Search

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

This study analyzes risk associations between metabolic syndrome (MetS) components and the extent and prognosis of renal cell cancer (RCC). The independent effect of each MetS component is unclear, but they may affect RCC prognosis.The study included 13,873 RCC patients (7720 men, 6153 women) diagnosed in Finland in 1995-2012. Data on MetS components (hypertension, dyslipidemia, diabetes and obesity) were obtained as recorded diagnoses or drug purchases related to these conditions. Risk of advanced RCC at diagnosis was estimated by logistic regression. Cox proportional hazard regression was used to evaluate risk associations for RCC death by MetS components after diagnosis. Components were analyzed as time-dependent variables, and included in analyses simultaneously to evaluate their independent effects.During follow-up (median 1.92, SD 4.35 years) 5179 participants died of RCC. Risk of advanced RCC at diagnosis was associated with hypertension [odds ratio (OR) 0.82, 95% confidence interval (CI) 0.74-90] and dyslipidemia (OR 0.52, 95% CI 0.48-0.57). After adjustment for tumor extent, hypertension remained associated with increased risk of RCC death (hazard ratio 1.44, 95% CI 1.35-1.54]. Other MetS components were not independently associated with RCC death when taking hypertension into account. Study limitations include the non-randomized design and lack of smoking status.The lower risk of advanced disease among hypertensive participants may reflect the higher proportion of incidental renal tumors found through more frequent physician contacts. Nevertheless, hypertension was independently associated with worse RCC survival, whereas other MetS components had no clear prognostic role.

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

BACKGROUND The prognostic role of preoperative serum lipid levels in patients undergoing radical prostatectomy (RP) for clinically localized prostate cancer (PCa) is unclear. The aim of the present study was to investigate preoperative serum lipid levels in patients with clinically localized PCa undergoing RP and their association with clinicopathological features and oncological outcome. METHODS Preoperative lipid levels (total cholesterol, LDL cholesterol, HDL cholesterol and triglycerides) and statin use from consecutive patients with clinically localized PCa undergoing RP in a tertiary referral center between 2008 and 2015 were recorded and patients were followed prospectively. Logistic regression analysis was used to test the association between lipid levels and clinicopathological parameters. Lipid values were analyzed both as continuous and dichotomized variables. Univariable and multivariable Cox regression analyses were performed to identify predictors for recurrence-free survival (RFS). Recurrence was defined as rising and verified PSA levels >0.1 ng/ml. RESULTS Our cohort consisted of 371 men with a median age of 63 years (range 41-78 years) and a median preoperative PSA value of 6.79 ng/ml (0.43-81.4 ng/ml). Median follow-up was 28 months (1-64). No association was found between lipid levels and adverse pathological characteristics such as ≥pT3, Gleason score ≥8, positive nodal status and positive surgical margins. Recurrence occurred in 49 patients (15.4%) at a median time of 18 months (2-51 month). Compared to low LDL cholesterol, high LDL cholesterol was associated with longer RFS in univariable analysis (continuous: Hazard Ratio (HR): 0.67, 95%-Confidence Interval (CI): 0.47-0.96, P = 0.03; 3 mM cut-point: HR: 0.44, 95%-CI: 0.24-0.79, P = 0.006). Neither levels of other lipids, nor statin use were associated with RFS. Preoperative LDL cholesterol remained an independent predictor for PCa recurrence in a multivariable model adjusted for age, preoperative PSA, statin use, tumor stage, Gleason score, nodal status and surgical margin status (continuous: HR: 0.66, 95%-CI: 0.44-0.99, P = 0.04; 3 mM cut-point: HR: 0.41, 95%-CI: 0.21-0.78, P = 0.007). CONCLUSIONS This is the first prospective study showing the potential adverse and independent prognostic role of low preoperative LDL cholesterol levels in patients with localized PCa undergoing RP. Prostate © 2017 Wiley Periodicals, Inc.

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

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.

In their article, Skriver and colleagues reported results from a Danish population-based cohort study estimating prostate cancer–specific survival by aspirin use among 29 136 patients with prostate...

Introduction Erectile dysfunction (ED) is strongly associated with physiological and metabolic disturbances, and hyperuricemia has been proposed to predict the onset of ED. Aim To investigate if hyperuricemia is an independent predictor for ED when all relevant confounding factors are taken into account. Methods This is a cross-sectional study of men aged between 45 and 70 years. The population was well characterized for established cardiovascular risk factors, metabolic syndrome, as well as kidney function, depression, and socioeconomic factors. Analysis was limited to 254 men with complete data and also serum uric acid (SUA) measurements were available. This included 150 men with and 104 without ED. The presence and severity of ED was evaluated using International Index of Erectile Function-5 questionnaire. Risk of ED by SUA level was calculated using univariate and multivariable-adjusted logistic regression. Effect modification by participant characteristics were evaluated in subgroup analyses. Main Outcome measures The main outcome measures of this study are prevalence and severity of erectile dysfunction. Results Patients with ED (59% of the study population) were older than men without ED (59 vs 54 years) and had lower serum testosterone (14.3, 95% CI 11.3–17.3 vs 15.1 nmol/l, 95% CI 12.1–18.8, respectively). Regarding all other variables, the groups were comparable. No significant difference was found for SUA by ED. SUA was not associated with ED risk in univariate or multivariable analysis (multivariable-adjusted OR 1.14, 95% CI 0.59–2.19, P = .7) for SUA level higher than median compared with median or lesser (OR 1.00, 95% CI 0.997–1.006, P = .7 for continuous variable). No subgroup analysis modified the association. After multivariable adjustment age, education level and depression were statistically significant predictors of ED. Conclusions Elevated SUA was not found to be an independent risk factor for ED. Metabolic syndrome, glomerular filtration rate, or cardiovascular risk factors did not modify this result. ED cannot be predicted based on the level of SUA.

Simple Summary Pharmacoepidemiologic research provides opportunities to evaluate how commonly used drug groups, such as cholesterol-lowering drugs, may affect the prostate cancer risk or mortality. However, such studies need to be carefully designed in order to avoid biases caused by systematic differences between medication users and non-users. Similarly, data must be carefully analyzed and interpreted while acknowledging possible biases that can lead to erroneous conclusions. Here, we review common pitfalls in such studies and describe ways to avoid them in an effort to aid future research. Abstract Pharmacoepidemiologic research provides opportunities to evaluate how commonly used drug groups, such as cholesterol-lowering or antidiabetic drugs, may affect the prostate cancer risk or mortality. This type of research is valuable in estimating real-life drug effects. Nonetheless, pharmacoepidemiological studies are prone to multiple sources of bias that mainly arise from systematic differences between medication users and non-users. If these are not appreciated and properly controlled for, there is a risk of obtaining biased results and reaching erroneous conclusions. Therefore, in order to improve the quality of future research, we describe common biases in pharmacoepidemiological studies, particularly in the context of prostate cancer research. We also list common ways to mitigate these biases and to estimate causality between medication use and cancer outcomes.

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

The anti-diabetic drug metformin and cholesterol-lowering statins inhibit prostate cancer cell growth in vitro and have been linked with lowered risk of prostate cancer in epidemiological studies. We evaluated the effects of these drugs on cancerous and non-cancerous prostate epithelial cell lines. Cancer (LNCaP) and normal (RWPE-1) prostate epithelial cell lines were treated with pharmacologic concentrations of metformin and simvastatin alone and in combinations. Relative changes in cell number were measured with crystal violet staining method. Drug effects on apoptosis and cell cycle were measured with flow cytometry. We also measured changes in the activation and expression of a set of reported target proteins of metformin and statins with Western blotting. Metformin decreased the relative cell number of LNCaP cells by inducing G1 cell cycle block, autophagy and apoptosis, and slightly increased cytosolic ATP levels, whereas RWPE-1 cells were resistant to metformin. However, RWPE-1 cells were sensitive to simvastatin, which induced G2 cell cycle block, autophagy and apoptosis, and increased cytosolic ATP levels in these cells. Combination of metformin and simvastatin synergistically decreased cytosolic ATP levels, increased autophagy and instead of apoptosis, induced necrosis in LNCaP cells. Synergistic effects were not observed in RWPE-1 cells. These results suggest, that prostate cancer cells may be more vulnerable to combined growth-inhibiting effects of metformin and simvastatin compared to normal cells. The data presented here provide evidence for the potency of combined metformin and statin, also at pharmacologic concentrations, as a chemotherapeutic option for prostate cancer.

Previous studies suggest that antiepileptic drugs with histone deacetylase (HDAC) inhibitor properties may have prostate cancer preventive effects. We evaluated the association between antiepileptic drug use and prostate cancer risk in a population-based case-control study. The study included all new prostate cancer cases diagnosed in Finland in 1995-2002 and matched controls (24,657 case-control pairs) identified from the Finnish Cancer Registry and the Population Register Center, respectively. Information on antiepileptic drug purchases was obtained from the national prescription reimbursement database. Odds ratios and their 95 % confidence intervals were estimated using age-adjusted and multivariable-adjusted conditional logistic regression analysis. Compared to never-users of antiepileptic drugs, the overall prostate cancer risk was decreased among users of phenobarbital, carbamazepine, and valproic acid (multivariable-adjusted odds ratio (OR) 0.47, 95 % CI 0.24-0.92; OR 0.82, 95 % CI 0.71-0.94, and OR 0.62, 95 % CI 0.42-0.92, respectively), but not among users of other antiepileptic drugs. Overall prostate cancer risk decreased in a dose-dependent manner by cumulative amount, duration and yearly dosage (intensity) of HDAC inhibitors valproic acid and carbamazepine. The risk of advanced prostate cancer was decreased only among carbamazepine users (OR 0.65, 95 % CI 0.44-0.96). Our results support possible prostate cancer preventive effects of HDAC inhibitors. However, also phenobarbital use was associated with decreased prostate cancer risk, despite not having HDAC inhibiting activity. The mechanism of action for antiepileptic drugs in prostate cancer deserves further study.

Background: A previous analysis of the placebo arm of the Prostate Cancer Prevention Trial (PCPT) reported 82% overall prevalence of intraprostatic inflammation and identified a link between inflammation and higher-grade prostate cancer and serum PSA. Here, we studied these associations in the PCPT finasteride arm. Methods: Prostate cancer cases (N = 197) detected either on a clinically indicated biopsy or on protocol-directed end-of-study biopsy, and frequency-matched controls (N = 248) with no cancer on an end-of-study biopsy were sampled from the finasteride arm. Inflammation in benign prostate tissue was visually assessed using digital images of hematoxylin and eosin–stained sections. Logistic regression was used for statistical analysis. Results: In the finasteride arm, 91.6% of prostate cancer cases and 92.4% of controls had at least one biopsy core with inflammation in benign areas (P < 0.001 for difference compared with placebo arm). Overall, the odds of prostate cancer did not differ by prevalence [OR, 0.90; 95% confidence interval (CI), 0.44–1.84] or extent (P trend = 0.68) of inflammation. Inflammation was not associated with higher-grade disease (prevalence: OR, 1.07; 95% CI, 0.43–2.69). Furthermore, mean PSA concentration did not differ by the prevalence or extent of inflammation in either cases or controls. Conclusion: The prevalence of intraprostatic inflammation was higher in the finasteride than placebo arm of the PCPT, with no association with higher-grade prostate cancer. Impact: Finasteride may attenuate the association between inflammation and higher-grade prostate cancer. Moreover, the missing link between intraprostatic inflammation and PSA suggests that finasteride may reduce inflammation-associated PSA elevation. Cancer Epidemiol Biomarkers Prev; 25(3); 463–9. ©2015 AACR.

Randomized clinical trials have shown that use of 5α-reductase inhibitors (5-ARIs) lowers overall prostate cancer (PCa) risk compared to placebo, while the proportion of Gleason 8-10 tumors is elevated. It is unknown whether this affects PCa-specific survival. We studied disease-specific survival by 5-ARI usage in a cohort of 6,537 prostate cancer cases diagnosed in the Finnish Prostate Cancer Screening Trial and linked to the national prescription database for information on medication use. Cox proportional hazards regression was used to estimate hazard ratios and 95% confidence intervals for prostate cancer-specific deaths. For comparison, survival among alpha-blocker users was also evaluated. During the median follow-up of 7.5 years after diagnosis a total of 2,478 men died; 617 due to prostate cancer and 1,861 due to other causes. The risk of prostate cancer death did not differ between 5-ARI users and nonusers (multivariable adjusted HR 0.94, 95% CI 0.72-1.24 and HR 0.98, 95% CI 0.69-1.41 for usage before and after the diagnosis, respectively). Alpha-blocker usage both before and after diagnosis was associated with increased risk of prostate cancer death (HR 1.29, 95% CI 1.08-1.54 and HR 1.56, 95% CI 1.30-1.86, respectively). The risk increase vanished in long-term alpha-blocker usage. Use of 5-ARIs does not appear to affect prostate cancer mortality when used in management of benign prostatic hyperplasia. Increased risk associated with alpha-blocker usage should prompt further exploration on the prognostic role of lower urinary tract symptoms.

This is the pre-peer reviewed version of the following article: ”Statin Use and Risk of Disease Recurrence and Death After Radical Prostatectomy”, which has been published in final form at The Prostate 76:469–478 (2016), DOI 10.1002/pros.23138. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.

Background: Repurposing statins for the treatment of ovarian cancer isappealing due to promising preclinical and epidemiologic data, broad access,low cost, and modest toxicity. To inform the design of a randomized clinicaltrial, we conducted a large observational study to identify subgroups ofovarian cancer (OC) patients that could benefit from statin treatment. Methods: Data from the Finnish national cancer registry waslinked to prescription claims on 10,062 women diagnosed with OC between 1995and 2015. A series of analyses were then conducted in OC patients to examinethe association between pre- and post-diagnostic statin use and mortality(cause-specific and all cause). Descriptive statistics were used tocharacterize patients at baseline. To address potential confounding due toindication for statin initiation we used time updated marginal structural Coxregression models with inverse probability of treatment weights to calculatehazard ratios (HR) and 95% confidence intervals (95% CIs) between users and neverusers. Analyses were adjusted for age at diagnosis, stage, OC subtype,treatments, year of diagnosis, and chronic disease medications. Results: The median (IQR) age of diagnosis among patients was 63(53-74) years, and median (IQR) follow up time was 4 (1.5-9.3) years. A totalof 2,621 patients were statin users of which 80% took statins classified aslipophilic. Median (IQR) duration of statin use was 7.5 (3.6-11.4) years.Eighty two percent of statin users filled 90% of their prescriptions. In timeupdated models, ever use of statins was associated with a 40% reduction in OCmortality compared to never use (HR Overall = 0.60(0.57-0.63).; HR Lipophilic = 0.78 (0.64-0.83).The benefit from statin use was greater in those being treated with curativeintent (HR=0.19; 0.18-0.20) rather than palliative intent (HR =0.41; 0.39-0.4).Further, reductions in OC mortality were also observed in women who primarilytook one specific lipophilic statin: HR Atorvastatin= 0.35;(0.22-0.50) and HR Simvastatin= 0.25;(0.22-0.34). Among women taking lipophilic statins, agreater reduction in mortality was observed with increasing statin dose (ptrend = 0.06). Lipophilic statin use was also associated with a reduction in OCmortality among most OC subtypes, but the magnitude of reduction varied: HighGrade Serous Carcinoma (HR= 0.43; 0.33-0.76); Endometroid (HR =0.65;0.34-0.78); Clear cell (HR= 1.02; 0.98-1.98); Mucinous (HR=0.60; 0.45-0.95);and Borderline (HR =0.30; 0.25-0.87). A reduction in OC mortality was alsoobserved in analyses limited to women who initiated lipophilic statinspost-diagnosis. Conclusion: Our results provide further evidence in support of theevaluation of lipophilic statins, particularly atorvastatin and/or simvastatin,for the treatment of OC in a randomized clinical trial. Citation Format: Kala Visvanathan, Shari Modur, Miia Artama, Teemu Murtola. Lipophilic Statins show promise for treatment of epithelial ovarian cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5782.

Background: Thymidine kinase 1 (TK1) is an enzyme involved in DNA synthesis. Thymidine kinases phosphorylate thymidine as part of the DNA synthetic pathway. TK1 expression is a marker of active cellular proliferation; intracellular concentrations are low during the G0/G1 phases of the cell cycle, increasing during the S/G2 phases. Previous studies have suggested that serum TK1 levels could be used as marker for presence of prostate cancer (PCa). Here, we evaluated whether serum TK1 levels could predict risk of PCa prognosis. Materials and Methods: The study population included 40 men with clinically defined T1/T2NxM0 PCa and 43 men with de novo metastatic cancer (M1) at diagnosis confirmed by bone scan imaging. All men were diagnosed and treated at the Tampere University Hospital between 2000-2010. All men provided a serum sample at the time of diagnosis. Information on deaths and causes of death were obtained from national causes of death registry. Serum TK1 concentrations were determined using the AroCell TK210 ELISA kit. Cox regression and Kaplan-Meier Curves with adjustment for tumor risk group (Gleason-grade, TNM stage and PSA level) were used to evaluate the risk of PCa death in relation to TK1 levels (median or below vs. above median). ROC analyses were used to evaluate the predictive accuracy of PSA, TK1 and their combination. Results: M1 cases were older than M0 cases; median age 72 vs 62 years, respectively. M1 cases were mainly managed with androgen deprivation therapy, whereas M0 cases were most often managed with radical prostatectomy. Median serum TK1 levels were significantly higher among M1 cases compared to M0 cases (p for difference 0.001). In the combined study population, serum TK1 levels were a significant predictor of PCa-specific (HR 8.33, 95% CI 2.05-33.88) and overall mortality (HR 5.53, 95% CI 1.93-15.85) after adjustment for established prognostic factors including tumor risk group. Kaplan-Meier survival curves defined by TK1 level started to differ within 24 months from PCa diagnosis. In ROC analyses TK1 alone or in combination with PSA was no more accurate than PSA alone in predicting PCa death. Conclusion: The proliferation biomarker TK1 in serum predicted survival after PCa diagnosis, demonstrating independent predictive value over established clinical risk factors. If confirmed in further and larger studies, this biomarker could be incorporated in PCa risk stratification when selecting optimal treatment and surveillance schedule. Citation Format: Teemu J. Murtola, Paavo Raittinen, Teuvo Tammela. Serum thymidine kinase 1 levels predict prostate cancer-specific survival [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-149.

Allopurinol reduces oxidative stress and may thus have an anti-inflammatory effect. Previous studies suggest that allopurinol use might decrease the risk of prostate cancer (PCa) among gout patients. We studied the association between allopurinol use and PCa incidence. The cohort consists of 76,874 men without prevalent PCa, originally identified for the Finnish Randomized Study of Screening for Prostate Cancer (FinRSPC). The follow-up started at entry to the trial. We excluded men using allopurinol in the year before entry (wash-out). PCa cases detected during 1996–2015 were identified from the Finnish Cancer Registry. Information on tumor Gleason score and TNM stage were obtained from medical files. Information on PSA level was obtained from screening samples for men in the FinRSPC screening arm and from laboratory databases for men in the control arm. Information on BMI was based on a questionnaire sent to men in the FinRSPC screening arm in 2004–2008. Drug purchase information were obtained from the national prescription database. We used Cox regression (adjusted for age, FinRSPC trial arm, PCa family history and use of other medication) to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) of PCa risk by allopurinol use. We analyzed medication as a time-dependent variable to minimize immortal time bias. There were 9062 new PCa diagnoses in the cohort. Follow-up time did not differ by allopurinol use (median 17 yr; IQR 11–19 vs median 17 yr; IQR 12.33–19). The risk of PCa did not differ by allopurinol use (multivariable adjusted HR 1.03; 95% CI 0.92–1.16). Allopurinol use did not associate with the risk of high-grade or metastatic cancer. Cumulative duration or average yearly dose of allopurinol use showed no association with PCa risk. No delayed risk associations were observed in the lag-time analyses. We observed no difference in the PCa risk by allopurinol use.

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.

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.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.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.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.

Long-term usage of the antiarrhythmic drug digoxin has been connected to lowered risk of prostate cancer. A recent study has suggested that beta-blockers might also have similar risk-decreasing effects. We evaluated the association between use of digoxin, beta-blocker sotalol, and other antiarrhythmic drugs and prostate cancer risk in a retrospective cohort study. Our study population consisted of men in the Finnish Prostate Cancer Screening Trial during 1996–2012 (n = 78,615). During median follow-up of 12 years, 6,639 prostate cancer cases were diagnosed. The national prescription database was the source of the information of antiarrhythmic drug purchases. Data were analyzed using Cox regression method with medication use as a time-dependent variable. No association was found for overall prostate cancer risk with antiarrhythmic drug use (HR 1.05 95% CI 0.94–1.18). Neither sotalol (HR 0.97 95% CI 0.76–1.24) nor digoxin (HR 1.01 95% CI 0.87–1.16) users had a decreased risk of prostate cancer. Similar results were obtained for high-grade (Gleason 7–10) and metastatic prostate cancer. Nevertheless, the risk estimates for Gleason 7–10 prostate cancer tended to decrease by duration of digoxin use (p for trend = 0.052), suggesting that the drug may reduce the risk in long-term usage (HR 0.71, 95% CI 0.49–1.03). In analysis stratified by screening trial arm, the protective association against Gleason 7–10 disease was observed only in the screening arm (HR 0.31, 95% CI 0.12–0.84 for men who had used digoxin for 5 years or longer). Digoxin or other antiarrhythmic drugs are not associated with any clear decrease in prostate cancer risk. However, digoxin might have a benefit in long-term use by reducing risk of high-grade disease. Further research will be needed to evaluate possible effects on prostate cancer survival.

Background Growing evidence suggests that aspirin is associated with decreased prostate cancer (PCa) mortality. The effect of other NSAID use on risk of PCa death remains controversial. We examined prostate cancer survival among aspirin and other NSAID users in the Finnish Prostate Cancer Screening Trial. Methods A total of 6,537 men were diagnosed with prostate cancer in 1996–2009 among the 80,144 men in the trial and 617 died from prostate cancer during the median follow-up of 7.5 years after the diagnosis. Prescription drug purchases information was obtained from the national reimbursement database. We calculated hazard ratios and 95% confidence intervals for PCa-specific survival using multivariable-adjusted Cox regression analysis separately for NSAID and aspirin usage before and after the diagnosis. Results We observed an increased risk of PCa death associated with both pre- and post-diagnostic NSAID usage (HR 1.30, 95%CI 1.07–1.58 and HR 2.09, 95%CI 1.75–2.50, respectively). An increasing risk trend was observed by cumulative dose and intensity of NSAID use. When the last three years were excluded from the analysis, the death risk diminished to a protective level (HR 0.42, 95%CI 0.34–0.51 and HR 0.30 95%CI 0.24–0.39). Aspirin use was not significantly associated with prostate cancer survival. Conclusions The survival decrease among NSAID users is likely explained by symptomatic treatment of metastatic pain in patients with advanced PCa. However, results of the lag time analysis support previous findings of a possible preventative action of NSAIDs. Prostate 75:1394–1402, 2015. © 2015 Wiley Periodicals, Inc.

Antiarrhythmic drug digoxin has been reported to have apoptosis-inducing and cytotoxic effects on prostate cancer cells. We evaluated the association between antiarrhythmic drug use and prostate cancer risk in a population-based case-control study. The study included all new prostate cancer cases diagnosed in Finland during 1995-2002 and matched controls (24,657 case-control pairs) obtained from the Finnish Cancer Registry and the Population Register Center, respectively. Information on antiarrhythmic drug purchases was obtained from national prescription database. Multivariable-adjusted conditional logistic regression model was used for data analysis. Compared to never-users of antiarrhythmic drugs, we found no significant association between digoxin use and prostate cancer risk overall [odds ratio (OR) 0.95, 95% confidence interval (CI): 0.89-1.01] or for advanced prostate cancer risk (OR: 0.90, 95% CI: 0.77-1.05). The result was similar also for other antiarrhythmic drugs, with the exception of sotalol, users of which had decreased risk of advanced prostate cancer (OR: 0.73, 95% CI: 0.56-0.96). Also the overall prostate cancer risk decreased by duration of sotalol use (p for trend 0.038). We show that digoxin or other common antiarrhythmic drugs generally do not associate with prostate cancer risk at population level during maximum follow-up of eight years. However, we cannot rule out longer term protective effects of digoxin. K(+) -channel blocker sotalol shows some promise as prostate cancer preventing agent. However, findings need to be confirmed in further studies.

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.

Purpose: Prostate cancer screening with prostate specific antigen reduces prostate cancer mortality but leads to over diagnosis of indolent prostate cancer. The use of 5 alpha-reductase inhibitors lowers prostate specific antigen and in theory could affect the performance of prostate specific antigen based screening. We evaluated the outcomes of prostate cancer screening in 5 alpha-reductase inhibitors users. Materials and Methods: The study was performed in FinRSPC (Finnish Randomized Study of Screening for Prostate Cancer). Of 80,454 men 31,866 were randomized to be screened at 4-year intervals during 1996 to 2004. Information on 5 alpha-reductase inhibitors reimbursements before prostate cancer during 1995 to 2009 was collected from the national prescription database for 78,615 men. We evaluated the effect of screening on prostate cancer risk and mortality by 5 alpha-reductase inhibitors using Cox regression. Results: Men receiving 5 alpha-reductase inhibitors had higher median prostate specific antigen and were more often screen positive than nonusers. Despite this, screening did not significantly affect prostate cancer detection (HR 0.89, 95% CI 0.7-1.01) or mortality (HR 0.82, 95% CI 0.51-1.32) compared to findings in the control arm among men on 5 alpha-reductase inhibitors. On ROC analysis prostate specific antigen and age did not predict Gleason 7-10 prostate cancer as accurately in 5 alpha-reductase inhibitors users as it did among nonusers (first screening round AUC 0.79 vs 0.88). Conclusions: Prostate specific antigen based screening among men receiving 5 alpha-reductase inhibitors did not improve the detection of high grade or metastatic prostate cancer, or prevent prostate cancer death.

BACKGROUND Inflammation may play a role in pathogenesis of benign prostatic hyperplasia (BPH). However, the role of non-steroidal anti-inflammatory drugs (NSAIDs) as BPH risk factor is unclear. The objective of this study was to examine risk of BPH by NSAID use in a population-based cohort. METHODS A total of 74 754 Finnish men without previous BPH at baseline in 1996-1999 were linked to national medication reimbursement database for information on physician-prescribed NSAID purchases during 1995-2009. Information on BPH procedures and diagnoses was obtained from national Care Register for Health Care. Cox regression with adjustment for age and use of cholesterol-lowering, antidiabetic and antihypertensive medication, with NSAID use as time-dependent variable was used to analyse the risk of BPH surgery, medication use, and recorded diagnosis. RESULTS Of the subjects 57 707 men (77.2%) used prescription NSAIDs. The risk of BPH was elevated among NSAID users compared to non-users: HR 2.04, 95% CI 1.97-2.10 for BPH medication use, HR 1.59, 95% CI 1.47-1.71 for recorded diagnosis and HR 1.61, 95% CI 1.49-1.74 for surgery. The risk increase correlated with duration of NSAID usage, less with annual dosage. Nevertheless, the risk increase was observed already at short-term and low-dosage use. CONCLUSIONS NSAID use is associated with an increased risk of BPH. The association is affected by systematic differences by NSAID use as the risk increase was observed already at short-term use. Nevertheless, the association correlated with duration of use, suggesting that NSAID usage or the conditions indicating it may increase BPH risk.

Diabetic men have lowered overall prostate cancer (PCa) risk, while their risk of high-grade disease may be elevated. The antidiabetic drug metformin may reduce the risk. This study evaluated PCa incidence among users of metformin and other antidiabetic drugs in the Finnish Randomized Study of Screening for Prostate Cancer (FinRSPC).The study population (78,615 men) was linked to the national prescription database. Hazard ratios (HRs) and 95% confidence intervals (CIs) for PCa were estimated using Cox regression, with medication use as a time-dependent variable. The effect of diabetes was estimated by comparing antidiabetic drug users to non-users, while drug-specific effects were evaluated within antidiabetic drug users. Analyses were performed in both study arms of FinRSPC.Compared to non-users, men using antidiabetic drugs had lowered overall PCa risk (HR 0.85, 95% CI 0.79-0.92), and this association was not affected by PCa screening. However, the risk of metastatic PCa was increased (HR 1.44, 95% CI 1.09-1.91). Among antidiabetic drug users, metformin decreased overall PCa risk (HR 0.81, 95% CI 0.69-0.95) in a dose-dependent manner. When stratified by FinRSPC study arm, the risk reduction was observed only in the screening arm. Sulphonylureas increased the risk of metastatic PCa (HR 2.04, 95% CI 1.11-3.77). Use of thiazoledenediones or insulin was not associated with PCa risk.Among antidiabetic drug users, metformin lowered the overall PCa risk, while the risk of metastatic disease was elevated in sulphonylurea users. As sulphonylureas stimulate insulin secretion, the results suggest that hyperinsulinemia may be a risk factor for PCa.

Prostate cancer patients using cholesterol-lowering statins have 30 % lower risk of prostate cancer death compared to non-users. The effect is attributed to the inhibition of the mevalonate pathway which is active in prostate cancer cells. Statin intervention also causes lipidome level shift in the serum. However, it is unknown whether statin intervention also affects intraprostatic lipidome (IPL) as well. We studied the lipidome level shift among Finnish males diagnosed with prostate cancer and scheduled for radical prostatectomy in a randomized, placebo-controlled double-blind clinical trial. Total number of participants was 86 where 41 were given placebo and 45 were treated daily with 80 mg of atorvastatin (AS) for a median of 27 days preceeding the surgery. The serum lipidome (SL) level was measured before and after the intervention using mass spectrometer, whereas the IPL level was measured after the surgery. SL contains 213 lipid aggregates, while the IPL contains 4,652 single-molecule lipids. Furthermore, we investigated if the baseline lipidome level or the shift during intervention displays relationship with tumor Gleason grade, PSA level, Ki67 proliferation marker level in the tissue, and / or intraprostatic inflammation. The relationship was studied using supervised random forest classification (RFC), and linear regression (LR) adjusted for age and body mass index. RFC robustness with respect to the intrinsic randomization was measured by repeating RFC 100 times. The 4,652 IPL molecules were reduced to 101 after limiting analysis to ones demonstrating statistically significant difference between placebo and AS group. The statistically significant difference was tested with t-test and Mann-Whitney test depending on the sample distribution. The SL difference before-after intervention separates the two groups with extremely low RFC error of 8.1 – 9.3 %. This indicates that the intervention has systematically altered the SL. The RFC error for the IPL was 29 – 37.7 % and does not separate the placebo and AS group as well as in the serum. Thus, the AS effect on IPL is not as strong as in the serum, although a suggestion of differing lipid profiles by treatment arm was observed. One serum lipid, Glycoproteinacetylsmainlya1acidglycoprotein (GP), did show a clear linear relationship with the PSA level change; however, it was independent of the AS intervention. Baseline SL did not predict high-grade prostate cancer, Ki67 level, or inflammation level in general, according to RFC or LR. AS intervention displays a clear effect on SL level, but only a modest effect on the IPL. Our finding suggests the AS affects the lipids in the prostate as well. GP serum lipid aggregate shows linear relationship with the PSA level change but it is independent of AS intervention. IPL does not correlate with the tumor Gleason grade or Ki-67 proliferation activity. Citation Format: Paavo V. Raittinen, Kati Niemistö, Seppo Auriola, Pauliina Ilmonen, Teemu J. Murtola. Serum and intraprostatic lipidome level shift during statin use among prostate cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3293.

BACKGROUND Two clinical trials have shown that users of 5α-reductase inhibitors finasteride and dutasteride (5-ARIs) have reduced overall prostate cancer risk, while the proportion of high-grade tumors is increased. We studied tumor characteristics, risk of biochemical recurrence and mortality after radical prostatectomy in 5-ARI and alpha-blocker users. METHODS The study cohort consisted of 1,315 men who underwent radical prostatectomy at the Tampere University Hospital during 1995–2009. Biochemical relapse was defined as serum PSA ≥ 0.2 ng/ml after the operation. Information on mortality and medication purchases was obtained from national registries. Cox proportional regression was used to analyze hazard ratios (HRs) and 95% confidence intervals (95% CI) of biochemical relapse and death. RESULTS The proportion of high-grade (Gleason 7–10) tumors was significantly elevated among men who had used 5-ARIs for 4 years or longer compared to the non-users (83.3% vs. 53.3%, respectively). Survival curves for biochemical relapse-free survival differed between long-term and short-term 5-ARI users, but the hazard ratio remained statistically non-significant. Risk of biochemical recurrence was elevated among alpha-blocker users (HR 1.68, 95% CI 1.37–2.06), but in sensitivity analyses this was evident only in men using alpha-blockers after prostatectomy. Mortality was not associated with medication usage. CONCLUSIONS Long-term users of finasteride or dutasteride had more often high-grade prostate cancer. Our results suggest also worse progression-free survival. The association between risk of biochemical recurrence and post-operative alpha-blocker usage suggests that voiding or storage symptoms after prostatectomy may predict biochemical relapse. Prostate 73: 923–931, 2013. © 2013 Wiley Periodicals, Inc.

Anticoagulants, especially vitamin K antagonists (VKAs) such as warfarin, have been hypothesized to have antitumor properties, and use of VKAs has been associated with a lower prostate cancer (PCa) risk. This study estimated PCa risk among users of warfarin and other anticoagulants.All anticoagulant use among 78,615 men during 1995-2009 was analyzed. Cox regression, adjusted for age, screening trial arm and use of other medications, with medication use as a time-dependent variable, was used to estimate PCa risk overall, and by tumor grade and stage.In total, 6537 men were diagnosed with PCa during 1995-2009 (1210 among warfarin users). Compared to non-users, warfarin use was associated with an increased risk of PCa [multivariable-adjusted hazard ratio (HR) = 1.11, 95% confidence interval (CI) 1.01-1.22]. This was limited to short-term, low-dose use, and was not observed in long-term use. A similar overall risk increase was observed for Gleason grade 7-10 PCa. Low-dose, short-term use of warfarin was associated with an increased risk of metastatic PCa. However, the increase in risk vanished with continued use. Compared to other anticoagulants, low-dose use of warfarin was associated with a slightly elevated overall PCa risk (HR = 1.19, 95% CI 1.00-1.43). The increase in risk disappeared in long-term, high-dose use.This study, which included a larger number of PCa cases with warfarin exposure than previous studies, does not support previous notions of decreased risk of PCa among warfarin users. A similar risk of PCa was found among warfarin users and the general population, and no difference in risk was found between warfarin and other anticoagulants.

We evaluated the effects of simvastatin and antiandrogen enzalutamide on growth and androgen signaling in androgen-sensitive LNCaP and VCaP prostate cancer cells. Simvastatin alone abolished androgen-induced growth in both cell lines but decreased androgen receptor (AR) and prostate-specific antigen protein expression only in LNCaP, indicating that statin-induced growth inhibition is beyond AR transcriptional activity in VCaP. Combination of simvastatin and enzalutamide exerted additive growth inhibition in both cell lines accompanied with strong induction of autophagy in LNCaP. The data provide new insight into statins' effects on androgen signaling and their proposed role in enhancing androgen deprivation therapy in prostate cancer.

The Finnish Randomized Study of Screening for Prostate Cancer (FinRSPC), the largest component of the European Randomized Study of Screening for Prostate Cancer (ERSPC), showed a smaller, nonsignificant reduction in prostate cancer-specific mortality by systematic prostate-specific antigen (PSA)-based screening compared with the overall ERSPC results. Nonsteroidal anti-inflammatory drugs (NSAIDs) reduce inflammation and also PSA elevations due to intraprostatic inflammation.To explore whether NSAID usage modifies the effects of PSA-based screening on prostate cancer incidence and mortality.A cohort of 78 165 men from the FinRSPC were linked to a comprehensive national prescription database to obtain information on NSAID reimbursements prior to screening.Prostate cancer risk and mortality were compared between the FinRSPC screening arm and the control arm among NSAID users and nonusers using an age-adjusted Cox regression model.Screening increased the detection of Gleason 6 (hazard ratio [HR] 1.59, 95% confidence interval [CI] 1.47-1.72 and HR 1.39, 95% CI 1.26-1.54) and localized prostate tumors (HR 1.25, 95% CI 1.18-1.32 and HR 1.11, 95% CI 1.03-1.20) more among baseline NSAID nonusers than among users, respectively (p for interaction0.04 for both). This difference was observed in all three screening rounds. Detection of metastatic prostate cancer was similar in both NSAID users and nonusers. Screening decreased prostate cancer mortality among men using NSAIDs at FinRSPC randomization (HR 0.66, 95% CI 0.49-0.90) but not among nonusers (HR 0.95, 95% CI 0.81-1.12); p for interaction=0.04.Screening detected fewer well-differentiated localized tumors among NSAID users than among nonusers. This suggests that PSA screening may cause less overdiagnosis within this subgroup, whereas mortality benefit may be greater among NSAID users.Prostate cancer screening causes less overdiagnosis of well-differentiated localized prostate tumors among men who use nonsteroidal anti-inflammatory drugs.

The prognostic role of preoperative serum lipid levels in patients undergoing radical prostatectomy (RP) for clinically localized prostate cancer (PCa) is unclear. The aim of the present study was to investigate preoperative serum lipid levels in patients with clinically localized PCa undergoing RP and their association with clinicopathological features and oncological outcome.Preoperative lipid levels (total cholesterol, LDL cholesterol, HDL cholesterol and triglycerides) and statin use from consecutive patients with clinically localized PCa undergoing RP in a tertiary referral center between 2008 and 2015 were recorded and patients were followed prospectively. Logistic regression analysis was used to test the association between lipid levels and clinicopathological parameters. Lipid values were analyzed both as continuous and dichotomized variables. Univariable and multivariable Cox regression analyses were performed to identify predictors for recurrence-free survival (RFS). Recurrence was defined as rising and verified PSA levels0.1 ng/ml.Our cohort consisted of 371 men with a median age of 63 years (range 41-78 years) and a median preoperative PSA value of 6.79 ng/ml (0.43-81.4 ng/ml). Median follow-up was 28 months (1-64). No association was found between lipid levels and adverse pathological characteristics such as ≥pT3, Gleason score ≥8, positive nodal status and positive surgical margins. Recurrence occurred in 49 patients (15.4%) at a median time of 18 months (2-51 month). Compared to low LDL cholesterol, high LDL cholesterol was associated with longer RFS in univariable analysis (continuous: Hazard Ratio (HR): 0.67, 95%-Confidence Interval (CI): 0.47-0.96, P = 0.03; 3 mM cut-point: HR: 0.44, 95%-CI: 0.24-0.79, P = 0.006). Neither levels of other lipids, nor statin use were associated with RFS. Preoperative LDL cholesterol remained an independent predictor for PCa recurrence in a multivariable model adjusted for age, preoperative PSA, statin use, tumor stage, Gleason score, nodal status and surgical margin status (continuous: HR: 0.66, 95%-CI: 0.44-0.99, P = 0.04; 3 mM cut-point: HR: 0.41, 95%-CI: 0.21-0.78, P = 0.007).This is the first prospective study showing the potential adverse and independent prognostic role of low preoperative LDL cholesterol levels in patients with localized PCa undergoing RP. Prostate 77:549-556, 2017. © 2017 Wiley Periodicals, Inc.

To evaluate the association between use of metformin and other antidiabetic drugs with tumor characteristics and survival in surgically managed prostate cancer (PCa) patients.The study population included 1314 men who underwent radical prostatectomy at the Tampere University Hospital during 1995-2009. Causes of deaths were collected from the Finnish Cancer Registry. Individual-level data on medication use during 1995-2009 was obtained from national prescription database. Fasting blood glucose and hemoglobin A1c values during the study period were gathered from hospital district database. Gleason grade and pathological stage were compared by drug use before surgery and separately by metformin usage. Risk of biochemical recurrence, all-cause death and PCa-specific death were calculated using Cox proportional hazard regression with adjustment for age, tumor characteristics, glycemic control and use of other drug groups.High-grade tumors were more common among antidiabetic drug users (P=0.032), including metformin users (P=0.012). Despite this, no difference in PSA levels was observed. Men who had used antidiabetic drugs before surgery had an increased risk of Gleason 7-10 disease (odds ratio (OR) 1.83, 95% confidence interval (CI) 1.04-3.23). The risk of high-grade PCa was higher among metformin users compared with other antidiabetic drug users (OR 3.11, 95% CI 1.16-8.33). During the median follow-up of 8.6 years after surgery, 551 men had biochemical recurrence and 244 died, 32 owing to PCa. Generally, no association with risk of disease recurrence was observed. Risk of death was increased by preoperative use of antidiabetic drugs (hazard ratio 1.81 95% CI 1.03-3.19), but no survival associations for postoperative use of antidiabetic drugs or metformin were observed.Diabetic men have more high-grade PCa at lower PSA levels, but that does not have a clear impact on disease-specific survival in the short term even when glycemic control is being considered.

Non-steroidal anti-inflammatory drugs (NSAIDs), especially aspirin, have been associated with lowered cancer incidence and mortality. We examined overall cancer mortality and mortality from specific cancer sites among the 80,144 men in the Finnish Prostate Cancer Screening Trial. Information on prescription drug use was acquired from the national drug reimbursement database. Over-the-counter use information was gathered by a questionnaire. Hazard ratios (HR) and 95% confidence intervals (CI) by prescription and over-the-counter NSAID use for overall and specific cancer deaths were calculated using Cox regression. During the median follow-up time of 15 years, 7,008 men died from cancer. Men with prescription NSAID use had elevated cancer mortality (HR 2.02 95% CI 1.91-2.15) compared to non-users. The mortality risk was increased for lung, colorectal and pancreas cancer mortality (HR 2.68, 95%CI 2.40-2.99, HR 1.91, 95% CI 1.57-2.32 and HR 1.93, 95% CI 1.58-2.37, respectively). The increased risk remained in competing risks regression (HR 1.11, 95% CI 1.05-1.18). When the usage during the last three years of follow-up was excluded, the effect was reversed (HR 0.69, 95% CI 0.65-0.73). Cancer mortality was not decreased for prescription or over-the-counter aspirin use. However, in the competing risk regression analysis combined prescription and over-the-counter aspirin use was associated with decreased overall cancer mortality (HR 0.76, 95% CI 0.70-0.82). Cancer mortality was increased for NSAID users. However, the risk disappeared when the last 3 years were excluded Public Library of Science open access

Recent studies have reported an inverse association between statin use and risk of advanced prostate cancer. Thus, it is possible that statin exposure delays progression of prostate tumors to an advanced stage. The study by Gutt and colleagues gives two important contributions to this field of research. With a cohort of 691 men undergoing curative-intent radiation therapy for prostate cancer between 1996 and 2008, and with a median follow-up of 50 months, they demonstrate that statin use is associated with improved relapse-free survival. The result supports the idea that statins could delay prostate cancer progression. In addition, they demonstrate that low low-density lipoprotein levels are associated with improved relapse-free survival, supporting the idea that the prostate cancer progression-preventing effects of statins could be, at least in part, mediated by their systemic low-density lipoprotein-lowering effect. The study adds to the growing body of evidence on statins' benefits against prostate cancer. The results have important implications when designing possible future clinical studies on this topic.

We study the association between non-steroidal anti-inflammatory drugs (NSAIDs), Statins, and Bisphosphonates (BPs), and prostate cancer (PCa) survival during androgen deprivation therapy (ADT). STAMPEDE trial has demonstrated better PCa-specific survival in men using combination of celecoxib (CEL) and zoledronic acid (ZA) during ADT compared to ADT alone. The mechanism is unclear. ZA inhibits mevalonate pathway (MevP) previously linked with cancer growth. We evaluated PCa survival among men on ADT and simultaneously using BPs including ZA or statins, another drug group inhibiting MevP, and NSAIDs including CEL. We hypothesized that combined use of a MevP inhibitor and NSAID would be associated with improved PCa survival. Our study cohort includes 4,428 men from the Finnish Randomized Study of PCa Screening (FinRSPC) initiating ADT in 1995-2015. Cox proportional hazards model with adjustment for age, FinRSPC study arm, tumor clinical characteristics and co-morbidities (obtained from national registries) was used to calculate HRs and 95% CI for PCa death. Medication use was analyzed as time-dependent variable. Compared to non-users, the risk of PCa death was increased in users of NSAIDs or acetaminophen, and lowered in statin users. Use of BPs or coxibs alone were not associated with the risk. Coxibs and statins together were associated with lowered risk to a similar degree as statins alone. No statistically significant risk differences were observed for other combinations. Statin users with high-risk prostate cancer undergoing ADT have lowered risk of PCa death. NSAID users have increased risk of PCa death, which becomes statistically insignificant when used with statins. Statin and BP use together shows no statistically significant evidence of negating the effects of statin. No clear additive benefit was observed for statins and coxibs together over statins alone. Our findings do not support additive benefits of MevP inhibitor and NSAIDs. Statistical significance codes: *** : p = 0.001, ** : p = 0.01, * : p = 0.1DrugHR95 % CISignificanceStatin0.780.680.90***Acetylsalisylic acid0.900.761.07Coxib1.070.941.22NSAID1.171.041.31**Acetaminophen1.661.511.82***Bisphosphonate0.790.381.64Bisphosphonate and NSAID0.890.551.42Statin and NSAID1.070.901.27Statin and Bisphosphonate1.140.861.50Coxib and Bisphosphonate0.850.421.74Coxib and Statin0.800.621.02*EAU tumor Risk Group2.662.353.00*** Citation Format: Paavo V. Raittinen, Kirsi Talala, Kimmo Taari, Teuvo L. Tammela, Pauliina Ilmonen, Anssi Auvinen, Teemu J. Murtola. Association between NSAID, statins, and bisphosphonates and prostate cancer survival during androgen deprivation therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4226.