Search

Prostate cancer (PCa) is the second-most common cause of male cancer-related death in western industrialized countries, and the emergence of metastases is a key challenge in the treatment of PCa. Accumulating studies have shown that long noncoding RNAs (lncRNAs) play an important role in the regulation of diverse cellular and molecular processes during the development and progression of cancer. Here, we utilized a unique cohort of castration-resistant prostate cancer metastases (mCRPC) and corresponding localized tumors and RNA sequencing (RNA-seq). First, we showed that patient-to-patient variability accounted for most of the variance in lncRNA expression between the samples, suggesting that genomic alterations in the samples are the main drivers of lncRNA expression in PCa metastasis. Subsequently, we identified 27 lncRNAs with differential expression (DE-lncRNAs) between metastases and corresponding primary tumors, suggesting that they are mCRPC-specific lncRNAs. Analyses of potential regulation by transcription factors (TFs) revealed that approximately half of the DE-lncRNAs have at least one binding site for the androgen receptor (AR) in their regulatory regions. In addition, transcription factor enrichment analysis revealed the enrichment of binding sites for PCa-associated TFs, such as FOXA1 and HOXB13, in the regulatory regions of the DE-lncRNAs. In a cohort of prostatectomy-treated prostate tumors, four of the DE-lncRNAs showed association with progression-free time, and two of them (lnc-SCFD2-2, and lnc-R3HCC1L-8) were independent prognostic markers. Our study highlights several mCRPC-specific lncRNAs that might be important in the progression of the disease to the metastatic stage and may also serve as potential biomarkers for aggressive PCa.

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

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

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

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

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. publishedVersion

Background: Studies for 3D-laparoscopic prostatectomy (3D-LRP) learning curve and surgical results are lacking. Combining 3D vision to LRP attenuates differences compared to Robotic assisted laparoscopic prostatectomy (RALP) with similar mini-invasiveness but lower costs. Materials and methods: Two hundred consecutive men with localized prostate cancer underwent 3D-LRP at Seinäjoki central hospital between 2013 and 2018. Oncological and functional results were documented. Long-term functional evaluation was done using EPIC-26 survey. Clavien-Dindo classification was used to assess complications during first 3 months. All operations were performed by a single surgeon (M.R.) with no experience of LRP or 3D-LRP. The learning curve was assessed by evaluating urethral anastomosis- and total operative time. Perioperative and postoperative data was collected prospectively during surgery and at subsequent control visits up to minimum of 1 year. Results: A plateau in anastomosis time was reached after 30 cases and in operative time after 60 cases. Median operative time was 114 min (78–258 min) and median time for anastomosis was 25 min (11–90 min). Median blood loss was 150 ml (10–800 ml); 93.5% of the patients were discharged within the first 3 days. Clavien-Dindo ≥3a complications occurred in 6.5%. Positive surgical margins occurred in 23%. One-year after the operation, 93.3% had PSA ≤ 0.1; 91.9% of the patients were dry or used one daytime pad. EPIC-26 scores were as follows: Urinary incontinence 79.25 (14.5–100), urinary irritative/obstructive 93.75 (31.25–100), bowel 100 (33.33–100), sexual 36.17 (0–100) and hormonal 95 (37.5–100). Conclusion: The learning curve for 3D laparoscopic prostatectomy is comparable to RALP, which makes it a cost-effective alternative with comparable oncological and functional results. publishedVersion

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.

IntroductionBlood cholesterol is likely a risk factor for prostate cancer prognosis and use of statins is associated with lowered risk of prostate cancer recurrence and progression. Furthermore, use of statins has been associated with prolonged time before development of castration resistance (CR) during androgen deprivation therapy (ADT) for prostate cancer. However, the efficacy of statins on delaying castration-resistance has not been tested in a randomised placebo-controlled setting.This study aims to test statins’ efficacy compared to placebo in delaying development of CR during ADT treatment for primary metastatic or recurrent prostate cancer. Secondary aim is to explore effect of statin intervention on prostate cancer mortality and lipid metabolism during ADT.Methods and analysisIn this randomised placebo-controlled trial, a total of 400 men with de novo metastatic prostate cancer or recurrent disease after primary treatment and starting ADT will be recruited and randomised 1:1 to use daily 80 mg of atorvastatin or placebo. All researchers, study nurses and patients will be blinded throughout the trial. Patients are followed until disease recurrence or death. Primary outcome is time to formation of CR after initiation of ADT. Serum lipid levels (total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL) and trigyserides) are analysed to test whether changes in serum cholesterol parameters during ADT predict length of treatment response. Furthermore, the trial will compare quality of life, cardiovascular morbidity, changes in blood glucose and circulating cell-free DNA, and urine lipidome during trial.Ethics and disseminationThis study is approved by the Regional ethics committees of the Pirkanmaa Hospital District, Science centre, Tampere, Finland (R18065M) and Tarto University Hospital, Tarto, Estonia (319/T-6). All participants read and sign informed consent form before study entry. After publication of results for the primary endpoints, anonymised summary metadata and statistical code will be made openly available. The data will not include any information that could make it possible to identify a given participant.Trial registration numberClinicaltrial.gov:NCT04026230, Eudra-CT: 2016-004774-17, protocol code: ESTO2, protocol date 10 September 2020 and version 6.

Statins have plausible biological effects against prostate cancer cells and are associated with improved disease-specific mortality. In current randomized placebo-controlled trial, low-dose atorvastatin caused no difference in relapses after radical prostatectomy in Asian men. Future trials should study higher statin doses at later disease stages with survival as the endpoint. See related article by Jeong et al., p. 5004

Background: Breast cancer incidence has been associated with hypertension, which might worsen disease prognosis, but few nationwide studies have investigated the association between antihypertensive drug use and breast cancer prognosis. Methods: A cohort of 73,170 women diagnosed with breast cancer during 1995–2013 identified from the Finnish Cancer Registry was combined with information on antihypertensive drug use during the same time period from a national prescription database. Antihypertensive drugs were analyzed in groups categorized by mechanism of action. Usage of antihypertensive drugs, statins, antidiabetic, and anticoagulative drugs was analyzed as time-dependent exposure to model for simultaneous use of multiple drug groups. Influence of protopathic bias was evaluated in lag-time analyses. Results: In prediagnostic use, only angiotensin receptor (ATR)-blockers were associated with decreased risk of breast cancer death as compared with nonusers (HR: 0.76, 95% confidence interval, CI: 0.69–0.82), and there was an inverse association with cumulative dose of use. Postdiagnostic use of ATR-blockers, angiotensin-converting enzyme (ACE)-inhibitors, beta-blockers, and calcium-channel blockers was dose dependently associated with better breast cancer survival compared with nonusers. The risk decrease was strongest for ATR-blockers (HR: 0.69, 95% CI: 0.63–0.75) and remained for exposures occurring up to 3 years earlier. Conclusions: Only ATR-blockers were associated with improved breast cancer survival in both prediagnostic and postdiagnostic use. The association was dose dependent and supported by a biological rationale as a causal explanation. In postdiagnostic use, similar reduction was found also for other antihypertensives, supporting a prognostic role of hypertension control. Impact: Inhibition of angiotensin receptor subtype 1 (AT1) could be a promising novel way to affect breast cancer progression.

Background: Various components of the coagulation cascade have been linked to breast cancer progression. In vivo results suggest that anticoagulants possess anticancer properties, but there are virtually no studies in human populations. Our nationwide study explored the association between anticoagulant use and breast cancer survival. Methods: All anticoagulants used from 1995 to 2015 in women (n = 73,170) diagnosed with invasive breast cancer in Finland between 1995 and 2013 were identified from the national prescription database; women were identified from the Finnish Cancer Registry. Cox regressions were performed to analyze breast cancer survival as a function of pre- and postdiagnostic anticoagulant use; analyses were conducted for different anticoagulant subtypes and overall. Models were adjusted for age, mammography screening, tumor clinical characteristics, comorbidities, statin use, antidiabetic use, and antihypertensive use. To control for immortal time bias, postdiagnostic anticoagulant use was analyzed as a time-dependent variable. Results: At a median of 5.8 years after breast cancer diagnosis, 10,900 (15%) women had died from breast cancer. In total, 25,622 (35%) women had used anticoagulants during the study period. Postdiagnostic anticoagulant use increased the risk of breast cancer death (HR = 1.41; 95% confidence interval, 1.33–1.49). The risk was especially high for low-molecular weight heparin, although the effect disappeared in long-term users. Conclusions: Anticoagulant use provides no clinical benefit for breast cancer survival; however, the association between thrombosis and cancer might mask potential survival benefits. Impact: Future pharmacoepidemiologic studies should adjust for anticoagulant use. Research should focus on the use of new oral anticoagulants because these are rarely studied and might be associated with improved breast cancer survival.

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

Contains fulltext : 291547.pdf (Publisher’s version ) (Open Access) OBJECTIVES: Genome-wide association studies have revealed over 200 genetic susceptibility loci for prostate cancer (PCa). By combining them, polygenic risk scores (PRS) can be generated to predict risk of PCa. We summarize the published evidence and conduct meta-analyses of PRS as a predictor of PCa risk in Caucasian men. PATIENTS AND METHODS: Data were extracted from 59 studies, with 16 studies including 17 separate analyses used in the main meta-analysis with a total of 20,786 cases and 69,106 controls identified through a systematic search of ten databases. Random effects meta-analysis was used to obtain pooled estimates of area under the receiver-operating characteristic curve (AUC). Meta-regression was used to assess the impact of number of single-nucleotide polymorphisms (SNPs) incorporated in PRS on AUC. Heterogeneity is expressed as I(2) scores. Publication bias was evaluated using funnel plots and Egger tests. RESULTS: The ability of PRS to identify men with PCa was modest (pooled AUC 0.63, 95% CI 0.62-0.64) with moderate consistency (I(2) 64%). Combining PRS with clinical variables increased the pooled AUC to 0.74 (0.68-0.81). Meta-regression showed only negligible increase in AUC for adding incremental SNPs. Despite moderate heterogeneity, publication bias was not evident. CONCLUSION: Typically, PRS accuracy is comparable to PSA or family history with a pooled AUC value 0.63 indicating mediocre performance for PRS alone. 01 april 2023

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

Modulation of lipid metabolism during cancer development and progression is one of the hallmarks of cancer in solid tumors; its importance in prostate cancer (PCa) has been demonstrated in numerous studies. Lipid metabolism is known to interact with androgen receptor signaling, an established driver of PCa progression and castration resistance. Similarly, immune cell infiltration into prostate tissue has been linked with the development and progression of PCa as well as with disturbances in lipid metabolism. Immuno-oncological drugs inhibit immune checkpoints to activate immune cells’ abilities to recognize and destroy cancer cells. These drugs have proved to be successful in treating some solid tumors, but in PCa their efficacy has been poor, with only a small minority of patients demonstrating a treatment response. In this review, we first describe the importance of lipid metabolism in PCa. Second, we collate current information on how modulation of lipid metabolism of cancer cells and the surrounding immune cells may impact the tumor’s immune responses which, in part, may explain the unimpressive results of immune-oncological treatments in PCa.

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

Simple Summary Prostate cancer is a major medical issue in men worldwide. In 2018, prostate cancer was the most frequently diagnosed cancer among men in developed countries. MicroRNAs seem to be important regulators of prostate cancer, but better understanding of their role in this disease is still needed to develop novel diagnostic tools and treatments. In this study, we aim to achieve insight on the microRNA profile of prostatic tissue environment in men with prostate cancer and to correlate this microRNA expression profile with risk factors of prostate cancer. We also examined the effects of cholesterol-lowering atorvastatin on the prostatic tissue microRNA profile. Our results provide new evidence from the effects of prostate cancer-related factors on the expression of prostate tissue microRNAs. Notably, this can reveal new pathways that may link risk factors to prostate cancer and pinpoint new therapeutic possibilities. Abstract MicroRNAs are important in prostate cancer development, progression and metastasis. The aim of this study was to test microRNA expression profile in prostate tissue obtained from prostate cancer patients for associations with various prostate cancer related factors and to pinpoint the predicted target pathways for these microRNAs. Prostate tissue samples were obtained at prostatectomy from patients participating in a trial evaluating impact of pre-operative atorvastatin on serum prostate specific antigen (PSA) and Ki-67 expression in prostate tissue. Prostate tissue microRNA expression profiles were analyzed using OpenArray® MicroRNA Panel. Pathway enrichment analyses were conducted for predicted target genes of microRNAs that correlated significantly with studied factors. Eight microRNAs correlated significantly with studied factors of patients after Bonferroni multiple testing correction. MiR-485-3p correlated with serum HDL-cholesterol levels. In atorvastatin-treated subjects, miR-34c-5p correlated with a change in serum PSA and miR-138-3p with a change in total cholesterol. In the placebo arm, both miR-576-3p and miR-550-3p correlated with HDL-cholesterol and miR-627 with PSA. In pathway analysis, these eight microRNAs related significantly to several pathways relevant to prostate cancer. This study brings new evidence from the expression of prostate tissue microRNAs and related pathways that may link risk factors to prostate cancer and pinpoint new therapeutic possibilities.

Background: 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. Materials and methods: 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. Results: 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). Conclusions: 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.

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.

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. 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. 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. 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.

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.

The original version of this Article contained an error in the spelling of the author Manuela Gago-Dominguez, which was incorrectly given as Manuela G. Dominguez. This has now been corrected in both the PDF and HTML versions of the Article.

This study describes a validated LC–MS/MS method for assaying 23 steroids within a single run from 150 μl of human plasma, serum or prostatic tissue homogenate. Isotope-labeled steroids were used as internal standards. Samples were extracted with toluene, and ketosteroids were derivatized with hydroxylamine prior to LC–MS/MS analysis. The steroids were separated on a C18 column and methanol was used as an organic solvent with the addition of 0.2 mM ammonium fluoride to improve underivatized estradiol (E2) ionization. Certified reference serums as well as plasma samples, and homogenates of prostate tissue were utilized in the method validation. The specificity of the method was inspected with a total of 27 steroids. The validation proved that the method was suitable for the quantitative analysis of a wide panel of androgens (testosterone, T (3.3 pM-13 nM); androstenedione, A4 (3.3 pM-13 nM); 5α-androstanedione, DHA4 (13 pM-13 nM); dehydroepiandrosterone, DHEA (67 pM-133 nM); dihydrotestosterone, DHT (33 pM-33 nM); 11-ketodihydrotestosterone, 11KDHT (13 pM-13nM); 11-ketotestosterone, 11KT (33 pM-6.7 nM); 11β-hydroxyandrostenedione, 11bOHA4 (33 pM-13 nM); 11β-hydroxytestosterone, 11OHT (13 pM-33 nM)), as well as estrogens (estrone, E1 (3.3 pM-13 nM)), progestagens (17α-hydroxypregnenolone, 17OHP5 (32 pM-127 nM); 17α-hydroxyprogesterone, 17OHP4 (67 pM-133 nM); progesterone, P4 (3.3 pM-13 nM); pregnenolone, P5 (6.6 pM-13 nM)), and glucocorticoids (cortisol, F (33 pM-134 nM); cortisone E (66 pM-131 nM); corticosterone, B (33 pM-67 nM); 11-deoxycortisol, S (33 pM-66 nM); 21-hydroxyprogesterone, 21OHP4 (32 pM-13 nM)). Furthermore, E2 (335 pM-134 nM) and 11α-hydroxyandrostenedione, 11aOHA4 (33 pM-33 nM) could be analyzed if the concentration in the sample was high enough. In addition, aldosterone, A (128 pM-64 nM) and 11-ketoandrostenedione, 11KA4 (33 pM-13 nM) could be analyzed semiquantitatively. The limits of quantification for all compounds ranged from 0.9 to 91 pg/ml, and from 0.009 to 0.9 pg/mg tissue. Compared to our previous method, this new method also permits the analysis of the more challenging steroids, like DHT, DHEA and P5, and a panel of 11-ketosteroids.

Introduction: Androgen-deprivation therapy (ADT) is standard in treatment of advanced prostate cancer (PCa). Common adverse effects include fatigue, weight gain, sarcopenia, and decreased libido leading to lowered quality of life (QoL). Supervised exercise improves overall QoL among PCa patients. Less is known, however, how it may affect metabolic adverse effects of ADT.The aim of the study was to explore the effect of exercise intervention on glucose and cholesterol levels, body composition, and to find out whether supervised exercise leads to greater physical activity in long-term compared to self-administered exercise in men with ADT. Materials and methods: Altogether, 45 men were recruited. One man withdrew the consent at baseline and 5 dropped out during the study. Thus, 39 men completed the study. Subjects were randomly assigned into either supervised exercise for 3 months (n=27) or control group of self-administered exercise (n=17). In the supervised group, participants attended 1.5-hour group exercise session twice per week. Training program included both aerobic and muscle strength exercises. The 3-month intervention was followed by 3-month follow-up of self-administered exercise. Control group received the same introduction to exercise and training instruction as the supervised group but exercised independently for the entire study period. Fasting cholesterol, plasma glucose, and body composition were evaluated at the baseline, 3 months after randomization, and at the end of the study, 6 months after randomization. Physical activity during the study period was measured using activity bracelets (Polar A370). Study protocol was approved by Pirkanmaa hospital ethics committee (R18021) and registered to Clinicaltrials.gov (NCT04050397). Results: Median total cholesterol increased during 6-month follow-up in both groups, but less in the supervised group compared to the control group (0.1 vs 0.4 mmol/l, respectively, p=0.02). LDL remained stable in supervised group but increased slightly in the control group (0 vs. 0.4 mmol/l, respectively, p=0.01). Fasting plasma glucose lowered slightly in both groups (-0.2 vs -0.4 mmol/l). Total active time per day was slightly higher in the supervised group compared to the control group after 3-month intervention (median 364 vs 293 min/day, respectively). This difference persisted after intervention stopped (median 331 vs 267 min/day, respectively). Median change in body fat percentage at 6 months was 0 in the supervised arm and -0.9 in the control arm. None of the participants dropped out due to exercise-related side-effects. Conclusion: This pilot study showed that it is safe to perform strength exercise in men with ADT. Supervised exercise is likely more effective in mitigating metabolic adverse effect of ADT and inducing long-term changes in physical activity than self-administered exercise. Larger studies with longer follow-up are needed to investigate whether this leads to survival advantage. Citation Format: Lauri Rantaniemi, Aino Siltari, Eeva Harju, Teemu J. Murtola. Can supervised exercise impact on metabolic markers and physical activity during androgen-deprivation therapy in prostate cancer patients? - randomized controlled pilot trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT171.

Introduction: Solid tumors typically favor non-oxygen related pathways on utilizing energy for cell metabolism. This helps tumor cells to survive in hypoxic microenvironment which is common in solid tumors such as prostate cancer (PCa). PCa cells characteristically store lipids, especially cholesterol. Furthermore, hypoxia and lipid metabolism are both associated with decreased responses to immune system and resistance to cancer treatments. Aim of this study was to investigate the impact of hypoxia on cell proliferation and lipid metabolism in advanced PCa cells at various stages of treatment resistance. Material and Methods: PCa cells, VCaPs, were cultured for months to form several unique, treatment resistant advanced PCa cell lines as follows: first, cells were cultured with high (10 nM) testosterone level until they required testosterone for growth to form testosterone sensitive cell line (VCaP-T, demonstrating metastatic hormone sensitive PCa); second, VCaP-T cells were cultured further under low testosterone (0.1 nM) until they gained ability to grow at low androgen level, forming castration resistant cell line (VCaP-CT); third, VCaP-CT cells were further cultured with bicalutamide and/or enzalutamide, androgen signaling inhibitors, until they again gained ability to grow despite the treatment, forming cell lines resistant to these drugs (VCaP-CT-BR, VCap-CT-ER, and VCaP-CT-BR-ER, demonstrating bicalutamide-, enzalutamide-, or mutually resistant cell lines, respectively).All cell lines were exposed to hypoxia (3% O2) with or without simvastatin (1 and 2.5 μM) for 3 days and compared to the cells growing in normoxia. Changes in proliferation was measured using crystal violet staining and amount of intracellular lipids were evaluated using Oil Red O staining. Results: Hypoxia decreased cell proliferation compared to normoxia by 20-25% in VCaP-T, VCaP-CT, and VCaP-CT-BR cells, but had no impact in enzalutamide-resistant cells VCaP-CT-ER or VCaP-CT-BR-ER. Simvastatin treatment decreased cell proliferation in all cell lines equally in hypoxia and normoxia.Compared to androgen-sensitive VCaP-T cells, all treatment resistant cell lines displayed greater intracellular lipid accumulation. Further analyses will address whether hypoxia and/or simvastatin treatment impacts amount of intracellular lipids and whether inhibition of lipid accumulation leads to less tolerance to hypoxia. Conclusion: Enzalutamide resistant cell lines displayed greater hypoxia tolerance compared to androgen sensitive or treatment naïve castration resistant cells. This indicates these cells are adopted to hypoxic microenvironment. All treatment resistant cell lines had greater intracellular lipid accumulation compared to testosterone-sensitive cells, suggesting importance of lipid metabolism in treatment resistance and hypoxia tolerance. Citation Format: Aino Siltari, Merja Bläuer, Heimo Syvälä, Teuvo L. Tammela, Teemu J. Murtola. Differential resistance to hypoxia is linked to increased lipid accumulation in treatment resistant prostate cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 121.

We tested whether intervention with atorvastatin affects the prostate beneficially compared with placebo in men with prostate cancer in a randomized clinical trial. A total of 160 statin-naive prostate cancer patients scheduled for radical prostatectomy were randomized to use 80mg atorvastatin or placebo daily from recruitment to surgery for a median of 27 d. Blinding was maintained throughout the trial. In total, 158 men completed the follow-up, with 96% compliance. Overall, atorvastatin did not significantly lower tumor proliferation index Ki-67 or serum prostate-specific antigen (PSA) compared with placebo. In subgroup analyses, after a minimum of 28 d of atorvastatin use, Ki-67 was 14.1% lower compared with placebo (p = 0.056). Among high-grade cases (International Society of Urological Pathology Gleason grade 3 or higher), atorvastatin lowered PSA compared with placebo: median change -0.6 ng/ml; p = 0.024. Intraprostatic inflammation did not differ between the study arms (p = 0.8). Despite a negative overall result showing no effect of statins on Ki67 or PSA overall, in post hoc exploratory analyses, there appeared to be benefit after a minimum duration of 28 d. Further studies are needed to verify this. PATIENT SUMMARY: Cholesterol-lowering atorvastatin does not lower prostate cancer proliferation rate compared with placebo overall, but exploratory analyses suggest a benefit in longer exposure.

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.

Simple Summary According to the literature, antihypertensive drugs may affect the survival of ovarian cancer patients. We examined the association between different groups of antihypertensive drugs and ovarian cancer survival taking into account dose and duration of use as well as the simultaneous use of other drugs. With a 5-year follow-up, antihypertensive drugs were not associated with survival from ovarian cancer but with 10-year follow-up, ACE-inhibitors and with longer follow-up times also other antihypertensive drugs were associated with improved survival from ovarian cancer. The association between ACE-inhibitor use and ovarian cancer survival should be clarified in the future. Abstract Ovarian cancer (OC) has a poor prognosis. Hypertension may be a prognostic factor for OC, but it is unclear whether antihypertensive (anti-HT) drug use of modifies OC prognosis. We performed a population-based analysis assessing the effect of anti-HT drug use on OC mortality. A cohort of 12,122 women identified from the Finnish Cancer Registry with OC in 1995–2013 was combined with information on their anti-HT drug use during the same time period. Use of each anti-HT drug was analysed as a time-dependent variable. Analyses were run for five, ten and full follow-up (19-year) mortality with cardiovascular morbidity risk evaluated in competing risk analysis. No anti-HT drug group was associated with OC survival within five years after OC diagnosis. At ten years, a dose-dependent association was observed between pre-diagnostic ACE-inhibitor use and improved OC survival. With full follow-up, post-diagnostic high-intensity use associated with reduced OC death risk for multiple anti-HT drug groups. In competing risk analysis, only the post-diagnostic use of ACE-inhibitors associated with increased OC survival. Anti-HT drugs were not associated with survival benefits within five years after OC diagnosis. ACE-inhibitors may confer survival benefits in women with OC, but further confirmatory studies are needed.

Prostate cancer is heterogeneous and patients would benefit from methods that stratify those who are likely to respond to systemic therapy. We employed single-cell assays for transposase-accessible chromatin (ATAC) and RNA sequencing in models of early treatment response and resistance to enzalutamide. In doing so, we identified pre-existing and treatment-persistent cell subpopulations that possess transcriptional stem-like features and regenerative potential when subjected to treatment. We found distinct chromatin landscapes associated with enzalutamide treatment and resistance that were linked to alternative transcriptional programs. Transcriptional profiles characteristic of persistent stem-like cells were able to stratify the treatment response of patients. Ultimately, we show that defining changes in chromatin and gene expression in single-cell populations from pre-clinical models can reveal hitherto unrecognized molecular predictors of treatment response. This suggests that the high analytical resolution of pre-clinical models enabled by single-cell methods may powerfully inform clinical decision-making.

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.

Take Home Message Prostate cancer (PCa) patients using metformin had a decreased risk of PCa death and progression compared with nonusers. Results differed from other antidiabetic drug groups, and metformin might be a favorable selection for the treatment of diabetes among PCa patients., Background Metformin has been linked to improved survival among diabetic prostate cancer (PCa) patients, while hyperinsulinemia and insulin usage has been related to worse prognosis. Objective To evaluate the association of metformin and other antidiabetic drugs with PCa death and androgen deprivation therapy (ADT). Design, setting, and participants The study cohort included 14 424 men who underwent radical prostatectomy in Finland during 1995–2013. Cases were identified, and clinical data were collected from patient files and national registries using personal identification numbers. Intervention Information on the use of each antidiabetic drug during 1995–2014 was collected from prescription registry of the Social Insurance Institution of Finland. Outcome measurements and statistical analysis The risks of PCa death and initiation of ADT were analyzed by antidiabetic drug use with the Cox regression method. Each antidiabetic drug group was analyzed separately to model simultaneous usage. Pre- and postdiagnostic uses were analyzed separately. Results and limitations Prediagnostic use of antidiabetic drugs in general had no association with the risk of PCa death. Prediagnostic use of metformin was related to a reduced risk of ADT initiation (hazard ratio [HR] 0.75, 95% confidence interval [CI] 0.59–0.96), while high-dose insulin users had an increased risk. Overall, antidiabetic drug use after PCa diagnosis was associated with an elevated risk of PCa death. Only postdiagnostic metformin use was associated with reduced risks of PCa death (HR 0.47, 95% CI 0.30–0.76) and ADT initiation compared with nonusers. Study limitations are missing information on glycemic control, smoking, living or exercise habits, prostate-specific antigen, and Gleason score. Conclusions Among surgically treated PCa patients, use of metformin was associated with improved disease-specific survival, while insulin and insulin secretagogues were associated with poor survival. Metformin might be a favorable diabetes treatment among men with PCa. Patient summary In this Finnish nationwide study, we found that the risks of prostate cancer death and cancer progression are lowered among metformin users, but not among other antidiabetic drug users. Metformin might be a favorable treatment choice for diabetes in men with prostate cancer.

Objectives: To determine whether macroscopic haematuria predicts urethrovesical anastomotic leakage after robot-assisted laparoscopic radical prostatectomy (RALP) as well as a cystogram.Patients an...

Tutkielmaan liittyva artikkeli / Article related to the thesis: Antihypertensive drugs and prostate cancer survival after radical prostatectomy in Finland - A nationwide cohort study. International journal of cancer, 2018 Aug 15., DOI: 10.1002/ijc.31802

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.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.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.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.

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

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.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.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.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.

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

Breast cancer (BC) and diabetes mellitus (DM) are major health problems. We examined the association between DM and BC stage at diagnosis and subsequent survival in a Finnish cohort of female BC patients. All BC cases (N = 73,170) diagnosed in 1995-2013 with dates and causes of death were identified from the Finnish Cancer Registry. Participation in organized mammography screening was obtained from Mass Inspection Registry. Information on DM diagnoses and background conditions recorded during 1995-2013 were obtained from national Care Register for Health Care and merged to data on medication use from the national Prescription Register. Logistic regression with adjustment for mammography screening and age at BC diagnosis was used to evaluate the risk of advanced stage BC at diagnosis. Cox regression was used to evaluate overall and BC survival. Analyses were adjusted for age, background conditions and mammography screening. Survival analyses were further adjusted for tumor extent, histology and primary treatment. Of the cohort 11,676 (16.0%) had DM. Screening participation did not differ by diabetes. Compared to non-diabetic women, diabetics had more often locally advanced (odds ratio, OR 1.26; 95% CI 1.18-1.35) or metastatic BC (OR 1.59; 95% CI 1.44-1.75) at diagnosis. During a median follow-up of 5.8 years after BC diagnosis 10,900 (14.9%) women died of BC. Risk of BC death was higher among diabetic compared to non-diabetic women (HR 1.36; 95% CI 1.27-1.46). Risk of BC death increased with duration of DM. This supports DM as a risk factor for fatal BC.

Background Neoadjuvant chemotherapy (NAC) is underutilized in the treatment of bladder cancer (BC). Objective To investigate the effect of NAC on the risk of surgical complications for radical cystectomy (RC) in a population-based setting. Design, setting, and participants All radical cystectomies performed in Finland during 2005–2014 were included in the study. Data were collected retrospectively using a web-based data collection platform. Complications were recorded for 90 d using the Clavien classification. Patients treated with NAC were compared to patients receiving RC alone using three cohorts and approaches: the entire cohort, a neoadjuvant period cohort, and a matched cohort. Outcome measurements and statistical analysis For all three cohorts, odds ratios (ORs) were estimated using simple binary logistic regression. In addition, a multivariable stratified logistic model with propensity score was used. For the matched cohort analysis, both univariate and adjusted analyses were carried out. Results and limitations During 2005–2014, 1427 RCs were performed in Finland, of which 1385 were included in the analyses. NAC was introduced in 2008, and 231 patients (16%) were assigned to NAC and 214 (15%) received two or more cycles of chemotherapy. Within 90 d, 61% of patients experienced complications and mortality was 4% (1.9% in the NAC group, and 4.4% in the RC-alone group). In simple binary logistic regression, NAC patients had significantly fewer complications, but this was not observed in multivariable or propensity score analyses. In the matched cohort analyses, no differences in complication rates could be observed. None of the analyses demonstrated higher complication rates in the NAC group. Conclusions Our retrospective study reports on nationwide use of NAC for BC and demonstrates that NAC does not increase RC morbidity. Patient summary Chemotherapy given before radical surgery does not increase severe postoperative complications in the treatment of bladder cancer.