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

Introduction The association between early and late phase sexual health-related quality of life (HRQoL) following radical prostatectomy (RP) is unclear. Moreover, factors that predict either early or late sexual HRQoL decline have not been fully investigated. Aim The aim of this study was to evaluate the correlation between early and late phase sexual HRQoL decline, and identify clinical parameters that predict substantial sexual HRQoL decline after surgery in the early phase (3 months) and late phase (20 months) following RP. Methods We analyzed data on 2,345 consecutive patients who underwent radical retropubic prostatectomy, radical perineal prostatectomy, or robotic-assisted laparoscopic prostatectomy between 2001 and 2009 from the Duke Prostate Center database. Main Outcome Measure Sexual HRQoL was assessed using the Expanded Prostate Cancer Index Composite instrument at baseline, early and late phase after surgery. The Spearman rank test was used to calculate correlation coefficients between early and late phase sexual HRQoL decline. Logistic regression analysis was performed to identify factors associated with substantial sexual HRQoL decline during both phases. Results Of 406 men who met our criteria, 217 (53.5%) men had normal erectile function, whereas 189 (46.5%) men had erectile dysfunction at baseline. Declines of sexual HRQoL during early phase had a significant association with that of a decline during late phase (r = 0.48, P Conclusions Sexual HRQoL at early and late phases after RP were strongly correlated. Additionally, several factors were identified to be a predictor for decline of sexual HRQoL. Our findings may be used to advise patients who possess aforementioned risk factors during both phases.

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.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.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, p0.001) 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.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.

The multidisciplinary approach is becoming increasingly encouraged but little is known about the multidisciplinary experience compared to routine care. For patients with prostate cancer the goal is to provide evaluations by urologists, medical and radiation oncologists at a single visit. Although additional resources are required, this strategy may enhance the overall health care experience. We compared utilization determinants between a multidisciplinary and a urology prostate cancer clinic at Duke University Medical Center and identified factors associated with pursuing treatment at the university medical center for multidisciplinary clinic patients.We retrospectively analyzed data on patients referred for primary prostate cancer treatment evaluation at Duke University Medical Center from 2005 to 2009. Comparisons between 701 multidisciplinary clinic and 1,318 urology prostate cancer clinic patients were examined with the rank sum and chi-square tests. Predictive factors for pursuing treatment at the university medical center were assessed using multivariate adjusted logistic regression.Compared to patients at the urology prostate cancer clinic those at the multidisciplinary clinic were more likely to be younger and white, have a higher income and travel a longer distance for evaluation. Of multidisciplinary clinic patients 58% pursued primary treatment at the university medical center. They were more likely to be younger, black and physician referred, have a lower income and reside closer to the medical center. Factors predictive of pursuing treatment at the medical center included high risk disease and physician referral. Factors predictive of not receiving care at the university medical center were income greater than $40,000 and a distance traveled of greater than 100 miles.A different patient demographic is using the multidisciplinary approach. However, when treatment is pursued at the institution providing multidisciplinary services, the patient demographic resembles that of the treating institution.

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.

INTRODUCTION AND OBJECTIVES: African-American men (AAM) are at higher risk for prostate cancer (PC) vs. Caucasian men (CM). The cause is likely multi-factorial. Though alcohol intake as a PC risk factor in the overall population is controversial, we recently reported that, among men undergoing prostate biopsy, alcohol intake was associated with increased PC risk only among AAM. Polymorphisms of the alcohol dehydrogenase (ADH) gene, that lead to bodily accumulation of acetaldehyde a carcinogen, occur more frequently in AAM. Whether these alleles interact with alcohol exposure to promote PC development is unknown. METHODS: DNA and alcohol intake surveys were obtained from 347 men from the Durham VA Hospital who underwent prostate biopsy (n 199) or were hospital-based controls (n 148 with no indication for biopsy) from 2007 to 2010. The DNA was genotyped for ADH1B*3 and dichotomized into carriers of the common allele (ADH1B*3-; C/C) and the variant allele (ADH1B*3 ; C/T or T/T). Alcohol intake was dichotomized into non-drinker and alcohol drinker. Two separate logistic regression models, adjusting for clinical covariates, were conducted: 1) Only among men who underwent a biopsy; 2) Comparing men with cancer on biopsy to the controls. RESULTS: A total of 60 (13%) men were heterozygous and 11 (2%) were homozygous for ADH1B*3. Nearly all ADH1B*3 subjects were AAM (n 69; 97%) with 35% of AAM carrying the variant allele. ADH1B*3 alcohol drinkers were 4 times more likely to have a positive biopsy than ADH1B*3non-drinkers (OR 3.7, 95%CI 1.0– 13.3). In crude analysis comparing biopsy men to controls, ADH1B*3 alcohol drinkers were 5 times more likely to have PC than ADH1B*3non-drinkers. There was a trend for increased PC risk among ADH1B*3 alcohol drinkers in multivariate analyses which did not reach statistical significance (p 0.11). In all models, PC risk for ADH1B*3 non-drinkers and ADH1B*3alcohol drinkers were not different from ADH1B*3non-drinkers. CONCLUSIONS: Our preliminary findings suggest the ADH1B*3 variant allele and alcohol intake is a novel gene-environment interaction for PC risk, nearly unique to AAM. If confirmed, this geneenvironment interaction may help explain increased PC risk in AAM who consume alcohol, while no effect is seen in CM.

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.

To investigate the predictors of secondary treatment for recurrent prostate cancer after radical prostatectomy (RP) among subjects from the Shared Equal Access Regional Cancer Hospital (SEARCH) database.We used Kaplan-Meier curves and Cox proportional hazard models to identify factors associated with time to secondary treatment and type of secondary treatment received among 697 men who developed biochemical recurrence (BCR) after RP.During a median follow-up of 45 months after BCR, 357 men received salvage treatment. The 1-, 3-, and 5-year risk of receiving any salvage treatment was 29% (95% confidence interval (CI) 26-33%), 48% (95%CI 44-52%), and 53% (95%CI 49-57%), respectively. In multivariate analysis, more recent year of recurrence, centre, shorter disease-free interval, and pathological high-grade disease (Gleason 8-10) predicted increased risk of salvage treatment (all P0.01). Predictors of specifically receiving radiotherapy were shorter disease-free interval, centre, and more recent year of BCR (all P0.001). Predictors of specifically receiving hormonal therapy were shorter disease-free interval, more recent year of BCR, centre, high Gleason score, and higher tumour stage (all P0.05). In a subset analysis of men with available prostate-specific antigen doubling time (PSADT) data, shorter PSADT predicted receipt of any salvage treatment as well as radiation and hormonal therapy separately. CONCLUSIONS; Among men who recur after RP, salvage treatment was associated with disease severity, centre and year of BCR; patient-specific factors (race, body mass index and age) were not predictive of secondary treatment. Although patients are being treated more aggressively in contemporary years, the affect on long-term survival is unknown.

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)

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.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.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).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.

OBJECTIVE To compare the efficacy and tolerability of peripheral androgen blockade using combined low-dose flutamide plus finasteride vs low-dose flutamide monotherapy for treating biochemical relapse after the definitive management of prostate adenocarcinoma. PATIENTS AND METHODS Fifty-six men treated for biochemical relapse of prostate cancer were enrolled prospectively in a phase II trial at the Walter Reed Army Medical Center from 1997 to 2001. Thirty-six men were treated with flutamide (125 mg twice daily) and finasteride (5 mg twice daily), and 20 men received low-dose flutamide only after biochemical recurrence (prostate-specific antigen, PSA, level ≥0.4 ng/mL). Cox proportional hazards analyses were used to compare the risk of progression between the groups. RESULTS Patients on combined and monotherapy had a median follow-up of 54 and 43.5 months, respectively. Seven men (19%) in the combined arm remain in the study with no progression, while five (25%) on monotherapy continue and are progression-free. Men on combined therapy had a greater decrease in their PSA level (P = 0.002). Multivariate analysis showed that men on combined therapy had significantly less risk of progression than men on monotherapy (hazard ratio 0.21, 95% confidence interval 0.07–0.63, P = 0.005). There was no significant difference in the frequency of side-effects between the groups. Toxicities were reported to be mild. CONCLUSIONS Our analysis suggests the therapeutic value of low-dose flutamide alone or combined with finasteride as first-line agents in a possible graduated approach for treating PSA-only recurrent prostate cancer. Due to unwanted metabolic effects associated with traditional hormonal agents, phase III trials comparing both regimens with current therapies are warranted.

In men with extracapsular disease or positive surgical margins after radical prostatectomy immediate adjuvant therapy decreases the risk of biochemical recurrence at the cost of increased toxicity. We further stratified these men into a low risk group in which watchful waiting after surgery may be preferred and a high risk cohort in which adjuvant therapy may be preferred.We performed a retrospective analysis of the records of 902 men treated with radical prostatectomy in the Shared Equal-Access Regional Cancer Hospital (SEARCH) database between 1988 and 2007 with positive surgical margins and/or extracapsular disease without seminal vesicle invasion or lymph node metastasis. The significant independent predictors of biochemical recurrence were determined using a multivariate Cox proportional hazards model. Based on the recurrence risk generated from the multivariate Cox proportional hazards regression model we generated tables to estimate the risk of recurrence-free survival 1, 3 and 5 years after surgery.At a median of 3 years of followup 346 patients (39%) had biochemical recurrence. On multivariate analysis the significant predictors of biochemical recurrence were age more than 60 years, prostate specific antigen more than 10 ng/ml, Gleason score 4 + 3 and 8-10, 2 or more sites of positive surgical margins and prostate specimen weight 30 gm or less. As determined by the concordance index, the overall predictive accuracy of the model was 0.67, while it was 0.60 for the postoperative Kattan nomogram in this patient population.We have developed a simple instrument that, once validated, may aid in the postoperative decision making process for men at intermediate risk for recurrence after prostatectomy.

Rising prostate-specific antigen (PSA) in nonmetastatic prostate cancer occurs in two main clinical settings: (1) rising PSA to signal failed initial local therapy and (2) rising PSA in the setting of early hormone-refractory prostate cancer prior to documented clinical metastases. Most urologists and radiation oncologists are very familiar with the initial very common clinical scenario, commonly called "biochemical recurrence." In fact, up to 70,000 men each year will have a PSA-only recurrence after failed definitive therapy. The ideal salvage therapy for these men is not clear and includes salvage local therapies and systemic approaches, of which the mainstay is hormonal therapy. Treatment needs to be individualized based upon the patient's risk of progression and the likelihood of success and the risks involved with the therapy. It is unknown how many men per year progress with rising PSA while on hormonal therapy without documented metastases. This rising PSA disease state is sometimes called, "PSA-only hormone-refractory prostate cancer." As in the setting of initial biochemical recurrence, evidence-based treatment options are limited, and taking a risk-stratified approach is justified. In this article, we will explore these prostate cancer disease states with an emphasis on practical, clinically applicable approaches.

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.

Background: Protein expression profiling for differences indicative of early cancer has promise for improving diagnostics. This report describes the first stage of a National Cancer Institute/Early Detection Research Network-sponsored multiinstitutional evaluation and validation of this approach for detection of prostate cancer. Methods: Two sequential experimental phases were conducted to establish interlaboratory calibration and standardization of the surface-enhanced laser desorption (SELDI) instrumental and assay platform output. We first established whether the output from multiple calibrated Protein Biosystem II SELDI-ionization time-of-flight mass spectrometry (TOF-MS) instruments demonstrated acceptable interlaboratory reproducibility. This was determined by measuring mass accuracy, resolution, signal-to-noise ratio, and normalized intensity of three m/z “peaks” present in a standard pooled serum sample. We next evaluated the ability of the calibrated and standardized instrumentation to accurately differentiate between selected cases of prostate cancer and control by use of an algorithm developed from data derived from a single site 2 years earlier. Results: When the described standard operating procedures were established at all laboratory sites, the across-laboratory measurements revealed a CV for mass accuracy of 0.1%, signal-to-noise ratio of ∼40%, and normalized intensity of 15–36% for the three pooled serum peaks. This was comparable to the intralaboratory measurements of the same peaks. The instrument systems were then challenged with sera from a selected group of 14 cases and 14 controls. The classification agreement between each site and the established decision algorithm were examined by use of both raw peak intensity boosting and ranked peak intensity boosting. All six sites achieved perfect blinded classification for all samples when boosted alignment of raw intensities was used. Four of six sites achieved perfect blinded classification with ranked intensities, with one site passing the criteria of 26 of 28 correct and one site failing with 19 of 28 correct. Conclusions: These results demonstrate that “between-laboratory” reproducibility of SELDI-TOF-MS serum profiling approaches that of “within-laboratory” reproducibility as determined by measuring discrete m/z peaks over time and across laboratories.

Prostate-specific antigen (PSA) test has become a widely used screening test in prostate cancer (CaP). However, low specificity of serum PSA leads to many false-positive and false-negative results and clinical uncertainty. Development of CaP-specific diagnostic and prognostic markers is needed. Detection of circulating PSA-expressing cells (CPECs) in blood and bone marrow of CaP patients has potential in molecular diagnosis and prognosis. Our novel observations of the frequent presence of CPECs in CaP patients with organ-confined disease by reverse transcription (RT)-PCR-PSA assay in epithelial cells enriched from peripheral blood (ERT-PCR/PSA) have led us to test the hypothesis that CPECs have diagnostic potential for CaP.Epithelial cells from peripheral blood of radical prostatectomy patients or prostate biopsy patients were isolated using antiepithelial cell antibody, Ber-EP4-coated magnetic beads, and total RNA specimens from these cells were analyzed for PSA expression by RT-PCR.Peripheral blood specimens of 108 of 135 (80.0%) CaP patients were positive in ERT-PCR/PSA assay. Peripheral blood specimens from 45 control men were virtually negative (97.8%). In the blinded investigation, 84 patients who had biopsy for suspicion of CaP were evaluated by ERT-PCR/PSA assay. Eighteen of 22 (81.8%) patients with biopsy-proven CaP were positive, and 54 of 62 (87.1%) patients with biopsy negative for CaP were negative in this assay (P0.001).Our study provides intriguing novel results showing that the majority of patients with clinically organ-confined CaP contain CPECs. Strong concordance between the biopsy results and ERT-PCR/PSA assay (sensitivity 81.8%; specificity 87.1%) suggests a potentially new diagnostic application of this type of assay in CaP diagnosis.

Purpose: The serum prostate specific antigen test has been widely used in the last decade as an effective screening tool for prostate cancer (CaP). However, the high false-positive rate of the serum prostate specific antigen test necessitates the development of more accurate diagnostic and prognostic biomarkers for CaP. Promising diagnostic potential of serum protein patterns detected by surface enhanced laser desorption/ionization time of flight mass spectrometry for CaP has recently been reported. Independent evaluation of this new technology is warranted to realize its translational utility. We determined whether serum protein profiling by surface enhanced laser desorption/ionization time of flight mass spectrometry and a decision tree algorithm classification system could accurately discriminate between patients with CaP and unaffected individuals. Materials and Methods: Proteomic spectra of crude serum were generated using the Ciphergen ProteinChip System and pattern detection was performed using Biomarker Patterns Software (Ciphergen Biosystems, Inc., Fremont, California). A total of 106 patients with CaP and 56 controls were randomly allocated to a training set and a test set. The training set, which consisted of 44 patients with cancer and 30 controls, was used to build a decision tree algorithm. The test set, which consisted of 62 patients with cancer and 26 controls, was used in blinded fashion to validate the decision tree. Results: Accuracy of classification using the test set was 67% and 42% for the weak cation exchange array and the copper metal affinity capture array, respectively. Combined spectral data from the weak cation exchange and copper metal affinity capture arrays generated an algorithm that achieved 85% sensitivity and 85% specificity for the detection of CaP. Conclusions: These preliminary findings support recent observations that complex protein profiles have promising potential for the early detection of CaP and warrant future studies with streamlined technology. Furthermore, the combined effect of using 2 array types can greatly enhance the ability of protein profile patterns, suggesting the potential usefulness of alternative approaches to evaluate this new emerging technology.

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