Daniel M. Moreira

Serum Testosterone and Dihydrotestosterone and Prostate Cancer Risk in the Placebo Arm of the Reduction by Dutasteride of Prostate Cancer Events Trial

BACKGROUND Findings of studies on the association between androgens and prostate cancer (PCa) are mixed. Androgens may affect prostate-specific antigen (PSA) levels, thereby influencing biopsy recommendations. Also, androgens may stimulate prostate growth at very low levels with no additional effects at higher levels (saturation model). OBJECTIVE To test whether androgens were associated with PCa risk in the placebo arm of a prospective study in which biopsies were performed regardless of PSA level. DESIGN, SETTING, AND PARTICIPANTS Of 8122 men in the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial, 4073 men (50.1%) received placebo. Key entry criteria were PSA 2.5-10 ng/ml and one prior negative biopsy. INTERVENTION Per-protocol biopsies at 2 and 4 yr; for-cause biopsies at physician discretion. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Multivariable logistic regression was used to test the association between baseline log-transformed testosterone and dihydrotestosterone (DHT) levels and the risk of detecting either PCa or low-grade PCa (Gleason score <6) compared with high-grade PCa (Gleason score >7). In secondary analysis, we stratified the analysis by low baseline androgen levels (testosterone <10 nmol/l; DHT <0.76 nmol/l) compared with normal baseline androgen levels. RESULTS AND LIMITATIONS Of 4073 men, 3255 (79.9%) had at least one biopsy after randomization and were analyzed. Androgen levels tested continuously or by quintiles were generally unrelated to PCa detection or grade. PCa detection was similar among men with low compared with normal baseline testosterone levels (25.5% and 25.1%; p=0.831). In secondary analysis, higher testosterone levels at baseline were associated with higher PCa detection (odds ratio: 1.23; 95% confidence interval, 1.06-1.43; p=0.006) only if men had low baseline testosterone (<10nmol/l). For men with normal baseline testosterone (≥10 nmol/l), higher testosterone levels at baseline were unrelated to PCa risk (p=0.33). No association was found for DHT and PCa (all p>0.85). CONCLUSIONS Baseline serum testosterone and DHT levels were unrelated to PCa detection or grade. Our findings of the lowest testosterone levels being associated with the lowest PCa risk with no further changes with higher testosterone support a saturation model but must be confirmed in future studies using an a priori defined hypothesis. CLINICALTRIALS.GOV IDENTIFIER: NCT00056407.

A Systematic Review and Meta-analysis of Tobacco Use and Prostate Cancer Mortality and Incidence in Prospective Cohort Studies

CONTEXT An association between tobacco smoking and prostate cancer (PCa) incidence and mortality was suggested in an earlier meta-analysis of 24 prospective studies in which dose-response associations and risks per unit of tobacco use were not examined. OBJECTIVE We investigated the association between several measures of tobacco use and PCa mortality (primary outcome) and incidence (secondary outcome) including dose-response association. EVIDENCE ACQUISITION Relevant articles from prospective studies were identified by searching the PubMed and Web of Science databases (through January 21, 2014) and reference lists of relevant articles. Combined relative risks (RRs) and 95% confidence intervals (CIs) were calculated using random effects methods. We also calculated population attributable risk (PAR) for smoking and PCa mortality. EVIDENCE SYNTHESIS We included 51 articles in this meta-analysis (11823 PCa deaths, 50349 incident cases, and 4,082,606 cohort participants). Current cigarette smoking was associated with an increased risk of PCa death (RR: 1.24; 95% CI, 1.18-1.31), with little evidence for heterogeneity and publication bias. The number of cigarettes smoked per day had a dose-response association with PCa mortality (p=0.02; RR for 20 cigarettes per day: 1.20). The PAR for cigarette smoking and PCa deaths in the United States and Europe were 6.7% and 9.5%, respectively, corresponding to >10000 deaths/year in these two regions. Current cigarette smoking was inversely associated with incident PCa (RR: 0.90; 95% CI, 0.85-0.96), with high heterogeneity in the results. However, in studies completed in 1995 or earlier (considered as completed before the prostate-specific antigen screening era), ever smoking showed a positive association with incident PCa (RR: 1.06; 95% CI, 1.00-1.12) with little heterogeneity. CONCLUSIONS Combined evidence from observational studies shows a modest but statistically significant association between cigarette smoking and fatal PCa. Smoking appears to be a modifiable risk factor for PCa death. PATIENT SUMMARY Smoking increases the chance of prostate cancer death. Not smoking prevents this harm and many other tobacco-related diseases.

The Relationship between Prostate-Specific Antigen and Prostate Cancer Risk: The Prostate Biopsy Collaborative Group

Purpose: The relationship between prostate-specific antigen (PSA) level and prostate cancer risk remains subject to fundamental disagreements. We hypothesized that the risk of prostate cancer on biopsy for a given PSA level is affected by identifiable characteristics of the cohort under study. Experimental Design: We used data from five European and three U.S. cohorts of men undergoing biopsy for prostate cancer; six were population-based studies and two were clinical cohorts. The association between PSA and prostate cancer was calculated separately for each cohort using locally weighted scatterplot smoothing. Results: The final data set included 25,772 biopsies and 8,503 cancers. There were gross disparities between cohorts with respect to both the prostate cancer risk at a given PSA level and the shape of the risk curve. These disparities were associated with identifiable differences between cohorts: for a given PSA level, a greater number of biopsy cores increased the risk of cancer (odds ratio for >6- versus 6-core biopsy, 1.35; 95% confidence interval, 1.18-1.54; P < 0.0005); recent screening led to a smaller increase in risk per unit change in PSA (P = 0.001 for interaction term) and U.S. cohorts had higher risk than the European cohorts (2.14; 95% confidence interval, 1.99-2.30; P < 0.0005). Conclusions: Our results suggest that the relationship between PSA and risk of a positive prostate biopsy varies, both in terms of the probability of prostate cancer at a given PSA value and the shape of the risk curve. This poses challenges to the use of PSA-driven algorithms to determine whether biopsy is indicated. Clin Cancer Res; 16(17); 4374–81. ©2010 AACR.

Cigarette Smoking Is Associated With an Increased Risk of Biochemical Disease Recurrence, Metastasis, Castration-Resistant Prostate Cancer, and Mortality After Radical Prostatectomy: Results From the SEARCH Database

The current study was conducted to analyze the association between cigarette smoking and metastasis (the primary outcome) as well as time to biochemical disease recurrence (BCR), metastasis, castration‐resistant prostate cancer (CRPC), and prostate cancer‐specific and overall mortality (secondary outcomes) after radical prostatectomy among men from the Shared Equal Access Regional Cancer Hospital cohort.

Diabetes and prostate cancer risk in the REDUCE trial

Men with diabetes mellitus are less likely to be diagnosed with prostate cancer (PCa). As diabetic men have lower serum PSA, it is unclear if this is due to lower PCa incidence or reflects detection bias from fewer PSA-triggered biopsies. To account for differential biopsy rates, we used multivariate regression to examine the link between diabetes and PCa risk in the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial, which required all subjects to undergo biopsy regardless of PSA. We further tested for interaction between diabetes and obesity. Diabetes status and body mass index (BMI) measurements were obtained at baseline. On multivariate analysis, diabetes was not associated with PCa risk (odds ratio (OR) 1.01, 95% confidence interval 0.79–1.30, P=0.92) or risk of low- or high-grade disease (all P⩾0.65). When stratified by obesity, diabetes was also not associated with PCa risk in any BMI category (all P⩾0.15). However, there was suggestion of effect modification by obesity for high-grade disease (P-interaction=0.053). Specifically, diabetes was associated with decreased risk of high-grade PCa in normal-weight men but increased risk in obese men (OR 0.35 vs 1.38). In the REDUCE trial, when all men underwent biopsy, diabetes was not associated with lower PCa risk, but rather equal risk of PCa, low-grade PCa and high-grade PCa.

Evaluation and Comparison of Urolithiasis Scoring Systems Used in Percutaneous Kidney Stone Surgery

PURPOSE Contemporary predictive tools for percutaneous nephrolithotomy outcomes include the Guy stone score, S.T.O.N.E. nephrolithometry and the CROES nephrolithometric nomogram. We compared each scoring system in the same cohort to determine which was most predictive of surgical outcomes. METHODS We retrospectively reviewed the records of patients who underwent percutaneous nephrolithotomy between 2009 and 2012 at a total of 3 academic institutions. We calculated the Guy stone score, the S.T.O.N.E. nephrolithometry score and the CROES nephrolithometric nomogram score based on preoperative computerized tomography images. A single observer at each institution reviewed all images and assigned scores. Univariate and multivariate analysis was done to determine the most predictive scoring system. RESULTS We enrolled 246 patients in study. In stone-free patients vs those with residual stones the mean Guy score was 2.2 vs 2.7, the mean S.T.O.N.E. score was 8.3 vs 9.5 and the mean CROES nomogram score was 222 vs 187 (each p <0.001). Logistic regression revealed that the Guy, S.T.O.N.E. nephrolithometry and CROES nomogram scores were significantly associated with stone-free status (p = 0.02, 0.004 and <0.001, respectively). The Guy and S.T.O.N.E. nephrolithometry scores were associated with estimated blood loss (p <0.0001 and 0.03) and length of stay (p = 0.03 and 0.009, respectively). The CROES nomogram did not predict estimated blood loss or length of stay. CONCLUSIONS All scoring systems and the stone burden equally predicted stone-free status. The Guy and S.T.O.N.E. nephrolithometry scores were associated with estimated blood loss and length of stay. A single scoring system should be adopted to unify reporting.

Evaluating the PCPT risk calculator in ten international biopsy cohorts: Results from the Prostate Biopsy Collaborative Group

ObjectivesTo evaluate the discrimination, calibration, and net benefit performance of the Prostate Cancer Prevention Trial Risk Calculator (PCPTRC) across five European randomized study of screening for prostate cancer (ERSPC), 1 United Kingdom, 1 Austrian, and 3 US biopsy cohorts.MethodsPCPTRC risks were calculated for 25,733 biopsies using prostate-specific antigen (PSA), digital rectal examination, family history, history of prior biopsy, and imputation for missing covariates. Predictions were evaluated using the areas underneath the receiver operating characteristic curves (AUC), discrimination slopes, chi-square tests of goodness of fit, and net benefit decision curves.ResultsAUCs of the PCPTRC ranged from a low of 56% in the ERSPC Goeteborg Rounds 2–6 cohort to a high of 72% in the ERSPC Goeteborg Round 1 cohort and were statistically significantly higher than that of PSA in 6 out of the 10 cohorts. The PCPTRC was well calibrated in the SABOR, Tyrol, and Durham cohorts. There was limited to no net benefit to using the PCPTRC for biopsy referral compared to biopsying all or no men in all five ERSPC cohorts and benefit within a limited range of risk thresholds in all other cohorts.ConclusionsExternal validation of the PCPTRC across ten cohorts revealed varying degree of success highly dependent on the cohort, most likely due to different criteria for and work-up before biopsy. Future validation studies of new calculators for prostate cancer should acknowledge the potential impact of the specific cohort studied when reporting successful versus failed validation.

Aspirin, NSAIDs, and Risk of Prostate Cancer: Results from the REDUCE Study

Purpose: A recent meta-analysis showed that aspirin was associated with reduced prostate cancer risk. As anti-inflammatory medications lower PSA levels, whether these findings reflect reduced prostate cancer detection or lower prostate cancer risk is unknown. We tested the association between aspirin and nonaspirin NSAID use on prostate cancer diagnosis in REDUCE, where all men received biopsies at 2 and 4 years largely independent of PSA. REDUCE tested dutasteride for prostate cancer risk reduction in men with a PSA of 2.5 to 10.0 ng/mL and a negative prestudy biopsy. Experimental Design: We examined the association between aspirin, NSAIDs, or both and total, low-grade (Gleason < 7), or high-grade (Gleason ≥ 7) prostate cancer versus no prostate cancer using multinomial logistic regression among 6,390 men who underwent ≥1 on-study biopsy. Multivariable analyses were adjusted for age, race, geographic region, PSA, prostate volume, digital rectal examination, body mass index, treatment arm, smoking, alcohol, statins, hypertension, diabetes, and cardiovascular disease. Results: Overall, 3,169 men (50%) were nonusers, 1,368 (21%) used aspirin, 1,176 (18%) used NSAIDs, and 677 (11%) used both. In unadjusted models, aspirin was associated with reduced prostate cancer risk (OR = 0.85, P = 0.036). In multivariable analyses, aspirin was associated with reduced total prostate cancer risk (OR = 0.81, P = 0.015). Use of NSAIDs or NSAIDs and aspirin was not associated with total, low-grade, or high-grade prostate cancer, though all ORs were <1 (all P ≥ 0.08). Therefore, we created a dichotomous variable of aspirin and/or NSAID users versus nonusers. On multivariable analysis, the use of aspirin and/or NSAIDs was significantly associated with decreased total (OR = 0.87, P = 0.030) and high-grade (OR = 0.80, P = 0.040), but not with low-grade, prostate cancer risk (OR = 0.90, P = 0.15). Results were similar in placebo and dutasteride arms. Conclusions: Among men with a negative biopsy, aspirin and/or NSAID use was associated with decreased prostate cancer risk. Additional studies are warranted. Clin Cancer Res; 21(4); 756–62. ©2014 AACR.

Baseline prostate inflammation is associated with a reduced risk of prostate cancer in men undergoing repeat prostate biopsy: Results from the REDUCE study

The current study was performed to evaluate whether baseline acute and chronic prostate inflammation among men with an initial negative biopsy for prostate cancer (PCa) increased the risk of subsequent PCa detection in a clinical trial with systematic biopsies.

Image-guided percutaneous renal cryoablation: Preoperative risk factors for recurrence and complications

Whats known on the subject? and What does the study add?