Faculty Bibliography

BACKGROUND: Prostate-specific antigen (PSA) is the only independent predictor of biochemical recurrence (BCR) following radical prostatectomy (RP) subject to change over time. OBJECTIVE: To determine whether an ultrasensitive PSA measured at 3 yr following RP is a predictor of subsequent BCR. DESIGN, SETTING, AND PARTICIPANTS: There were 1197 consecutive men with clinically localized prostate cancer who underwent an open radical retropubic prostatectomy (ORRP) at a tertiary referral academic medical center. Exclusions included 107 men (8.9%) who developed a PSA level >/=0.2 ng/ml or underwent hormone therapy or radiation therapy (RT) within the first 3 r after surgery, 191 men (16%) who did not undergo a 3-yr ultrasensitive PSA assay, and 98 men (8.2%) who had PSA levels >/=0.1 and <0.2 at 3 yr. The remaining 801 men were stratified into two groups based on their ultrasensitive PSA level at 3 yr postoperatively: group 1, which consisted of patients whose PSA was </=0.04 (n=765), and group 2, which consisted of patients whose PSA was >0.04 and <0.10 (n=36). MEASUREMENTS: Delayed BCR was the primary end point and represented those men in this cohort who developed a PSA level >/=0.2 or underwent salvage RT for a persistently rising PSA level after 3 yr of follow-up. RESULTS AND LIMITATIONS: The 7-yr cumulative BCR-free survival rate for groups 1 and 2 was 0.957 (95% confidence interval [CI], 0.920-0.978) and 0.654 (95% CI, 0.318-0.855), respectively. In multivariable Cox proportional hazards models, ultrasensitive PSA level at 3 yr remained the only significant predictor of delayed BCR (likelihood ratio chi(2) for full model: 27.03; df=1; p < 0.001). A limitation of the study is that no uniform PSA assay was obtained. CONCLUSIONS: Our findings provide compelling evidence that an ultrasensitive PSA at 3 yr following RP provides useful insights into delayed BCR and is a source of reassurance for the overwhelming majority of men being followed for delayed recurrences

The optimal management of men with very favorable clinicopathological factors who develop biochemical recurrence (BCR) after radical prostatectomy (RP) has not been previously reported. Both local and systemic recurrences are unlikely in this cohort. This study examines their management and outcomes. Between October 2000 to March 2010, 1627 men underwent open RP by a single surgeon. In all, 448 (27.5%) met the following criteria for extremely low risk disease: preoperative PSA level <10 ng ml(-1), clinical stage T1c/T2a, Gleason score </=6, estimated cancer volume in the surgical specimen </=5% and no evidence for positive surgical margin. Undetectable PSA was defined as </=0.04 ng ml(-1). BCR was defined as PSA >/=0.2 ng ml(-1) or initiation of salvage radiation therapy (SRT) for progressively rising PSA. At 54 months mean follow-up (range 3-114 months), 9 (2%) of the 448 men developed BCR. Mean time to BCR was 63 months (range 12-93) and mean PSA doubling time was 15 months (range 6-27). Six underwent SRT, two elected surveillance and one was lost to follow-up. All men undergoing SRT exhibited more than 75% reduction in pre-SRT PSA, indicating the presence of local disease recurrence. All men undergoing SRT maintained PSA levels <0.1 at last follow-up. The BCR of 2% confirmed that we selected a cohort with extremely low risk for BCR after RP. We demonstrated that men fulfilling our criteria who develop BCR all harbor local disease based on favorable response to SRT. These men should be managed with SRT if recurrence is felt to be biologically significant

We have shown previously that during branching morphogenesis of the mouse prostate gland, Bone morphogenetic protein 7 functions to restrict Notch1-positive progenitor cells to the tips of the prostate buds. Here, we employed prostate-specific murine bi-genic systems to investigate the effects of gain and loss of Notch function during prostate development. We show that Nkx3.1(Cre) and Probasin(Cre) alleles drive expression of Cre recombinase to the prostate epithelium and periepithelial stroma. We investigated the effects of gain of Notch function using the Rosa(NI1C) conditional allele, which carries a constitutively active intracellular domain of Notch1 receptor. We carried out the analysis of loss of Notch function in Nkx3.1(Cre/+);RBP-J(flox/flox) prostates, where RBP-J is a ubiquitous transcriptional mediator of Notch signaling. We found that gain of Notch function resulted in inhibition of the tumor suppressor PTEN, and increase in cell proliferation and progenitor cells in the basal epithelium and smooth muscle compartments. In turn, loss of Notch/RBP-J function resulted in decreased cell proliferation and loss of epithelial and smooth muscle progenitors. Gain of Notch function resulted in an early onset of benign prostate hyperplasia by three months of age. Loss of Notch function also resulted in abnormal differentiation of the prostate epithelium and stroma. In particular, loss of Notch signaling and increase in PTEN promoted a switch from myoblast to fibroblast lineage, and a loss of smooth muscle. In summary, we show that Notch signaling is necessary for terminal differentiation of the prostate epithelium and smooth muscle, and that during normal prostate development Notch/PTEN pathway functions to maintain patterned progenitors in the epithelial and smooth muscle compartments. In addition, we found that both positive and negative modulation of Notch signaling results in abnormal organization of the prostate tissue, and can contribute to prostate disease in the adult organ

OBJECTIVES: To evaluate the accuracy and potential clinical value of intraoperative frozen section analysis (FSA) on urethral margin (UM) tissue during radical prostatectomy. Positive surgical margins increase the risk of post-operative cancer recurrence. Positive surgical margins are frequently found at the apex. The utility of intraoperative FSA of the margins is controversial. METHODS: We reviewed a consecutive series of radical prostatectomy cases (n = 1669) performed at our institution, in which UMs were routinely evaluated by intraoperative FSA. RESULTS: The submitted UM tissue contained cancer glands in 111 cases (6.7%). On FSA, the pathologists detected cancer in 55 cases (3.3%), missed cancer in 38 (2.3%), and reported atypical glands in 18 (1.1%). FSA of the UMs had a sensitivity of 59.1%, specificity of 99.8%, and positive and negative predictive value of 94.8% and 97.6%, respectively. The low sensitivity resulted from a substantial false-negative rate (n = 38), which was largely attributed to limited sampling on FSA (n = 31). Of the 55 patients (3.3%) whose positive UMs were detected by FSA, 20 (1.2%) had cancer-free margins after tissue re-excision. A positive final UM was associated with greater biochemical recurrence (P = .0073). However, the few patients limited the statistical analysis of the benefit of margin conversion through tissue re-excision (P = .35). CONCLUSIONS: Although experienced pathologists can evaluate the UMs on FSA with good accuracy, FSA has a relatively low sensitivity. Our data have indicated a low yield and a questionable value of routine FSA during radical prostatectomy

PURPOSE: The development of new effective therapeutic agents with minimal side effects for prostate cancer (PC) treatment is much needed. Indirubin, an active molecule identified in the traditional Chinese herbal medicine-Qing Dai (Indigo naturalis), has been used to treat leukemia for decades. However, the anticancer properties of Natura-alpha, an indirubin derivative, are not well studied in solid tumors, particularly in PC. EXPERIMENTAL DESIGN: The growth kinetics and invasion ability of on human PC cell lines with or without Natura-alpha treatment were measured by cell proliferation and invasion assays. The antitumor effects of Natura-alpha were examined in nude mice tumor xenograft models, and in a patient with advanced hormone-refractory metastatic PC. Signal network proteins targeted by Natura-alpha were analyzed by using proteomic pathway array analysis (PPAA) on xenografts. RESULTS: Natura-alpha inhibited the growth of both androgen-dependent (LNCaP) and androgen-independent (LNCaP-AI, PC-3, and DU145) PC cells with IC(50) between 4 to 10 mmol/L, and also inhibited invasion of androgen-independent PC cells. Its antitumor effects were further evident in in vivo tumor reduction in androgen-dependent and androgen-independent nude mice tumor xenograft models and reduced tumor volume in the patient with hormone refractory metastatic PC. PPAA revealed that antiproliferative and antiinvasive activities of Natura-alpha on PC might primarily be through its downregulation of Forkhead box M1 (FOXM1) protein. Forced overexpression of FOXM1 largely reversed the inhibition of growth and invasion by Natura-alpha. CONCLUSION: Natura-alpha could serve as a novel and effective therapeutic agent for treatment of both hormone-sensitive and hormone-refractory PC with minimal side effects.

PURPOSE: We evaluated the efficacy and safety of 2 doses of silodosin vs placebo in men with moderate to severe abacterial chronic prostatitis/chronic pelvic pain syndrome who had not been treated previously with alpha-blockers for chronic prostatitis/chronic pelvic pain syndrome. MATERIALS AND METHODS: In this multicenter, randomized, double-blind, phase II study, men 18 years old or older with chronic prostatitis/chronic pelvic pain syndrome, a total National Institutes of Health Chronic Prostatitis Symptom Index score of 15 or greater and a National Institutes of Health Chronic Prostatitis Symptom Index pain score of 8 or greater received 4 or 8 mg silodosin, or placebo once daily for 12 weeks. The primary efficacy end point was change from baseline to week 12 in National Institutes of Health Chronic Prostatitis Symptom Index total score. RESULTS: Of 151 patients (mean age 48 years) 52 received 4 mg silodosin, 45 received 8 mg silodosin and 54 received placebo. Silodosin 4 mg was associated with a significant decrease in total National Institutes of Health Chronic Prostatitis Symptom Index score (mean +/- SD change -12.1 +/- 9.3) vs placebo (-8.5 +/- 7.2, p = 0.0224), including a decrease in urinary symptom (-2.2 +/- 2.7, placebo -1.3 +/- 3.0, p = 0.0102) and quality of life (-4.1 +/- 3.1, placebo -2.7 +/- 2.5, p = 0.0099) subscores. The 4 mg dose of silodosin also significantly increased Medical Outcomes Study Short Form 12 physical component scores (4.2 +/- 8.1, placebo 1.7 +/- 9.0, p = 0.0492). During global response assessment 56% of patients receiving 4 mg silodosin vs 29% receiving placebo reported moderate or marked improvement (p = 0.0069). Increasing the dose of silodosin to 8 mg resulted in no incremental treatment effects. CONCLUSIONS: Silodosin 4 mg relieved symptoms and improved quality of life in men with chronic prostatitis/chronic pelvic pain syndrome but its efficacy requires confirmation in additional studies

PURPOSE: To assess ultrahigh (UH; prostate-specific antigen [PSA] levels >/=50 ng/ml) patient outcomes by comparison to other high-risk patient outcomes and to identify outcome predictors. METHODS AND MATERIALS: Prostate cancer patients (PCP) from two Phase III Radiation Therapy Oncology Group clinical trials (studies 9202 and 9413) were divided into two groups: high-risk patients with and without UH baseline PSA levels. Predictive variables included age, Gleason score, clinical T stage, Karnofsky performance score, and treatment arm. Outcomes included overall survival (OS), distant metastasis (DM), and biochemical failure (BF). Unadjusted and adjusted hazard ratios (HRs) were calculated using either the Cox or Fine and Gray's regression model with associated 95% confidence intervals (CI) and p values. RESULTS: There were 401 patients in the UH PSA group and 1,792 patients in the non-UH PSA PCP group of a total of 2,193 high-risk PCP. PCP with UH PSA were found to have inferior OS (HR, 1.19; 95% CI, 1.02-1.39, p = 0.02), DM (HR, 1.51; 95% CI, 1.19-1.92; p = 0.0006), and BF (HR, 1.50; 95% CI, 1.29-1.73; p < 0.0001) compared to other high-risk PCP. In the UH cohort, PSA level was found to be a significant factor for the risk of DM (HR, 1.01; 95% CI, 1.001-1.02) but not OS and BF. Gleason grades of 8 to 10 were found to consistently predict for poor OS, DM, and BF outcomes (with HR estimates ranging from 1.41-2.36) in both the high-risk cohort and the UH cohort multivariable analyses. CONCLUSIONS: UH PSA levels at diagnosis are related to detrimental changes in OS, DM, and BF. All three outcomes can be modeled by various combinations of all predictive variables tested

Lymphoid enhancer-binding factor (LEF)1 is a major mediator and a target in canonical Wnt/beta-catenin pathway. Interactions between the androgen receptor (AR) and canonical Wnt pathways have been implicated in the development of the genitourinary organs. Here, we investigated the localization and role of LEF1-positive cells during development of the prostate gland in human and in the murine model. We show that during human prostate development, LEF1 is restricted to the basal epithelial layer of the urogenital sinus. During mouse development, Lef1 is also present in the urogenital mesenchyme in addition to the basal epithelial layer of the urogenital sinus. In the course of elongation and branching of the prostatic ducts, Lef1 is localized to the proliferating epithelium at the distal tips of the buds. Notably, during branching morphogenesis, domains of Lef1 and AR are mutually exclusive. We further employed the TOPGAL reporter strain to examine the dynamics of Wnt signaling in the context of prostate regression upon a 7-d treatment with a competitive AR inhibitor, bicalutamide. We found that Wnt/Lef1-positive basal cells are not dependent upon androgen for survival. Furthermore, upon bicalutamide treatment, Wnt/Lef1-positive basal progenitors repopulated the luminal compartment. We conclude that Wnt/Lef1 activity identifies an androgen-independent population of prostate progenitors, which is important for embryonic development and organ maintenance and regeneration in the adult

PURPOSE: To identify predictors of apical surgical margin (ASM) and apical soft tissue margin (ASTM), determine if the ASTM is a better predictor of biochemical recurrence (BR) than the ASM, and ascertain the impact of apical biopsies on BR rates. MATERIALS AND METHODS: One thousand three hundred eight consecutive men underwent open radical retropubic prostatectomy (RP) between October 2000 and December 2006. Circumferential biopsies of the ASTM were obtained intraoperatively and submitted for frozen section analysis. Logistic regression models were utilized to identify the factors associated with the presence of positive ASMs and ASTMs. The estimated 5-year risk of BR was calculated by the Kaplan-Meier method. RESULTS: Overall, 43 (3.3%) and 86 (6.6%) of cases exhibited positive ASM and ASTM, respectively. ASM was significantly associated with higher mean serum prostate-specific antigen levels, presence of perineural invasion, and greater volume of tumor in the biopsy specimen. None of these factors were observed to be associated with the presence of cancer in the ASTMs. In the multivariate analysis, only the presence of perineural invasion was a significant independent predictor of ASMs. The estimated 5-year BR rates in the positive ASMs only, ASTMs only, and both positive ASMs and ASTMs groups were 48.6%, 4.7%, and 38.8%, respectively. CONCLUSIONS: A positive ASM was associated with a significantly greater risk of BR compared with a positive ASTM. The very low estimated risk of BR at 5 years in cases with ASTM suggests that performing the ASTM biopsies may increase the cure rates achieved with RP

Data from phase 3 studies (NCT00224107, NCT00224120) of silodosin for treatment of BPH symptoms were analyzed to examine the relationship between treatment efficacy and occurrence of abnormal ejaculation. Men aged >/=50 years with International Prostate Symptom Scores (IPSS) >/=13 and peak urinary flow rates (Qmax) of 4-15 ml s(-1) received placebo or silodosin 8 mg once daily for 12 weeks. Silodosin-treated patients were stratified by absence or presence of 'retrograde ejaculation' (RE). Groups were compared using analysis of covariance (for change from baseline) and responder analyses. Of the 466 patients receiving silodosin, 131 (28%) reported RE and 335 (72%) did not; 4 of the 457 patients receiving placebo (0.9%) reported RE. Most RE events in silodosin-treated patients (110/134; 82%) were reported as 'orgasm with absence of seminal emission.' Silodosin-treated patients with (+) and without (-) RE showed significant improvement in IPSS, Qmax and quality of life versus placebo (P<0.02). RE+ patients versus RE- patients experienced numerically greater improvement, but differences were not statistically significant (P>0.05). For RE+ patients, the odds of achieving improvement of >/=3 points in IPSS and >/=3 ml s(-1) in Qmax by study end were 1.75 times those for RE- patients (P=0.0127). Absence of seminal emission may predict superior treatment efficacy of silodosin in individual patients.