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Purpose: This study aimed to assess the medium-term oncologic outcomes of an active surveillance protocol, replacing confirmatory biopsy with serial multiparametric magnetic resonance imaging., Materials and Methods: A total of 172 men were enrolled in this single-arm prospective trial. Men with prostate cancer (Gleason 3+3=6 or Gleason 3+4=7 with ≤10% Gleason pattern 4 overall and <2 cores Gleason pattern 4) eligible for surveillance were included in the study. Men underwent baseline multiparametric magnetic resonance imaging and template ± targeted biopsy, then multiparametric magnetic resonance imaging at years 1 and 2 with a 3-year end-of-protocol biopsy. Biopsies during the 3-year protocol period were triggered by abnormalities on multiparametric magnetic resonance imaging and/or increases in prostate specific antigen density (>0.2 ng/ml/cc)., Results: The sensitivity, specificity, positive predictive value, and negative predictive value of multiparametric magnetic resonance imaging to detect progression to clinically significant prostate cancer were 57% (95% CI 39%-74%), 82% (95% CI 74%-89%), 50% (95% CI 38%-62%), and 86% (95% CI 81%-90%), respectively. Both multiparametric magnetic resonance imaging and prostate specific antigen density were significant predictors for progression (multiparametric magnetic resonance imaging OR 6.20, 95% CI 2.72-14.16, P < .001; prostate specific antigen density OR 6.19, 95% CI 2.14-17.92, P = .001). Only 2.3% (4/172) of patients had false-negative multiparametric magnetic resonance imaging and high-risk pathological features (pT3 or high-volume International Society of Urological Pathology >2). After a median 69 months (Q1-Q3 56-79) follow-up of all patients in the cohort, freedom from biochemical recurrence, metastasis, and prostate cancer-related death were 99.3%, 100%, and 100%, respectively., Conclusions: Final analysis of the Magnetic Resonance Imaging in Active Surveillance trial indicates that there is minimal risk to omitting 1-year confirmatory biopsy during active surveillance if baseline magnetic resonance-targeted + saturation template biopsy was performed; however, standardized 3-year systematic biopsy should be performed due to occasional magnetic resonance imaging-invisible tumors.

Purpose: Prospective studies are lacking in assessing the diagnostic utility of serial multiparametric magnetic resonance imaging to predict biopsy proven progression to clinically significant prostate cancer in men on active surveillance, as well as the oncologic safety of baseline magnetic resonance imaging and saturation diagnostic biopsy in replacing early confirmatory biopsy during active surveillance., Materials and Methods: A total of 172 men were enrolled in this single arm prospective trial. Men with cT2 or lower histologically proven prostate cancer (Gleason 3+3=6 or Gleason 3+4=7 with 10% or less Gleason pattern 4 overall and less than 2 cores Gleason pattern 4) eligible for surveillance were included in the study. Men underwent baseline multiparametric magnetic resonance imaging and saturation biopsy followed by serial annual multiparametric magnetic resonance imaging until a 3-year end point per protocol saturation biopsy. The standardized 1-year confirmatory biopsy was omitted and biopsies during the protocol were triggered based on new abnormalities on multiparametric magnetic resonance imaging and prostate specific antigen density., Results: We report the prespecified interim analysis of the first 100 men at 3 years. At baseline the median age was 64.5 (IQR 57.25-69) years, prostate specific antigen was 4.7 ng/ml (IQR 3.4-6.6), 91% had Gleason 3+3=6 prostate cancer and multiparametric magnetic resonance imaging was negative (Prostate Imaging Reporting and Data System 1/2/3) in 87% of men. Within 3 years 21% experienced pathological progression. The positive predictive value, negative predictive value, sensitivity and specificity for detection of clinically significant prostate cancer by surveillance multiparametric magnetic resonance imaging was 45%, 89%, 61% and 80%, respectively. Positive surveillance magnetic resonance imaging (p=0.002) and prostate specific antigen density greater than 0.2 ng/ml (p=0.042) had significant predictive value for clinically significant prostate cancer., Conclusions: Our novel active surveillance protocol incorporating multiparametric magnetic resonance imaging detected most cases of disease progression and may enable confirmatory biopsy to be deferred, but should not replace 3-year surveillance biopsy altogether due to occasional magnetic resonance imaging invisible tumors.

Purpose: To evaluate in a multi-institutional study whether radiomic features useful for prostate cancer (PCa) detection from 3 Tesla (T) multi-parametric MRI (mpMRI) in the transition zone (TZ) differ from those in the peripheral zone (PZ)., Materials and Methods: 3T mpMRI, including T2-weighted (T2w), apparent diffusion coefficient (ADC) maps, and dynamic contrast-enhanced MRI (DCE-MRI), were retrospectively obtained from 80 patients at three institutions. This study was approved by the institutional review board of each participating institution. First-order statistical, co-occurrence, and wavelet features were extracted from T2w MRI and ADC maps, and contrast kinetic features were extracted from DCE-MRI. Feature selection was performed to identify 10 features for PCa detection in the TZ and PZ, respectively. Two logistic regression classifiers used these features to detect PCa and were evaluated by area under the receiver-operating characteristic curve (AUC). Classifier performance was compared with a zone-ignorant classifier., Results: Radiomic features that were identified as useful for PCa detection differed between TZ and PZ. When classification was performed on a per-voxel basis, a PZ-specific classifier detected PZ tumors on an independent test set with significantly higher accuracy (AUC = 0.61-0.71) than a zone-ignorant classifier trained to detect cancer throughout the entire prostate (P < 0.05). When classifiers were evaluated on MRI data from multiple institutions, statistically similar AUC values (P > 0.14) were obtained for all institutions., Conclusion: A zone-aware classifier significantly improves the accuracy of cancer detection in the PZ., Level of Evidence: 3 Technical Efficacy: Stage 2 J. MAGN. RESON. IMAGING 2017;46:184-193., (© 2016 International Society for Magnetic Resonance in Medicine.)

Objective: To evaluate the accuracy of combined multiparametric magnetic resonance imaging (mpMRI) and transperineal template-guided mapping biopsy (TTMB) for identifying lobes with significant prostate cancer (PCa) for the application of hemi-ablative focal therapy (FT)., Patients and Methods: From January 2012 to January 2014, 89 consecutive patients, aged ≥40 years, with a PSA level ≤15 ng/mL, underwent in sequential order: mpMRI, TTMB and radical prostatectomy (RP) at a single centre. Analysis was performed on 50 patients who met consensus guidelines for FT. Lobes were stratified into lobes with significant cancer (LSC), lobes with insignificant cancer and lobes with no cancer. Using histopathology at RP, the predictive performance of combined mpMRI + TTMB in identifying LSC was evaluated., Results: The sensitivity, specificity and positive predictive value for mpMRI + TTMB for LSC were 97, 61 and 83%, respectively. The negative predictive value (NPV), the primary variable of interest, for mpMRI + TTMB for LSC was 91%. Of the 50 patients, 21 had significant unilateral disease on mpMRI + TTMB. Two of these 21 patients had significant bilateral disease on RP not identified on mpMRI + TTMB., Conclusions: In the selection of candidates for FT, a combination of mpMRI and TTMB provides a high NPV in the detection of LSC., (© 2015 The Authors BJU International © 2015 BJU International Published by John Wiley & Sons Ltd.)

Background: There are conflicting results in the literature regarding the tumor volume (TV) threshold that defines insignificant prostate cancer (PCa). In this study, we retrospectively evaluate the association of an increasing TV with biochemical recurrence (BCR) following radical prostatectomy (RP) in order to provide further clarification surrounding the TV threshold definition for insignificant PCa., Methods: RP patients were recruited from January 2004 to December 2009. Inclusion criteria were localized (stage ≤pT2c, negative surgical margins) Gleason 6 PCa with a total TV of ≤2.50 cm(3) . BCR was the primary outcome and defined as a PSA of ≥0.1. All cases with BCR were re-evaluated by the pathologist with reassessment of tumor grade, pathological stage and surgical margin status., Results: From 1,636 patients, 178 men (10.9%) met all inclusion criteria. Ninety-six patients (53.9%) had a TV <0.5 cm(3) and 82 patients (46.1%) had a TV 0.5-2.5 cm(3) . Three out of 178 patients (1.7%) presented with BCR during follow-up. One of these had TV <0.5 cm(3) and two had TV 0.5-2.5 cm(3) . These three cases of BCR underwent re-review of pathology; one patient was found to have a positive surgical margin and one patient was upgraded to Gleason 3 + 4 = 7. The third patient was re-reported as having positive margins for a benign hyperplastic nodule (incomplete RP specimen). Subsequently, these three cases were excluded from final analysis as they did not fit inclusion criteria. Median follow-up duration was 84 months (IQR 70-102 months). On final analysis, there were no patients with BCR, corresponding with a final BCR rate of 0% for both patients with a TV of <0.5 cm(3) and 0.5-2.5 cm(3) ., Conclusions: Our results have shown that, with a median follow-up of 84 (IQR 70-102) months, patients in our cohort with localized Gleason 6 PCa with a total TV 0.5-2.5 cm(3) have a BCR rate of 0%. We would support a more liberal total TV threshold of 2.5 cm(3) for the further development of algorithms to identify patients suitable for active surveillance., (© 2015 Wiley Periodicals, Inc.)

Purpose: Multiparametric magnetic resonance imaging appears to improve prostate cancer detection but prospective studies are lacking. We determined the accuracy of multiparametric magnetic resonance imaging for detecting significant prostate cancer before diagnostic biopsy in men with abnormal prostate specific antigen/digital rectal examination., Materials and Methods: In this single center, prospective study men older than 40 years with abnormal prostate specific antigen/digital rectal examination and no previous multiparametric magnetic resonance imaging underwent T2-weighted, diffusion-weighted and dynamic contrast enhanced imaging without an endorectal coil. Imaging was allocated alternately to 1.5/3.0 Tesla. Imaging was double reported independently using PI-RADS (Prostate Imaging Reporting and Data System) by specialist radiologists. Transperineal grid directed 30-core biopsy was performed with additional magnetic resonance imaging directed cores for regions of interest outside template locations. Four significant cancer definitions were tested. Chi-square and logistic regression analysis was done. Men undergoing prostatectomy were analyzed., Results: Of the 165 men who enrolled in the study 150 were analyzed. Median age was 62.4 years, median prostate specific antigen was 5.6 ng/ml, 29% of patients had an abnormal digital rectal examination and 88% underwent initial biopsy. Multiparametric magnetic resonance imaging was positive (PI-RADS 3 to 5) in 66% of patients, 61% had prostate cancer and 30% to 41% had significant prostate cancer (definitions 1 to 4). For significant cancer sensitivity was 93% to 96%, specificity was 47% to 53%, and negative and positive predictive values were 92% to 96% and 43% to 57%, respectively (definitions 1 to 4). Radical prostatectomy results in 48 men were similar. Aggregate PI-RADS (4 to 20) performed similarly to overall PI-RADS (1 to 5). Negative and positive predictive values (100% and 71%, respectively) were similar in men at higher risk, defined as prostate specific antigen greater than 10 ng/ml with abnormal digital rectal examination. On multivariate analysis PI-RADS score was associated with significant prostate cancer (p <0.001) but magnet strength was not. Adding PI-RADS to the multivariate model improved the AUC from 0.810 to 0.913 (95% CI 0.038-0.166, p = 0.002). Radiologist agreement was substantial (weighted κ = 0.626)., Conclusions: Multiparametric magnetic resonance imaging reported by expert radiologists achieved an excellent negative predictive value and a moderate positive predictive value for significant prostate cancer at 1.5 and 3.0 Tesla., (Copyright © 2014 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Background: The aim of this study was to determine the incidence and tumour characteristics of incidental prostatic cancer in Australian men with primary bladder cancer undergoing radical cystoprostatectomy (RCP)., Method: Cystoprostatectomy specimens were reviewed for a 10-year period from a leading pathology centre in the state of New South Wales, Australia. Stamey classification was used to define significant prostate cancer., Results: One hundred twenty-nine patients underwent RCP, 50 (39%) had prostatic adenocarcinoma, of which 35 (70%) were clinically significant. Apical involvement was seen in 10 (20%) of which 8 (16%) were clinically significant. High-grade intraepithelial neoplasia was seen in 27 (21%) and urothelial carcinoma or extension of bladder tumour was seen in 15 (12%) and 10 (8%) respectively. Bladder carcinoma in situ (CIS) was strongly associated with presence of urethral disease (P = 0.008)., Conclusion: High rates of prostatic involvement with adenocarcinoma and as well as urothelial malignancy was detected in patients with primary bladder cancer undergoing cystoprostatectomy. Large proportions of prostate adenocarcinoma were clinically significant. Presence of bladder CIS was significantly associated with presence of prostatic urethral disease., (© 2012 The Authors. ANZ Journal of Surgery © 2012 Royal Australasian College of Surgeons.)

Objective: To present the template-guided transperineal prostate biopsy (TPB) outcomes for patients of two urologists from a single institution., Patients and Methods: We conducted a prospective study of 409 consecutive men who underwent TPB between December 2006 and June 2008 in a tertiary referral centre using a standardized 14-region technique. The procedure was performed as day surgery under general anaesthesia with fluoroquinolone antibiotic cover. Follow-up took place within 2 weeks, during which time men were interviewed using a standardized template. Results were compared with those of the Australian national prostate biopsy audits performed by the Urological Society of Australia and New Zealand (USANZ)., Results: Indications for biopsy included elevated prostate-specific antigen (PSA) level (75%), with a median PSA level of 6.5 ng/mL, abnormal digital rectal examination (8%) and active surveillance (AS) re-staging (18%). The mean patient age was 63 years and two-thirds of patients were undergoing their first biopsy. A positive biopsy was found in 232 men, 74% of whom had a Gleason score of ≥7. The overall cancer detection rate was 56.7% (USANZ 2005 national audit = 56.5%). Stratified between those having their first TPB or a repeat procedure (after a previous negative biopsy), the detection rates were 64.4 and 35.6%, respectively. Significantly higher detection rates were found in prostates <50 mL in volume than in larger prostates (65.2 vs 38.3%, respectively, P < 0.001). Haematuria was the most common side effect (51.7%). Others included dysuria (16.4%), acute urinary retention (4.2%) and fever (3.2%). One patient (0.2%) had septicaemia requiring i.v. antibiotics. Repeat biopsy was not associated with increased complication rates., Conclusions: TPB is a safe and efficacious technique, with a cancer detection rate of 56.7% in the present series, and a low incidence of major side effects. Stratified by prostate volume, the detection rate of TPB was higher in smaller glands. Given the relatively low rate of serious complications, clinicians could consider increasing the number of TPB biopsy cores in larger prostates as a strategy to improve cancer detection within this group. Conversely, in patients on AS programmes, a staging TPB may be a superior approach for patients undergoing repeat biopsy so as to minimize their risk of serious infection., (© 2013 BJU International.)

Objective: • To compare long-term biochemical control of high-risk prostate cancer in those men receiving high-dose rate brachytherapy (HDRB) and radical prostatectomy (RP)., Patients and Methods: • The 10-year biochemical freedom from relapse (BFR) was calculated for 243 patients who underwent either RP or combined therapy with HDRB + external beam radiotherapy + androgen deprivation between 1998 and 2000. •, Inclusion Criteria: clinical stage ≥ T2b, or Gleason sum ≥ 8, or PSA level of > 20 ng/mL. Groups were appraised using the Kattan nomogram for surgery to calculate progression-free probability (PFP)., Results: • For the RP group (153 patients) the median PSA level was 8.1 ng/mL and the median age was 62.2 years. The median 5- and 10-year predicted PFP for RP was 64% and 56 %, respectively. The 5- and 10-year BFR was 65.5% and 55.4%. There was no significant difference between the predicted and the actual PFP for the RP group (P= 0.525). • For HDRB group (90 patients). The median PSA level was 14.2 ng/mL and the median age was 67.6 years. The median 5- and 10-year predicted PFP for HDRB was 46% and 35%, respectively. The 5- and 10-year BFR was 79.6% and 53.6%. There was a significant improvement between the actual and the predicted PFP for the HDRB group (P= 0.002)., Conclusions: • Amongst a high-risk cohort, patients undergoing RP performed as predicted by the pre-treatment surgical nomogram, whereas the patients undergoing HDRB performed significantly better than was predicted by the surgical nomogram at 10 years., (© 2012 THE AUTHORS. BJU INTERNATIONAL © 2012 BJU INTERNATIONAL.)

Purpose: Anterior tumors are estimated to constitute 20% of prostate cancers. Current data indicate that transperineal biopsy is more reliable than transrectal biopsy in identifying these tumors. If correct, this superior reliability should result in an increased proportion of anterior tumors identified by transperineal biopsy. We investigated this hypothesis with reference to prostatectomy specimens., Materials and Methods: Radical prostatectomy histopathology records were retrospectively examined. Patients were grouped based on primary transperineal or transrectal biopsy as the modality used to identify the initial cancer. After grouping, tumor location and size were recorded and, thus, the proportion of anterior tumors was determined., Results: A total of 1,132 (414 transperineal and 718 transrectal) prostatectomy specimens were examined. Overall mean tumor size (1.8 and 2.0 cm(3)), stage (pT2 63.3% and 61%) and significance (5.1% and 5.1%) for the transperineal and transrectal methods were similar. However, the transperineal method was associated with proportionally more anterior tumors (16.2% vs 12%, p = 0.046), and identified them at a smaller size (1.4 vs 2.1 cm(3), p = 0.03) and lower stage (extracapsular extension 13% vs 28%, p = 0.03) compared to the transrectal method. The pT3 positive surgical margin rate for anterior vs other tumors was 69% vs 34.9%, respectively., Conclusions: Overall transrectal and transperineal biopsy identify cancers that are similar in size, stage and significance. However, transperineal biopsy detected proportionally more anterior tumors (16.2% vs 12%), and identified them at a smaller size (1.4 vs 2.1 cm(3)) and stage (extracapsular extension 13% vs 28%) compared to transrectal biopsy. Identifying anterior tumors early is important because the positive surgical margin rate for anterior pT3 lesions is significantly higher., (Copyright © 2012 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: We determined whether systematic template guided transperineal biopsies can accurately locate and sensitively detect prostate cancer. In addition, we reported discrepancies between diagnostic and pathological Gleason scores, and investigated whether prostate size had an effect on the cancer detection rate., Materials and Methods: This retrospective diagnostic accuracy study compares the results of primary transperineal biopsies with the radical prostatectomy pathology of 414 consecutive patients treated at a single institution between November 2002 and August 2010., Results: The average sensitivity and specificity for the detection of cancer in all prostates across all biopsy zones was 48% (95% CI 42.6-53.4) and 84.1% (95% CI 80-88.2), respectively. There was a statistically significant decrease in the sensitivity of transperineal biopsy in larger prostates (t11=4.687, p=0.001). The overall Kappa value was 0.255 (95% CI 0.212-0.298). Grading concordance between biopsy and pathology specimens was achieved in 65.7% of patients. Upgrading of Gleason scores occurred in 25.6% of patients and downgrading occurred in 8.8%., Conclusions: Our current transperineal biopsy method has only demonstrated fair agreement with the histopathology findings of the corresponding radical prostatectomy specimens. This finding is most likely due to the small, multifocal nature of prostate cancer in the patient series. The cancer detection rate was lower in larger prostates. Thus, clinicians may consider increasing the number of cores in larger prostates as a strategy to improve cancer detection., (Copyright © 2012 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Studies to elucidate dysregulated gene expression patterns in premalignant prostate lesions have identified several candidate genes with the potential to be targeted to prevent the development and progression of prostate cancer and act as biomarkers of early disease. Herein, we explored the importance of two proteins, neuropeptide Y (NPY) and macrophage inhibitory cytokine-1 (MIC-1), as biomarkers of preinvasive prostate disease and investigated the relationship of expression to biochemical recurrence following treatment for localized prostate cancer. NPY and MIC-1 protein expression was determined by immunohistochemistry on tissue microarrays containing 1,626 cores of benign, low-grade prostatic intraepithelial neoplasia (PIN), high-grade PIN (HGPIN), and prostate cancer tissue from 243 radical prostatectomy patients. Both NPY and MIC-1 showed higher proportional immunostaining in HGPIN and prostate cancer compared with benign epithelium (P < 0.0001). NPY and MIC-1 immunostaining was higher in low-grade PIN compared with other benign tissues (both P < 0.0001) and was equivalent to immunostaining in HGPIN. NPY immunostaining of prostate cancer was independently associated with relapse, after adjusting for traditional prognostic factors, as a categorical variable in 20% intervals (P = 0.0449-0.0103) and as a continuous variable (P = 0.0017). Low MIC-1 immunostaining (20% categories) was associated with pathologic stage >2C after adjusting for predictors of pathologic stage (P = 0.3894-0.0176). This is the first study to show that altered NPY and MIC-1 expression are significantly associated with prostate cancer progression and suggests that these molecules be developed further as biomarkers in the management of prostate disease.

Objectives: To assess sexual function after prostate brachytherapy and compare outcomes in different age groups., Methods: This cross-sectional study consisted of 96 sexually active patients (mean age 64 years) who underwent iodine-125 seed implantation between 1997 and 2003 to treat early-stage prostate cancer (Stage T1-T2). Patients completed a questionnaire adapted from the validated Rand 36-Item Health Survey and the University of California, Los Angeles, Prostate Cancer Index., Results: The median follow-up was 2.5 years (range 3 months to 6.2 years). The mean value for sexual function was 54.8. The mean score for erectile function was 55.0, and the mean score for the ability to reach orgasm was 54.0. No significant relationship was found between sexual function and time since treatment (P = 0.9897). Pain on orgasm was reported after brachytherapy by 38 patients (40%) and hematospermia by 16 patients (17%). A negative correlation was observed between pain on orgasm and time since treatment (P = 0.021), but no significant relationship was found between hematospermia and time since treatment (P = 0.427). A significant difference in sexual function was observed between patients younger than 60 years and patients older than 60 years (66.3 +/- 7.0 versus 47.7 +/- 7.2; P = 0.002)., Conclusions: A large variation in sexual potency is present after brachytherapy with no significant relationship to the time since treatment. Age is an indicator of sexual function after brachytherapy, with younger patients experiencing less sexual dysfunction than older patients. Other aspects of sexual function (pain on orgasm, hematospermia) are also significant side effects of brachytherapy and must be considered in the treatment decision for low-risk prostate cancer.

Beta-catenin in its role as a nuclear signaling molecule has been implicated in prostate carcinogenesis primarily through modulation of androgen receptor activity. We defined the pattern of beta-catenin protein expression in the nuclei of normal, hyperplastic and malignant human prostate tissue and determined whether differences in expression were associated with disease progression and prognosis. Five normal prostates, 26 benign prostatic hypertrophy specimens, 232 radical prostatectomy specimens from patients with clinically localized prostate cancer (PC) and 20 cases of advanced PC were assessed for beta-catenin expression using immunohistochemistry. Nuclear beta-catenin expression in localized PC was significantly lower than that in benign prostate tissue (p < 0.001) and significantly higher than that in advanced PC tissue (p < 0.001). In addition, lower levels of nuclear beta-catenin expression (< 10% of cancer cells) predicted for a shorter biochemical relapse-free survival in patients with localized PC (p = 0.008) and were inversely correlated with preoperative prostate-specific antigen (PSA) levels (p = 0.01). Analysis of the low-risk subgroup of patients with preoperative PSA levels < 10 ng/ml demonstrated that lower levels of nuclear beta-catenin expression (< 10% of cancer cells) again predicted for a poorer prognosis (p = 0.006). In conclusion, lower levels of nuclear beta-catenin expression are found in malignant compared to benign prostate tissue. In addition, lower nuclear beta-catenin expression is associated with a poorer prognosis in localized PC, in particular, in the low-risk subgroup of patients with preoperative PSA levels < 10 ng/ml. Thus, the level of nuclear beta-catenin expression may be of clinical utility as a preoperative prognostic marker in low-risk localized PC.

Background: The role of the bone morphogenetic protein (BMP) pathway in prostate cancer (PC) is unclear. This study aimed to characterize aspects of the BMP pathway in PC by assessing BMP2, Smad8, and Smad4 expression in normal, hyperplastic, and malignant prostate tissue, and to correlate findings with progression to PC., Methods: Radical prostatectomy (RP) specimens from 74 patients with clinically localized PC (median follow-up 51 months, range 15-152), 44 benign prostatic hypertrophy (BPH) lesions, and 4 normal prostates (NPs) were assessed for BMP2, Smad8, and Smad4 expression using immunohistochemistry., Results: Both BMP2 (P < 0.001) and nuclear Smad4 (P < 0.0001) expression were significantly decreased in PC compared to benign prostate tissue. Nuclear Smad8 was present in normal/benign prostate tissue but absent in PC and adjacent hyperplasia. Furthermore, loss of BMP2 (P < 0.001) and decreased nuclear Smad4 (P = 0.05) expression correlated with increasing Gleason score., Conclusions: These data suggest that decreased BMP2, nuclear smad8 and nuclear Smad4 expression are associated with the progression to PC, and in particular loss of BMP2 and Smad4 are related to progression to a more aggressive phenotype., (Copyright 2004 Wiley-Liss, Inc.)

Purpose: Activation of the Wnt-signaling pathway is implicated in aberrant cellular proliferation in a variety of cancers. Secreted frizzled-related protein 4 (sFRP4) is a secreted protein with putative inhibitory activity of the Wnt-signaling cascade through binding and sequestering Wnt ligands. Because sFRP4 mRNA is overexpressed in prostate cancers (PCs), the aim of this study was to define the pattern of sFRP4 protein expression in normal and malignant human prostate tissue and to determine whether changes in expression were associated with disease progression and prognosis, as well as to define the phenotype of sFRP4-overexpression in an in vitro model of PC., Experimental Design: Polyclonal antibodies were raised against a COOH-terminal peptide of sFRP4, characterized and used to assess sFRP4 protein expression in benign prostate tissue and 229 patients with clinically localized PC (median follow-up 77 months, range 1-156). In vitro studies of the function of sFRP4 overexpression were performed using PC3 cells transfected with sFRP4., Results: Benign and malignant prostate tissue demonstrated cytoplasmic sFRP4 immunoreactivity, but there was a decrease in the expression of membranous sFRP4 in PCs compared with the hyperplastic lesions (P < 0.0001). Kaplan-Meier analysis revealed that patients whose PC expressed membranous sFRP4 in >20% of cells had improved relapse-free survival compared with those with

Background: In the current study, the authors sought to further stratify the prognosis of patients with Gleason score (GS) 7 prostate carcinoma. They assessed the influence on outcome of a predominant poorly differentiated Gleason pattern (primary Gleason pattern [GP] 4) and/or a coincident small focus of poorly differentiated tumor of higher grade (tertiary GP 5)., Methods: The authors studied 412 patients (mean postoperative follow-up, 33 months) with GS 7 tumors treated with radical prostatectomy at a single Australian campus between November 1989 and December 2002. The chi-square test, Kaplan-Meier method, and Cox proportional hazards analyses were used to evaluate the correlation between primary GP 4 and tertiary GP 5 with the occurrence of adverse pathologic features and disease recurrence., Results: In this cohort, 307 patients (75%) had primary GP 3 tumors, 105 (25%) had primary GP 4 tumors, and 17 (2.3%) had a tertiary element of high-grade tumor (GP 5). Patients with primary GP 4 tumors displayed higher rates of seminal vesicle involvement and extraprostatic extension and, along with patients with tertiary GP 5, had significantly shorter times to disease recurrence. Univariate analysis demonstrated that primary GP 4 (P = 0.0003) and tertiary GP 5 (P < 0.0001) were strong predictors of disease recurrence. Primary GP 4 (P = 0.0122) remained an independent predictor of disease recurrence on stepwise multivariate analysis., Conclusions: Primary GP 4 tumors represented an aggressive subset of GS 7 prostate carcinomas. Primary GP was an easily accessible and clinically relevant predictor of disease recurrence in patients with GS 7 prostate carcinoma., (Copyright 2003 American Cancer Society.)

We have utilized oligonucleotide microarrays to identify novel genes of potential clinical and biological importance in prostate cancer. RNA from 74 prostate cancers and 164 normal body samples representing 40 different tissues were analysed using a customized Affymetrix GeneChip oligonucleotide microarray representative of over 90% of the expressed human genome. The gene for the zinc transporter ZnT4 was one of several genes that displayed significantly higher expression in prostate cancer compared to normal tissues from other organs. A polyclonal antipeptide antibody was used to demonstrate ZnT4 expression in the epithelium of all 165 elements of benign and 326 elements of localized prostate cancers examined and in nine of 10 advanced prostate cancer specimens by immunohistochemistry. Interestingly, decreased intensity of ZnT4 immunoreactivity occurred in the progression from benign to invasive localized prostate cancer and to metastatic disease. Immunofluorescence analysis and surface biotinylation studies of cells expressing ZnT4 localised the protein to intracellular vesicles and to the plasma membrane. These findings are consistent with a role for ZnT4 in vesicular transport of zinc to the cell membrane and potentially in efflux of zinc in the prostate.

Background: Predicting outcome for men with clinically localized prostate carcinoma treated with curative intent remains imprecise and further evaluation of accepted and potential predictive factors is needed., Methods: The authors studied 696 men with localized prostate carcinoma diagnosed on transrectal biopsy and treated with radical prostatectomy at one institution between 1986 and 1999 to determine the relation between putative pretreatment prognostic factors and disease-free survival. Clinical stage, Gleason score, perineural invasion, number of biopsies containing tumor, and serum prostate specific antigen (PSA) were evaluated as predictors of extracapsular extension, seminal vesicle involvement, lymph node metastases, and surgical margin involvement as well as outcome after surgery. Kaplan-Meier method and Cox regression analyses were used to evaluate the contribution of different factors to adverse pathologic features and relapse., Results: At mean follow-up of 56.9 months (range, 1.0-177.9 months; median, 54.9 months), 26.1% (182 of 696 patients) of patients had developed a disease recurrence. Pretreatment serum PSA concentration, biopsy Gleason score, and clinical stage as well as number of biopsies involved with tumor as a percentage of the total number obtained were found to be independent predictors of outcome. In patients with PSA > 10 ng/mL, biopsy perineural invasion and percentage of biopsies containing tumor were found to independently predicted disease recurrent. Increased number of biopsies involved with tumor independently predicted extracapsular extension, margin involvement, seminal vesicle, and lymph node involvement., Conclusions: This study demonstrated that the proportion of prostate biopsy cores containing tumor is an independent predictor of outcome after subsequent radical prostatectomy and suggested that perineural invasion has a predictive role in patients with a preoperative PSA > 10 ng/ml., (Copyright 2003 American Cancer Society.)