Comparative Analysis of PSA Density and an MRI-Based Predictive Model to Improve the Selection of Candidates for Prostate Biopsy.

This study is a head-to-head comparison between mPSAD and MRI-PMbdex. The MRI-PMbdex was created from 2432 men with suspected PCa; this cohort comprised the development and external validation cohorts of the Barcelona MRI predictive model. Pre-biopsy 3-Tesla multiparametric MRI (mpMRI) and 2 to 4-core transrectal ultrasound (TRUS)-guided biopsies for suspicious lesions and/or 12-core TRUS systematic biopsies were scheduled. Clinically significant PCa (csPCa), defined as Gleason-based Grade Group 2 or higher, was detected in 934 men (38.4%). The area under the curve was 0.893 (95% confidence interval [CI]: 0.880−0.906) for MRI-PMbdex and 0.764 (95% CI: 0.774−0.783) for mPSAD, with p < 0.001. MRI-PMbdex showed net benefit over biopsy in all men when the probability of csPCa was greater than 2%, while mPSAD did the same when the probability of csPCa was greater than 18%. Thresholds of 13.5% for MRI-PMbdex and 0.628 ng/mL2 for mPSAD had 95% sensitivity for csPCa and presented 51.1% specificity for MRI-PMbdex and 19.6% specificity for mPSAD, with p < 0.001. MRI-PMbdex exhibited net benefit over mPSAD in men with prostate imaging report and data system (PI-RADS) <4, while neither exhibited any benefit in men with PI-RADS 5. Hence, we can conclude that MRI-PMbdex is more accurate than mPSAD for the proper selection of candidates for prostate biopsy among men with suspected PCa, with the exception of men with a PI-RAD S 5 score, for whom neither tool exhibited clinical guidance to determine the need for biopsy.

Application of One-Step Nucleic Acid Amplification (OSNA) in different cancer entities and usefulness in prostate cancer: a systematic review.

BACKGROUND: Lymph node (LN) status is a key prognostic factor in the decision-making process of different cancer entities, including prostate cancer (PCa). Sectioning and haematoxylin and eosin (H&E) staining technique remain the gold standard for the evaluation of LN metastases despite some limitations, especially low sensitivity in detecting an accurate tumour burden within the LN, as well as a subjective and time-consuming result. One-step nucleic acid amplification (OSNA) quantifies mRNA copies of cytokeratin 19 (CK19) in a fast, objective, automated, and reproducible way, raising a general interest to explore its utility for lymphatic metastasis identification in different malignancies. METHODS: To present the latest evidence related to the detection of LN metastases in several tumours by using OSNA compared with the conventional H&E method, a systematic review of articles published since March 2021 was conducted using PubMed, Cochrane Library, and Web of Science databases. References from primary papers and review articles were checked to obtain further potential studies. Our procedure for evaluating records identified during the literature search followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses criteria. With the aim to design and justify future clinical routine use of OSNA in PCa, novel PCa evidence has been included in this review for the first time. RESULTS: Twenty five studies were included. LN from six different groups of tumours: breast, gastrointestinal, gynecological, lung, head and neck and prostate cancers has been assessed. OSNA was compared with post-operative formalin-fixed paraffin-embedded tissue sections with H&E staining as the reference standard. Contingency tables were created, and concordance rate, sensitivity, specificity and predictive values were reported. Seventeen studies analysed the discordant cases using different techniques. CONCLUSION: OSNA method has a high diagnostic accuracy for the detection of LN metastases in several CK19 expressing tumours. Available evidence might encourage future investigations about its usage in PCa patients to improve LN staging and prognosis.

Multiparametric Magnetic Resonance Imaging Grades the Aggressiveness of Prostate Cancer.

We sought to find further evidence showing the increase in PCa aggressiveness as PI-RADS score increases from four surrogates of PCa aggressiveness: i. prostate biopsy GG (≤3 vs. >3), ii. type of pathology in surgical specimens (favourable vs. unfavourable), iii. clinical stage (localised vs. advanced), and risk of recurrence of localised PCa after primary treatment (low-intermediate vs. high). A group of 692 PCa patients were diagnosed after 3-T multiparametric MRI (mpMRI) and guided and/or systematic biopsies, showing csPCa (GG ≥ 2) in 547 patients (79%) and insignificant PCa (iPCa) in 145 (21%). The csPCa rate increased from 32.4% in PI-RADS < 3 to 95.5% in PI-RADS 5 (p < 0.001). GG ≥ 3 was observed in 7.6% of PCa with PI-RADS < 3 and 32.6% in those with PI-RADS > 3 (p < 0.001). Unfavourable pathology was observed in 38.9% of PCa with PI-RAD < 3 and 68.3% in those with PI-RADS > 3 (p = 0.030). Advanced disease was not observed in PCa with PI-RADS ≤ 3, while it existed in 12.7% of those with PI-RADS > 3 (p < 0.001). High-risk recurrence localised PCa was observed in 9.5% of PCa with PI-RADS < 3 and 35% in those with PI-RADS > 3 (p = 0.001). The PI-RADS score was an independent predictor of all surrogates of PCa aggressiveness as PSA density. We confirmed that mpMRI grades PCa aggressiveness.

The Barcelona Predictive Model of Clinically Significant Prostate Cancer.

A new and externally validated MRI-PM for csPCa was developed in the metropolitan area of Barcelona, and a web-RC designed with the new option of selecting the csPCa probability threshold. The development cohort comprised 1486 men scheduled to undergo a 3-tesla multiparametric MRI (mpMRI) and guided and/or systematic biopsies in one academic institution of Barcelona. The external validation cohort comprised 946 men in whom the same diagnostic approach was carried out as in the development cohort, in two other academic institutions of the same metropolitan area. CsPCa was detected in 36.9% of men in the development cohort and 40.8% in the external validation cohort (p = 0.054). The area under the curve of mpMRI increased from 0.842 to 0.897 in the developed MRI-PM (p < 0.001), and from 0.743 to 0.858 in the external validation cohort (p < 0.001). A selected 15% threshold avoided 40.1% of prostate biopsies and missed 5.4% of the 36.9% csPCa detected in the development cohort. In men with PI-RADS <3, 4.3% would be biopsied and 32.3% of all existing 4.2% of csPCa would be detected. In men with PI-RADS 3, 62% of prostate biopsies would be avoided and 28% of all existing 12.4% of csPCa would be undetected. In men with PI-RADS 4, 4% of prostate biopsies would be avoided and 0.6% of all existing 43.1% of csPCa would be undetected. In men with PI-RADS 5, 0.6% of prostate biopsies would be avoided and none of the existing 42.0% of csPCa would be undetected. The Barcelona MRI-PM presented good performance on the overall population; however, its clinical usefulness varied regarding the PI-RADS category. The selection of csPCa probability thresholds in the designed RC may facilitate external validation and outperformance of MRI-PMs in specific PI-RADS categories.

The current recommendation for the management of isolated high-grade prostatic intraepithelial neoplasia.

OBJECTIVE: To analyse the current predictive value of isolated high-grade prostatic intraepithelial neoplasia (HGPIN) for clinically significant prostate cancer (csPCa) detection in repeat biopsies. PATIENTS AND METHODS: A cohort of 293 men with isolated HGPIN detected in previous biopsies performed without multiparametric magnetic resonance imaging (mpMRI), and who underwent repeat biopsy within 1 to 3 years, was analysed. Pre-repeat biopsy mpMRI and guided biopsies to suspicious lesions (Prostate Imaging - Reporting and Data System [PI-RADS] ≥3) and/or and systematic biopsies were performed. Persistent prostate cancer (PCa) suspicion, defined as sustained serum prostate-specific antigen level >4 ng/mL and/or abnormal digital rectal examination, was present in 248 men (84.6%), and was absent in 45 men (15.4%). A control group of 190 men who had no previous HGPIN, atypical small acinar proliferation or HGPIN with atypia who were scheduled to undergo repeat biopsy due to persistent PCa suspicion were also analysed. csPCa was defined as tumours of Grade Group ≥2. RESULTS: In the subset of 45 men with isolated HGPIN, in whom PCa suspicion disappeared, only one csPCa (2.2%) and one insignificant PCa (iPCa) were detected. csPCa was detected in 34.7% of men with persistent PCa suspicion and previous HGPIN, and in 28.4% of those without previous HGPIN (P =0.180). iPCa was detected in 12.1% and 6.3%, respectively (P =0.039). Logistic regression analysis showed that the risk of csPCa detection was not predicted by previous HGPIN: odds ratio (OR) 1.369 (95% confidence interval [CI] 0.894-2.095; P =0.149); however, previous HGPIN increased the risk of iPCa detection: OR 2.043 (95% CI 1.016-4.109; P =0.006). CONCLUSION: The risk of csPCa in men with isolated HGPIN, in whom PCa suspicion disappears, is extremely low. Moreover, in those men in whom PCa suspicion persists, the risk of csPCa is not influenced by the previous finding of HGPIN. However, previous HGPIN increases the risk of iPCa detection. Therefore, repeat prostate biopsy should not be recommended solely because of a previous HGPIN.

Prediction of clinically significant prostate cancer after negative prostate biopsy: The current value of microscopic findings.

OBJECTIVE: To assess the current ability of atypical small acinar proliferation (ASAP), multifocal high-grade prostatic intraepithelial neoplasia (mHGPIN), HGPIN with atypia (PINATYP) and other non-malignant lesions to predict clinically significant prostate cancer (csPCa) in repeat prostate biopsies. METHODS: This retrospective study analyzed 377 repeat prostate biopsies, carried out between 2.014 and 2.017, and excluding those with previous PCa or 5-alpha reductase inhibitors treatment. ASAP, mHGPIN, PINATYP, prostatic atrophy, prostatic hyperplastic atrophy, proliferative inflammatory atrophy (PIA), chronic prostatitis, acute prostatitis, or granulomatous prostatitis, were prospectively reported after 12-core transrectal ultrasound (TRUS) systematic negative previous biopsies. 3T-multiparametric magnetic resonance imaging (mpMRI) was performed previous repeat biopsies. At least 2-core TRUS targeted biopsies of Prostate Imaging-Reporting and Data Systemv2 lesions ≥3, and/or 12-core TRUS systematic biopsy were performed in repeat prostate biopsies. The main outcome measurements were csPCa detection, which was defined when the International Society of Uro-Pathology group grade >1 and avoided biopsies. After logistic regression analysis the most efficient model was selected, nomogram was designed with internal validation, and clinical utility was analyzed. RESULTS: Normal benign tissue alone was present in less than 2% of previous negative biopsies. mHGPIN (39.7%), ASAP (4.3%) and PINATYP (3.7%) failed to predict csPCa risk in repeat biopsies. The finding of PIA (38.2%) associated with a decreased the risk of csPCa with an Odd ratio of 0.54 (95% confidence interval: 0.31-0.95), P= 0.031. The area under the curve, to predict csPCa, of mpMRI was 0.736, increasing up to 0.860 (95% confidence internal:0.82-0.90) when PSA density, age, digital rectal examination, and differential PSA between biopsies and PIA finding were integrated in a predictive model. At 6% threshold, more than 20% of repeat prostate biopsies were saved without missing csPCa. CONCLUSION: Currently, mHGPIN in negative prostate biopsy seems not able to predict the risk of future csPCa. The low incidence of ASAP and PINATYP, in our series, did not allow us to draw conclusions. PIA finding associated with a reduced risk of csPCa, and it could be integrated in a useful based-mpMRI predictive nomogram.

Prostatic-specific antigen density behavior according to multiparametric magnetic resonance imaging result.

OBJECTIVE: To analyze prostatic-specific antigen density (PSAD) according to the Prostate Imaging Reporting and Data System (PIRADSv.2) score, in order to determine how it should be used. METHODS: This correlative series considered 952 men with prostatic-specific antigen >3 ng/ml and/or abnormal digital rectal examination who were subjected to prostatic biopsy (PB) between 2016 and 2017. Of these men, 768 had no previous 5-α-reductase inhibitor use or history of prostate cancer (CaP) and had previously undergone 3-T multiparametric magnetic resonance imaging (mpMRI). In this sample, 549 men were biopsy-naïve and 219 had at least 1 previous negative PB. A 12-core transrectal ultrasound-guided PB was performed in all participants, as well as at least 2-core targeted biopsies of every detected lesion with a PIRADSv.2 score ≥3. Significant CaP (sCaP) was defined as an International Society of Uropathologist grade >1 or tumor length >4 mm. RESULTS: The overall CaP detection was 41.7%, with sCaP detected in 37.4%. sCaP was detected in 4.3% of PIRADSv.2 <3, 21.5% of PIRADSv.2 =3, 56.6% of PIRADSv.2 =4, and 78.5% of PIRADSv.2 =5, (P < 0.001). Insignificant CaP detection ranged from 6.5% to 1.5% respectively (P = 0.099). PSAD was an independent predictor of sCaP (odds ratios 1.971, 95% confidence interval [1.633, 2.378], P <0.001) and mpMRI (OR 3.179, 95%CI [2.593, 4.950], P < 0.001). Age (P = 0.013), family history of CaP (P = 0.021), and the type of PB (initial vs. repeated, P < 0.001) were also independent predictors of sCaP. PSAD was determined by PIRADSv.2 (P = 0.013) and the presence of sCaP (P < 0.001). PSAD increased with PIRADSv.2 score, even in men with CaP (P < 0.001) and slightly in men without CaP (P = 0.019). The area under the curve for mpMRI increased from 0.830 to 0.869 when PSAD was associated, (P < 0.001). The area under the curve of PSAD decreased from 0.727 in men with a PIRADSv.2 score <3 to 0.706 in those with a score of 5. CONCLUSIONS: The efficacy of PSAD to detect sCaP decreases with PIRADSv.2. Predictors other than mpMRI and PSAD exist. Considering these conditions, independent predictors should be integrated in a nomogram and risk-calculator to personalize PB recommendation.

Who Benefits from Multiparametric Magnetic Resonance Imaging After Suspicion of Prostate Cancer?

BACKGROUND: Prostate cancer (PC) suspicion is based on prostate-specific antigen (PSA) and digital rectal examination (DRE). Multiparametric magnetic resonance imaging (mpMRI) increases prostate biopsy (PBx) specificity and sensitivity for detection of aggressive PC. OBJECTIVE: To identify who benefits from mpMRI according to biopsy scenario (initial biopsy [IBx] vs repeated biopsy [RBx]) and the risk of aggressive PC according to PSA-DRE groups (G1, PSA <10ng/ml and -DRE; G2, PSA <10ng/ml and +DRE; G3, PSA ≥10ng/ml and -DRE; G4, PSA ≥10ng/ml and +DRE). DESIGN, SETTING, AND PARTICIPANTS: We carried out a retrospective analysis for 768 consecutive men with PC suspicion and scheduled for PBx in a referral institution in 2016 and 2017. INTERVENTION: Pelvic 3-T mpMRI scanning, targeted biopsy (TBx) for suspicious lesions (Prostate Imaging-Reporting and Data System [PI-RADS] score >1), and 12-core systematic biopsy (SBx). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We measured the rate of PBx procedures that could be avoided and the rate of high-grade PC (HGPC) that would be missed among men with negative mpMRI, and the increase in HGPC detection due to TBx. Univariate and multivariate analyses were performed. RESULTS AND LIMITATIONS: The rate of avoidable biopsies (PI-RADS <3) was 24.2% overall, with 25.7% for IBx and 20.5% for RBx (p=0.057). The IBx and RBx rates were 31.2% and 19.8% in G1, 13.5% and 30.4% in G2, 23.7% and 21.9% in G3, and 2.5% and 0% in G4, respectively. The overall rate of missed HGPC was 1.0% for IBx and 6.5% for RBx (p=0.170), while the IBx and RBx rates were 1.1% and 5.2% for G1, 2.0% and 11.1% for G2, 0% and 7.7% for G3, and 0% and 0% for G4, respectively (p<0.001). The rate of HGPC (PI-RADS 3-5) diagnosed following TBx increased to 23.9% for IBx and to 32.6% for RBx overall (p<0.001), while the IBx and RBx rates were 29.0% and 45.5% for G1, 20.0% and 33.3% for G2, 40.0% and 38.9% for G3, and 0% and 0% for G4, respectively (p<0.001). Limitations are the single-institution design, the lack of randomisation, and small samples for subgroup analyses. CONCLUSIONS: mpMRI was of no benefit for men with PSA ≥10ng/ml and +DRE. Among the other men, mpMRI was of benefit in IBx and RBx as would reduce the biopsy rate by up to 25.7% and increase the net HGPC detection rate by up to 28.4%. PATIENT SUMMARY: All men with suspected prostate cancer could benefit from multiparametric prostate cancer and targeted biopsy except for those with prostate-specific antigen ≥10ng/ml and positive digital rectal examination. The benefits include avoiding unnecessary prostate biopsy procedures and increasing the detection of aggressive cancer.

Clinical Significance of Proliferative Inflammatory Atrophy in Negative Prostatic Biopsies.

PURPOSE: To analyze the association between prostatic proliferative inflammatory atrophy finding in negative prostate biopsies and future detection of prostate cancer (PCa) and its aggressiveness in men subjected to repeat biopsies, due to persistent suspicion of PCa. MATERIALS AND METHODS: Prospective and observational study of 474 men scheduled to repeated PBs. Assessment of PIA and its extension in the previous biopsy. PCa detection rate and tumor aggressiveness. Age, serum total PSA, free PSA, percent free PSA (%fPSA), digital rectal exam (DRE), prostate volume (PV), PSA density (PSAD), PSA kinetics (PSAV and PSADT) findings of PIA and HGPIN, and number of affected cores in previous PBs were included in the univariate and multivariate analysis. Aggressive tumors were considered when any Gleason pattern 4 was found. RESULTS: PCa was detected in 133 men (28.1%). Age, serum total PSA, %fPSA, PV, PSAD, PSAV, PSADT, and PIA finding were significantly associated to PCa detection. However, only age, OR: 1.06 (95%CI: 1.03-1.10), P < 0.01; DRE, OR: 1.76 (95%CI: 1.05-2.92), P = 0.03; %fPSA, OR: 0.96 (95%CI: 0.93-0.99), P = 0.03; PV, OR: 0.98 (95%CI: 0.97-0.99) and PIA finding, OR: 0.49 (95%CI: 0.29-0.83), P < 0.01, were independent predictors of PCa detection. PCa was found in 18% of 159 men with previous PIA finding while in 33% of 315 men without previous PIA (P < 0.01). None of the studied parameters including PIA in the previous biopsy were related with subsequent PCa aggressiveness. CONCLUSIONS: PIA finding in negative biopsies correlates with a decreased frequency of detecting PCa in men with persistent suspicion of PCa. The aggressiveness of future detected tumors was not associated with previous PIA finding. Prostate 76:1501-1506, 2016. © 2016 Wiley Periodicals, Inc.

Clinical significance of proliferative inflammatory atrophy finding in prostatic biopsies.

BACKGROUND: Proliferative inflammatory atrophy (PIA) has been involved in prostatic carcinogenesis. However, little is known about the clinical significance of a PIA finding in prostatic biopsies (PBs). The aim of this study is to determine the incidence of prostate inflammatory atrophy (PIA) in prostate biopsies (PBs), its association to high-grade prostatic intraepithelial neoplasia (HGPIN), prostate cancer (PCa), and tumor aggressiveness. METHODS: Prospective and observational study of PIA lesion in 528 extended PBs and 200 radical prostatectomy specimens (RPS). OUTCOME MEASUREMENTS: PIA, HGPIN, PCa incidence, Gleason score, clinical and pathologic tumor stage and insignificant tumor rate. Univariate and multivariate analysis. RESULTS: Overall incidence of PIA and HGPIN was 30.3% and 54%. In RPS, the incidence was 30.5% and 72%, respectively. No significant association was found between PIA and HGPIN. Overall PCa detection rate in PBs was 38.1%. PCa was found in 27.5% PBs with PIA and 42.7% of those without PIA, P < 0.001. In contrast, PCa was detected in 50.9% of PBs with HGPIN and 23% of those without HGPIN, P = 0.001. Multivariate analysis revealed that PIA decreased the risk of PCa, OR:0.59 (95%CI:0.37-0.95), P = 0.029, while HGPIN increased OR:3.16 (95%CI:2.04-4.90), P = 0.001. PIA was not related to Gleason grade and clinical stage, however it was associated to an insignificant tumors increase, OR:3.08 (95%CI:1.09-8.7), P = 0.033. The information in RPS suggests that PIA is associated with less aggressive tumors and a higher probability of insignificant tumors. CONCLUSIONS: PIA is present in one third of PBs, HGPIN in one half of them, and no association exists between both lesions. Contrary to HGPIN, PIA finding is associated to lower risk of PCa detection. Tumors accompanying PIA seem to be less aggressive and have a greater probability of being insignificant.

Metabolic syndrome increases the risk of aggressive prostate cancer detection.

UNLABELLED: WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: Metabolic syndrome can identify patients at high risk of cardiovascular disease. The prevalence of metabolic syndrome is increasing worldwide and is associated with increased age, obesity and hypogonadism. The association between metabolic syndrome and prostate cancer development has not been studied comprehensively, and published studies report divergent results. This study indicates that tumours detected in men with metabolic syndrome are more aggressive than those detected in men without this condition. OBJECTIVE: To further examine the association between metabolic syndrome (MS), prostate cancer (PC) detection risk and tumour aggressiveness. PATIENTS AND METHODS: From 2006 to 2010, 2408 men not receiving 5α-reductase inhibitors were scheduled for prostatic biopsy due to PSA above 4 ng/mL and/or abnormal digital rectal examination. MS was evaluated according to the National Cholesterol Education Program Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults, Adult Treatment Panel III definition. Tumour aggressiveness was evaluated through biopsy Gleason score, clinical stage and risk of biochemical recurrence after primary treatment. RESULTS: The rates of PC detection were 34.5% and 36.4% respectively in men with and without MS, P = 0.185. High grade PC rates (Gleason score 8-10) were 35.9% and 23.9% respectively, P < 0.001. The advanced disease rates (cT3-4 N0-1 M0-1) were 17% and 12.7% respectively, P = 0.841. The high risk PC rates (cT2c-4 or Gleason score 8-10 or PSA > 20) were 38.5% and 33.0% respectively, P = 0.581. Multivariate analysis confirmed that MS was not associated with the risk of PC detection but it was associated with an increased risk of high grade tumours (odds ratio 1.75, 95% CI 1.26-2.41), P < 0.001. CONCLUSION: MS seems not be associated with an increased risk of PC detection but it is associated with an increased risk of more aggressive tumours.

Behavior of the PCA3 gene in the urine of men with high grade prostatic intraepithelial neoplasia.

OBJECTIVE: An ideal marker for the early detection of prostate cancer (PCa) should also differentiate between men with isolated high grade prostatic intraepithelial neoplasia (HGPIN) and those with PCa. Prostate Cancer Gene 3 (PCA3) is a highly specific PCa gene and its score, in relation to the PSA gene in post-prostate massage urine (PMU-PCA3), seems to be useful in ruling out PCa, especially after a negative prostate biopsy. Because PCA3 is also expressed in the HGPIN lesion, the aim of this study was to determine the efficacy of PMU-PCA3 scores for ruling out PCa in men with previous HGPIN. PATIENTS AND METHODS: The PMU-PCA3 score was assessed by quantitative PCR (multiplex research assay) in 244 men subjected to prostate biopsy: 64 men with an isolated HGPIN (no cancer detected after two or more repeated biopsies), 83 men with PCa and 97 men with benign pathology findings (BP: no PCa, HGPIN or ASAP). RESULTS: The median PMU-PCA3 score was 1.56 in men with BP, 2.01 in men with HGPIN (p = 0.128) and 9.06 in men with PCa (p = 0.008). The AUC in the ROC analysis was 0.705 in the subset of men with BP and PCa, while it decreased to 0.629 when only men with isolated HGPIN and PCa were included in the analysis. Fixing the sensitivity of the PMU-PCA3 score at 90%, its specificity was 79% in men with BP and 69% in men with isolated HGPIN. CONCLUSIONS: The efficacy of the PMU-PCA3 score to rule out PCa in men with HGPIN is lower than in men with BP.

Antiproliferative and apoptotic effects of the herbal agent Pygeum africanum on cultured prostate stromal cells from patients with benign prostatic hyperplasia (BPH).

BACKGROUND: Previous reports show that the herbal agent Pygeum africanum (PA) used to treat benign prostatic hyperplasia (BPH) inhibits proliferation of prostate stromal cells from BPH tissues. To determine underlying mechanisms, we compared proliferative and apoptotic responses to PA between BPH and non-BPH prostate stromal cells with a focus on the specific reaction displayed by stromal cell subsets. An interaction of PA with growth factors and hormones was also investigated. METHODS: Primary prostate stromal cells from BPH/LUTS patients undergoing open prostatectomy (n = 3) and patients without benign prostatic hyperplasia (BPH) undergoing cystectomy (n = 3) were treated with PA. Cells were characterized by immunofluorescence. Sensitivity to PA was determined using proliferation assays. Apoptosis, transforming growth factor B1 (TGFB1), fibroblast growth factor 2 (FGF2), vimentin, alpha smooth muscle actin (alphaSMA), and smoothelin expression were examined after PA treatment. Cell immunophenotype and proliferation were tested after incubating cells with PA plus either FGF2, TGFB1, vascular endothelial growth factor (VEGF), dihydrotestosterone (DHT) or 17beta-estradiol (E2). RESULTS: Antiproliferative potency and apoptosis induced by PA on stromal cells were increased in BPH versus non-BPH cells. Apoptosis targeted alphaSMA+ cells, more abundant in BPH cells. Downregulation of TGFB1 expression was induced by PA. FGF2 increased cells sensitivity to PA. Incubation with other mitogenic factors like VEGF, DHT, and E2 decreased sensitivity to PA. Both TGFB1 and E2 blocked the antiproliferative activity of PA. CONCLUSIONS: Results suggest that PA is antiproliferative and apoptotic on proliferative prostate fibroblasts and myofibroblasts but not on smooth muscle cells. Mechanisms of action include TGFB1 downregulation and inhibition of FGF2 specific signaling.

Evaluation of the serum testosterone to prostate-specific antigen ratio as a predictor of prostate cancer risk.

OBJECTIVE: To analyse the ratio of serum testosterone (sT) to prostate-specific antigen (PSA) as a predictor of prostate cancer risk, as low levels of sT have been related to a greater risk of prostate cancer, and its ratio with serum PSA level was recently proposed as a new tool to increase the specificity of PSA. PATIENTS AND METHODS: In all, 439 consecutive men with a normal digital rectal examination and a serum PSA level of 4.1-20 ng/mL had a transrectal ultrasonography-guided biopsy using a 10-core scheme, with an additional 1-8 cores according to prostate volume and patient age. The sT level was determined before the procedure using a chemiluminescent assay, and the ratio of sT to PSA (sT/PSA) was calculated after transforming sT measurements from ng/dL to ng/mL. The percentage free PSA (%fPSA) and PSA density were also included in this analysis. RESULTS: The overall cancer detection rate was 42.1%. The median sT level was 469 ng/dL in men with cancer and 499 ng/dL in those without (P = 0.521). The median sT/PSA was 0.68 and 0.74, respectively (P = 0.215). However, the median %fPSA was 14 in men with cancer and 17 in men without (P < 0.001) and the median PSA density was 0.22 and 0.16, respectively (P < 0.001). The multivariate analysis confirmed the independent predictive value only for %fPSA (odds ratio 0.94, 95% confidence interval 0.91-0.98) and PSA density (5.8, 3.42-19.8). CONCLUSION: These results do not support the use of sT/PSA for predicting the risk of prostate cancer and to increase the specificity of PSA.

The relationship between total and free serum testosterone and the risk of prostate cancer and tumour aggressiveness.

OBJECTIVE: To analyse the relationship between the levels of total and free serum testosterone and the risk of prostate cancer and tumour aggressiveness. PATIENTS AND METHODS: Total and free serum testosterone were determined in 478 patients consecutively assessed by transrectal ultrasonography-guided prostate biopsy because of an abnormal digital rectal examination and/or serum prostate-specific antigen (PSA) level of >4.0 ng/mL. Tumour aggressiveness was assessed according to serum PSA level, biopsy Gleason score and clinical stage in the subset of 216 patients with cancer (45.2%). We also compared prostate cancer risk and tumour aggressiveness in 80 hypogonadal patients (16.7%) and 398 eugonadal patients (83.3%). RESULTS: The median total serum testosterone level in patients without and with prostate cancer was 466.0 and 466.5 ng/dL, respectively (P > 0.05); the median levels of free serum testosterone were 9.9 and 10.0 pg/mL, respectively (P > 0.05). The cancer detection rate in hypogonadal patients was 41.3% (33/80) and 46.0% in eugonadal patients (183/398) (P > 0.05). The median level of total testosterone was 433 ng/dL in patients with low-risk prostate cancer, 467 ng/dL in those with intermediate-risk tumours and 468 ng/dL in those with high-risk tumours (P > 0.05); the median levels of free testosterone were 9.4, 9.8 and 10.3 pg/mL, respectively (P > 0.05). CONCLUSIONS: Prostate cancer risk and tumour aggressiveness are not related to serum levels of total and free testosterone, but hypogonadal patients do not have a greater risk of prostate cancer and tumour aggressiveness.

PTOV1 expression predicts prostate cancer in men with isolated high-grade prostatic intraepithelial neoplasia in needle biopsy.

PURPOSE: To analyze the expression of PTOV1 in high-grade prostatic intraepithelial neoplasia (HG-PIN) and to explore its usefulness to predict prostate cancer in patients with isolated HG-PIN in needle biopsy (prostate needle biopsy). EXPERIMENTAL DESIGN: PTOV1 expression in HG-PIN lesions from 140 patients was analyzed by immunohistochemistry in a semiquantitative manner (Histo-score). HG-PIN derived from 79 radical prostatectomies for prostate cancer and from 11 cistoprostatectomies for bladder cancer without prostate cancer were used as positive and negative controls, respectively. Fifty patients with HG-PIN without concomitant cancer at their first prostate needle biopsy were chosen as the study group. Patients were followed by a mean of 2.5 repeated prostate needle biopsies (1-5), during a mean period of 12.4 months (1-39). RESULTS: PTOV1 expression in HG-PIN from radical prostatectomies showed a significantly higher Histo-score (162.6) compared with specimens from cistoprostatectomies (67.0). In the study group, PTOV1 expression was significantly higher in samples with cancer in the follow-up (11 patients, 22%) compared with samples in which cancer was not detected (151.4 versus 94.6). PTOV1 expression was the only independent predictor of cancer in the multivariate analysis and the area under the curve was 0.803 (95% confidence interval, 0.728-0.878). A threshold of 100 for PTOV1 expression provided 90.9% sensitivity, 51.3% specificity, 34.5% positive predictive value, and 95.2% negative predictive value. CONCLUSIONS: PTOV1 is overexpressed in HG-PIN associated with cancer and is a potential marker for studying the carcinogenesis and progression of prostate cancer. Prostate needle biopsy with PTOV1 expression in HG-PIN above a threshold of 100 should be repeated immediately for the likely presence of undiagnosed cancer.

The percentage of free prostatic-specific antigen is also useful in men with normal digital rectal examination and serum prostatic-specific antigen between 10.1 and 20 ng/ml.

OBJECTIVE: The percentage of free prostatic-specific antigen (PSA) has been introduced as a tool to avoid unnecessary biopsies in men with normal digital rectal examination (DRE) and serum PSA between 4.1 and 10 ng/ml. In this series we also analyze its utility in men with normal DRE and serum PSA between 10.1 and 20 ng/ml. MATERIALS AND METHODS: A series of 1149 consecutive men with normal DRE and serum PSA between 4.1 and 20 ng/ml submitted for the first ultrasound guided sextant biopsy is analyzed. In 921 (80.2%) the serum PSA was from 4.1 to 10 ng/ml and in 228 (19.8%) from 10.1 to 20 ng/ml. Total and free serum PSA determinations were done by the inmunoradiometric assays Tandem and Tandem free PSA (Hybritech Inc.). RESULTS: The overall detection rate of prostate cancer was 27.9%. In the group of men which serum PSA ranged from 4.1 to 10 ng/ml the rate of detection was 25.4% and 37.7% when it was between 10.1 and 20 ng/ml. Using 25% or less of percent free PSA as a criterion for performing prostatic biopsy it would have detected 95.3% and 95.4% of the prostate cancers, respectively. The rate of unnecessary avoided biopsies would be 17.5% when serum PSA ranged from 4.1 to 10 ng/ml and 17.6% between 10.1 and 20 ng/ml. CONCLUSIONS: This prospective study demonstrates that the percentage of free PSA seems to have similar utility when serum PSA levels are between 4.1 and 10 ng/ml and between 10.1 and 20 ng/ml, at the time of the first prostatic biopsy indication.