Transforming growth factor-beta1 induced myofibroblasts regulate LNCaP cell death.

PURPOSE: Reactive stroma represents a generic wound response phenomenon, which has been identified in areas of tissue injury and carcinogenesis. To determine whether reactive stroma influences prostate tumor cell growth 3 primary prostate stromal cell lines were treated with transforming growth factor-beta1 (TGF-beta1) to induce the reactive stroma phenotype and then co-cultured with LNCaP cells. MATERIALS AND METHODS: Flow cytometry was performed in LNCaP cells that had been co-cultured with induced reactive stroma or control stroma and an index of cell death and proliferation was obtained. Using the previously described 3 way differential reactive stroma xenograft tumor model consisting of LNCaP cells, stromal cells and Matrigel (Collaborative Research, Bedford, Massachusetts) LNCaP cell apoptosis was evaluated using TUNEL staining in a background of varying degrees of reactive stroma. RESULTS: Flow cytometric analysis revealed that LNCaP cells co-cultured with TGF-beta1 induced stromal cells demonstrated a significantly decreased rate of cell death compared with controls (p <0.001). In an animal model LNCaP cells of the 3 way xenograft constructs treated with TGF-beta1 latency associated peptide, an inhibitor of TGF-beta1, showed increased apoptosis by TUNEL staining (p <0.001). Double label immunohistochemistry analysis demonstrated that TGF-beta1 induced stromal cells had an increased proportion of myofibroblasts, the identifying cell type of reactive stroma. Furthermore, the degree of reactive stroma inversely corresponded to the degree of LNCaP cell death. CONCLUSIONS: These findings indicate that reactive stroma influences prostate cancer cell growth and warrant investigation of the regulatory mechanisms between reactive stroma and prostate cancer cells.

Effects of systematic 12-core biopsy on the performance of percent free prostate specific antigen for prostate cancer detection.

PURPOSE: The performance characteristics of percent free (f) prostate specific antigen (PSA) for differentiating between benign prostatic hyperplasia and prostate cancer were originally established using primarily sextant biopsy. We determined whether the addition of 6 laterally directed cores to the traditional sextant prostate biopsy affects the performance of percent fPSA. MATERIALS AND METHODS: We retrospectively evaluated a cohort of 350 consecutive biopsies in men with negative digital rectal examinations and PSA between 4 and 10 ng/ml who underwent systematic 12 core biopsy (S12C) biopsy at Scott Department of Urology between March 1999 and January 2003. The effects of 6 additional, laterally directed biopsies on the sensitivity, specificity and area under the ROC curve for percent fPSA was evaluated in the 277 men in whom percent fPSA was measured. RESULTS: Cancers detected exclusively in the 6 laterally directed cores were associated with percent fPSA values similar to those in patients with a benign S12C biopsy. This resulted in a modest and yet predictable decrease in the sensitivity of percent fPSA at each biopsy threshold value without affecting specificity. There was a nonstatistically significant decrease in the area under the ROC curve with the addition of 6 laterally directed cores to sextant biopsy (medial sextant cores 0.66 vs S12C 0.60). CONCLUSIONS: The 12 core biopsy strategies have a higher cancer detection rate than sextant biopsies and they are gaining widespread acceptance. The addition of 6 laterally directed cores to traditional sextant biopsy may result in a modest decrease in the sensitivity of percent fPSA at each selected biopsy threshold without affecting specificity.

Impact of unilateral interposition sural nerve grafting on recovery of urinary function after radical prostatectomy.

OBJECTIVES: To test the hypothesis that unilateral sural nerve graft (SNG) interposition may improve the rate of urinary function (UF) recovery after radical retropubic prostatectomy (RRP) in patients undergoing unilateral nerve resection (UNR). METHODS: We studied 111 consecutive patients who underwent RRP with purposeful UNR performed by a single surgeon. Of the 111 patients, 53 underwent unilateral SNG interposition. All patients were invited to complete a questionnaire that included the validated University of California, Los Angeles, Prostate Cancer Index. The time to UF recovery above the median value of the group and urinary control status were evaluated. RESULTS: The median follow-up was 26 and 12 months for the UNR and UNR+SNG patients, respectively. At 12 months after RRP, 94.7% of patients with UNR+SNG reported having complete urinary control or leakage of only a few drops of urine compared with 58.3% of patients with UNR alone (P = 0.012). In multivariate Cox regression models, UNR+SNG was associated with a 9.95 times greater rate of reaching a UF score above the median versus UNR alone (P <0.001). In multivariate logistic regression analyses, SNG status increased the odds of having complete urinary control or leakage of only a few drops of urine by 14.99 and 29.19 at 6 and 12 months after RRP, respectively (both P <0.05). CONCLUSIONS: In patients undergoing UNR surgery, SNG interposition is associated with a greater rate of UF recovery and a higher likelihood of urinary control after RRP. These findings need to be validated in larger, multicenter, prospective, randomized studies.

Serum BPSA outperforms both total PSA and free PSA as a predictor of prostatic enlargement in men without prostate cancer.

OBJECTIVES: To determine whether the serum concentration of BPSA, a distinct form of free prostate-specific antigen (PSA) enriched in the nodular transition zone (TZ) tissue of benign prostatic hyperplasia (BPH), can predict TZ volume and diagnose BPH-associated prostatic enlargement in patients without prostate cancer. METHODS: We studied 91 consecutive patients without prostate cancer who underwent a 10-core or greater biopsy of the prostate. The associations between prostate volume, age, International Prostate Symptom Score, and serum concentrations of PSA, free PSA, and BPSA were evaluated by receiver operating characteristic curve and linear and binary logistic regression analyses. RESULTS: BPSA and free PSA showed stronger correlations with both age (BPSA = 0.38, free PSA = 0.40, PSA = 0.24) and TZ volume (BPSA = 0.67, free PSA = 0.64, PSA = 0.55) than did PSA. The percent free PSA had no statistically significant correlation with TZ volume (P = 0.08). Subtraction of BPSA from free PSA reduced its correlation with TZ volume to below that of PSA (from 0.64 to 0.48). Linear regression analyses showed that, unlike PSA, both BPSA and free PSA displayed an age-independent relationship to TZ volume. The receiver operating characteristic curve (for TZ greater than 30 cm3) and binary logistic regression analyses showed that BPSA (area under the curve = 0.844) outperformed both free PSA (area under the curve = 0.799) and PSA (area under the curve = 0.749) in its ability to predict clinically significant TZ enlargement. CONCLUSIONS: In patients without prostate cancer, the serum concentration of BPSA displayed an age-independent, log-linear relationship to TZ volume and was a better predictor of prostatic enlargement than either PSA or free PSA. BPSA may also predict clinical parameters of BPH and is under evaluation as a marker of BPH progression and response to therapy.

Predictors of prostate cancer after initial negative systematic 12 core biopsy.

PURPOSE: We determined the cancer detection rate at initial systematic 12 core (S12C) biopsy and identified features associated with cancer at repeat S12C biopsy after an initial negative S12C biopsy in patients with prostate specific antigen (PSA) parameters associated with a higher risk of prostate cancer. MATERIALS AND METHODS: Between February 1999 and June 2002, 841 patients underwent initial S12C biopsy. Of these patients 99 underwent repeat S12C biopsy after initial negative S12C because of a percent free-to-total PSA of 15.0 or less and/or a yearly PSA velocity of 0.75 ng/ml or greater. The association between parameters revealed by initial biopsy and cancer at repeat biopsy was assessed. RESULTS: Of the 99 patients 21 (21.2%) had cancer at repeat biopsy. Age (p = 0.01), PSA transitional zone density (p = 0.05), and high grade PIN at initial biopsy (p = 0.01) were associated with cancer at repeat biopsy. CONCLUSIONS: In this select group of patients with PSA parameters associated with a higher risk of prostate cancer the cancer detection rate after initially negative S12C biopsy was 21%. Patients with high grade PIN on initial biopsy, advanced age and higher PSA transition zone density are at increased risk for cancer at repeat biopsy. Larger prospective studies are required to confirm these results and construct a nomogram that determines the probability of finding prostate cancer at subsequent biopsy.

Improved detection of clinically significant, curable prostate cancer with systematic 12-core biopsy.

PURPOSE: While systematic 12-core (S12C) biopsy detects more cancers than sextant biopsy, to our knowledge the clinical significance of these additionally detected tumors has not been established. We studied pathological parameters of prostatectomy specimens from patients undergoing radical prostatectomy for prostate cancer detected with a S12C biopsy to determine the clinical significance of these cancers in comparison with sextant detected cancers. MATERIALS AND METHODS: A total of 179 consecutive patients undergoing radical prostatectomy for clinically localized prostate cancer detected by S12C biopsy were studied. The groups compared consisted of the sextant core subset of the S12C and the entire S12C set. Total tumor volume, Gleason score, organ confined status, surgical margin status, seminal vesicle invasion, lymph node involvement, and clinical significance of tumors detected by sextant and by S12C templates were compared. RESULTS: S12C biopsy detected a greater number of cancers scored as moderate (Gleason score 2 to 6) or high (Gleason score 7 or greater) grade, and cancers of all sizes regardless of organ confined status than the sextant cores alone (all p <0.05). S12C biopsy identified a greater number of biologically significant and insignificant tumors regardless of how they were defined. CONCLUSIONS: Compared with the sextant set S12C biopsy detects a significantly greater number of surgically curable, biologically significant tumors as well as those that might be considered clinically insignificant.

Six additional systematic lateral cores enhance sextant biopsy prediction of pathological features at radical prostatectomy.

PURPOSE: We evaluated the contribution of 6 additional systematically obtained, laterally directed biopsy cores to traditional sextant biopsy for the prediction of final pathological findings in the radical prostatectomy specimen. MATERIALS AND METHODS: We studied 178 consecutive patients with no history of prostate biopsy in whom prostate cancer was diagnosed during an initial systematic 12 core biopsy and who subsequently underwent radical prostatectomy. Of the systematic 12 cores we compared the subset of the 6 traditional sextant cores (S6C), the set of 6 laterally directed cores (L6C) and the complete 12 core set, which included the 6 traditional sextant and the 6 laterally directed cores. Biopsy Gleason score, number of positive cores, total cancer length and percent of tumor in the biopsy sets were examined for their ability to predict extracapsular extension, total tumor volume and pathological Gleason score. RESULTS: On univariable analyses the biopsy parameters of the complete 12 core set correlated more strongly with extracapsular extension and total tumor volume than the biopsy parameters of S6C or L6C. On multivariable analyses S6C and L6C were independent predictors of pathological features at prostatectomy. CONCLUSIONS: The addition of 6 systematically obtained, laterally directed cores to traditional sextant biopsy improved the ability to predict pathological features at prostatectomy by a statistically and prognostically significant margin. Preoperative nomograms that use data from a full complement of 12 systematic cores, specifying sextant and laterally directed biopsy cores, should demonstrate improved performance in predicting prostatectomy pathology.

Renal-type clear cell carcinoma occurring in the prostate.

Clear cell lesions of the urinary tract often present diagnostic challenges. We report a previously undescribed lesion in the prostate, occurring in a 73-year-old man who presented with hematuria and subsequently underwent transurethral resection of the prostate. A total of 24 g of tissue was removed, and in 4 of 17 blocks submitted a lesion morphologically and immunohistochemically similar to clear cell carcinoma of the kidney was noted. A thorough cystoscopic and full-body, radiologic workup was performed, but no renal tumor was discovered. Random cystoscopic biopsies of the bladder and prostatic urethra as well as bladder washings were benign. Subsequent needle biopsies of the prostate were also benign. The patient underwent a pelvic lymph node dissection with radical cystoprostatectomy and orthotopic Studer pouch diversion. There was organ-confined, ordinary-type prostatic adenocarcinoma (Gleason's 3 + 3) present bilaterally in the peripheral zone; no residual clear cell carcinoma was identified. All lymph nodes were negative, and the urinary bladder showed no dysplasia or neoplasia. We think this tumor represents a primary renal type of clear cell carcinoma arising in the prostate. To our knowledge, this type of tumor has not been previously reported to arise in an extrarenal location.