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Statins are associated with lower PSA levels. As PSA is the primary method for prostate cancer (PC) screening, this confounds any associations between statins and risk of being diagnosed with PC. Thus, we examined the association between statins and cancer and high-grade cancer in REDUCE, where biopsies were largely PSA-independent.Post-hoc secondary analysis of REDUCE, which was a prospective multinational randomized controlled trial of dutasteride vs placebo for 4 years among men aged 50-75 years with PSA of 2.5-10.0 ng ml(-1) and a negative biopsy at baseline, and included PSA-independent biopsies mandated at 2- and 4-years. Analyses were limited to men who underwent at least one biopsy while under study (n=6729). The association between baseline statin use and risk of overall, high-grade (Gleason ≥ 7) or low-grade (Gleason ≤ 6) PC vs no cancer was examined using multinomial logistic regression adjusting for age, race, baseline PSA, prostate volume, rectal examination findings, body mass index (BMI), comorbidities, smoking, alcohol intake and treatment arm.Of 6729 men who had at least one biopsy while on study, 1174 (17.5%) were taking a statin at baseline. Men taking statins were older, had lower PSA levels, higher BMI values and lower serum testosterone and dihydrotestosterone levels, though differences, were slight. Statin use was not associated with overall PC diagnosis (multivariable OR 1.05, 95% CI 0.89-1.24, P=0.54). When stratified by grade, statin use was not associated with low-grade (multivariable OR 1.03, 95% CI 0.85-1.25, P=0.75) or high-grade cancer (multivariable OR 1.11, 95% CI 0.85-1.45, P=0.46). The major limitation is the inclusion of only men with a negative baseline biopsy.Among men with a negative baseline biopsy and follow-up biopsies largely independent of PSA, statins were not associated with cancer or high-grade cancer.

Inflammation may play a role in the development and progression of many cancers, including prostate cancer. We sought to test whether histological inflammation within prostate cancer was associated with more aggressive disease.The slides of prostatectomy specimens were reviewed by a board-certified pathologist on 287 men from a Veterans Affairs Medical Center treated with radical prostatectomy from 1992 to 2004. The area with the greatest tumor burden was scored in a blinded manner for the degree of inflammation: absent, mild, or marked. We used logistic and Cox proportional hazards regression analysis to examine whether categorically coded inflammation score was associated with adverse pathology and biochemical progression, respectively.No inflammation was found in 49 men (17%), while 153 (53%) and 85 (30%) had mild and marked inflammation. During a median follow-up of 77 months, biochemical recurrence occurred among 126 (44%) men. On multivariate analysis, more inflammation was associated with greater risk of positive margins, capsular penetration, and seminal vesicle invasion (all p0.05). Marked inflammation was associated with increased PSA recurrence risk when adjusting for preoperative features only (HR 2.08, 95% CI 1.02-4.24), but not after adjusting for pathologic features.Inflammation within prostate cancer was associated with more advanced disease, although it is unclear whether aggressive disease caused increased inflammation or inflammation caused aggressive disease.

Prostate cancer is the most common cancer among men. The prospective discrimination of aggressive and clinically insignificant tumors still poses a significant and, as yet, unsolved problem. PITX2 DNA methylation is a strong prognostic biomarker in prostate cancer. Recently, a diagnostic microarray for prostate cancer prognosis based on PITX2 methylation has been developed and validated. Because this microarray requires nonstandard laboratory equipment, its use in a diagnostic setting is limited. This study aimed to develop and validate an alternative quantitative real-time PCR assay for measuring PITX2 methylation that can easily be established in clinical laboratories, thereby facilitating the implementation of this biomarker in clinical practice. A methylation cut-off for patient stratification was established in a training cohort (n = 157) and validated in an independent test set (n = 523) of men treated with radical prostatectomy. In univariate Cox proportional hazards analysis, PITX2 hypermethylation was a significant predictor for biochemical recurrence (P < 0.001, hazard ratio = 2.614). Moreover, PITX2 hypermethylation added significant prognostic information (P = 0.003, hazard ratio = 1.814) to the Gleason score, pathological T stage, prostate-specific antigen, and surgical margins in a multivariate analysis. The clinical performance was particularly high in patients at intermediate risk (Gleason score of 7) and in samples containing high tumor cell content. This assay might aid in risk stratification and support the decision-making process when determining whether a patient might benefit from adjuvant treatment after radical prostatectomy.

Active surveillance (AS) is increasingly utilized in low-risk prostate cancer (PC) patients. Although black race has traditionally been associated with adverse PC characteristics, its prognostic value for patients managed with AS is unclear.A retrospective review identified 145 patients managed with AS at the Duke Prostate Center from January 2005 to September 2011. Race was patient-reported and categorized as black, white or other. Inclusion criteria included PSA10 ng ml(-1), Gleason sum ≤ 6, and ≤ 33% of cores with cancer on diagnostic biopsy. The primary outcome was discontinuation of AS for treatment due to PC progression. In men who proceeded to treatment after AS, the trigger for treatment, follow-up PSA and biopsy characteristics were analyzed. Time to treatment was analyzed with univariable and multivariable Cox proportional hazards models and also stratified by race.In our AS cohort, 105 (72%) were white, 32 (22%) black and 8 (6%) another race. Median follow-up was 23.0 months, during which 23% percent of men proceeded to treatment. The demographic, clinical and follow-up characteristics did not differ by race. There was a trend toward more uninsured black men (15.6% black, 3.8% white, 0% other, P = 0.06). Black race was associated with treatment (hazard ratio (HR) 2.93, P = 0.01) as compared with white. When the analysis was adjusted for socioeconomic and clinical parameters at the time of PC diagnosis, black race remained the sole predictor of treatment (HR 3.08, P = 0.01). Among men undergoing treatment, the trigger was less often patient driven in black men (8 black, 33 white, 67% other, P = 0.05).Black race was associated with discontinuation of AS for treatment. This relationship persisted when adjusted for socioeconomic and clinical parameters.

Background: Coronary artery disease (CAD) and prostate cancer (PCa) are not only common diseases, but share many risk factors. To date, only a few studies have explored the relationship between CAD and PCa risk, with conflicting results. Methods: The four-year REDUCE study tested dutasteride 0.5 mg daily for PCa risk reduction in men with prostate specific antigen (PSA) of 2.5 to 10.0 ng/mL and a negative biopsy. Among men who underwent at least one on-study biopsy (n = 6,729; 82.8%), the association between CAD and overall PCa risk and disease grade was examined with logistic and multinomial logistic regression adjusting for clinicopathologic features, respectively. Results: Overall, 547 men (8.6%) had a history of CAD. Men with CAD were significantly older and had higher body mass index, PSA, and larger prostate volumes and were more likely to have diabetes, hypertension, and hypercholesterolemia and take aspirin and statins. On multivariate analysis, CAD was associated with a 35% increased risk of PCa diagnosis (OR = 1.35, 95% CI: 1.08–1.67, P = 0.007), while elevating risk of both low- (OR = 1.34, 95% CI: 1.05–1.73, P = 0.02) and high-grade disease (OR = 1.34, 95% CI: 0.95–1.88, P = 0.09). Conclusions: In a post hoc hypothesis developing secondary analysis of the REDUCE study, CAD was significantly associated with increased PCa diagnosis. Impact: If confirmed in other studies, this suggests CAD may be a novel PCa risk factor and suggests common shared etiologies. Whether lifestyle changes shown to reduce CAD risk (i.e., weight loss, exercise, cholesterol reduction, etc.) can reduce PCa risk, warrants further study. Cancer Epidemiol Biomarkers Prev; 21(4); 576–81. ©2012 AACR.

To analyze the association of diabetes mellitus (DM) with risk of prostate cancer and cancer grade among men undergoing prostate biopsy and to analyze how obesity and race modify these associations. Retrospective analysis of 998 men from the Durham VA undergoing first prostate biopsy between 2001 and 2009 with complete data available. History of DM was determined by chart review. Patients’ characteristics at biopsy were analyzed with chi-square and ranksum. Multivariable analyses of DM and risk of cancer and cancer grade were done using logistic regression adjusting for PSA, body mass index, race, age, year, and digital rectal exam. At biopsy, 284 (28%) men had DM. DM was associated with African American (AAM; p = 0.010) and higher BMI (p

A wide array of biomarkers is being investigated as predictors of prostate cancer (PCa) diagnosis and recurrence. We compared the expression of a small panel of these biomarkers as a function of race among men undergoing radical prostatectomy (RP). Prostate needle biopsy specimens from 131 patients treated with RP at the Durham Veterans Affairs Medical Center were hematoxylin and eosin stained and immunofluorescent assayed for α-methylacyl CoA racemase (AMACR), androgen receptor (AR) and Ki67. Proprietary image analysis was used to identify six biometric feature combinations that were significantly associated with progression in a previous study. Analysis of population characteristics, stratified by race, was performed using rank-sum and χ(2)-test. The effect of race on expression of these biomarker profiles was analyzed using multivariate linear regression. All six biomarker features were expressed at higher levels in black men than white men, with Norm AR (P=0.006) and Ki67 (P=0.02) attaining statistical significance. On multivariate analysis, all markers were expressed at higher levels in black men, with Norm AR (P=0.001), Ki67 (P=0.007) and Ki67/lum (P=0.022) reaching significance. These data support the hypothesis that PCa may be biologically more aggressive among black men.

Prostate growth is dependent on circulating androgens which can be influenced by hepatic function. Liver disease has been suggested to influence prostate cancer (CaP) incidence. However, the effect of hepatic function on CaP outcomes has not been investigated. A total of 1,181 patients who underwent radical prostatectomy (RP) between 1988 and 2008 at four Veterans Affairs hospitals that comprise the Shared Equal Access Regional Cancer Hospital (SEARCH) database and had available liver function test (LFT) data were included in the study. Independent associations of LFTs with unfavorable pathological features and biochemical recurrence were determined using logistic and Cox regression analyses. Serum glutamic oxaloacetic transaminase (SGOT) and serum glutamic pyruvic transaminase (SGPT) levels were elevated in 8.2% and 4.4% of patients, respectively. After controlling for CaP features, logistic regression revealed a significant association between SGOT levels and pathological Gleason sum ≥7(4+3) cancer (odds ratio=2.12; 95% confidence interval=1.11-4.05; p=0.02). Mild hepatic dysfunction was significantly associated with adverse CaP grade but was not significantly associated with other adverse pathological features or biochemical recurrence in a cohort of men undergoing R. The effect of moderate to severe liver disease on disease outcomes in CaP patients managed non-surgically remains to be investigated.

Obesity is associated with increased risk of positive surgical margins and prostate specific antigen (PSA) recurrence among men undergoing radical prostatectomy. To what degree positive margins contribute to poorer outcome is unclear. Thus, we sought to examine the association between body mass index (BMI) and more objective measures of tumor aggressiveness, tumor grade and size. We carried out a retrospective analysis of 2302 patients treated with radical prostatectomy at the Duke Prostate Center from 1988-2007. Tumor volume was calculated by multiplying prostate weight by percent of specimen involved with cancer. Associations between BMI and tumor volume and high-grade disease (Gleasonor=4+3) independent of pre-operative clinical characteristics of age, race, PSA, clinical stage, biopsy Gleason sum, and year of surgery were assessed using linear and logistic regression, respectively. Mean and median BMI among all subjects was 28.1 and 27.6 kg m(-2), respectively. Increased BMI was significantly associated with younger age (P0.001), black race (P0.001), more recent year of surgery (P0.001), and positive surgical margins (P0.001). After adjusting for multiple clinical pre-operative characteristics, higher BMI was associated with a greater percent of the prostate involved with cancer (P=0.003), increased tumor volume (P0.001), and high-grade disease (P=0.007). Men with a BMIor=35 kg m(2) had nearly 40% larger mean tumor volumes than normal weight men (5.1 versus 3.7 cc), after adjustment for multiple clinical characteristics. In this study, obese men undergoing radical prostatectomy had higher-grade and larger tumors, providing further evidence that obese men undergoing radical prostatectomy have more aggressive prostate cancers.

The literature contains conflicting data on preoperative predictors of estimated blood loss (EBL) at radical retropubic prostatectomy (RRP). We sought to examine preoperative predictors of EBL at the time of RRP among patients from the SEARCH database to lend clarity to this issue. A total of 1154 patients were identified in the SEARCH database who underwent RRP between 1988 and 2008 and had EBL data available. We examined multiple preoperative factors for their ability to predict EBL using multivariate linear regression analysis. Median EBL was 900 ml (s.d. 1032). The 25th and 75th percentile for EBL were 600 and 1500 ml, respectively. EBL increased significantly with increasing body mass index (BMI) and increasing prostate size and decreased with more recent year of RRP (all P0.001). The mean-adjusted EBL in normal-weight men (BMI25 kg/m(2)) was 807 ml compared to 1067 ml among severely obese men (BM Ior=35 kg/m(2)). Predicted EBL for men with the smallest prostates (20 g) was 721 ml, compared to 1326 ml for men with prostatesor=100 g. Finally, statistically significant differences between centers were observed, with mean-adjusted EBL ranging from 844 to 1094 ml. Both BMI and prostate size are predictors of increased EBL. Prostate size is of particular note, as a nearly twofold increased EBL was seen from the smallest (20 g) to the largest prostates (or=100 g). Over time, average EBL significantly decreased. Finally, significant differences in EBL were observed between centers. Patients with multiple risk factors should be forewarned they are at increased risk for higher EBL, which may translate into a greater need for blood transfusion.

Obese men have been reported to have lower serum PSA values relative to normal-weight men in population-based studies, screening cohorts, and in men with prostate cancer (CaP) treated with surgery. There are concerns that PSA may be less accurate in detecting prostate cancer in men with increased body mass index (BMI). We determine whether the diagnostic potential of PSA is negatively influenced by obesity by comparing its operating characteristics across BMI categories among men undergoing prostate biopsy.Demographic, clinical, and histopathological data on 917 men who underwent trans-rectal ultrasound-guided prostate needle biopsy from 2002 to 2010 at a University hospital in Italy were used in the study. Men were categorized for BMI as follows:25 kg/m(2) (normal weight), 25-29.9 kg/m(2) (overweight), and ≥ 30 kg/m(2) (obese). Receiver operator characteristics (ROC) curves were used to assess PSA accuracy for predicting prostate cancer overall and then stratified according to digital rectal examination (DRE) findings using the area under the ROC curve (AUC).The obesity rate of the study cohort was 21 %. There was no statistically significant difference in the overall AUCs of PSA for predicting CaP among normal-weight (AUC = 0.56), overweight (AUC = 0.60), and obese men (AUC = 0.60; p = 0.68) in either DRE-positive or negative men.In a cohort of Italian men undergoing prostate biopsy, the performance accuracy of PSA as a predictor of CaP is not significantly altered by BMI. Obesity does not negatively impact the overall ability of PSA to discriminate between CaP and benign conditions.

To investigate racial differences in tumor burden (cancer volume, cancer percentage and cancer to PSA ratios) in a large cohort of men undergoing radical prostatectomy (RP).Demographic, clinical and pathological data of patients undergoing RP between 1993-2010 were reviewed and compared between African-American (AA) and non African-American (nAA) men. Further assessments of pathological tumor burden (estimated tumor volume, percent of cancer involvement, and estimated tumor volume/PSA ratios) were performed across Gleason score categories.Of 4157 patients in the analysis, 604 (14.5%) were AA. Overall, AA patients were younger, had higher Gleason scores, PSA levels and incidence of palpable disease (all P0.001). Despite comparable prostate weights (39.4 vs. 39.6 g), AA men had higher percent cancer involvement and estimated tumor volume (all P0.001) but similar estimated tumor volume/PSA ratios ( P0.05). When stratified by Gleason scores, prostate weights were comparable; however, estimated tumor volume, percent cancer involvement and estimated tumor volume/PSA ratios were higher in AA men with low grade (≤ 6) prostate cancer (PCa), similar in intermediate grade (7-8) and lower in high grade (9-10) PCa compared to nAA men.In this large series, AA patients had higher disease burden (estimated tumor volume, percent cancer involvement, estimated tumor volume/PSA ratios) compared to nAA but this association was especially pronounced in low grade (Gleason ≤ 6) cancers. These data depict a complex picture of relations between race and tumor burden across the spectrum of PCa aggressiveness. Further investigation is warranted to understand the mechanisms of racial disparities in PCa.

To assess preoperative parameters that may be predictive of pathologic stage T2a (pT2a) and pathologic Gleason score (pGS) ≤ 6 disease in low-risk prostate cancer patients considering active surveillance. A cohort of 1,495 men with low-risk prostate cancer between 1993 and 2009 was utilized. Preoperative assessment focused on patient age, race, diagnostic PSA level, clinical stage, diagnostic biopsy Gleason score, and prostate cancer laterality. Kaplan–Meier curves and a Cox regression model were used for analysis of PSA recurrence. Preoperative parameters were analyzed by univariate and multivariate logistic regression methods. Of 1,495 patients, 187 (12.5 %) were identified with pT2a and pGS ≤ 6 disease. Of the 187 men with pT2a and pGS ≤ 6 disease, only 6 (3.2 %) cases had PSA recurrence. Kaplan–Meier PSA recurrence-free survival curves identified a difference between prostate cancers with pT2a and pGS ≤ 6 and prostate cancers with >pT2a or pGS ≥ 7 disease (p = 0.002). Only biopsy tumor unilaterality (OR, 10.452; p ≤ 0.001) and low diagnostic PSA levels (OR, 0.887; p = 0.003) were independent predictors of prostate cancers with pT2a and pGS ≤ 6 disease on univariate and multivariate logistic regression. Biopsy tumor unilaterality and low diagnostic PSA levels are the independent predictors of pT2a and pGS ≤ 6 disease in low-risk prostate cancer patients. Unilateral cancer by prostate biopsy and low diagnostic PSA level may be the reference to improving the selection of appropriate candidates for active surveillance within a low-risk prostate cancer cohort.

To find the predictors of Gleason score upgrading in a cohort of low-risk prostate cancer patients, data were analyzed comprising 1,632 consecutive men with low-risk prostate cancer who underwent radical prostatectomy between 1993 and 2009. Assessment focused on preoperative parameters including patient age, race, diagnostic prostate-specific antigen (PSA) levels, clinical stage and biopsy Gleason score, along with pathological parameters including percentage of tumor involvement (PTI), tumor laterality, pathological stage, extra-capsular extension, seminal vesicle invasion, and surgical margins. These parameters were analyzed using univariate and multivariate methods. Kaplan–Meier curves compared differences in biochemical disease-free survival in men having cancers with and without Gleason score upgrading. Cases involving pathological Gleason score upgrading were identified in 723 (44.3 %) of 1,632 patients. Kaplan–Meier PSA recurrence-free survival curves showed a difference in outcome between men with and without Gleason score upgrading (p

BACKGROUND: Exercise is a modifiable lifestyle risk factor associated with prostate cancer risk reduction. However, whether this association is different as a function of race is unclear. In the current study, the authors attempted to characterize the link between exercise and prostate cancer (CaP) in white and black American men. METHODS: Using a prospective design, 307 men (164 of whom were white and 143 of whom were black) who were undergoing prostate biopsy completed a self-reported survey that assessed exercise behavior (metabolic equivalent [MET] hours per week). Crude and adjusted logistic regression analyses were used to estimate the risk of prostate cancer controlling for age, body mass index, digital rectal examination findings, previous biopsy, Charlson comorbidity score, and family history of CaP stratified by self-reported race. RESULTS: There was no significant difference noted with regard to the amount of exercise between racial groups (P = .12). Higher amounts of MET hours per week were associated with a decreased risk of CaP for white men in both crude (P = .02) and adjusted (P = .04) regression models. Among whites, men who exercised ≥ 9 MET hours per week were less likely to have a positive biopsy result compared with men exercising < 9 MET hours per week (odds ratio, 0.47; 95% confidence interval, 0.22-0.99 [P = .047]). There was no association noted between MET hours per week and risk of CaP among black men in both crude (P = .79) and adjusted (P = .76) regression models. CONCLUSIONS: In a prospective cohort of men undergoing biopsy, increased exercise, measured as MET hours per week, was found to be associated with CaP risk reduction among white but not black men. Investigating race-specific mechanisms by which exercise modifies CaP risk and why these mechanisms disfavor black men in particular are warranted. Cancer 2013. © 2013 American Cancer Society.

Prostate-specific antigen (PSA) screening has increased the detection of small, organ-confined tumors, and studies suggest that these patients may have favorable outcomes following radical prostatectomy (RP). To date, there are limited data available on the outcomes of patients diagnosed with low PSA (≤ 4 ng/ml) who underwent RP. This study aimed to evaluate long-term oncological outcomes of patients undergoing RP with preoperative PSA2.5 and 2.5-4 ng/ml compared with PSA 4.1-10 ng/ml.Data were analyzed from 3,621 men who underwent RP between 1988 and 2010 at our institution. Patients were stratified into 3 PSA groups:2.5 ng/ml (n = 280), 2.5-4 ng/ml (n = 563), and 4.1-10 ng/ml (n = 2,778). Patient and disease characteristics were compared. Overall, biochemical disease-free (bDFS), and PCa-specific survivals were analyzed and compared between the groups. Multivariable analyses were conducted using proportional hazards model.Compared with the 4.1-10 ng/ml PSA group, Gleason score7, extracapsular extension, and non-organ-confined disease were less common in patients with PSA ≤ 4 ng/ml (all P0.001). The incidence of organ-confined disease was similar between the PSA2.5 and 2.5-4 ng/ml groups while perineural invasion (P = 0.050) and Gleason score ≥ 7 (P = 0.026) were more common in the 2.5-4 ng/ml PSA group. Estimated 10-year overall and PCa-specific survivals were comparable across all PSA groups, whereas bDFS was significantly lower in PSA 4.1-10 group (P0.001). bDFS was not statistically different between PSA2.5 and 2.5-4 groups (P = 0.300). 10-year bDFS were 59.0%, 70.1%, and 76.4% in PSA 4.1-10, 2.5-4, and2.5, respectively. For the PSA ≤ 4 ng/ml groups, age, race, margin status, pathologic stage, but not PSA were independent predictors of bDFS, whereas age, pathologic Gleason, and biochemical recurrence were associated with overall survival.Long-term oncological outcomes (overall, bDFS, PCa-specific survivals) of patients presenting with low PSA (≤ 4 ng/ml) were excellent in this study. Compared with PSA 4.1-10 ng/ml, patients presenting with PSA ≤ 4 ng/ml had better bDFS outcomes. However, there was no difference in long-term outcomes between PSA2.5 and 2.5-4 ng/ml.

Purpose Epidemiological data are conflicting regarding the association between androgenetic alopecia (AA) and prostate cancer (CaP). We examined the relationship between these two conditions.

Background The study aims to investigate the relationship between obesity and prostate cancer diagnosis at biopsy. Methods From 2005 onwards, a consecutive series of patients undergoing 12-core prostate biopsy for PSA value ≥ 4 ng/ml and/or positive digital rectal examination (DRE) were enrolled. Before the biopsy, patients underwent a physical examination, including height and weight measurement. Obesity was defined as body mass index (BMI) ≥30 kg/m 2 . Blood samples were drawn from all patients and analyzed for total PSA and testosterone. Results 885 patients were enrolled with a median age and PSA of 67 years (range 37–95) and 6.4 ng/ml (range 1–30) respectively. Median BMI was 27.1 kg/m 2 (range 18–46.6) with 185 patients classified as obese. 363 patients had cancer at biopsy; 76 were obese. PSA was independently associated with a higher risk of cancer (OR 1.09 per 1 unit PSA, p = 0.01). On multivariate analysis, the BMI was not significantly associated with an increased prostate cancer risk ( p = 0.19). Out of 363 patients with prostate cancer, 154 had a Gleason score 6 (23 were obese) and 209 a Gleason score ≥7 (53 were obese). Among men with cancer, a higher BMI on univariate ( p = 0.001) and multivariate analysis ( p = 0.005) was associated with high-grade disease (Gleason ≥ 7). Conclusions In our single center study and less aggressively screened cohort, obesity is associated with an increased risk of a high-grade Gleason score when prostate cancer is diagnosed at biopsy.

INTRODUCTION AND OBJECTIVES: Prior studies suggest statins are associated with lower PSA levels. As PSA is the primary method for prostate cancer screening, this may confound any associations between statins and prostate cancer risk. We examined the association between statins and cancer and high-grade cancer risk in the REDUCE study, where biopsies were largely independent of PSA. METHODS: The 4-year REDUCE study tested dutasteride 0.5 mg daily for prostate cancer risk reduction in men with PSA of 2.5–10.0 ng/mL and a negative biopsy. Among men who underwent at least one on-study biopsy (n 6,729; 82.8%), the association between baseline statin use and risk of high-grade (Gleason 7) or low-grade prostate cancer (Gleason 7) vs. no cancer was examined using multinomial logistic regression adjusting for age, race, baseline PSA, prostate volume, rectal examination findings and body mass index. RESULTS: Overall, 1,174 men (17.5%) were on a statin at baseline. Men taking statins were older, had lower PSA levels, higher BMI values, and lower serum testosterone and dihydrotestosterone levels. Statin use was not associated with lowor high-grade cancer risk on crude analysis. On multivariate analyses, statin use remained not significantly related to low-grade (RRR 1.05, 95%CI 0.87–1.27, p 0.62) or high-grade cancer (RRR 1.14, 95%CI 0.87–1.49, p 0.34). CONCLUSIONS: Among men with a negative baseline biopsy and follow-up biopsies that were independent of PSA, statins were not related to cancer or high-grade cancer. These findings do not support a role for statins in primary prostate cancer prevention.

The American Cancer Society's updated screening guidelines for prostate cancer (CaP) render digital rectal examination (DRE) optional. We investigated the impact of DRE on CaP detection among obese men. Data from 2794 men undergoing initial prostate biopsy at three centers were analyzed to assess CaP risk attributed to abnormal DRE across body mass index (BMI) categories. Predictive accuracies of a combination of PSA, age, race, center and biopsy year including or excluding DRE findings were compared by areas under the receiver-operating characteristics curves. In all cohorts, obese men were less likely to have abnormal DREs diagnosed than non-obese men. As BMI category increased, abnormal DREs became stronger predictors for overall CaP in individual (P-trends ≤ 0.05) and combined (P-trend0.001) cohorts, and for high-grade CaP in the Italian (P-trend=0.03) and combined (P-trend=0.03) cohorts. DRE inclusion improved the predictive accuracy for overall and high-grade CaP detection among all obese men (P ≤ 0.032) but not normal-weight men (P ≥ 0.198). DRE inclusion also near-significantly improved overall CaP detection in obese men with PSA4 ng ml(-1) (P=0.081). In conclusion, the predictive value of DRE is dependent on obesity and is significantly higher among obese men than normal-weight men.

Radical prostatectomy and brachytherapy are widely used treatments for favorable risk prostate cancer. We estimated the risk of prostate cancer specific mortality following radical prostatectomy or brachytherapy in men with low or intermediate risk prostate cancer using prospectively collected data.The study cohort comprised 5,760 men with low risk prostate cancer (prostate specific antigen 10 ng/ml or less, clinical category T1c or 2a and Gleason score 6 or less), and 3,079 with intermediate risk prostate cancer (prostate specific antigen 10 to 20 ng/ml, clinical category T2b or T2c, or Gleason score 7). Competing risks multivariable regression was performed to assess the risk of prostate cancer specific mortality after radical prostatectomy or brachytherapy, adjusting for age, year of treatment, cardiovascular comorbidity and known prostate cancer prognostic factors.After a median followup of 4.2 years (IQR 2.0-7.4) for low risk and 4.8 years (IQR 2.2-8.1) for intermediate risk men, there was no significant difference in the risk of prostate cancer specific mortality among low risk (adjusted hazard ratio 1.62, 95% CI 0.59-4.45, p = 0.35) or intermediate risk men (AHR 2.30, 95% CI 0.95-5.58, p = 0.07) treated with brachytherapy compared with radical prostatectomy. The only factor associated with an increased risk of prostate cancer specific mortality (AHR 1.05, 95% CI 1.01-1.10, p = 0.03) was increasing age at treatment in intermediate risk men.The risk of prostate cancer specific mortality in men with low or intermediate risk prostate cancer was not significantly different following radical prostatectomy vs brachytherapy.

Although controversial, evidence suggests statins may reduce the risk of advanced prostate cancer (PC), and recently statin use was associated with prostate-specific antigen (PSA) reductions among men without PC. The authors sought to examine the association between statin use and PSA recurrence after radical prostatectomy (RP).The authors examined 1319 men treated with RP from the Shared Equal Access Regional Cancer Hospital (SEARCH) Database. Time to PSA recurrence was compared between users and nonusers of statin at surgery using Cox proportional hazards models adjusted for multiple clinical and pathological features.In total, 236 (18%) men were taking statins at RP. Median follow-up was 24 months for statin users and 38 for nonusers. Statin users were older (P.001) and underwent RP more recently (P.001). Statin users were diagnosed at lower clinical stages (P=.009) and with lower PSA levels (P=.04). However, statin users tended to have higher biopsy Gleason scores (P=.002). After adjusting for multiple clinical and pathological factors, statin use was associated with a 30% lower risk of PSA recurrence (hazard ratio "HR", 0.70; 95% confidence interval "CI", 0.50-0.97; P=.03), which was dose dependent (relative to no statin use; dose equivalentsimvastatin 20 mg: HR, 1.08; 95% CI, 0.66-1.73; P=.78; dose equivalent=simvastatin 20 mg: HR, 0.57; 95% CI, 0.32-1.00; P=.05; dose equivalentsimvastatin 20 mg: HR, 0.50; 95% CI, 0.27-0.93; P=.03).In this cohort of men undergoing RP, statin use was associated with a dose-dependent reduction in the risk of biochemical recurrence. If confirmed in other studies, these findings suggest statins may slow PC progression after RP.

Objective To analyze the association of diabetes mellitus (DM) with risk of prostate cancer and cancer grade among men undergoing prostate biopsy and to analyze how obesity and race modify these associations.

Purpose: Radical prostatectomy is potentially curative in patients with clinically localized prostate cancer. However, biochemical recurrence affects 15% to 30% of men who undergo radical prostatectomy. We previously reported the prognostic potential of PITX2 gene promoter methylation using conventional assays. In the current study we validated PITX2 methylation status as a biochemical recurrence predictor after radical prostatectomy using a novel microarray based platform in a multi-institutional setting. Materials and Methods: PITX2 methylation status was assessed in formalin fixed, paraffin embedded prostatectomy tumor tissue samples from 476 patients from a total of 4 institutions on customized EpiChip (TM) PITX2 microarrays. Associations between PITX2 methylation and biochemical recurrence were assessed using the log rank test and Cox regression controlling for prostate cancer features. Results: On multivariate analysis men with high methylation status were at significantly higher risk for biochemical recurrence than those with low methylation status (HR 3.0, 95% CI 2.0-4.5, p

BACKGROUND: Across multiple studies, obesity has been associated with an increased risk of higher grade disease and prostate-specific antigen (PSA) recurrence after radical prostatectomy (RP). Whether these associations vary by race is unknown. In the current study, the authors examined the association between obesity and outcome after RP stratified by race. METHODS: A retrospective analysis was performed on 1415 men in the Shared Equal Access Regional Cancer Hospital (SEARCH) database who underwent RP between 1989 and 2008. The association between increased body mass index (BMI) and adverse pathology and biochemical recurrence was examined using multivariate logistic regression and Cox models, respectively. Data were examined stratified by race. RESULTS: After adjusting for preoperative clinical characteristics, higher BMI was associated with higher tumor grade (P = .008) and positive surgical margins (P < .001) in white men, and similar but statistically nonsignificant trends were observed in black men. No significant interaction was noted between race and BMI for associations with adverse pathology (Pinteraction≥.12). After adjusting for preoperative clinical characteristics, higher BMI was associated with an increased risk of recurrence in both white men (P = .001) and black men (P = .03). After further adjusting for pathologic variables, higher BMI was associated with significantly increased risk of recurrence in white men (P = .002) and black men (P = .01). No significant interactions were observed between race and BMI for predicting biochemical progression adjusting either for preoperative factors (Pinteraction = .35) or for preoperative and pathologic features (Pinteraction = .47). CONCLUSIONS: Obesity was associated with a greater risk of recurrence among both black men and white men. Obesity did not appear to be more or less influential in 1 race than another but, rather, was identified as a risk factor for aggressive cancer regardless of race. Cancer 2009. © 2009 American Cancer Society.

Background: African American men with prostate cancer are at higher risk for cancer-specific death than Caucasian men. We determine whether significant delays in management contribute to this disparity. We hypothesize that in an equal-access health care system, time interval from diagnosis to treatment would not differ by race. Methods: We identified 1,532 African American and Caucasian men who underwent radical prostatectomy (RP) from 1988 to 2007 at one of four Veterans Affairs Medical Centers that comprise the Shared Equal-Access Regional Cancer Hospital (SEARCH) database with known biopsy date. We compared time from biopsy to RP between racial groups using linear regression adjusting for demographic and clinical variables. We analyzed risk of potential clinically relevant delays by determining odds of delays >90 and >180 days. Results: Median time interval from diagnosis to RP was 76 and 68 days for African Americans and Caucasian men, respectively (P = 0.004). After controlling for demographic and clinical variables, race was not associated with the time interval between diagnosis and RP (P = 0.09). Furthermore, race was not associated with increased risk of delays >90 (P = 0.45) or >180 days (P = 0.31). Conclusions: In a cohort of men undergoing RP in an equal-access setting, there was no significant difference between racial groups with regard to time interval from diagnosis to RP. Thus, equal-access includes equal timely access to the operating room. Given our previous finding of poorer outcomes among African Americans, treatment delays do not seem to explain these observations. Our findings need to be confirmed in patients electing other treatment modalities and in other practice settings. (Cancer Epidemiol Biomarkers Prev 2009;18(4):1208–12)

Background: This report and a companion report describe a validation of the ability of serum proteomic profiling via SELDI-TOF mass spectrometry to detect prostatic cancer. Details of this 3-stage process have been described. This report describes the development of the algorithm and results of the blinded test for stage 1. Methods: We derived the decision algorithm used in this study from the analysis of serum samples from patients with prostate cancer (n = 181) and benign prostatic hyperplasia (BPH) (n = 143) and normal controls (n = 220). We also derived a validation test set from a separate, geographically diverse set of serum samples from 42 prostate cancer patients and 42 controls without prostate cancer. Aliquots were subjected to randomization and blinded analysis, and data from each laboratory site were subjected to the decision algorithm and decoded. Results: Using the data collected from the validation test set, the decision algorithm was unsuccessful in separating cancer from controls with any predictive utility. Analysis of the experimental data revealed potential sources of bias. Conclusion: The ability of the decision algorithm to successfully differentiate between prostate cancer, BPH, and control samples using data derived from serum protein profiling was compromised by bias.

Cancer cells gain selection advantages by the coordinated silencing of protective and by the activation of cell proliferation/cell survival genes. Evaluations of epithelial cell transcriptome of benign and malignant prostate glands by laser capture microdissection (LCM) identified Lactotransferrin (LTF) as the most significantly downregulated gene in prostate cancer (CaP) cells (p10(-6)). Frequent downregulation, significant association of LTF with PSA recurrence-free survival in CaP patients and the established anti-tumorigenic effects of LTF in experimental cancer models have provided impetus to evaluate LTF expression features and mechanisms in CaP specimens.LTF mRNA expression analysis was performed in LCM derived benign and malignant prostate epithelial cells by using Affymetrix GeneChip and QRT-PCR. LTF protein expression was assessed in tissue specimens by immunohistochemistry and in serum samples from CaP patients compared to healthy male control by using ELISA. Mechanism of LTF downregulation was analyzed in 5-azadeoxycytidine treated LNCaP and LAPC4 cells using MALDI-TOF MS. Proliferation and cell cycle analysis of CaP cells by FACS flow cytrometry was assessed in LNCaP cell cultures.Quantitative analysis of LTF mRNA expression in tumor cells revealed marked downregulation of LTF with significant associations to decreased PSA recurrence-free survival of CaP patients (n = 100, por = 0.0322). Moreover, low levels of LTF protein expression was observed in tumor tissues as well as in sera from CaP patients (por = 0.0001). LTF promoter downstream CpG island methylation was found in LNCaP and LAPC4 cells. Furthermore, replenishing of LTF by supplementing growth media with LTF protein resulted in reduced cell growth. Cell cycle analysis revealed robust increases in apoptosis in response to LTF treatment.This study highlights the potential for LTF in chemoprevention and to become a biologically relevant prognostic marker of CaP, suggesting that silencing of the LTF gene may be causally linked to CaP progression.

State-of-the-art proteomics technologies are currently being assessed for utility in the study of prostatic malignancy. This review aims to provide background information on the current proteomics techniques employed in prostate cancer research, recent reports showing the potential application of proteomics in urological practice, and the future direction of proteomics in prostate cancer research and management.Proteomic profiling of serum as a diagnostic tool and a platform for biomarker discovery in prostate cancer continues to draw favorable attention as well as close scrutiny as technological enhancements and multi-center study results are reported. In-vitro studies on prostate cell lines provide positive proof-of-principle results. The application of proteomics to query prostate tissue specimens yields novel prostate cancer biomarkers requiring further validation. The integration of proteomics with immunology also yields promising findings that may translate into clinically relevant biological assays.The study of proteomics is an emerging research field, and current studies continue to display potential future usage in prostate cancer management. Succeeding scientific investigations will probably yield new diagnostic and prognostic tools for prostate cancer, provide insights into its underlying biology, and contribute to the development of novel treatment strategies.

110 Background: Clinical stage T2c (cT2c) is an indeterminate factor in the algorithm for prostate cancer (CaP) risk stratification. According to the D’Amico risk stratification and the American Urological Association (AUA) guidelines, cT2c is high−risk, whereas the National Comprehensive Cancer Network (NCCN) and EUA classify cT2c as intermediate−risk. Since determining whether cT2c is intermediate- or high-risk has implications for treatment, it is important to define what exact risk cT2c portends. Thus, we sought to assess whether cT2c tumors, without associated other high−risk factors (cT2c not otherwise specified (cT2c−nos)), behave as intermediate− or high−risk by analyzing biochemical recurrence (BCR) after radical prostatectomy (RP). Methods: We retrospectively analyzed 2,759 men who underwent RP from 1988 to 2011 from the Shared Equal Access Regional Cancer Hospital (SEARCH) database. Comparisons in time to BCR between cT2c−nos patients and intermediate−risk (prostate-specific antigen [PSA] 10 to 20 ng/ml or Gleason sum (GS) =7 or cT2b), and high−risk (PSA greater than 20 ng/ml, GS 8 to 10, cT3) patients was performed using log−rank test and Cox proportional hazards analyses. Given changes in CaP, we adjusted for year of surgery (continuous) and to adjust for case mix among centers contributing to SEARCH we included a categorical term for center. Results: A total of 99 men (4%) were classified as cT2c−nos. During a median follow-up of 66 months (IQR: 34−101 months), cT2c−nos patients had similar BCR risk as intermediate-risk (p=0.27), but significantly lower BCR risk versus high-risk patients (p

Currently, one in four deaths in both Europe and the United States is the result of cancer. The American Cancer Society identified prostate cancer (PCa) as the most commonly diagnosed non-dermatologic malignancy among American men, and it remains the second most fatal cancer. Similar incidence and mortality figures are reported by the European Association of Urology (EAU). ThegoalofPCascreeningistodetectpotential fatalcancers at a time when they may still be curable. The downside of screening is the diagnosis and overtreatment of tumours destined to pose no threat to themanduring his lifetime. The upsideof screening is thedetectionofhigh-risk cancerswhile still clinically localised. In a heavily screened population, this ‘‘high-risk’’ group accounts for 15% of men with clinically localiseddiseaseand likelyahigherpercentage in lessheavily screened populations [1]. Ultimately, the best treatment for this group of men is unclear, though we would suggest that they are at risk for undertreatment. The exact definition of high risk is a matter of debate. High-risk, clinically localised diseasewas classically defined by D’Amico et al as any combination of the following factors: a prostate-specific antigen (PSA) score>20 ng/ml, a Gleason score of 8–10, or clinical stage T2C or greater [2]. More recently, the National Comprehensive Cancer Network and EAU have modified this definition to include any combination of a clinical T3, a PSA score >20 ng/ml, or a Gleason score of 8–10. Regardless of the definition used, the optimal treatment for these men remains unknown, although common treatments include surgery, radiation, or primary androgen-deprivation therapy. However, it is clear that regardless of the treatment used, some men fair

56 Background: Image-guided radiation therapy (IGRT) has been widely adopted for both definitive and post-operative prostate radiotherapy. In the postoperative setting, numerous studies of prostate bed motion have recommended tight planning margins (0.2 ng/ml and rising or initiation of salvage ADT. CTCAE v 4.0 and the RTOG/LENT late morbidity scores were used to grade acute and late toxicities. Risk for biochemical failure and late Grade 2+ GI toxicity were compared between IGRT (N = 113) and non-IGRT (N = 173) patients using multivariable adjusted Cox regression controlling for age, treatment technique (3D vs IMRT), radiation dose, androgen suppression, pathologic Gleason Score, margin status, pathologic stage, and pre-radiotherapy PSA level. Results: The median margin size for patients with IGRT was 7mm (IQR 6-10mm) and 15mm (IQR 7-15mm) for those without IGRT (p < 0.001). Median follow up was 21 months (IQR 15-33 mo) for patients with IGRT and 49 months (IQR 30-73 mo) for those without IGRT (p < 0.001). On multivariate analysis, patients treated with IGRT had a greater risk of progression versus non-daily imaging (HR = 2.51, p < 0.001), as did patients who received salvage versus adjuvant radiotherapy (HR = 2.41, p = 0.005). Higher pathologic Gleason Score (HR = 1.96, p = 0.026) and pathologic stage (HR = 1.93, p = 0.003) conferred increased risk of progression, while positive margin status was protective (HR = 0.53, p = 0.002). Age, radiation dose, androgen suppression, and treatment technique did not affect biochemical outcome (p > 0.1). There were no differences in acute or late GI toxicity according to treatment technique or use of IGRT (both p > 0.1). Conclusions: The use of IGRT was associated with increased biochemical recurrence for patients receiving post-operative prostate radiotherapy. For these patients, we recommend using treatment margins of at least 10mm to address subclinical disease and organ motion.

4670 Background: As concerns mount regarding overtreatment and over-diagnosis of prostate cancer (CaP), active surveillance (AS) is increasingly utilized in low risk patients. While African-American (AA) race is associated with adverse outcomes after prostatectomy, its effect on patients managed with AS is not known. Methods: A retrospective review identified 222 patients managed with AS at the Duke Prostate Center from January 2005 to September 2011. All men had CaP diagnosed on biopsy performed at our center, and elected AS over treatment. Failure was defined as progression to treatment. In men who failed AS, the reasons for failure, follow-up PSA and biopsy characteristics were analyzed. The primary outcome - time from diagnosis to failure of AS for a reason other than patient choice - was analyzed with univariable and multivariable Cox proportional hazards models. Results: In our AS cohort, 73% are Caucasian and 23% AA. Median follow-up is 25.4 months. Age, household income, BMI, PSA, clinical stage, family history, prostate volume, number of cores with cancer, and Gleason grade on initial biopsy did not differ by race. The number of biopsies and PSA tests performed on AS did not differ by race. A higher proportion of AA men tended to fail from biopsy progression (72.7% vs. 63.8%) while a lower proportion failed by choice (9.1% vs. 14.9%) compared to Caucasians (p = 0.114). AA men had a significantly shorter time to failure (HR 1.74, p = 0.045) compared to Caucasians. There was a trend toward increased Gleason grade 8 or higher cancer on follow-up biopsy in AA compared to Caucasian men (10% vs. 2.5%, p = 0.08). AA race remained a predictor (HR 1.76, p = 0.058) of failure on multivariable analysis, as did initial PSA (HR 1.90, p = 0.031) and number of cores with cancer on initial biopsy (HR 1.29, p = 0.013). Conclusions: AA race was associated with higher risk for failure of AS. There was a trend toward AA men failing due to biopsy progression and with higher grade cancer. Additional follow-up is necessary to determine how this affects the long term outcomes of these men.