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Syndecan-1 (CD138) is a transmembrane proteoglycan expressed in various normal and malignant tissues. It is of interest due to a possible prognostic effect in tumors and its role as a target for the antibody-drug conjugate indatuximab ravtansine. Here, we analyzed 17,747 prostate cancers by immunohistochemistry. Membranous and cytoplasmic CD138 staining was separately recorded. In normal prostate glands, CD138 staining was limited to basal cells. In cancers, membranous CD138 positivity was seen in 19.6% and cytoplasmic CD138 staining in 11.2% of 12,851 interpretable cases. A comparison with clinico-pathological features showed that cytoplasmic CD138 staining was more linked to unfavorable tumor features than membranous staining. Cytoplasmic CD138 immunostaining was associated with high tumor stage ( p < 0.0001), high Gleason grade ( p < 0.0001), nodal metastases ( p < 0.0001), positive surgical margin ( p < 0.0001), and biochemical recurrence ( p < 0.0001). This also holds true for both V-ets avian erythroblastosis virus E26 oncogene homolog (ERG) fusion positive and ERG fusion negative tumors although the cytoplasmic CD138 expression was markedly more frequent in ERG positive than in ERG negative tumors ( p < 0.0001). Comparison with 11 previously analyzed chromosomal deletions identified a conspicuous association between cytoplasmic CD138 expression and 8p deletions ( p < 0.0001) suggesting a possible functional interaction of CD138 with one or several 8p genes. Multivariate analysis revealed the cytoplasmic CD138 expression as an independent prognostic parameter in all cancers and in the ERG positive subgroup. In summary, our study indicates the cytoplasmic CD138 expression as a strong and independent predictor of poor prognosis in prostate cancer. Immunohistochemical measurement of CD138 protein may thus-perhaps in combination with other parameters-become clinically useful in the future., Competing Interests: The authors have no conflict of interest to declare., (Copyright © 2020 Simon Kind et al.)

The transcriptional coactivator YAP1 controls the balance between cell proliferation and apoptosis. YAP1 overexpression is linked to poor prognosis in many cancer types, yet its role in prostate cancer is unknown. Here, we applied YAP1 immunohistochemistry to a tissue microarray containing 17,747 clinical prostate cancer specimens. Cytoplasmic and nuclear YAP1 staining was seen in 81% and 63% of tumours. For both cytoplasmic and nuclear YAP1 staining, high levels were associated with advanced tumour stage, classical and quantitative Gleason grade, positive nodal stage, positive surgical margin, high KI67 labelling index, and early biochemical recurrence (p < 0.0001 each). The prognostic role of YAP1 staining was independent of established prognostic features in multivariate models (p < 0.001). Comparison with previously studied molecular markers identified associations between high YAP1 staining, TMPRSS2:ERG fusion (p < 0.0001), high androgen receptor (AR) expression (p < 0.0001), high Ki67 labelling index (p < 0.0001), and PTEN and 8p deletions (p < 0.0001 each). In conclusion, high YAP1 protein expression is an independent predictor of unfavourable disease course in prostate cancer. That cytoplasmic and nuclear YAP1 staining is equally linked to phenotype and prognosis fits well to a model where YAP1 activation during tumour progression includes up regulation, cytoplasmic accumulation and subsequent translocation to the nucleus.

Introduction: The purpose of this study was to investigate adherence to recommended adjuvant radiotherapy (aRT) in radical prostatectomy (RP) patients with adverse pathologic features and to analyse the outcome of patients who followed or denied this recommendation., Patients and Methods: We included 1140 consecutive RP patients (2006-2015) with non-organ confined (pT3) prostate cancer and either positive surgical margins (R1) and/or lymph node involvement (pN1) and non-detectable postoperative prostate-specific antigen who received multidisciplinary aRT recommendations. Patients were stratified into adherence versus non-adherence to recommendations. Additionally, subgroups within pathologic criteria (pT3R1N0, pT3R0N1, pT3R1N1) were analyzed. Kaplan-Meier, as well as multivariable Cox regression analyses were used to assess biochemical recurrence (BCR)-free survival, metastasis-free survival, cancer-specific survival, and overall survival., Results: Overall, 508 (44.6%) patients were non-adherent. Of those, 273 (53.6%) did not receive any RT, and 235 (46.4%) received salvage RT. At 8 years, BCR-free survival was 57.7 versus 20.1%, metastasis-free survival was 76.5 versus 75.4%, cancer-specific survival was 91.7 versus 87.4%, and overall survival was 80.4 versus 75.8% in adherent versus non-adherent patients, respectively (P < .001). In multivariable Cox regression predicting BCR, metastatic progression, cancer-specific mortality, and overall mortality, non-adherence to aRT recommendation represented an independent predictor (hazard ratio [HR], 3.8; 95% confidence interval [CI], 3.1-4.5; HR, 1.6; 95% CI, 1.2-2.2; HR, 2.8; 95% CI, 1.5-5.3; and HR, 1.8; 95% CI, 1.2-2.8, respectively)., Conclusions: Only about 55% of patients followed our multidisciplinary recommendations. Adherent patients were significantly less likely to experience BCR, metastatic progression, cancer-specific mortality, and overall mortality. Thus, patients with high risk of recurrence may be advised about the possibility of improved oncologic outcomes in case of adherence to aRT recommendations., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Prostate Stem Cell Antigen (PSCA) is frequently expressed in prostate cancer but its exact function is unclear., Methods: To clarify contradictory findings on the prognostic role of PSCA expression, a tissue microarray containing 13,665 prostate cancers was analyzed by immunohistochemistry., Results: PSCA staining was absent in normal epithelial and stromal cells of the prostate. Membranous and cytoplasmic PSCA staining was seen in 53.7% of 9642 interpretable tumors. Staining was weak in 22.4%, moderate in 24.5% and strong in 6.8% of tumors. PSCA expression was associated with favorable pathological and clinical tumor features: Early pathological tumor stage (p < 0.0001), low Gleason grade (p < 0.0001), absence of lymph node metastasis (p < 0.0001), low pre-operative PSA level (p = 0.0118), negative surgical margin (p < 0.0001) and reduced PSA recurrence (p < 0.0001). PSCA expression was an independent predictor of prognosis in multivariate analysis (hazard ratio 0.84, p < 0.0001)., Conclusions: The absence of statistical relationship to TMPRSS2:ERG fusion status, chromosomal deletion or high tumor cell proliferation argues against a major role of PSCA for regulation of cell cycle or genomic integrity. PSCA expression is linked to favorable prognosis. PSCA measurement is a candidate for inclusion in multi-parametric prognostic prostate cancer tests.

Background: Presence of small (tertiary) Gleason 5 pattern is linked to a higher risk of biochemical recurrence in prostate cancer. It is unclear, however, how to integrate small Gleason 5 elements into clinically relevant Gleason grade groups., Objective: To analyze the prognostic impact of Gleason 5 patterns in prostate cancer and to develop a method for integrating tertiary Gleason 5 patterns into a quantitative Gleason grading system., Design, Setting, and Participants: Prostatectomy specimens from 13 261 consecutive patients and of 3295 matched preoperative biopsies were available. Percentages of Gleason 3, 4, and 5 had been recorded for each cancer. Outcome measurements and statistical analysis: RESULTS AND LIMITATIONS: Our data demonstrate that minimal Gleason 5 areas have strong prognostic impact in Gleason 7 carcinomas, while further expansion of the Gleason 5 pattern population has less impact. We thus defined an integrated quantitative Gleason score (IQ-Gleason) by adding a lump score of 10 to the percentage of unfavorable Gleason pattern (Gleason 4/5) if any Gleason 5 was present and by adding another 7.5 points in case of a Gleason 5 fraction >20%. There was a continuous increase of the risk of prostate-specific antigen recurrence with increasing IQ-Gleason. This was also true for subgroups with identical Cancer of the Prostate Risk Assessment Postsurgical scores (p<0.0001) or Gleason grade groups (p<0.0001)., Conclusions: The IQ-Gleason represents a simple and efficient approach for combining both quantitative Gleason grading and tertiary Gleason grades in one highly prognostic numerical variable., Patient Summary: Prostatectomy specimens (13 261) were analyzed to estimate the relevance of small Gleason 5 elements in prostate cancers. Even the smallest Gleason 5 areas markedly increased the risk of prostate-specific antigen recurrence after surgery. Larger fractions of Gleason 5 patterns had less further impact on prognosis. Based on this, a numerical Gleason score (integrated quantitative Gleason score) was defined by the percentages of Gleason 4 and 5 patterns, enabling a refined estimate of patient prognosis., (Copyright © 2017. Published by Elsevier B.V.)

FOXA1 (Fork-head box protein A1, HNF-3a) is a transcription factor involved in androgen signaling with relevance for lineage-specific gene expression of the prostate. The expression was analyzed by immunohistochemistry on a tissue microarray containing 11152 prostate cancer specimens. Results were compared with tumor phenotype, biochemical recurrence, androgen receptor expression, ETS-related gene (ERG) status and other recurrent genomic alterations. FOXA1 expression was detectable in 97.6% of 8227 interpretable cancers and considered strong in 28.5%, moderate in 46.2% and weak in 22.9% of cases. High FOXA1 expression was associated with TMPRSS2:ERG rearrangement and ERG expression (P < 0.0001). High FOXA1 expression was linked to high Gleason grade, advanced pathological tumor (pT) stage and early PSA recurrence in ERG negative cancers (P < 0.0001), while these associations were either weak or absent in ERG positive cancers. In ERG negative cancers, the prognostic role of FOXA1 expression was independent of Gleason grade, pathological tumor stage, lymph node stage, surgical margin status and preoperative PSA. Independent prognostic value became even more evident if the analysis was limited to preoperatively available features such as biopsy Gleason grade, preoperative PSA, cT stage and FOXA1 expression (P < 0.0001). Within ERG negative cancers, FOXA1 expression was also strongly associated with PTEN and 5q21 deletions (P < 0.0001). High expression of FOXA1 is an independent prognostic parameter in ERG negative prostate cancer. Thus, FOXA1 measurement might provide clinically useful information in prostate cancer., (© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Introduction: Obesity negatively affects several prostate cancer (PCa) outcomes, including mortality to PCa. However, the validity of several such associations is still under debate, including its effect on pathological stage at radical prostatectomy (RP) and subsequent biochemical recurrence (BCR), which represents the focus of this study., Methods: We relied on patients with PCa treated with RP at the Martini-Klinik Prostate Cancer Center between 2004 and 2015. First, multivariable logistic regression analyses tested for association between obesity and non-organ-confined disease (≥pT3 or pN1). Second, multivariable Cox regression analyses examined obesity effect on BCR. Last, in a propensity score-matched cohort, Kaplan-Meier analyses assessed BCR-free survival according to body mass index (kg/m 2 ) (BMI) strata (≥30 vs.<25)., Results: Of 16,014 individuals, 2,403 (15%) men were obese (BMI≥30). Median follow-up was 36.4 months (interquartile range: 13.3-60.8). Obese patients were more likely to harbor non-organ-confined disease at final pathology (odds ratio = 1.27; 95% CI: 1.13-1.43; P<0.001) but did not have higher BCR rates (hazard ratio = 0.98; 95% CI: 0.86-1.11; P = 0.7). Similarly, BCR-free survival was not different between obese and nonobese men, after propensity score matching (log rank P = 0.9)., Conclusion: Obesity (BMI ≥30) might predispose to higher rates of non-organ-confined disease at RP. However, obesity was not an independent predictor of BCR after surgery. Consequently, the unfavorable effect of obesity on PCa might be limited to local spread of the disease and might be neutralized after RP., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Introduction: The presence of circulating tumor cells (CTCs) is an established marker for prognosis in men with castration-resistant prostate cancer. A cutoff of ≥5 CTCs/7.5ml blood in the CellSearch Epithelial Cell Test has been shown to stratify prognostic groups and predict outcome of abiraterone treatment. In contrast, the value of CTC detection in men with localized prostrate cancer before radical prostatectomy (RP) is unknown., Materials and Methods: A total of 152 patients treated with RP between 06/2009 and 09/2009 were included. Peripheral venous blood drawn the day before RP was evaluated for CTCs by the CellSearch system. The detection of CTCs was correlated with prostate-specific antigen (PSA) and the histopathological outcome of the RP specimen. A cutoff of 0 vs. ≥1 CTC/7.5ml blood was defined as the threshold for positive vs. negative CTC status., Results: Median age was 62 years and median PSA was 6.7ng/dl. Staging revealed 62.5% pT2, 26.3% pT3a, and 11.2% pT3b tumors, and high-grade disease (≥Gleason 4+3) was determined in 25.6% of patients. CTCs were detected in 17 patients (11%) with a median CTC count/7.5ml of 1 (range: 1-clusters with>100 epithelial cells) without significant correlations to PSA levels, pT stage, or Gleason scores. Postoperative pT stage was a significant predictor of biochemical recurrence (BCR) in univariable logistic regression models and as a composite measure together with positive CTC counts (P<0.0001). CTC positivity alone tended to have a higher hazard ratio for BCR, but this was not statistically significant (P = 0.1). After a median follow-up of 48 months, there was no significant difference in BCR-free survival between patients with or without CTCs (P = 0.7)., Conclusion: Using the CellSearch system, we infrequently detected CTCs in patients with localized tumors before RP. The detection of CTCs did not correlate significantly with PSA, disease characteristics, or the development of BCR. However, larger cohorts with extended follow-up are needed to validate our findings., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Enhancer of zeste homolog 2 (EZH2) plays an important role in tumor development and progression by interacting with histone and nonhistone proteins. In the current study, we analyzed prevalence and prognostic impact of EZH2 in prostate cancer. EZH2 expression was analyzed by immunohistochemistry on a tissue microarray containing more than 12400 prostate cancer specimens. Results were compared to tumor phenotype, biochemical recurrence and molecular subtypes defined by ERG status as well as genomic deletions of 3p, 5q, 6q and PTEN. EZH2 immunostaining was detectable in 56.6% of 10168 interpretable cancers and considered strong in 1.1%, moderate in 12.2% and weak in 43.3% of cases. High EZH2 expression was strongly associated with high Gleason grade (P < 0.0001), advanced pathological tumor stage (P < 0.0001), positive nodal status (P < 0.0001), elevated preoperative PSA level (P = 0.0066), early PSA recurrence (P < 0.0001) and increased cell proliferation P < 0.0001). High-level EZH2 staining was also associated with TMPRSS2:ERG rearrangement and ERG expression in prostate cancers (P < 0.0001) and was linked to deletions of PTEN, 6q15, 5q21 and 3p13 (P < 0.0001 each) particularly in ERG-negative cancers. The prognostic impact of EZH2 was independent of established pre- and postoperatively assessed clinicopathological parameters. EZH2 has strong prognostic impact in prostate cancer and might contribute to the development of a fraction of genetically instable and particularly aggressive prostate cancers. EZH2 analysis might therefore be of clinical value for risk stratification of prostate cancer., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Purpose: Sequestosome 1 (p62) is a multifunctional adapter protein accumulating in autophagy-defective cells., Experimental Design: To evaluate the clinical impact and relationship with key genomic alterations in prostate cancer, p62 protein levels were analyzed by immunohistochemistry on a tissue microarray containing 12,427 prostate cancers. Data on ERG status and deletions of PTEN, 3p13, 5q21, and 6q15 were available from earlier studies., Results: p62 immunostaining was absent in benign prostatic glands but present in 73% of 7,822 interpretable prostate cancers. Strong cytoplasmic p62 staining was tightly linked to high Gleason grade, advanced pathologic tumor (pT) stage, positive nodal status, positive resection margin, and early PSA recurrence (P < 0.0001 each). Increased levels of p62 were significantly linked to TMPRSS2-ERG fusions, both by FISH and immunohistochemical analysis (P < 0.0001 each). For example, moderate or strong p62 immunostaining was seen in 28.5% of cancers with TMPRSS2-ERG fusion detected by FISH and in 23.1% of cancers without such rearrangements (P < 0.0001). Strong p62 staining was significantly linked to the presence of all tested deletions, including PTEN (P < 0.0001), 6q15 (P < 0.0001), 5q21 (P = 0.0002), 3p13 (P = 0.0088), and 6q15 (P < 0.0001), suggesting a link between p62 accumulation and loss of genomic stability. The prognostic role of p62 protein accumulation was striking and independent of Gleason grade, pT stage, pN stage, surgical margin status, and preoperative PSA, regardless of whether preoperative or postoperative parameters were used for modeling., Conclusions: Our study identifies cytoplasmic accumulation of p62 as a strong predictor of an adverse prognostic behavior of prostate cancer independently from established clinicopathologic findings., (©2015 American Association for Cancer Research.)

Purpose: To assess the association between blood loss, blood transfusion (BT) and biochemical recurrence (BCR)-free, metastasis-free and overall survival after radical prostatectomy (RP) in a large single-center cohort of patients. Perioperative BT at oncologic surgery has been reported to be a potential risk factor for cancer recurrence and survival in several cancer entities. Current studies addressing the relationship between BT, blood loss and BCR-free survival in prostate cancer patients are controversial and include only series with fairly small patient cohorts., Materials and Methods: The data of 11,723 patients who underwent RP between 01/1992 and 08/2011 were analyzed. Cox regression analysis, including preoperative PSA level, pT stage, lymph node status, Gleason score, margin status, blood loss, transfusion rate (allogeneic or autologous), tested the relationship between blood loss, transfusion and BCR-free, metastasis-free and overall survival. Additionally, propensity score-matching analysis was performed to adjust differences in tumor characteristics., Results: There was no statistically significant relationship between blood loss or BT and BCR-free, metastasis-free or overall survival. In multivariate analysis PSA level, pT stage, Gleason score, margin status and lymph node status were independent factors for a BCR (p < 0.0001). These results were identical after propensity score matching analysis, comparing patients with and without BT., Conclusions: This large-scale analysis revealed no correlation between blood loss, blood transfusion and oncological outcome in prostate cancer patients treated with RP. Therefore, the association between higher blood loss or transfusion rate and cancer recurrence as described in other surgical treated tumor entities seems to be irrelevant in prostate cancer patients.

HOXB13 is a prostate cancer susceptibility gene which shows a cancer predisposing (G84E) mutation in 0.1-0.6% of males. We analyzed the prognostic impact of HOXB13 expression by immunohistochemistry on a tissue microarray containing more than 12,400 prostate cancers. Results were compared to tumor phenotype, biochemical recurrence, androgen receptor (AR) and prostate specific antigen (PSA) as well as molecular subtypes defined by ERG status and genomic deletions of 3p, 5q, 6q, and PTEN. HOXB13 immunostaining was detectable in 51.7% of 10,216 interpretable cancers and considered strong in 9.6%, moderate in 19.7% and weak in 22.3% of cases. HOXB13 expression was linked to advanced pT stage, high Gleason grade, positive lymph node status (p < 0.0001 each), high pre-operative PSA levels (p = 0.01), TMPRSS2:ERG fusion, PTEN deletions, AR expression, cell proliferation, reduced PSA expression and early PSA recurrence (p < 0.0001 each). The prognostic value of HOXB13 was independent from established parameters including Gleason, stage, nodal stage and PSA. Co-expression analysis identified a subset of tumors with high HOXB13 and AR but low PSA expression that had a particularly poor prognosis. HOXB13 appears to be a promising candidate for clinical routine tests either alone or in combination with other markers, including AR and PSA.

The VEGFR-1 is suggested to promote tumor progression. In the current study we analyzed prevalence and prognostic impact of the VEGFR-1 by immunohistochemistry on a tissue microarray containing more than 3000 prostate cancer specimens. Results were compared to tumor phenotype, ETS-related gene (ERG) status, and biochemical recurrence. Membranous VEGFR-1 expression was detectable in 32.6% of 2669 interpretable cancers and considered strong in 1.7%, moderate in 6.7% and weak in 24.2% of cases. Strong VEGFR-1 expression was associated with TMPRSS2:ERG fusion status as determined by fluorescence in situ hybridization (FISH) and immunohistochemistry (p < 0.0001 each). Elevated VEGFR-1 expression was linked to high Gleason grade and advanced pT stage in TMPRSS2:ERG negative cancers (p = 0.0008 and p = 0.001), while these associations were absent in TMPRSS2:ERG positive cancers. VEGFR-1 expression was also linked to phosphatase and tensin homolog (PTEN) deletions. A comparison with prostate specific antigen (PSA) recurrence revealed that the 1.7% of prostate cancers with the highest VEGFR-1 levels had a strikingly unfavorable prognosis. This could be seen in all cancers, in the subsets of TMPRSS2:ERG positive or negative, PTEN deleted or undeleted carcinomas (p < 0.0001 each). High level VEGFR-1 expression is infrequent in prostate cancer, but identifies a subgroup of aggressive cancers, which may be candidates for anti-VEGFR-1 targeted therapy.

Purpose: Experimental evidence suggests that phosphodiesterase type 5 inhibitors may suppress tumor growth, postpone metastasis and prolong survival, but clinical data are lacking. We studied the effect of phosphodiesterase type 5 inhibitors on biochemical recurrence after radical prostatectomy for prostate cancer., Materials and Methods: The study was comprised of 4,752 consecutive patients with localized prostate cancer treated with bilateral nerve sparing radical prostatectomy between January 2000 and December 2010. Of these patients 1,110 (23.4%) received phosphodiesterase type 5 inhibitors postoperatively while 3,642 (76.6%) did not. The risk of biochemical recurrence was compared between the phosphodiesterase type 5 inhibitor group and the nonphosphodiesterase type 5 inhibitor group. Cox multivariate proportional hazard models and confidence intervals were used to estimate the hazard ratio of biochemical recurrence associated with phosphodiesterase type 5 inhibitor use. Propensity score matched analysis was performed., Results: Median followup was 60.3 months (IQR 36.7-84.5). Five-year biochemical recurrence-free survival estimates in the phosphodiesterase type 5 inhibitor vs nonphosphodiesterase type 5 inhibitor groups were 84.7% (95% CI 82.1-87.0) and 89.2% (95% CI 88.1-90.3), respectively (p=0.0006). Multivariate regression analysis showed that phosphodiesterase type 5 inhibitor use was an independent risk factor for biochemical recurrence (HR 1.38, 95% CI 1.11-1.70, p=0.0035) and this was also true after propensity score matching., Conclusions: Contrary to experimental data, the use of phosphodiesterase type 5 inhibitors after radical prostatectomy may adversely impact biochemical recurrence. Further studies are needed to validate our results., (Copyright © 2015 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: The prognostic significance of a tertiary Gleason pattern in the radical prostatectomy specimen is controversial. We tested the impact of a tertiary Gleason pattern on adverse histopathological features and biochemical recurrence rates after radical prostatectomy., Materials and Methods: We assessed data on 11,226 consecutive patients treated with radical prostatectomy at our institution between June 2007 and February 2013. We compared 2,396 patients with (22.4%) and 8,260 without (77.5%) a tertiary Gleason pattern for adverse histopathological features (extraprostatic extension, seminal vesicle invasion, positive surgical margins and lymph node invasion) using the chi-square test. The effect of a tertiary Gleason pattern on biochemical recurrence was tested in univariable and multivariable models. Subanalyses were then done for different radical prostatectomy Gleason groups (6 or less, 3 + 4 and 4 + 3)., Results: A tertiary Gleason pattern was statistically significantly associated with all evaluated histopathological parameters (each p <0.001). It was an independent predictor of biochemical recurrence (HR 1.43, p <0.001). On subanalysis only a tertiary Gleason pattern independently predicted biochemical recurrence in the patient cohort with a radical prostatectomy Gleason score of 3 + 4 and 4 + 3. However, it failed to attain independent predictor status in patients with a radical prostatectomy Gleason score of 6 or less., Conclusions: A tertiary Gleason pattern is a significant and independent predictor of biochemical recurrence after radical prostatectomy with the strongest prognostic effect in cases with Gleason scores 3 + 4 and 4 + 3. Therefore, a tertiary Gleason pattern should be recorded in the pathological report., (Copyright © 2014 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Objective: To address the biochemical and functional outcomes after radical prostatectomy (RP) of men aged <50 years in a large European population., Patients and Methods: Among 13,268 patients who underwent RP for clinically localised prostate cancer at our centre (1992-2011), 443 (3.3%) men aged <50 were identified. Biochemical recurrence (BCR) and functional outcomes (International Index of Erectile Function [IIEF-5], use of pads), were prospectively evaluated and compared between men aged <50 years and older patients., Results: Men aged <50 years were more likely to harbour D'Amico low-risk (49.4 vs 34.9%, P < 0.001), organ-confined (82.6 vs 69.4%, P < 0.001) and low-grade tumours (Gleason score <7: 33.1 vs 28.7%, P < 0.001). Multivariate Cox regression analysis showed that age <50 years (hazard ratio 0.99; confidence interval 0.72-1.31; P = 0.9) was not a predictor of BCR. Urinary continence was more favourable in younger patients, resulting in continence rates of 97.4% vs 91.6% in most recent years (2009-2011) for patients aged <50 vs ≥50 years. After RP, a median IIEF-5 drop of 4 points in younger men vs 8 points in older patients was recorded (P < 0.001). Favourable recovery of urinary continence and erectile function in patients aged <50 years compared with their older counterparts was confirmed after multivariable adjustment., Conclusion: Men aged <50 years diagnosed with localised prostate cancer should not be discouraged from RP, as the postoperative rates of urinary incontinence and erectile dysfunction are low and probability of BCR-free survival at 2 and 5 years is high., (© 2013 The Authors. BJU International © 2013 BJU International.)

Lysophosphatidylcholine acyltransferase 1 (LPCAT1) has been suggested to play a role in cancer. To assess its role in prostate cancer, LPCAT1 expression was analyzed on a tissue microarray containing samples from 11,152 prostate cancer patients. In benign prostate glands, LPCAT1 immunostaining was absent or weak. In prostate cancer, LPCAT1 positivity was found in 73.8% of 8786 interpretable tumors including 29.2% with strong expression. Increased LPCAT1 expression was associated with advanced tumor stage (pT3b/T4) (p < 0.0001), high Gleason score (≥4 + 4) (p < 0.0001), positive nodal involvement (p = 0.0002), positive surgical margin (p = 0.0005), and early PSA recurrence (p < 0.0001). High LPCAT1 expression was strongly linked to ERG-fusion type prostate cancer. Strong LPCAT1 staining was detected in 45.3% of ERG positive but in only 16.7% of ERG negative tumors (p < 0.0001). Within ERG negative cancers, LPCAT1 staining was strongly increased within the subgroup of PTEN deleted cancers (p < 0.0001). Further subgroup analyses revealed that associations of high LPCAT1 expression with PSA recurrence and unfavorable tumor phenotype were largely driven by ERG negative cancers (p < 0.0001) while these effects were substantially mitigated in ERG positive cancers (p = 0.0073). The prognostic impact of LPCAT1 expression was independent of histological and clinical parameters. It is concluded, that LPCAT1 measurement, either alone or in combination, may be utilized for better clinical decision-making. These data also highlight the potentially important role of lipid metabolism in prostate cancer biology., (Copyright © 2013 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.)

Background: The serine peptidase inhibitor, Kazal type 1 (SPINK1) has been suggested to define an aggressive molecular subtype of ERG-fusion negative prostate cancer. It was the aim of this study to further study the clinical relevance of SPINK1 expression and its relationship with other key genomic alterations of prostate cancer., Methods: A tissue microarray containing more than 10,000 prostate cancers with clinical follow-up was used for immunohistochemical SPINK1 analysis. Data on ERG status as well as PTEN, 6q, 5q, and 3p deletions were available for comparison., Results: SPINK1 expression was absent in benign prostate glands and detectable in 5.9% of 9,503 interpretable prostate cancers. Presence of SPINK1 expression was markedly more frequent in ERG negative (10.4%) than in ERG positive cancers (0.3%; P < 0.0001). However, SPINK1 expression was unrelated to tumor phenotype and biochemical recurrence in all cancers and in the subgroup of ERG negative cancers. Further subgroup analyses revealed, however, that--within ERG negative cancers--SPINK1 expression was significantly linked to deletions at 6q15 (P < 0.0001) and 5q21 (P = 0.0042)., Conclusions: Our results exclude SPINK1 as a relevant prognostic prostate cancer biomarker. However, the data demonstrate that SPINK1 overexpression is tightly linked to the small subsets of 6q15- and 5q21-deleted ERG negative prostate cancers. These findings support the concept of molecularly defined subtypes of prostate cancers., (© 2013 Wiley Periodicals, Inc.)

The extracellular matrix metalloproteinase inducer CD147 has been suggested as a prognostic marker in prostate cancer. CD147 expression was analyzed by immunohistochemistry on a tissue microarray containing 11,152 prostate cancer specimens. Results were compared to tumor phenotype, biochemical recurrence, ERG status and deletions on PTEN, 3p13, 6q15 and 5q21. CD147 expression was strong in benign prostatic glands and often reduced in prostate cancers. CD147 immunostaining was found in 71.7% of 7628 interpretable cases. CD147 staining was considered strong in 34.6%, moderate in 24.3% and weak in 12.8% of cancers while 28.3% did not show any CD147 reactivity. Reduced CD147 staining was strongly associated with both TMPRSS2-ERG-rearrangement and ERG expression (p<0.0001 each). Within the subgroups of ERG positive and negative cancers, deletions of PTEN, 3p13, 6q15 and 5q21 were unrelated to the CD147 expression status. Decreased CD147 expression was significantly linked to high preoperative PSA values, high Gleason grade, advanced tumor stage (p<0.0001 each), and positive lymph node involvement (p=0.0026) in all cancers. There was a marginal, but statistically significant, association of reduced CD147 expression with early biochemical recurrence (p=0.0296). The significant reduction of CD147 expression in ERG positive prostate cancer provides further evidence for marked biological differences between "fusion type" and "non-fusion type" prostate cancer. Despite a weak association with PSA recurrence, CD147 cannot be considered a relevant prognostic biomarker., (© 2013.)

Unlabelled: Study Type--Prognosis (case series) Level of Evidence 4. What's known on the subject? and What does the study add? Different tools allow the individual estimation of the various endpoints in patients with prostate cancer. The Cancer of the Prostate Risk Assessment (CAPRA) score is an easy to calculate prediction tool, based on a large population based database. However, little is known about the performance of this prediction tool in European patients. The data obtained in the present study demonstrate differences in tumour characteristics between European patients and the initial development cohort from the USA. However, the concordance index of the CAPRA scores for predicting biochemical recurrence and metastatic recurrence was 76.2 and 78.5, respectively, in European patients. Therefore, the CAPRA score also allows reliable prediction of the examined endpoints in European patients., Objectives: • To assess the ability of the Cancer of the Prostate Risk Assessment Score (CAPRA) score for predicting biochemical recurrence (BCR) and metastatic recurrence (MR) by using a large cohort of European patients with prostate cancer. • The CAPRA score was initially developed using patients treated in community-based hospitals in the USA and allows a prediction of the risk of different clinical endpoints, without incorporating the surgical margin status., Patients and Methods: • BCR and metastatic recurrence rates were studied in 2937 patients who underwent radical prostatectomy in a tertiary referral centre after a mean (median, range) follow-up of 49 (56, 12-220) months. • The association between the examined endpoints, individual CAPRA scores and pathological features was analyzed by using Kaplan-Meier, proportional hazard and logistic regressions analyses. • Graphical representation assessed the calibration of the CAPRA score for predicting both endpoints., Results: • Compared to the initial development cohort, worse tumour characteristics and a lower overall positive surgical margin rate (17.2% vs 32.4%) were detected in the European cohort. • Overall, 530 (18.4%) and 58 (1.9%) of patients developed BCR and MR. Increasing CAPRA scores were related to less favourable pathological characteristics and higher BCR and metastatic recurrence rates. • For example, the 5-year BCR and metastatic recurrence rates were markedly different at the extremes of 0-1 vs ≥ 8 (9.2% vs 70.8% and 0.7% vs 16.4%, respectively). • The concordance index for the prediction of BCR and metastatic recurrence was 76.2 and 78.5, respectively., Conclusions: • Despite differences between the present cohort and the initial development cohort with respect to clinical features and the outcomes achieved, the data obtained in the present study shows the generalizability of the CAPRA score. • Specifically, the data allow the precise identification of those European patients who are at high risk for BCR and MR., (© 2012 BJU INTERNATIONAL.)

Purpose: A positive surgical margin after radical prostatectomy is considered an adverse prognostic feature. However, few groups have explored the potential interaction between surgical margin status and other cancer characteristics, specifically pathological stage. We addressed the first degree of interaction between positive surgical margins and other established adverse predictors of biochemical recurrence after radical prostatectomy., Materials and Methods: We used univariate and multivariate analysis to test the effect of surgical margin status on biochemical recurrence in 4,490 patients treated at a single institution between 1992 and 2008. We systematically tested all first-degree interactions between surgical margin status, and pretreatment prostate specific antigen, pT and pN stage, and radical prostatectomy Gleason sum. If interactions were significant, we quantified the effect on the biochemical recurrence rate., Results: Overall 850 patients (18.9%) had positive surgical margins. In those with negative vs positive surgical margins the 5-year biochemical recurrence-free survival rate was 95% vs 83%, 74% vs 62% and 47% vs 29% for pT2, pT3a and pT3b disease, respectively. In multivariate models only the pT stage-surgical margin status interaction achieved independent predictor status (p = 0.003). Negative vs positive surgical margin multivariate HRs were 1 vs 2.9, 2.3 vs 4.3 and 4.1 vs 5.6 in pT2, pT3a and pT3b cases, respectively., Conclusions: Compared to negative surgical margins, positive surgical margins increase the absolute biochemical recurrence 5-year rate by 12% to 18%. More importantly, positive surgical margins may substantially worsen the prognosis beyond that of the original pathological disease stage., (Copyright © 2010 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: To test the validity of an updated version of the preoperative Kattan nomogram for prediction of recurrence after radical prostatectomy (RP), published by Stephenson et al., Methods and Materials: We relied on clinical and postoperative prostate-specific antigen follow-up data of 1978 patients treated with open RP at our institution between 1992 and 2006. The accuracy of the nomogram-derived recurrence-free survival predictions were separately tested at 1 to 10 years after RP. Moreover, the relationship between the nomogram-predicted recurrence-free survival rate and the observed recurrence-free survival rate was graphically explored in calibration plots., Results: Median follow-up of censored patients was 32 months. For nomogram-derived recurrence-free survival predictions at 1 to 10 years, the accuracy of the nomogram ranged from 70% to 76%. The calibration between the predicted and observed recurrence-free survival rates was good at 1 and 2 years after RP. However, at all other examined time points, departures from ideal predictions were recorded., Conclusions: Our findings indicate that the preoperative biochemical recurrence nomogram reported by Stephenson et al. can be applied to European patients with good accuracy. However, its calibration was only suboptimal for predictions made 3 or more years after RP, with a tendency to overestimate the probability of recurrence-free survival. This potential limitation should be considered when this tool is applied to European patients., ((c) 2010 Elsevier Inc. All rights reserved.)

Study Type: Therapy (case series) Level of Evidence 4., Objective: To examine the long-term rates of biochemical recurrence (BCR)-free survival, cancer-specific mortality (CSM)-free survival, and overall survival (OS) in patients with prostate cancer treated with open radical prostatectomy (RP) in the prostate-specific antigen (PSA) era., Patients and Methods: The study comprised 436 patients who were treated with RP between 1992 and 1997 at our institution. None received adjuvant/salvage therapy in the absence of BCR. The BCR-free, CSM-free and OS rates were defined using the Kaplan-Meier method. Multivariable Cox-regression models were used to test the effect of age, preoperative PSA level, neoadjuvant hormonal therapy, pT stage, lymph node status, RP Gleason sum and surgical margin status on BCR., Results: The median follow-up of censored patients was 122, 128, and 132 months for, respectively, BCR-free, CSM-free and OS estimates. The 10-year event-free survival rates for the same endpoints were 60%, 94% and 86%, respectively. Preoperative PSA level, RP Gleason sum, pT stage, lymph node status, and surgical margin status were independent predictors of BCR (all adjusted P < 0.05)., Conclusions: This study is the first to evaluate the long-term cancer control outcomes after RP from a European country in the PSA era. Our data indicate that RP provides excellent long-term survival rates in patients with clinically localized prostate cancer. Although approximately 40% of patients have BCR after 10 years of follow-up, the CSM rate after 10 years is as low as 6%.

Background: Several models can predict the rate of biochemical recurrence (BCR) after radical prostatectomy (RP)., Objective: We tested the three most commonly used models-the D'Amico risk stratification scheme, the Cancer of the Prostate Risk Assessment (CAPRA) score, and the Stephenson nomogram-in a European cohort of RP patients., Design, Setting, and Participants: We relied on preoperative characteristics and prostate-specific antigen follow-up data of 1976 patients, as required by the three tested models. All patients were treated with an open RP between 1992 and 2006., Measurements: Analyses included tests of accuracy (Harrell's concordance index) and calibration between predicted and observed BCR rates at 3 yr and 5 yr after RP. Additionally, we relied on decision curve analyses to compare the three models directly in a head-to-head fashion., Results and Limitations: The median follow-up of censored patients was 32 mo. BCR-free rates at 3 yr and 5 yr after RP were 80.2% and 72.6%, respectively. The concordance index for 3-yr BCR predictions was 70.4%, 74.3%, and 75.2% for the D'Amico, CAPRA, and Stephenson models, respectively, versus 67.4%, 72.9%, and 73.5% for 5-yr BCR predictions. Calibration results supported the use of either the CAPRA or Stephenson models. Decision curve analyses indicated a small benefit for the CAPRA score relative to the Stephenson nomogram. Our findings apply to German patients treated with RP at a high-volume tertiary care centre. Consequently, the rank order reported in this paper may not be the same in North American or other European cohorts., Conclusions: Different methods yield different results, and it may be difficult to reconcile concordance index, calibration, and decision curve analysis findings. Our data suggest that the CAPRA score outperforms the other models when decision curve analysis and calibration were used as benchmarks. Conversely, the Stephenson nomogram outperformed the other models when concordance index was used as a metric., (Crown Copyright © 2009. Published by Elsevier B.V. All rights reserved.)

Study Type: Diagnosis (case series)., Level of Evidence: 4., Objective: To test whether the number or percentage of positive biopsy cores can be used to discriminate between patients with prostate cancer of a favourable and less favourable Gleason score (GS) < or =3 + 3, as prognostically, not all GS 3 + 3 prostate cancers are the same., Patients and Methods: In all, 1106 consecutive patients with a prostate-specific antigen (PSA) level of < or =10 ng/mL and a biopsy GS of < or =3 + 3 or 3 + 4 had an open radical prostatectomy. The number of positive biopsy cores (< or =2 vs > or =3) were stratified into low- vs high-risk groups. Subsequently, we stratified patients according to the GS and the percentage of positive biopsy cores (<50% vs > or =50%). The pathological stage and the 5-year biochemical recurrence (BCR)-free survival rates were examined in univariable and multivariable models., Results: Based on the number of positive cores, the rate of extraprostatic disease was 11.7% and 23.3%, respectively, in the low-and high-risk GS < or =3 + 3 groups (P < 0.001). The 5-year BCR-free survival rates were 95.0%, 77.8%, 81.2% and 66.5% for, respectively, low- and high-risk GS < or =3 + 3 and for low- and high-risk GS 3 + 4 patients. Univariable and multivariable intergroup BCR rate differences were statistically significant between low- vs high-risk GS 3 + 3 patients (P < 0.001), but not significant between high-risk GS < or =3 + 3 vs low-risk GS 3 + 4 patients (P = 0.6). Comparable results were obtained when comparisons were made according to the percentage of positive biopsy cores., Conclusions: Our results corroborate the finding that not all patients with a biopsy GS of < or =3 + 3 prostate cancer have low-risk disease. High-risk GS < or =3 + 3 patients have a similar risk profile as more favourable GS 3 + 4 patients. This finding warrants consideration when deciding on treatment.