Hospital, Finland. METHODS: A total of 158 men with localized prostate cancer and scheduled for RALP were randomized 1:1 into endopelvic fascia-preserving RALP or a control group that is, standard operation. All operations were performed by a single surgeon. OUTCOMES: Urinary and sexual function were evaluated by the Expanded Prostate Cancer Index Composite-26 questionnaire at baseline and 3, 6, and 12 months after the surgery. RESULTS: There was no difference in urinary incontinence or sexual function between the groups at any time point (urinary incontinence domain at 12 months after RALP for fascia preserving and control group 73.6 ± 3 vs 78.9 ± 2.5 and sexual domain 43 ± 3.2 vs 40.3 ± 3, respectively). Clinical and pathologic tumor characteristics, duration of surgery, blood loss, rate of complications, and time to hospital discharge were similar between the study arms. Compliance of filling out the Expanded Prostate Cancer Index Composite-26 questionnaire varied from 91% to 98%, with no difference between study arms. CLINICAL IMPLICATIONS: Based on our results, endopelvic fascia preservation alone during RALP is not recommended over the standard surgical method. STRENGTHS & LIMITATIONS: This is a randomized clinical study with sufficient statistical power. As a limitation, only a minority of participants underwent magnetic resonance imaging before the operation, thus we could not evaluate the role of urethral length or shape of the prostate. Urinary and sexual function results are based on questionnaires filled out by the patients, however, participants completed the surveys independently unassisted by health care personnel. CONCLUSION: Endopelvic fascia-preserving RALP does not improve urinary continence or sexual function as compared with the standard surgical technique. Future studies aiming to improve functional outcomes after RALP should focus on evaluating other technique modifications. Siltari A, Riikonen J, Murtola TJ. Preservation of Endopelvic Fascia: Effects on Postoperative Incontinence and Sexual Function - A Randomized Clinical Trial. J Sex Med 2021;18:327-338.

Antihypertensive drugs and prostate cancer survival after radical prostatectomy in Finland-A nationwide cohort study.

Antihypertensive (anti-HT) drugs targeting renin-angiotensin-aldosterone (RAA)- system have been associated with improved prostate cancer (PCa)-specific survival. Challenge is that often multiple drugs are used simultaneously. We evaluated the association between use of anti-HT drugs and PCa survival among 14,422 surgically treated Finnish PCa patients. Information on drug purchases was obtained from a national prescription database. We used Cox regression to calculate hazard ratios (HRs) and 95% confidence intervals (95% CIs) for risk of PCa death and initiation of androgen deprivation therapy (ADT) with adjustment for age, tumor extent, use of statins and for Charlson Comorbidity Index. Angiotensin-converting enzyme (ACE)- inhibitors, angiotensin- receptor (ATR)-blockers, diuretics, calcium-channel blockers, beta-blockers and other anti-HT drugs were analyzed as separate time-dependent variables to model simultaneous use. Overall anti-HT drugs were associated with an increased risk of PCa death. Conversely use of ATR-blockers was associated with decreased risk of PCa death (HR: 0.43, 95% CI: 0.26-0.72 and HR: 0.60, 95% CI 0.37-0.97 for pre- and post-diagnostic use). Similar risk decrease was not observed in other drug groups. Anti-HT drugs were also associated with an increased risk of starting ADT, with the exception of ATR-blockers (HR: 0.81 CI:0.71-0.92). ATR- blockers differ from other anti-HT drugs as the survival is better in users of this drug group. The result partly supports the role of RAA system in PCa progression. Nevertheless, the risk decrease was not observed in ACE-inhibitor users. Further research is needed to elucidate the molecular mechanism for the potential anticancer effect of ATR- blockers.

Prostate cancer survival among statin users after prostatectomy in a Finnish nationwide cohort.

BACKGROUND: Improved prostate cancer (PCa) survival by statin use has been reported among PCa patients managed with radiation or androgen deprivation therapy (ADT), while results are controversial for men managed surgically. We evaluate the association between cholesterol-lowering medication with initiation of ADT and disease-specific death among PCa cases who underwent radical prostatectomy in Finland between 1995 and 2013. METHODS: The study cohort included 14 424 men with PCa who underwent radical prostatectomy in Finland between 1995 and 2013. Cases were identified from national hospital discharge registry. Clinical data were amended from patient files of the treating hospitals. Information on co-morbidities, additional radiation- or chemotherapy, and causes of deaths were collected from national registries. Personal-level data on medication use during 1995-2014 were gathered from national prescription database. Registry linkages were carried out using personal identification number. Lipid-lowering drugs were categorized into statins and non-statin drugs. Risk of PCa death and initiation of ADT was analyzed using Cox-regression model with adjustment for age, radiation therapy, chemotherapy, co-morbidities and other drug use. Statin use was analyzed as time-dependent variable. Delayed risk associations were evaluated in lag-time analysis. RESULTS: Compared to non-users the risk of PCa death was significantly lower among statin users before PCa diagnosis (HR 0.70, 95%CIs 0.52-0.95). For statin use after PCa diagnosis the risk was lowered in age-adjusted analysis (HR 0.76 95%CIs 0.62-0.93) but not after multivariable-adjustment. Post-diagnostic statin use was associated with improved PCa-specific survival in 1, 3 and 5 years lag-time analyses. The risk reduction was clearest for statin use initiated 5 years earlier (HR 0.71 95%CIs 0.55-0.92). Use of statins both before and after PCa diagnosis was associated with reduced risk of ADT use (HR 0.72 95%CIs 0.65-0.80 and HR 0.73, 95%CI 0.67-0.80, respectively). The risk of ADT decreased by increasing intensity of statin use before diagnosis. CONCLUSION: Statin use among surgically treated PCa patients has significant association with decreased risk of starting ADT and PCa death. The risk is lowered especially among men with statin use before PCa diagnosis and in men who used statins at high-dose. Our results are hypothesis generating due to retrospective study design.

Access and concentrations of atorvastatin in the prostate in men with prostate cancer.

BACKGROUND: Statins have anticancer effects on prostate cancer both in vitro and in vivo. It is unclear whether this is due to systemic cholesterol-lowering or direct local growth inhibition in the prostate. It is also unclear whether statins can access the prostate; lipophilic statins could, in theory, pass lipid-enriched cell membranes by passive diffusion. However, statin concentrations in the human prostate have not been measured before. METHODS: The study population was based on a randomized clinical trial where 158 men with prostate cancer were randomized to use 80 mg atorvastatin (ATV) or placebo daily for a median of 27 days before radical prostatectomy. ATV and atorvastatin lactone (ATV-Lactone) concentrations in the plasma and in the prostate were measured with mass spectrometry in men randomized to the ATV arm. Linear trends between intraprostatic concentration and plasma concentration, body mass index, age, and duration of intervention were examined. The relative tissue concentrations of ATV and ATV-Lactone were calculated in prostatic tissue and plasma to evaluate drug homeostasis. Subgroup analyses were stratified by tumor and population characteristics. RESULTS: The analysis involved a total of 55 men. When limited to men whose tissue concentrations of ATV was measurable (n = 28, 50%), median ATV concentration was 212% higher in the tissue (median concentration 17.6 ng/g) compared to the plasma (median concentration 3.6 ng/mL). Also, ATV-L concentration was 590% higher in the tissue as compared to the plasma concentration. No statistically significant linear trends between the plasma and tissue concentrations were observed. When comparing the relative concentration of atorvastatin lactone over ATV, the concentrations were in balance in the plasma, In the prostate, however, the relative concentration of atorvastatin lactone was 57% lower compared to ATV (P = .009 for the difference between prostate tissue and plasma). No effect modification by tumor or population characteristics was observed. CONCLUSIONS: Measurable ATV concentrations in the prostate support ATV's ability to access the prostate from the circulation. ATV may accumulate in the prostate as intraprostatic concentrations are elevated compared to the plasma concentration.

Effects of Preoperative Atorvastatin Treatment On Erectile Function After Radical Prostatectomy: Results From a Subgroup of ESTO1, a Randomized, Double-Blind, Placebo-Controlled Study.

INTRODUCTION: Erectile dysfunction is common after radical prostatectomy because of damage to the cavernous nerves. Thus, it is important to identify new ways to avoid this problem. For example, statins have shown positive effects on erectile function and may have anti-inflammatory effects that improve recovery after surgery. AIM: The aim of this exploratory analysis of a subgroup from ESTO1, a randomized, double-blind, placebo-controlled study, was to evaluate the preoperative use of atorvastatin on erectile function after radical prostatectomy. METHOD: Patients were randomized to either 80 mg atorvastatin or placebo daily before undergoing radical prostatectomy from study inclusion to the day of surgery. Altogether 118 men with prostate cancer and scheduled for radical prostatectomy were asked to fill out the 5-item version of the International Index of Erectile Function (IIEF-5) questionnaire before surgery and at 3, 6, 9, and 12 months after surgery. MAIN OUTCOME MEASUREMENTS: The study was exploratory, with the main outcome being the overall difference between IIEF-5 scores in the 2 groups at 12 months. Several hypotheses generating sub-analyses were conducted. RESULTS: Overall, 85% filled out the IIEF-5 questionnaire before their operation and 85%, 81%, 78%, and 78% completed it at 3, 6, 9, and 12 months follow-up, respectively. 52% of men had information available at all time points. There were no statistically significant differences between the groups at baseline in either erectile function, comorbidities, or tumor characteristics. The median duration of use of atorvastatin and placebo before surgery was 27 and 25 days, respectively. Preoperative atorvastatin treatment had no statistically significant effect on erectile function after prostatectomy as compared with placebo, although IIEF-5 scores were higher at all time points in the statin arm. Furthermore, atorvastatin treatment compared with placebo improved IIEF-5 scores at 12 months after surgery when the cavernous nerves were at least partially intact bilaterally (P < .04, n = 65); however, after full bilateral or unilateral nerve-sparing, the difference was not statistically significant. CLINICAL IMPLICATION: Short-term statin treatment did not improve recovery of erectile function after prostatectomy; however, further studies are needed before final conclusions. STRENGTHS & LIMITATIONS: This was a randomized placebo-controlled study. Original ESTO1 study was designed to detect a difference in prostate cancer biomarkers. CONCLUSION: Short-term atorvastatin treatment before radical prostatectomy had no statistically significant effect on the recovery of erectile functions in a non-selected cohort of patients undergoing radical prostatectomy. Further studies will be needed to clarify the role of long-term atorvastatin use before and after prostatectomy. Siltari A, Riikonen J, Fode M, et al. Effects of Preoperative Atorvastatin Treatment On Erectile Function After Radical Prostatectomy: Results From a Subgroup of ESTO1, a Randomized, Double-Blind, Placebo-Controlled Study. J Sex Med 2019;16:1597-1605.

Fasting blood glucose, glycaemic control and prostate cancer risk in the Finnish Randomized Study of Screening for Prostate Cancer.

BACKGROUND: Diabetic men have lowered overall risk of prostate cancer (PCa), but the role of hyperglycaemia is unclear. In this cohort study, we estimated PCa risk among men with diabetic fasting blood glucose level. METHODS: Participants of the Finnish Randomized Study of Screening for Prostate Cancer (FinRSPC) were linked to laboratory database for information on glucose measurements since 1978. The data were available for 17,860 men. Based on the average yearly level, the men were categorised as normoglycaemic, prediabetic, or diabetic. Median follow-up was 14.7 years. Multivariable-adjusted Cox regression was used to calculate hazard ratios (HRs) and 95% confidence intervals (95% CIs) for prostate cancer overall and separately by Gleason grade and metastatic stage. RESULTS: In total 1,663 PCa cases were diagnosed. Compared to normoglycaemic men, those men with diabetic blood glucose level had increased risk of PCa (HR 1.52; 95% CI 1.31-1.75). The risk increase was observed for all tumour grades, and persisted for a decade afterwards. Antidiabetic drug use removed the risk association. Limitations include absence of information on lifestyle factors and limited information on BMI. CONCLUSIONS: Untreated diabetic fasting blood glucose level may be a prostate cancer risk factor.

Bladder Cancer Survival of Men Receiving 5α-Reductase Inhibitors.

PURPOSE: Androgens may have a role in bladder carcinogenesis. We studied whether 5α-reductase inhibitors were associated with bladder cancer specific mortality in a population based cohort of men with bladder cancer. MATERIALS AND METHODS: The study cohort consisted of 10,720 Finnish men with bladder cancer newly diagnosed in 1997 to 2012 who were identified in a national cancer registry. Median followup was 4.17 years after bladder cancer diagnosis. We analyzed the HR and 95% CI of the risk of bladder cancer death by 5α-reductase inhibitor administration using Cox regression adjusted for age, gender, comorbidities, primary bladder cancer treatment and tumor extent at diagnosis. Lag time analyses were performed to assess the long-term risk association. Simultaneous administration α-blockers was considered to estimate possible confounding by indication. RESULTS: Administering 5α-reductase inhibitors before bladder cancer diagnosis was associated with a lower risk of bladder cancer death (HR 0.84, 95% CI 0.73-0.97). The risk decrease became stronger with years of use. Conversely prediagnostic administration of α-blockers was not associated with bladder cancer survival (HR 1.02, 95% CI 0.91-1.13). Similarly 5α-reductase inhibitor administration after diagnosis was associated with a decreased risk of bladder cancer death (HR 0.77, 95% CI 0.68-0.88). Bladder cancer survival was not associated with α-blockers (HR 0.98, 95% CI 0.90-1.07). The risk decrease due to 5α-reductase inhibitors persisted up to 5 years. CONCLUSIONS: Patients who receive 5α-reductase inhibitors have improved disease specific survival after bladder cancer diagnosis compared to those who do not receive them while α-blockers were not associated with survival. This supports the benefits of 5α-reductase inhibitors in bladder cancer.