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Both anti- and proinflammatory effects of cigarette smoking have been described. As prostate inflammation is common, we hypothesized smoking could contribute to prostate inflammation. Thus, we evaluated the association of smoking status with acute and chronic inflammation within the prostate of men undergoing prostate biopsy. We retrospectively analyzed 8,190 men ages 50 to 75 years with PSA levels between 2.5 and 10 ng/mL enrolled in the Reduction by Dutasteride of Prostate Cancer Events study. Smoking status was self-defined as never, former, or current. Prostate inflammation was assessed by systematic central review blinded to smoking status. The association of smoking with inflammation in the baseline, 2-year, and 4-year biopsies was evaluated with univariable and multivariable logistic regressions. At study enrollment, 1,233 (15%), 3,203 (39%), and 3,754 (46%) men were current, former, and never smokers, respectively. Current smokers were significantly younger and had smaller prostates than former and never smokers (all P < 0.05). Former smokers were significantly heavier than current and never smokers (P < 0.001). Acute and chronic prostate inflammations were identified in 1,261 (15%) and 6,352 (78%) baseline biopsies, respectively. In univariable analysis, current smokers were more likely to have acute inflammation than former (OR, 1.35; P, 0.001) and never smokers (OR, 1.36; P, 0.001). The results were unchanged at 2- and 4-year biopsies. In contrast, current smoking was linked with chronic inflammation in the baseline biopsy, but not at 2- and 4-year biopsies. In conclusion, among men undergoing prostate biopsy, current smoking was independently associated with acute and possibly chronic prostate inflammations., (©2015 American Association for Cancer Research.)

Purpose/objective(s): Recent in vitro and in vivo evidence has suggested that statin medications may have anticancer activity. We sought to determine whether statin use was associated with improved clinical outcome in men treated with brachytherapy for prostate cancer., Materials/methods: A database of men with prostate cancer treated with permanent Iodine-125 brachytherapy between January 1999 and February 2009 was retrospectively analyzed. Standard guidelines (i.e., American Brachytherapy Society selection criteria) were used for selecting patients for brachytherapy. Biochemical failure was defined using the Phoenix definition., Results: From a total of 247 men with prostate adenocarcinoma treated with brachytherapy, 174 patients (70 %) were identified as using statin medications, either during initial visit or during follow-up. Median PSA follow-up was 51 months after date of implant (range 9.4-140.35). Overall biochemical failure rate was 7.3 % (18 patients). On univariate analysis, statin use was associated with significantly improved freedom from biochemical failure [hazard ratio (HR) 0.28; 95 % CI 0.10-0.72; p < 0.01 by log-rank test]. In multivariate Cox analysis performed with the variables statin use, pretreatment PSA, clinical T stage, Gleason score, and D90 or V100, statin use remained significantly associated with improved freedom from biochemical failure (HR 0.288; 95 % CI 0.086-0.886; p = 0.0299)., Conclusions: Statin use was associated with a significant improvement in freedom from biochemical failure in this cohort of men treated with brachytherapy for prostate cancer. Further investigation into the favorable effect of statin use on brachytherapy and radiation therapy in general is warranted, including prospective trials.

Objectives: To determine whether PTEN status in prostate biopsy represents a predictor of intermediate and long-term oncological outcomes after radical prostatectomy, and whether PTEN status predicts response to androgen deprivation therapy., Methods: In a retrospective analysis of 77 men treated by radical prostatectomy who underwent diagnostic biopsy between 1992-2006, biopsy samples were stained for PTEN expression by the PREZEON assay with >10% staining reported as positive. Cox proportional hazards and log-rank models were used to assess the correlation between PTEN loss and clinical outcomes., Results: During a median follow-up period after radical prostatectomy of 8.8 years, 39 men (51%) developed biochemical recurrence, four (5%) had castration-resistant prostate cancer, two (3%) had metastasis and two (3%) died from prostate cancer. PTEN loss was not significantly associated with biochemical recurrence (hazard ratio 2.1, 95% confidence interval 0.9-5.1, P = 0.10), but significantly predicted increased risk of castration-resistant prostate cancer, metastasis and prostate cancer-specific mortality (all log-rank, P < 0.0001), and time from androgen deprivation therapy to castration-resistant prostate cancer (log-rank, P = 0.003). No patient without PTEN loss developed metastases or died from prostate cancer., Conclusions: PTEN loss at the time of biopsy seems to predict time to development of metastasis, prostate cancer-specific mortality and, for the first time, castration-resistant prostate cancer and response to androgen deprivation therapy after radical prostatectomy. If confirmed by larger studies, this would support the use of PTEN loss as an early marker of aggressive prostate cancer., (© 2014 The Japanese Urological Association.)

Purpose: Although the relationship between smoking and prostate cancer risk is inconsistent, some studies show that smoking is associated with prostate cancer mortality. Whether this reflects delayed diagnosis or direct smoking-related effects is unknown. REDUCE, which followed biopsy-negative men with protocol-dictated prostate-specific antigen (PSA)-independent biopsies at 2 and 4 years, provides an opportunity to evaluate smoking and prostate cancer diagnosis with minimal confounding from screening biases., Experimental Design: Logistic regression was conducted to test the association between smoking and cancer on the first on-study biopsy (no cancer, low-grade Gleason 4-6, high-grade Gleason 7-10) in REDUCE., Results: Of 6,240 men with complete data and ≥1 on-study biopsy, 2,937 (45.8%) never smoked, 929 (14.5%) were current smokers, and 2,554 (39.8%) were former smokers. Among men with negative first on-study biopsies, smokers were 36% less likely to receive a second on-study biopsy (P < 0.001). At first on-study biopsy, 941 (14.7%) men had cancer. Both current and former smoking were not significantly associated with either total or low-grade prostate cancer (all P > 0.36). Current (OR = 1.44, P = 0.028) but not former smokers (OR = 1.21, P = 0.12) were at increased risk of high-grade disease. On secondary analysis, there was an interaction between smoking and body mass index (BMI; Pinteraction = 0.017): current smokers with BMI ≤ 25 kg/m(2) had an increased risk of low-grade (OR = 1.54, P = 0.043) and high-grade disease (OR = 2.45, P = 0.002), with null associations for BMI ≥ 25 kg/m(2)., Conclusion: Among men with elevated PSA and negative pre-study biopsy in REDUCE, in which biopsies were largely PSA independent, smoking was unrelated to overall prostate cancer diagnosis but was associated with increased risk of high-grade prostate cancer., (©2014 American Association for Cancer Research.)

Purpose: The cell cycle progression score is associated with prostate cancer outcomes in various clinical settings. However, previous studies of men treated with radical prostatectomy evaluated cell cycle progression scores generated from resected tumor tissue. We evaluated the prognostic usefulness of the score derived from biopsy specimens in men treated with radical prostatectomy., Materials and Methods: We evaluated the cell cycle progression score in cohorts of patients from the Martini Clinic (283), Durham Veterans Affairs Medical Center (176) and Intermountain Healthcare (123). The score was derived from simulated biopsy (Martini Clinic) or diagnostic biopsy (Durham Veterans Affairs Medical Center and Intermountain Healthcare) and evaluated for an association with biochemical recurrence and metastatic disease., Results: In all 3 cohorts the cell cycle progression score was associated with biochemical recurrence and metastatic disease. The association with biochemical recurrence remained significant after adjusting for other prognostic clinical variables. On combined analysis of all cohorts (total 582 patients) the score was a strong predictor of biochemical recurrence on univariate analysis (HR per score unit 1.60, 95% CI 1.35-1.90, p=2.4×10(-7)) and multivariate analysis (HR per score unit 1.47, 95% CI 1.23-1.76, p=4.7×10(-5)). Although there were few events (12), the cell cycle progression score was the strongest predictor of metastatic disease on univariate analysis (HR per score unit 5.35, 95% CI 2.89-9.92, p=2.1×10(-8)) and after adjusting for clinical variables (HR per score unit 4.19, 95% CI 2.08-8.45, p=8.2×10(-6))., Conclusions: The cell cycle progression score derived from a biopsy sample was associated with adverse outcomes after surgery. These results indicate that the score can be used at disease diagnosis to better define patient prognosis and enable more appropriate clinical care., (Copyright © 2014 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Background: 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., Methods: A retrospective analysis was performed of 6238 men aged 50 years to 75 years with prostate-specific antigen levels between 2.5 ng/mL and 10 ng/mL and a prior negative biopsy in the REduction by DUtasteride of PCa Events study who completed a 2-year biopsy. PCa, acute prostate inflammation, and chronic prostate inflammation were assessed by central review. The association between inflammation in baseline prostate biopsies and positive 2-year and 4-year repeat biopsies was evaluated with the chi-square test and logistic regression analysis adjusting for baseline covariates., Results: Acute and chronic inflammation and both were detected in 46 baseline biopsies (1%), 3931 baseline biopsies (63%), and 892 baseline biopsies (14%), respectively. Acute and chronic inflammation were found to be significantly associated with each other (P<.001). Acute inflammation at baseline biopsy was associated with younger age, lower prostate-specific antigen levels, and a smaller prostate (all P<.01), whereas chronic inflammation was associated with older age and larger prostate glands (all P<0.01). At the 2-year biopsy, the prevalence of PCa was 14% (N=900 patients). On univariable and multivariable analysis, both acute and chronic inflammation were found to be significantly associated with a lower PCa risk (acute univariable: odds ratio [OR], 0.65 [P<.001] and multivariable: OR, 0.75 [P=.012] and chronic univariable: OR, 0.61 [P<.001] and multivariable: OR, 0.65 [P<.001]). At the time of 4-year biopsy, only acute inflammation was found to be associated with a lower PCa risk., Conclusions: Baseline acute and chronic inflammation were both found to be independently associated with a lower PCa risk. From a clinical standpoint, inflammation in negative biopsies for PCa may lower the risk of subsequent PCa detection., (© 2013 American Cancer Society.)

Background: While epidemiologic studies suggest that metformin use among diabetics may decrease prostate cancer (PC) incidence, the effect of metformin use on PC outcome is unclear. We investigated the association between pre-operative metformin use, dose and duration of use and biochemical recurrence (BCR) in PC patients with diabetes who underwent radical prostatectomy (RP)., Methods: We conducted a retrospective cohort analysis within the Shared Equal Access Regional Cancer Hospital (SEARCH) database of 371 PC patients with diabetes who underwent RP. Time to BCR between metformin users and non-users, and by metformin dose and duration of use was assessed using multivariable Cox proportional analysis adjusted for demographic, clinical and/or pathologic features. Time to castrate-resistant PC (CRPC), metastases and PC-specific mortality were explored as secondary outcomes using unadjusted analyses., Results: Of 371 diabetic men, 156 (42%) were using metformin before RP. Metformin use was associated with more recent year of surgery (P<0.0001) but no clinical or pathologic characteristics. After adjustment for year of surgery, clinical and pathologic features, there were no associations between metformin use (hazard ratio (HR) 0.93; 95% confidence interval (CI) 0.61-1.41), high metformin dose (HR 0.96; 95% CI 0.57-1.61) or duration of use (HR 1.00; 95% CI 0.99-1.02) and time to BCR. A total of 14 patients (3.8%) developed CRPC, 10 (2.7%) distant metastases and 8 (2.2%) died from PC. Unadjusted analysis suggested that high metformin dose vs non-use was associated with increased risk of CRPC (HR 5.1; 95% CI 1.6-16.5), metastases (HR 4.8; 95% CI 1.2-18.5) and PC-specific mortality (HR 5.0; 95% CI 1.1-22.5)., Conclusions: Metformin use, dose or duration of use was not associated with BCR in this cohort of diabetic PC patients treated with RP. The suggestion that higher metformin dose was associated with increased risk of CRPC, metastases and PC-specific mortality merits testing in large prospective studies with longer follow-up.

Purpose: 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., Methods: 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., Results: 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 p < 0.05). 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., Conclusions: 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.

Purpose: To evaluate, in a phase 1 study, the safety of neoadjuvant whole-pelvis radiation therapy (RT) administered immediately before radical prostatectomy in men with high-risk prostate cancer., Methods and Materials: Twelve men enrolled and completed a phase 1 single-institution trial between 2006 and 2010. Eligibility required a previously untreated diagnosis of localized but high-risk prostate cancer. Median follow-up was 46 months (range, 14-74 months). Radiation therapy was dose-escalated in a 3 × 3 design with dose levels of 39.6, 45, 50.4, and 54 Gy. The pelvic lymph nodes were treated up to 45 Gy with any additional dose given to the prostate and seminal vesicles. Radical prostatectomy was performed 4-8 weeks after RT completion. Primary outcome measure was intraoperative and postoperative day-30 morbidity. Secondary measures included late morbidity and oncologic outcomes., Results: No intraoperative morbidity was seen. Chronic urinary grade 2+ toxicity occurred in 42%; 2 patients (17%) developed a symptomatic urethral stricture requiring dilation. Two-year actuarial biochemical recurrence-free survival was 67% (95% confidence interval 34%-86%). Patients with pT3 or positive surgical margin treated with neoadjuvant RT had a trend for improved biochemical recurrence-free survival compared with a historical cohort with similar adverse factors., Conclusions: Neoadjuvant RT is feasible with moderate urinary morbidity. However, oncologic outcomes do not seem to be substantially different from those with selective postoperative RT. If this multimodal approach is further evaluated in a phase 2 setting, 54 Gy should be used in combination with neoadjuvant androgen deprivation therapy to improve biochemical outcomes., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: 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., Methods: 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., Results: 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., Conclusions: 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.

Purpose: To evaluate the prognostic utility of the cell cycle progression (CCP) score, a RNA signature based on the average expression level of 31 CCP genes, for predicting biochemical recurrence (BCR) in men with prostate cancer treated with external beam radiation therapy (EBRT) as their primary curative therapy., Methods and Materials: The CCP score was derived retrospectively from diagnostic biopsy specimens of men diagnosed with prostate cancer from 1991 to 2006 (n=141). All patients were treated with definitive EBRT; approximately half of the cohort was African American. Outcome was time from EBRT to BCR using the Phoenix definition. Median follow-up for patients without BCR was 4.8 years. Association with outcome was evaluated by Cox proportional hazards survival analysis and likelihood ratio tests., Results: Of 141 patients, 19 (13%) had BCR. The median CCP score for patient samples was 0.12. In univariable analysis, CCP score significantly predicted BCR (P=.0017). The hazard ratio for BCR was 2.55 for 1-unit increase in CCP score (equivalent to a doubling of gene expression). In a multivariable analysis that included Gleason score, prostate-specific antigen, percent positive cores, and androgen deprivation therapy, the hazard ratio for CCP changed only marginally and remained significant (P=.034), indicating that CCP provides prognostic information that is not provided by standard clinical parameters. With 10-year censoring, the CCP score was associated with prostate cancer-specific mortality (P=.013). There was no evidence for interaction between CCP and any clinical variable, including ethnicity., Conclusions: Among men treated with EBRT, the CCP score significantly predicted outcome and provided greater prognostic information than was available with clinical parameters. If validated in a larger cohort, CCP score could identify high-risk men undergoing EBRT who may need more aggressive therapy., (Published by Elsevier Inc.)

Nerves are a common feature of the microenvironment, but their role in tumor growth and progression remains unclear. We found that the formation of autonomic nerve fibers in the prostate gland regulates prostate cancer development and dissemination in mouse models. The early phases of tumor development were prevented by chemical or surgical sympathectomy and by genetic deletion of stromal β2- and β3-adrenergic receptors. Tumors were also infiltrated by parasympathetic cholinergic fibers that promoted cancer dissemination. Cholinergic-induced tumor invasion and metastasis were inhibited by pharmacological blockade or genetic disruption of the stromal type 1 muscarinic receptor, leading to improved survival of the mice. A retrospective blinded analysis of prostate adenocarcinoma specimens from 43 patients revealed that the densities of sympathetic and parasympathetic nerve fibers in tumor and surrounding normal tissue, respectively, were associated with poor clinical outcomes. These findings may lead to novel therapeutic approaches for prostate cancer.

Background: Although obesity has been associated with larger prostate volumes (PV), few studies have actually investigated whether obesity enhances PV growth, especially among men using 5α-reductase inhibitors., Objective: To examine whether obesity is associated with enhanced PV growth measured by serial transrectal ultrasound (TRUS) measurements., Design, Setting, and Participants: We conducted a secondary analysis of the REduction by DUtasteride of prostate Cancer Events (REDUCE) trial, which was originally aimed at cancer risk reduction among high-risk men with a single negative prestudy biopsy., Intervention: Per-protocol randomization to placebo or dutasteride and mandatory TRUS-guided biopsies at 2 yr and 4 yr., Outcome Measurements and Statistical Analysis: Percentage change in PV at 2 yr and 4 yr from baseline. We tested its association with baseline body mass index (BMI) groups of <25, 25-29.9, and ≥ 30 kg/m(2) using multivariable linear regression. Secondarily, we tested whether BMI was associated with the likelihood of having no PV reduction among men randomized to dutasteride using multivariable logistic regression., Results and Limitations: Of 8122 participants, we analyzed 71.8% and 54.5% with complete 2-yr and 4-yr PV data, respectively. In multivariable analysis, men on placebo with BMI ≥ 30 versus < 25 kg/m(2) had enhanced PV growth from baseline (at 2 yr: 17.0% vs 10.7%, p<0.001; at 4 yr: 29.4% vs 20.1%; p=0.001). Men on dutasteride with BMI ≥ 30 versus < 25 kg/m(2) had attenuated PV reduction from baseline (at 2 yr: -14.3% vs -18.5%; p=0.002; at 4 yr: -13.2% vs -19.3%; p=0.001) and higher likelihood of having no PV reduction (at 2 yr: odds ratio [OR]: 1.44; 95% confidence interval [CI], 1.08-1.93; p=0.014; at 4 yr: OR: 1.62; 95% CI, 1.18-2.22; p=0.003). We found no significant interactions between BMI and dutasteride on PV change at 2 yr and 4 yr (p interaction ≥ 0.36). No clinical outcomes or effects of weight change were assessed., Conclusions: Obesity enhanced PV growth and attenuated PV reduction by dutasteride. The null interaction between obesity and dutasteride for PV change implies that the effect of obesity on dutasteride-treated men is likely a combination of dutasteride-driven PV reduction with obesity-driven PV growth rather than decreased dutasteride efficacy., (Copyright © 2013 European Association of Urology. All rights reserved.)

Purpose: Epidemiological data are conflicting regarding the association between androgenetic alopecia (AA) and prostate cancer (CaP). We examined the relationship between these two conditions., Materials and Methods: We performed a case-control study at a Veterans Affairs Hospital among 708 men: 312 healthy controls, 167 men with CaP, and 229 men without CaP on prostate biopsy. Participants were asked to self-describe hair patterns at ages 30 and 40 and at study enrollment. We tested the association between hair pattern (overall, vertex, or frontal) and CaP status using logistic regression analysis adjusting for multiple clinical features. Disease grade was similarly examined as a secondary outcome., Results: Relative to healthy controls, younger age of AA onset was significantly associated with increased CaP risk (p = 0.008). Similar patterns were noted for frontal (p = 0.005) and not vertex balding (p = 0.22). When compared with biopsy-negative men, a similar pattern was seen with younger age of AA onset having higher risk of CaP, though this was not significant (p = 0.07). A suggestion for younger age of AA onset for frontal (p = 0.07) being associated with CaP versus biopsy-negative men was also observed. Overall balding (yes/no) was associated with greater than twofold increase in high-grade disease (p = 0.02)., Conclusions: Men reporting earlier AA onset were at increased CaP risk and suggestively had more aggressive disease. Contrary to other studies, frontal balding was the predominant pattern associated with elevated CaP risk. Further study is required to confirm these findings in a larger sample and to better understand the role of AA, androgens, and CaP biology.

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., (Copyright © 2013 American Cancer Society.)

Background: 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)., Methods: 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., Results: 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 P < 0.001). Despite comparable prostate weights (39.4 vs. 39.6 g), AA men had higher percent cancer involvement and estimated tumor volume (all P < 0.001) but similar estimated tumor volume/PSA ratios ( P> 0.05). 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., Conclusions: 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.

Changes in sexual bother (SB) following radical prostatectomy (RP) negatively affect health-related quality of life (HRQoL) of prostate cancer survivors. However, post-operative SB tends to be neglected whereas sexual function (SF) is thoroughly assessed in clinical practice and few studies have focused on and evaluated patients' SB. We retrospectively reviewed 2 345 consecutive patients who underwent RP between 2001 and 2009 at a single institution. SF and SB were assessed using Expanded Prostate Cancer Index Composite (EPIC) questionnaires. We stratified our cohort by SB recovery and post-operative SF status, including a subset of men who recovered SB despite persistent post-RP sexual dysfunction. Multivariable logistic regression analyses were conducted to identify factors for men who have SB recovery. Of 319 eligible patients, 133 (41.7%) recovered their SB at a mean of 20 months after RP. Among the 133 men who demonstrated SB recovery, 109 had post-operative sexual dysfunction. Patients with SB recovery despite post-RP sexual dysfunction were more likely to be old (p = 0.004), to have higher clinical T stage (p < 0.001), to have more non-nerve-sparing RP (p < 0.001), to have lower pre-operative EPIC-SF/SB scores (p < 0.001), to have more extracapsular extension (p = 0.031) and to be PDE5i non-users after surgery (p < 0.001). In multivariable analysis, predictors for this subset were lower comorbidity (OR 0.62, p = 0.043), higher clinical cancer stage (OR 2.35, p = 0.026), worse pre-operative SF (OR 0.98, p = 0.010), SB (OR 0.98, p < 0.010) and no PDE5i use (OR 0.37, p = 0.002); age was not related (OR 0.99, p = 0.555). As SB can influence patients' overall HRQoL, expectations of SB recovery should be provided to patients in the same way that SF recovery is presented. This study may help clinicians to discuss SB with patients and assess their potential for SB recovery following RP., (© 2012 American Society of Andrology and European Academy of Andrology.)

Aims: Uridine diphosphate-glucuronosyltransferase 2B (UGT2B) enzymes conjugate testosterone metabolites to enable their excretion in humans. The functional significance of the UGT2B genetic variants has never been described in humans. We evaluated UGT2B variants in relation to plasma androstane-3α,17β-diol-glucuronide (AAG) levels and the prostate cancer risk., Results: AAG levels were measured in sera from 150 controls and compared to the polymorphisms of UGT2B17, UGT2B15, and UGT2B7. Genomic DNA from controls (301) and cases (148) was genotyped for the polymorphisms, and odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated using unconditional logistic regression analyses. Having two copies of UGT2B17 was associated with higher AAG levels in controls among Whites (p=0.02), but not Blacks (p=0.82). Logistic regression models adjusting for age and race revealed that homozygosity for the G allele of the UGT2B15(D85Y) polymorphism was directly associated with the prostate cancer risk (OR=2.70, 95% CI=1.28, 5.55)., Conclusions: While the small sample size limits inference, our findings suggest that an association between the UGT2B17 copy number variant (CNV) and serum AAG levels in Whites, but unexpectedly not in Blacks. This novel observation suggests that genetic determinants of AAG levels in Blacks are unrelated to the UGT2B17 CNV. This study replicates the results that show an association of UGT215(D85Y) with an increased prostate cancer risk.

Background: Obesity is associated with an increased risk of biochemical recurrence (BCR) after radical prostatectomy (RP). It is unclear whether this is due to technical challenges related to operating on obese men or other biologic factors., Objective: To examine whether obesity predicts higher prostate-specific antigen (PSA) nadir (as a measure of residual PSA-producing tissue) after RP and if this accounts for the greater BCR risk in obese men., Design, Setting, and Participants: A retrospective analysis of 1038 RP patients from 2001 to 2010 in the multicenter US Veterans Administration-based Shared Equal Access Regional Cancer Hospital database with median follow-up of 41 mo., Intervention: All patients underwent RP., Outcome Measurements and Statistical Analysis: We evaluated the relationship between body mass index (BMI) and ultrasensitive PSA nadir within 6 mo after RP. Adjusted proportional hazards models were used to examine the association between BMI and BCR with and without PSA nadir., Results and Limitations: Mean BMI was 28.5 kg/m2. Higher BMI was associated with higher PSA nadir on both univariable (p=0.001) and multivariable analyses (p<0.001). Increased BMI was associated with increased BCR risk (hazard ratio [HR]: 1.06; p=0.007). Adjusting for PSA nadir slightly attenuated, but did not eliminate, this association (HR: 1.04, p=0.043). When stratified by PSA nadir, obesity only significantly predicted BCR in men with an undetectable nadir (p=0.006). Unfortunately, other clinically relevant end points such as metastasis or mortality were not available., Conclusions: Obese men are more likely to have a higher PSA nadir, suggesting that either more advanced disease or technical issues confound an ideal operation. However, even after adjusting for the increased PSA nadir, obesity remained predictive of BCR, suggesting that tumors in obese men are growing faster. This provides further support for the idea that obesity is biologically associated with prostate cancer progression., (Published by Elsevier B.V.)

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., (Copyright © 2012 European Association of Urology. All rights reserved.)

Background: The impact of race and socioeconomic status (SES) in prostate cancer (CaP) outcomes has been well-studied, but controversy remains. The associations of race/SES with intermediate CaP outcomes, including positive surgical margin (PSM) and biochemical recurrence (BCR), were explored in an equal-access setting., Methods: Data were retrospectively collected from 2502 men in the Shared Equal Access Regional Cancer Hospitals (SEARCH) database who underwent radical prostatectomy from 1989 to 2010. SES (income, education, employment, and poverty) was estimated from linkage of home ZIP code to census data. Logistic regression with adjustment for pre- and postoperative covariates estimated risk for associations between race/SES and pathologic outcomes. Cox proportional hazards models estimated risk for associations between race/SES and time to BCR., Results: Black men were more likely to have lower SES than white men (P < .001). On multivariate analysis, race was not associated with PSM, but higher SES was associated with less PSM and fewer Gleason sum ≥ 7 pathologic tumors when SES was assessed by education, employment, or poverty (P trend ≤ .051) and income, employment, or poverty (P trend ≤ 0.059), respectively. Crude Cox models showed black men had higher BCR risk (hazards ratio = 1.20, 95% confidence interval = 1.05-1.38, P = .009) that persisted after adjustment for covariates including SES (hazards ratio ≥ 1.18, P ≤ .040). Higher SES measured by income and poverty were associated with less BCR, but only for black men (P trend ≤ .048)., Conclusions: Even in an equal-access setting, higher SES predicted lower PSM risk, and race persisted in predicting BCR despite adjustment for SES. Low SES black patients may be at greatest risk for postprostatectomy BCR., (Copyright © 2012 American Cancer Society.)

Objectives: To analyze the association between prostate-specific antigen doubling time with prostate cancer risk and grade among men with prostate-specific antigen levels ≥4.0 ng/mL undergoing repeat prostate biopsy., Methods: A total of 286 patients with prostate-specific antigen ≥4 ng/mL and available prostate-specific antigen doubling time data, who underwent repeat prostate biopsy from 1996-2009, were included in this analysis. Prostate-specific antigen doubling time was divided into three groups: >9 years, 3-9 years and <3 years. Multivariate analyses of prostate-specific antigen doubling time with cancer risk and grade (≤3 + 4 vs ≥4 + 3) were carried out using logistic regression adjusting for prebiopsy prostate-specific antigen, race, age, digital rectal examination, year of biopsy and number of prior negative biopsies., Results: The median prostate-specific antigen doubling time before biopsy was 4.5 years (interquartile range = 2.5-10). Shorter prostate-specific antigen doubling time was associated with higher prostate-specific antigen (P < 0.001), but it was unrelated to age, digital rectal examination or race. Shorter prostate-specific antigen doubling time as a continuous variable was associated with greater prostate cancer risk in both uni- (hazard ratio = 0.99, 95% confidence interval = 0.98-0.99, P = 0.001) and multivariate analysis (hazard ratio = 0.99, 95% confidence interval = 0.98-0.99, P = 0.004). The prevalence of cancer among prostate-specific antigen doubling time groups (>9, 3-9, <3 years) was 17%, 37% and 40%, respectively. Shorter prostate-specific antigen doubling time groups were associated with higher cancer risk (P = 0.001). Stratified by grade, short prostate-specific antigen doubling time as a continuous variable significantly predicted both low- (P = 0.010) and high-grade disease (P = 0.049). The inclusion of prostate-specific antigen doubling time groups in a multivariate model to predict biopsy positivity increased its accuracy from 0.69 to 0.74., Conclusion: Prostate-specific antigen doubling time seems to provide further cancer risk assessment in men undergoing repeat biopsy for prostate-specific antigen ≥4.0 ng/mL. If validated in future studies, the present findings support the use of prostate-specific antigen doubling time in the risk stratification of this patient population., (© 2012 The Japanese Urological Association.)

Background: To what degree the associations between PCa risk and family history of prostate cancer (PCa) and/or breast cancer (BCa) are attributable to screening biases is unclear. We examined these questions within the REDUCE study, where biopsies were largely independent of prostate specific antigen (PSA) minimizing screening biases., Methods: Data were from REDUCE, which tested dutasteride 0.5 mg daily for PCa risk reduction in men with PSA 2.5-10.0 ng mL(-1) and a negative prestudy biopsy. Among men undergoing at least one on-study biopsy with complete data (n = 6415; 78.1%), the association between family history and PCa risk was tested using multivariate logistic regression adjusting for clinicodemographic characteristics., Results: A family history of PCa alone was associated with increased PCa diagnosis (OR: 1.47, 95%CI: 1.22-1.77). In North America, PCa family history was not related to PCa diagnosis (OR: 1.02, 95%CI: 0.73-1.44), whereas outside North America, PCa family history was significantly related to diagnosis (OR: 1.72, 95%CI: 1.38-2.15) (P-interaction = 0.01). A family history of both PCa and BCa (OR: 2.54, 95%CI: 1.72-3.75) but not BCa alone (OR: 1.04, 95%CI: 0.84-1.29) was associated with increased PCa risk versus no family history and irrespective of geographical region., Conclusions: In REDUCE, PCa family history was significantly related to PCa diagnosis, although only for men outside North America. The presence of both PCa and BCa family history significantly increased risk versus PCa family history alone, irrespective of geographical region. Ultimately, our observations may support the need for changes in how we address family history in terms of both risk of PCa diagnosis and general risk stratification., (© 2012 The Association for the Publication of the Journal of Internal Medicine.)

Introduction: Erectile dysfunction (ED) is related to several co-morbidities including obesity, metabolic syndrome, cigarette smoking, and low testosterone, all of which have been reported to be associated with adverse prostate cancer features., Aim: To examine whether preoperative ED has a relationship with adverse prostate cancer features in patients who underwent radical prostatectomy (RP)., Methods: We analyzed data from our institution on 676 patients who underwent RP between 2001 and 2010. Crude and adjusted logistic regression models were used to investigate the association between preoperative ED and several pathological parameters. The log-rank test and multivariate proportional hazards model were conducted to determine the association of preoperative ED with biochemical recurrence (BCR)., Main Outcome Measures: The expanded prostate cancer index composite (EPIC) instrument was used to evaluate preoperative erectile function (EF). Preoperative normal EF was defined as EPIC-SF ≥ 60 points while ED was defined as preoperative EPIC-SF lower than 60 points., Results: Preoperatively, a total of 343 (50.7%) men had normal EF and 333 (49.3%) men had ED. After adjusting for covariates, preoperative ED was identified a risk factor for positive extracapsular extension (OR 1.57; P = 0.029) and high percentage of tumor involvement (OR 1.56; P = 0.047). In a Kaplan-Meier curve, a trend was identified that patients with ED had higher incidence of BCR than men with normal EF (P = 0.091). Moreover, using a multivariate Cox model, higher preoperative EF was negatively associated with BCR (HR 0.99; P = 0.014)., Conclusions: These results suggest that the likelihood for adverse pathological outcomes as well as BCR following prostatectomy is higher among men with preoperative ED, though these results require validation in larger datasets. The present study indicates that preoperative ED might be a surrogate for adverse prostate cancer outcomes following RP., (© 2011 International Society for Sexual Medicine.)

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., (©2012 AACR.)

Purpose: We previously found that patients undergoing robotic assisted laparoscopic radical prostatectomy vs radical retropubic prostatectomy had a higher likelihood of not being satisfied, independent of side effect profile. We hypothesized that differential preoperative expectations might contribute to this finding. In the current study we compared expectations of patients undergoing robotic assisted laparoscopic radical prostatectomy vs radical retropubic prostatectomy., Materials and Methods: A questionnaire on expectations regarding recovery was administered to 171 patients electing to undergo robotic assisted laparoscopic radical prostatectomy or radical retropubic prostatectomy from 2008 to 2010. We prospectively collected data on patient expectations before surgery. Differences between patients undergoing robotic assisted laparoscopic radical prostatectomy vs radical retropubic prostatectomy were assessed with adjusted proportional odds models., Results: Patients who underwent robotic assisted laparoscopic radical prostatectomy (97) did not differ significantly from those treated with radical retropubic prostatectomy (74) in age, race, income, time between survey and surgery, and prostate specific antigen (p ≥0.4). Patients who underwent radical retropubic prostatectomy had significantly higher clinical stage and Gleason grade disease (p ≤0.007). After adjusting for socioeconomic factors, clinical stage and grade on multivariate analysis, patients who underwent robotic assisted laparoscopic radical prostatectomy expected a significantly shorter length of stay (OR 0.07, p <0.001) and earlier return to physical activity (OR 0.36, p = 0.005). The choice of robotic assisted laparoscopic radical prostatectomy (OR 0.41, p = 0.012), younger age (OR 0.49, p = 0.001) and higher preoperative International Index of Erectile Function-5-item version score (OR 0.60, p = 0.017) were independently associated with the expectation of earlier return of erections but not of continence on multivariate analysis., Conclusions: The body of evidence surrounding robotic assisted laparoscopic radical prostatectomy supports shorter hospitalization but there is no conclusive evidence that the robotic approach results in earlier return to physical activity or improved disease specific outcomes. Nonetheless we found that patients who underwent robotic assisted laparoscopic radical prostatectomy had higher expectations regarding these outcomes, particularly that of erectile function recovery, than did their radical retropubic prostatectomy counterparts., (Copyright © 2012 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Objective: The objective of this study was to examine the association between calcium intake and prostate cancer risk. We hypothesized that calcium intake would be positively associated with lower risk for prostate cancer., Methods: We used data from a case-control study conducted among veterans between 2007 and 2010 at the Durham Veterans Affairs Medical Center. The study consisted of 108 biopsy-positive prostate cancer cases, 161 biopsy-negative controls, and 237 healthy controls. We also determined whether these associations differed for blacks and whites or for low-grade (Gleason score <7) and high-grade prostate cancer (Gleason score ≥7). We administered the Harvard food frequency questionnaire to assess diet and estimate calcium intake. We used logistic regression models to obtain odds ratios (ORs) and 95% confidence intervals (CIs)., Results: Intake of calcium from food was inversely related to risk for prostate cancer among all races in a comparison of cases and biopsy-negative controls (P = .05) and cases and healthy controls (P = .02). Total calcium was associated with lower prostate cancer risk among black men but not among white men in analyses of healthy controls. The highest tertile of calcium from food was associated with lower risk for high-grade prostate cancer in a comparison of high-grade cases and biopsy-negative controls (OR, 0.37; 95% CI, 0.15-0.90) and high-grade cases and healthy controls (OR, 0.38; 95% CI, 0.17-0.86)., Conclusion: Calcium from food is associated with lower risk for prostate cancer, particularly among black men, and lower risk for high-grade prostate cancer among all men.

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-trend<0.001) 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 PSA<4 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.

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.

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.

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., Materials and Methods: 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., Results: At biopsy, 284 (28%) men had DM. DM was associated with African American (AAM; p = 0.010) and higher BMI (p < 0.001). DM was not associated with prostate cancer risk on either bivariate (p = 0.600) or multivariate analysis (p = 0.485). Similar results were found after stratification by race and obesity. In multivariable analysis, DM was associated with greater risk of high-grade disease (RR = 2.13, p = 0.024). The association was stronger among obese men (RR = 3.84, p = 0.020) and null in non-obese subjects (RR = 1.39, p = 0.460). After further stratification by race, DM was associated with high-grade disease only in obese Caucasian men (CM; RR = 5.81, p = 0.025) but not in obese AAM. DM was not associated with risk of low-grade disease in all men together or after stratification by obesity or race., Conclusion: History of DM was associated with greater risk of high-grade disease. The association was strongest among obese CM suggesting the effect of DM on high-grade prostate cancer is modified by race and obesity.

Experimental studies suggest omega-3 (n-3) polyunsaturated fatty acids (PUFA) suppress and n-6 PUFA promote prostate tumor carcinogenesis. Epidemiologic evidence remains inconclusive. The objectives of this study were to examine the association between n-3 and n-6 PUFA and prostate cancer risk and determine if these associations differ by race or disease aggressiveness. We hypothesize that high intakes of n-3 and n-6 PUFA will be associated with lower and higher prostate cancer risk, respectively. A case-control study comprising 79 prostate cancer cases and 187 controls was conducted at the Durham VA Medical Center. Diet was assessed using a food frequency questionnaire. Logistic regression analyses were used to obtain odds ratios (ORs) and 95% confidence intervals (95% CI) for the associations between n-3 and n-6 PUFA intakes, the dietary ratio of n-6/n-3 fatty acids, and prostate cancer risk. Our results showed no significant associations between specific n-3 or n-6 PUFA intakes and prostate cancer risk. The highest dietary ratio of n-6/n-3 was significantly associated with elevated risk of high-grade (OR, 3.55; 95% CI, 1.18-10.69; P(trend) = 0.03), but not low-grade prostate cancer (OR, 0.95; 95% CI, 0.43-2.17). In race-specific analyses, an increasing dietary ratio of n-6/n-3 fatty acids correlated with higher prostate cancer risk among white men (P(trend) = 0.05), but not black men. In conclusion, our findings suggest that a high dietary ratio of n-6/n-3 fatty acids may increase the risk of overall prostate cancer among white men and possibly increase the risk of high-grade prostate cancer among all men., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: Cholesterol-lowering drugs known as statins have been reported to have significant anti-inflammatory properties. Given that inflammation may contribute to prostate cancer progression and that statins may reduce the risk for advanced prostate cancer, we investigated whether statin use was associated with reduced intratumoral inflammation in radical prostatectomy (RP) specimens., Methods: Inflammation within index tumors of 236 men undergoing RP from 1996 to 2004 was graded by a single pathologist as grade 0 (absent), 1 (mild: < or =10%), and 2 (marked: >10%). Preoperative statin use was analyzed by grouping subjects as statin users or nonusers. Type and dosage of statin was accounted for using dose equivalents with 20 mg simvastatin as reference. Logistic regression was used to determine the association between statin use and intratumoral inflammation controlling for age, race, body mass index, prostate-specific antigen, year of surgery, clinical stage, pathologic Gleason sum, surgical margin status, extracapsular extension, seminal vesicle invasion, prostate weight, time from prostate biopsy to RP, and nonsteroidal anti-inflammatory drug use., Results: Preoperative statin use was significantly associated with lower risk for any (grade > or =1) intratumoral inflammation (odds ratio, 0.31; 95% confidence interval, 0.10-0.98; P = 0.047) on multivariable analysis, with doses > or =20 mg simvastatin equivalents being more strongly associated (relative to nonuse; odds ratio, 0.22; 95% confidence interval, 0.06-0.79; P = 0.02)., Conclusion: In a cohort of men undergoing RP, statin use was associated with significantly lower risk of any inflammation within prostate tumors., Impact: Given previous reports that inflammation is associated with advanced prostate cancer, and statin use is associated with decreased prostate cancer progression risk, our findings suggest that inhibition of inflammation within tumors may be a potential mechanism for purported anti-prostate cancer properties of statins.

Objectives: To validate the Shared Equal Access Regional Cancer Hospital (SEARCH) nomogram to better risk stratify men with intermediate-risk pathology after prostatectomy (positive surgical margins, PSM, and/or extracapsular disease, ECE, without seminal vesicle or lymph node involvement) in a tertiary referral centre (the Duke Prostate Center, DPC)., Patients and Methods: We retrospectively analysed 485 men in the DPC cohort with PSM and/or ECE but without seminal vesicle or lymph node involvement. The predicted risk of biochemical progression-free probability at 1, 3 and 5 years was estimated by the SEARCH and updated Kattan postoperative nomograms. Calibration plots were generated and accuracy assessed with the concordance index., Results: The SEARCH nomogram appeared to be well calibrated, with the highest-risk quartile having a predicted <60% progression-free probability at 5 years, vs >80% for the lowest risk. In comparison, overall external calibration appeared to be similar for the updated Kattan nomogram, although there was less separation between the highest- and lowest-risk quartiles. The SEARCH model had an overall predictive accuracy of 0.65, which compared favourably with the updated Kattan nomogram (0.57)., Conclusion: In an external dataset, the SEARCH nomogram to predict progression-free probability for men at intermediate risk after prostatectomy was well calibrated and performed better than the updated postoperative Kattan nomogram.

Purpose: Epidemiological and molecular evidence suggest potential associations between exercise and prostate cancer risk reduction. We further characterized this relationship by examining exercise and cancer risk among men undergoing prostate needle biopsy., Materials and Methods: A total of 190 men who underwent prostate biopsy at the Durham Veterans Affairs Medical Center completed a questionnaire on current exercise behavior. Participants were asked average frequency of mild, moderate and strenuous intensity exercise in a typical week, as well as average duration as assessed by the Godin Leisure Time Exercise Questionnaire. Total current exercise was calculated in terms of metabolic equivalent task hours per week. Primary outcome measures were prostate biopsy result and Gleason sum., Results: After adjusting for age, race, body mass index, prostate specific antigen, digital rectal examination, family history, previous prostate biopsy and comorbidity score, men who reported 9 or more metabolic equivalent task hours per week of exercise were significantly less likely to have cancer on biopsy (OR 0.35, CI 0.17-0.75, p = 0.007). Furthermore, among men with malignant biopsy results, reporting moderate exercise (3 to 8.9 metabolic equivalent task hours weekly) was associated with a lower risk of high grade disease (Gleason 7 or greater, OR 0.14, CI 0.02-0.94, p = 0.04)., Conclusions: To our knowledge these results provide the first evidence of an association between exercise and prostate cancer risk as well as grade at diagnosis in men scheduled to undergo prostate biopsy. Specifically moderate exercise was associated with a lower risk of prostate cancer and in men with cancer, lower grade disease. Further investigation using an objective measure of exercise in a larger sample size is required to confirm these findings.

Purpose: Prostate cancer frequently progresses from an initial androgen dependence to androgen independence, rendering the only effective androgen ablation therapy useless. The mechanism underlying the androgen-independent progression is incompletely understood. Interleukin (IL)-6 has been implicated in this androgen-independent progression. In this study, we tested whether IL-6 induces androgen-independent growth both in vitro and in vivo., Experimental Design: IL-6 was expressed in androgen-sensitive LNCaP cells. The effects of IL-6 on androgen receptor activity was determined by Northern blots and gel shift assays. The effects of IL-6 on LNCaP cell growth were determined in vitro by MTT assay and in vivo., Results: IL-6 can enhance the growth of androgen-sensitive LNCaP cells in the androgen-deprived condition in vitro, which is accompanied by elevation of androgen-regulated prostate-specific antigen mRNA expression. IL-6 promotes androgen-sensitive LNCaP cell tumor growth in the castrated male mice. IL-6 enhances androgen receptor DNA binding activity and nuclear translocation. The androgen-independent phenotype induced by IL-6 in LNCaP cells is accompanied by significant activation of signal transducers and activators of transcription 3 and mitogen-activated protein kinase signal pathways., Conclusions: These studies clearly provide experimental evidence that IL-6 initiates and/or enhances the transition of prostate cancer cells from an androgen-dependent to an androgen-independent phenotype.