AZGP1 Protein Expression in Hormone-Naïve Advanced Prostate Cancer Treated with Primary Androgen Deprivation Therapy.

Biomarkers for predicting the risk of castration-resistant prostate cancer (CRPC) in men treated with primary androgen deprivation therapy (ADT) are lacking. We investigated whether Zinc-alpha 2 glycoprotein (AZGP1) expression in the diagnostic biopsies of men with hormone-naïve prostate cancer (PCa) undergoing primary ADT was predictive of the development of CRPC and PCa-specific mortality. The study included 191 patients who commenced ADT from 2000 to 2011. The AZGP1 expression was evaluated using immunohistochemistry and scored as high or low expression. The risks of CRPC and PCa-specific mortality were analyzed using stratified cumulative incidences and a cause-specific COX regression analysis for competing risk assessment. The median follow-up time was 9.8 (IQR: 6.1-12.7) years. In total, 94 and 97 patients presented with low and high AZGP1 expression, respectively. A low AZGP1 expression was found to be associated with a shorter time to CRPC when compared to patients with a high AZGP1 expression (HR: 1.5; 95% CI: 1.0-2.1; p = 0.03). However, the multivariable analysis demonstrated no added benefit by adding the AZGP1 expression to prediction models for CRPC. No differences for PCa-specific mortality between the AZGP1 groups were observed. In conclusion, a low AZGP1 expression was associated with a shorter time to CRPC for PCa patients treated with first-line ADT but did not add any predictive information besides well-established clinicopathological variables.

Predictive value of AZGP1 following radical prostatectomy for prostate cancer: a cohort study and meta-analysis.

AIMS: Zinc-alpha 2-glycoprotein (AZGP1) is a promising tissue biomarker to predict outcomes in men undergoing treatment for localised prostate cancer (PCa). We aimed to examine the association between AZGP1 expression and the endpoints: risk of biochemical failure (BF), initiating castration-based treatment, developing castration-resistant PCa (CRPC) and PCa-specific mortality following radical prostatectomy (RP). METHODS: The study included a prospective cohort of 302 patients who underwent RP for PCa from 2002 to 2005. AZGP1 expression was analysed using immunohistochemistry on tissue microarray RP specimens and was scored semiquantitively as low or high expression. Risk of all endpoints was analysed using stratified cumulative incidences and cause-specific Cox regression, and validated with receiver operating curves, calibration and discrimination in competing-risk analyses. A meta-analysis was performed including previous studies investigating AZGP1 expression and risk of BF following RP. RESULTS: Median time of follow-up was 14.0 years. The cumulative incidence of all endpoints was significantly higher in patients with low AZGP1 expression compared with patients with high AZGP1 expression (p<0.001). In a multivariate analysis, low AZGP1 expression increases the risk of BF (HR 2.7; 95% CI 1.9 to 3.8; p<0.0001), castration-based treatment (HR 2.2; 95% CI 1.2 to 4.2; p=0.01) and CRPC (HR 2.3; 95% CI 1.1 to 5.0; p=0.03). Validation showed a low risk of prediction error and a high model performance for all endpoints. In a meta-analysis, low AZGP1 was associated with BF (HR 1.7; 95% CI 1.2 to 2.5). CONCLUSIONS: Low AZGP1 expression is associated with the risk of aggressive time-dependent outcomes in men undergoing RP for localised PCa.

Prognostic implication of gait function following treatment for spinal cord compression in men diagnosed with prostate cancer.

Background: Malignant spinal cord compression (MSCC) is a severe complication of metastatic prostate cancer (PCa) and may compromise neurological functions, including gait function. This study aimed to evaluate the association between survival and gait function prior to, immediately after and 6 weeks following radiotherapy for MSCC in PCa patients.Patient sample: All PCa patients admitted with MSCC at Rigshospitalet, Denmark from January 1, 2010 to December 31, 2011 were included. Patients were followed until death to analyze gait function as a prognostic factor.Methods: Of the 76 included patients, four patients underwent surgical decompression followed by radiotherapy and 72 patients received only radiotherapy. Gait was evaluated prior to radiotherapy, immediately after radiotherapy and at 6 weeks follow-up.Results: Before radiotherapy, 88% had normal gait function and 12% had complete loss of gait function. Corresponding percentages after radiotherapy were 72% and 28%, respectively. Median overall survival following MSCC was 4.9 months (95% CI = 3.6-6.2) with a 3-, 6-, and 12-months survival probability of 64%, 42%, and 21%, respectively. Multivariate analyses demonstrated that patients without gait function after radiotherapy had a 2.6-2.8-fold increased risk of dying compared to men with gait function. Patients with more than two vertebrae involved had a 2.3-3.4-fold increased risk of dying when compared to patients with 1-2 vertebral metastases.Conclusions: PCa patients with MSCC have a poor prognosis. Most likely reflecting differences in tumor burden, preserved gait function following radiotherapy is associated with better prognosis. Further prospective studies are required to confirm this association.

5hmC Level Predicts Biochemical Failure Following Radical Prostatectomy in Prostate Cancer Patients with ERG Negative Tumors.

This study aimed to validate whether 5-hydroxymethylcytosine (5hmC) level in combination with ERG expression is a predictive biomarker for biochemical failure (BF) in men undergoing radical prostatectomy (RP) for prostate cancer (PCa). The study included 592 PCa patients from two consecutive Danish RP cohorts. 5hmC level and ERG expression were analyzed using immunohistochemistry in RP specimens. 5hmC was scored as low or high and ERG was scored as negative or positive. Risk of BF was analyzed using stratified cumulative incidences and multiple cause-specific Cox regression using competing risk assessment. Median follow-up was 10 years (95% CI: 9.5⁻10.2). In total, 246 patients (41.6%) had low and 346 patients (58.4%) had high 5hmC level. No significant association was found between 5hmC level or ERG expression and time to BF (p = 0.2 and p = 1.0, respectively). However, for men with ERG negative tumors, high 5hmC level was associated with increased risk of BF following RP (p = 0.01). In multiple cause-specific Cox regression analyses of ERG negative patients, high 5hmC expression was associated with time to BF (HR: 1.8; 95% CI: 1.2⁻2.7; p = 0.003). In conclusion, high 5hmC level was correlated with time to BF in men with ERG negative PCa, which is in accordance with previous results.

Predictive value of combined analysis of pro-NPY and ERG in localized prostate cancer.

This study aimed to investigate if combined analysis of pro-Neuropeptide Y (NPY) and ERG expression in tumor tissue are associated with biochemical failure (BF), castration-based treatment, castration-resistant prostate cancer (CRPC), and prostate cancer (PCa)-specific death for men undergoing radical prostatectomy (RP) for PCa. This study included 315 patients, who underwent RP from 2002 to 2005. Both pro-NPY and ERG expression were analyzed using immunohistochemistry and were scored as low or high and negative or positive, respectively. Risk of BF, castration-based treatment, CRPC, and PCa-specific death were analyzed with multiple cause-specific Cox regression analyses and stratified cumulative incidences using competing risk assessment. Median follow-up was 13.0 years (95% CI: 12.7-13.2). In total, 85.7% were pro-NPY high and 14.3% were pro-NPY low. The combined analyses of pro-NPY and ERG expression was not associated with risk of BF (p = 0.7), castration-based treatment (p = 0.8), CRPC (p = 0.4) or PCa-specific death (p = 0.5). In the multiple cause-specific Cox regression analysis, pro-NPY high and ERG positivity was not associated with BF (HR: 1.02; 95% CI 0.6-1.7; p = 0.94). In conclusion the combination of pro-NPY and ERG expression did not show association with risk of BF, castration-based treatment, CRPC, and PCa-specific death following RP.

The CPC Risk Calculator: A New App to Predict Prostate-specific Antigen Recurrence During Follow-up After Radical Prostatectomy.

BACKGROUND: It can be challenging to predict the risk of biochemical recurrence (BR) during follow-up after radical prostatectomy (RP) in men who have undetectable prostate-specific antigen (PSA), even years after surgery. OBJECTIVE: To establish and validate a contemporary nomogram that predicts the absolute risk of BR every year after RP in men with undetectable PSA while accounting for competing risks of death. DESIGN, SETTING, AND PARTICIPANTS: A total of 3746 patients from Rigshospitalet (Copenhagen, Denmark) and Stanford Urology (Stanford, CA, USA) who underwent RP between 1995 and 2013 were included. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Time to BR was defined as the first PSA result ≥0.2 ng/ml. BR risk was computed using multiple cause-specific Cox regression including preoperative PSA, pT category, RP Gleason score (GS), and surgical margin (R) status. Death without BR was considered a competing event. The nomogram presents the future risk of BR for a man who is alive and without BR at the time of follow-up. Validation assessed the discrimination and accuracy using time-dependent area under the curve and Brier scores. RESULTS AND LIMITATIONS: The nomogram predicts risk of BR up to 12 yr after RP at an individual level. As example, the risk of BR for a man with pT3a, R-, GS 3 + 4, and preoperative PSA ≤10 ng/ml followed for 5 yr with undetectable PSA is 18% for the next 5 yr. External validation demonstrated both high accuracy and discrimination. The CPC Risk Calculator is available as a free Android and iOS App. Declining discrimination and accuracy after 7 yr of follow-up is the main limitation. CONCLUSIONS: This nomogram can be used as a tool to inform men with undetectable PSA during follow-up after RP about their future risk of BR, and may aid in decisions on the necessity for further follow-up. The nomogram is the first to be available as a free app. PATIENT SUMMARY: We developed an easily interpretable nomogram to evaluate the risk of prostate-specific antigen elevation (cancer recurrence) following complete removal of the prostate (radical prostatectomy). The tool can aid both physicians and patients in evaluating the future risk of cancer recurrence during follow-up after surgery. The model is available as a free mobile app that can be downloaded from the App Store.

Cytoreductive prostatectomy in metastatic prostate cancer: a systematic review.

The impact of cytoreductive radical prostatectomy on oncological outcome in patients with prostate cancer and limited number of bone metastases is unclear. Data from cancer registries, multi-institutional databases and a single institutional case-control study indicate a possible benefit of combined cytoreduction and hormonal therapy compared to hormonal therapy alone. However, the results may be biased by a number of factors. The evidence from studies on cytoreductive prostatectomy is reviewed.

Temporal Trends in Clinical and Pathological Characteristics for Men Undergoing Radical Prostatectomy Between 1995 and 2013 at Rigshospitalet, Copenhagen, Denmark, and Stanford University Hospital, United States.

PURPOSE: To analyze how prostate-specific antigen (PSA) screening and practice patterns has affected trends in tumor characteristics in men undergoing radical prostatectomy (RP) in the United States and Denmark. Unlike in the United States, PSA screening has not been recommended in Denmark. PATIENTS AND METHODS: We performed an observational register study using pre- and postoperative data on 2168 Danish patients from Rigshospitalet, Copenhagen, Denmark, and 2236 patients from Stanford University Hospital, Stanford, CA, who underwent RP between 1995 and 2013. Patients were stratified according to Cancer of the Prostate Risk Assessment-Postsurgical (CAPRA-S) risk groups and D'Amico risk classification and were clustered into 4 time periods (1995-1999, 2000-2004, 2005-2009, and 2010-2013). Temporal trends in the proportions of patients of a given variable at the 2 institutions were evaluated with Cochran-Armitage test for trends and chi-square testing. RESULTS: A total of 4404 patients were included. Temporal changes in preoperative PSA, age, grade, and stage was found in both cohorts. Median preoperative PSA declined in both cohorts, while median age increased, with the Danish cohort showing the greatest changes in both PSA and age. In both cohorts, there was a trend for higher-risk preoperative features before RP over time. In 2010-2013, 27.7% and 21.8% of the patients were in the D'Amico high-risk group at Copenhagen and Stanford, respectively. CONCLUSION: Despite recommendation against PSA screening in Denmark, Danish men undergoing RP at Rigshospitalet to a considerable extent now resemble American men undergoing RP at Stanford. At both sites, there is continued trend to reduce the number of men undergoing RP for low-risk prostate cancer.

Associations between statin use and progression in men with prostate cancer treated with primary androgen deprivation therapy.

INTRODUCTION: In several observational studies, statin use has been associated with reduced risk of progression and mortality in men with prostate cancer (PCa). The study aim was to investigate the association between statin use at time of PCa diagnosis and time to PCa progression in men with advanced or metastatic PCa receiving androgen deprivation therapy (ADT) as primary treatment. PATIENTS AND METHODS: The study population consisted of all men receiving ADT as primary therapy at two Danish Urological Departments in 2007-2013. The primary outcome was time to progression defined as castration-resistant PCa (CRPC) or PCa death. Survival analyses were conducted with Kaplan-Meier analyses, cause specific Cox proportional hazards models, and competing risk analyses. RESULTS: A total of 537 men were included, of whom 141 were statin users at time of diagnosis. The median follow-up time was 5.7 years (95% CI: 5.1-6.2). No significant difference in progression-free survival between statin users and non-statin users was observed at 5 years; 29% for statin users (95% CI: 19-40%) and 28% (95% CI: 23-34%) for non-statin users, p = 0.31. In multivariable Cox analyses, there was no significant association between statin use and risk of progression, HR 0.98 (95% CI: 0.72-1.32). In competing risk analyses the 5-year cumulative incidence of progression was 55% (95% CI: 46-64%) for statin users and 62% (95% CI: 57-67%) for non-statin users, p = 0.11. CONCLUSION: In the current study, statin use at time of PCa diagnosis was unrelated to time to progression in men primarily treated with ADT.

Laparoscopic and robotic nephroureterectomy: does lymphadenectomy have an impact on the clinical outcome?

PURPOSE: To evaluate the effect of lymphadenectomy (LND) in conjunction with nephroureterectomy on cancer-specific mortality (CSM) and overall survival (OS) for patients with muscle-invasive UTUC. METHODS: A retrospective, multicenter study of patients with UTUC, clinical stage N0M0, who underwent nephroureterectomy between January 2008 and December 2014 was conducted. Outcome measures were OS and CSM. RESULTS: In total, 298 patients underwent robot-assisted or laparoscopic radical nephroureterectomy with a final histological diagnosis of UTUC. LND was performed in 46 (15.4%). One hundred and seventy-two patients (62%) had non-muscle-invasive disease (NMID); 105 patients (38%) had muscle-invasive disease (MID). Median time of follow-up was 43.5 months (95% CI 36.0-47.2). For patients with MID, the 5-year cumulative incidence of all-cause mortality and CSM was 73.5% (95% CI 60.4-86.6) and 52.4% (95% CI 38.9-65.9), respectively (p < 0.0001). There was no significant difference in OS between patients with N1 and patients with N0 disease (p = 0.53). The 5-year OS rates were 30.5% (95% CI 6.6-54.4) and 25.7% (95% CI 10.9-40.5), respectively. This study is limited by its retrospective nature. There may also have been bias in the selection of patients undergoing LND. CONCLUSIONS: Five-year OS and CSM are comparable between patients with N1 and N0 MID. This evidence may support the use of the LND procedure in patients with muscle-invasive UTUC.

The risk of biochemical recurrence for intermediate-risk prostate cancer after radical prostatectomy.

OBJECTIVES: To report oncological outcomes including biochemical recurrence (BR) following radical prostatectomy (RP) from a large consecutive cohort operated in an 18-year period. Additionally, an in-depth analysis of outcomes among D'Amico intermediate-risk patients is presented. MATERIALS AND METHODS: A total of 2,091 patients with PCa who underwent RP at Department of Urology, Rigshospitalet, Copenhagen, Denmark between 1995 and 2013 were included. Univariate and multiple cause-specific Cox regression analyses for BR were applied using competing risk models. Death prior to BR was considered a competing event. BR was defined as the first PSA ≥0.2 ng/ml. No patient received adjuvant therapy prior to BR. RESULTS: Overall, the 5- and 10-years cumulative incidence of BR was 21.9% and 32.0%. The 10-year cumulative incidence of BR was 17.9%, 31.9% and 47.9% for D'Amico low-, intermediate- and high-risk patients, respectively. Among intermediate-risk patients, the 10-year cumulative incidence of BR was 24.0%, 39.9%, and 47.9% for patients harboring one, two or three risk factors, respectively (Gray test: p < 0.0001). In multivariate analysis, PSA, RP GS, pT category, and positive surgical margins were significantly associated with an increased risk of BR. CONCLUSIONS: The risk of BR among patients with intermediate-risk disease is not uniform and is highly dependent on the number of risk factors per patient. Intermediate-risk patients have a comparable risk of recurrence as high-risk patients, and this should be taken into consideration when counseling patients prior to RP.

Plasma levels of intact and cleaved urokinase plasminogen activator receptor (uPAR) in men with clinically localised prostate cancer.

AIMS: Lymph node metastasis (N1) is an adverse prognostic factor for men with clinically localised prostate cancer (PCa), but the prediction of N1 disease remains difficult. Urokinase plasminogen activator receptor (uPAR) plays an important role in angiogenesis and tumorigenesis. We analysed whether plasma levels of the soluble uPAR forms uPAR(I-III), uPAR(II-III) and uPAR(I) were associated with the risk of N1 disease in men with clinically localised PCa. METHODS: The present study includes all men (n=518) who underwent radical prostatectomy (RP) for clinically localised PCa, 29 of whom had N1 disease. Soluble uPAR forms were measured using three time-resolved fluorescence immunoassays. The prognostic value of the different uPAR forms together with clinicopathological parameters for N1 disease were analysed using logistic regression, receiver operating characteristic (ROC) regression analysis and quantified using the areas under the ROC curve (AUC). RESULTS: All soluble uPAR levels were significantly (p=0.03) higher in patients with N1 disease compared with patients with N0/x disease. ROC curves including clinical tumour stage, biopsy Gleason score, prostate-specific antigen and percent positive biopsies had an AUC of 87.7% for prediction of N1 disease. With the addition of uPAR(I) to the model, the AUC increased to 88.4%. CONCLUSIONS: Addition of uPAR(I) level to known diagnostic parameters did not increase the prediction of N1 disease following RP in men with clinically localised PCa. Our results indicate that the plasma levels at diagnosis of the different uPAR forms do not hold important predictive or prognostic information in men with clinically localised PCa.

Robot-assisted pyeloplasty and pyelolithotomy in patients with ureteropelvic junction stenosis.

OBJECTIVE: Approximately one in five patients with ureteropelvic junction stenosis (UPJS) also present with renal or ureteral stones. For patients with UPJS, the European Association of Urology guidelines currently recommend that robot-assisted pyeloplasty (RAP) and pyelolithotomy are performed as two separate procedures. The aim of the present study was to evaluate the feasibility and safety of RAP with concomitant pyelolithotomy (RAP + P) in patients diagnosed with UPJS and renal stones. MATERIALS AND METHODS: In total, 56 RAP procedures and 18 RAP + P procedures were performed between December 2012 and January 2014. Patient records were retrospectively reviewed for operation time (OT), estimated blood loss (EBL), length of hospital stay (LOS), complications, stone burden and stone-free rates at 1, 3 and 6 months following surgery. RESULTS: A significant difference in the OT was demonstrated between RAP and RAP + P, with a median of 120 min [interquartile range (IQR) 100-134 min] and 151 min (IQR 128-185 min), respectively (p < 0.0001). In contrast, no difference in LOS [median 2 days (IQR 2-3 days) vs 3 days (2-4 days), p = 0.50) or EBL [median 0 ml (IQR 0-50 ml) vs 20 ml (0-50 ml), p = 0.64] was observed between RAP and RAP + P. The median total stone burden was 1.5 cm (IQR 1.0-4.3 cm; range 1-10 cm). The stone-free rate at 1, 3 and 6 months was 94%, 83% and 72%, respectively. No grade 3-5 complications were observed in the RAP + P group. CONCLUSIONS: RAP + P can safely be offered to patients with UPJS and renal stones, with an acceptable stone-free rate.

Radical prostatectomy in Denmark: Survival analysis and temporal trends in clinicopathological parameters with up to 20 years of follow-up.

OBJECTIVES: To describe mortality, cause of death, and temporal trends in clinicopathological parameters with up to 20 years of follow-up in a nationwide cohort of prostate cancer (PCa) patients who underwent radical prostatectomy (RP). MATERIALS AND METHODS: A total of 6857 patients with PCa treated with RP at six different hospitals in Denmark between 1995 and 2011. Data were extracted from the nationwide DaPCa database. Histopathology reports from the RP specimens were manually reviewed. Date and cause of death were obtained from national registries and cross-checked in patient files. The cumulative incidence of PCa specific mortality (PCSM) was analysed with the Aalen-Johansen method for competing risks with non-PCa death as a competing event. Risk of PCSM was analysed in a multivariate Cox regression model using age, preoperative PSA level, surgical margin status, RP Gleason score (GS), pathological T-category, and N-category as explanatory variables. RESULTS: The median follow-up was 6.4 years. Significant temporal changes in clinicopathological parameters were observed. During the study period, median age at surgery increased from 61.4 to 64.8 years and median preoperative PSA declined from 12.0 to 8.0 ng/ml. The proportion of men with pT2 PCa increased from 65% to 75% whereas the proportion of pT3 cancers decreased from 28% to 25%. The percentage of men with positive surgical margins decreased from 37% to 20%. During follow-up, 644 patients died, whereof 189 (29.3%) died from PCa. The cumulative incidence of PCSM and other-cause mortality after 15 years was 10.3% (95% CI 8.0-12.7) and 18.2% (95% CI 15.4-20.9), respectively. In a multivariate analysis, RP GS (P ≤ 0.001) and pT-category (P ≤ 0.001) were significantly associated with the risk of PCSM. Compared with GS ≤6, both GS +4 (HR 1.47), GS 4 + 3 (HR 2.32), GS 8 (HR 4.8) and GS 9 or 10 (HR 5.26) significantly increased the risk of PCa death. T3a PCa and T3b/T4 was also a significant predictor of PCSM with an increased risk of PCa death compared with pT2 of 2.24 and 4.5, respectively. CONCLUSIONS: In a complete national cohort of men treated with RP during a 17-year period, we described the incidence of mortality after RP and predictors of PCSM. We demonstrated that RP GS and pT-category are the most significant predictors of PCa mortality. We found that an increasing proportion of men undergo RP for low-risk PCa suggesting that early detection of PCa is indeed undergoing in Denmark despite national recommendations. The Danish national results seem to concur with findings from international single- and multi-institutional reports.

Improved survival for patients with de novo metastatic prostate cancer in the last 20 years.

INTRODUCTION: During recent years, several new life-prolonging therapeutic options have been introduced for patients with metastatic prostate cancer (mPCa). The aim of the present study was to evaluate the changes in the survival of patients diagnosed with mPCa prior to and in the early period of the implementation of these new agents. PATIENTS AND METHODS: The study population consisted of 207 men diagnosed in 1997 and 316 men diagnosed in the period 2007-2013 with de novo mPCa and managed with initial endocrine therapy. Men were followed for overall survival and PCa-specific survival. RESULTS: At the time of diagnosis, men diagnosed in the period 2007-2013 had less co-morbidity, lower prostrate-specific antigen levels and lower clinical tumour categories than men diagnosed in 1997. A significantly higher proportion of men diagnosed in 1997 were managed with surgical castration (57% versus 9%). Only one patient diagnosed in 1997 received second-line therapy compared with 81 men (26%) diagnosed in the period 2007-2013. The median overall survival was significantly longer for men diagnosed between 2007 and 2013 compared with men diagnosed in 1997 (39.4 months versus 24.2 months, p < 0.0001). Likewise, the cumulative incidence of PCa-specific death was higher among men diagnosed in 1997 compared with men diagnosed between 2007 and 2013, with 5-year cumulative incidences of 72% and 47%, respectively (p < 0.0001). CONCLUSION: Survival in men diagnosed with metastatic PCa has improved significantly over time. The improved survival can in part be explained by lead-time bias, but also by the introduction of new life-prolonging treatments.

The prognostic and predictive value of TMPRSS2-ERG gene fusion and ERG protein expression in prostate cancer biopsies.

BACKGROUND: The clinical course of prostate carcinoma (PCa) is very heterogeneous. Consequently, a personalised approach for risk stratification and treatment planning is important. Recently, it has become evident that PCa, also at the genomic level, is heterogeneous. An early and common alteration is the gene fusion between the transmembrane protease serine 2 (TMPRSS2) gene and the v-ets avian erythroblastosis virus E26 oncogene homolog (ERG) gene resulting in expression of the oncoprotein ERG. The gene fusion is present in approximately half of PCa patients and the resultant two subgroups demonstrate marked differences in their genomic signatures. It has been hypothesised that genomic alterations can explain some of the observed heterogeneity in the clinical course of PCa. In order to conduct an analysis of the prognostic and predictive value of ERG protein expression in PCa biopsies, the thesis sought to evaluate: 1) the concordance in ERG expression between biopsies and radical prostatectomies: 2) the association between expression of ERG protein and the risk of PCa progression during active surveillance (AS), and 3) the association between ERG protein expression and response to primary castration-based treatment for advanced PCa. MATERIAL AND METHODS: The included patients derived from the institutional AS cohort and an institutional cohort of advanced PCa patients undergoing first line castration-based androgen deprivation therapy (ADT). The 265 patients in the AS cohort were enrolled prospectively between October 2002 and October 2012 and were followed with regular digital rectal examinations, PSA measurements, and repeated biopsies. The advanced PCa cohort comprised of 194 patients diagnosed between January 2000 and December 2011 and was established retrospectively by a standardised extraction of patient data. Immunohistochemical (IHC) assessment for ERG protein expression was performed in all tumours containing diagnostic specimens (AS cohort: n = 459; advanced PCa cohort: n = 968), re-biopsies during AS (n = 402), and deferred radical prostatectomy specimens following AS (n = 86). An anti-ERG rabbit monoclonal primary antibody (clone: EPR3864, dilution 23 µg/ml) was used. Fluorescence in situ hybridisation (FISH) for the TMPRSS2-ERG gene fusion was performed in 76 selected biopsies from the AS cohort using the ZytoLight TriCheck Probe, SPEC ERG/TMPRSS2. RESULTS: Based on the AS cohort, Study 1 found a 97.3% concordance between the FISH assay and the IHC assay. The IHC assessments of ERG expression in diagnostic biopsies, re-biopsies, and radical prostatectomy specimens demonstrated a low proportion of temporal ERG reclassification. During four rounds of re-biopsies, 6.6% of the patients experienced ERG reclassification, and depending on the number biopsy specimens included 5.8-10.5% of the patients were ERG reclassified after radical prostatectomy. In Study 2, 46.4% of the AS patients were categorised as ERG-positive, whereas 53.6% were categorised as ERG-negative. After median 4.1 years follow-up, a significantly higher risk of disease progression was observed in men with ERG-positive tumours corresponding to a two-year cumulative incidence of 58.6% (95% CI: 48.7-68.5) and 21.7% (95% CI: 14.3-29.1) in the ERG-positive and the ERG-negative group, respectively. In the multiple causespecific Cox analyses, ERG expression was a strong and independent predictor of overall disease progression (HR: 2.45, 95% CI: 1.62-3.72) and histopathological progression in repeated biopsies (HR: 3.06, 95% CI: 1.78-5.26), and ERG status increased the discriminative ability for predicting disease progression significantly. Study 3 included 194 patients with advanced PCa treated with firstline ADT. In total, 54.1% had ERG-positive tumours and 45.9% had ERG-negative tumours. With a median of 6.8 years of follow-up, the risk of developing castration-resistant PCa (CRPC) did not differ between the ERG subgroups (p = 0.51). Finally, inclusion of ERG status in a multiple cause-specific Cox model did not increase the discriminative ability for predicting CRPC development during the first 8 years of ADT. CONCLUSION: The thesis has demonstrated that assessment of ERG protein expression is feasible in biopsy specimens, and a high concordance was found between the IHC assay and FISH assessment of ERG rearrangement. The low proportion of ERG reclassification between biopsies and prostatectomies supports the use of ERG assessment in biopsies to characterise the individual patient's ERG status. ERG status harbours important prognostic value in terms of tumour progression for patients managed on AS, whereas ERG expression has no predictive value for ADT response in men with advanced PCa undergoing first-line castration-based ADT. The overall conclusion of the thesis is that ERG protein expression provides valuable prognostic information in low-risk PCa managed observationally, and ERG expression might be used to personalise follow-up regimens in future AS programmes.

Anastomotic complications after robot-assisted laparoscopic and open radical prostatectomy.

Objective Anastomotic complications are well known after radical prostatectomy (RP). The vesicourethral anastomotic technique is handled differently between open and robotic RP. The aim of the study was to investigate whether the frequency of anastomotic leakages and strictures differed between patients undergoing retropubic radical prostatectomy (RRP) and robot-assisted radical prostatectomy (RARP) and to identify risk factors associated with these complications. Materials and methods The study included 735 consecutive patients who underwent RRP (n = 499) or RARP (236) at the Department of Urology, Rigshospitalet, Denmark, in a complete 3 year period from 2010 to 2012. Univariate and multivariate logistic regression analysis was used to analyse associations between surgical procedure (RRP vs RARP) and anastomotic complications. Analyses included age, smoking status, diabetes, hypertension, surgeon, prostate volume and anastomotic leakage as variables. Owing to a low number of events, multivariable analyses only included smoking status, diabetes and prostate volume for anastomotic leakage, and age, smoking status, prostate volume and anastomotic leakage for anastomotic strictures. Results The frequency of anastomotic leakage was 2.9%. Anastomotic stricture was seen in 4.9% of patients during follow-up. No differences were found in the frequency of anastomotic leakage (p = 0.35) or strictures (p = 0.35) between RRP and RARP. Univariate analysis demonstrated an association between surgeon and the risk of anastomotic strictures in RRP patients (p = 0.02). No other independent risk factors were identified. Conclusion Overall, the anastomotic complication rate in this cohort is similar to other published reports. No obvious risk factors for anastomotic complications could be identified, which in part was due to the low number of events.

Systematic review: does endocrine therapy prolong survival in patients with prostate cancer?

Objective Primary androgen deprivation therapy (ADT) remains the gold standard in the management of patients with advanced prostate cancer (PCa). ADT relieves symptoms and reduces tumor burden, but it has never been demonstrated to increase either PCa-specific or overall survival per se. Several trials have challenged this dogma. The aim of this study was to evaluate how endocrine therapy (ET) affects survival in different clinical settings of PCa. Materials and methods A review of published phase II, III and IV studies evaluating the effect of ET on survival was performed. Results In localized and locally advanced non-metastatic PCa, neoadjuvant ET before radical prostatectomy has no effect on survival. Neoadjuvant and adjuvant ET in combination with curatively intended radiotherapy results in PCa-specific and overall survival benefit, although the duration of ET remains under debate. In N + disease, the timing of ET is under debate, although data suggest that early ET is associated with decreased PCa-specific and overall mortality. In M + disease, no proper randomized trials have been performed in patients with newly diagnosed M1 disease. In metastatic castration-resistant PCa, two novel endocrine agents have been proven to increase overall survival significantly compared to placebo. Conclusions ET has never been proven to increase survival in newly diagnosed metastatic PCa in a randomized clinical trial. Nonetheless, a number of trials supports that ET with proper timing, sequencing and in combination with other therapeutic modalities increases survival in several stages of PCa.

TRPM4 protein expression in prostate cancer: a novel tissue biomarker associated with risk of biochemical recurrence following radical prostatectomy.

BACKGROUND: Transient receptor potential cation channel, subfamily M, member 4 (TRPM4) messenger RNA (mRNA) has been shown to be upregulated in prostate cancer (PCa) and might be a new promising tissue biomarker. We evaluated TRPM4 protein expression and correlated the expression level with biochemical recurrence (BR) following radical prostatectomy (RP). MATERIAL AND METHODS: The study included 614 patients who had undergone RP. TRPM4 immunohistochemical staining was performed on samples of benign tissue, tissue containing PIN glands and PCa tissue using a commercially available polyclonal antibody. Staining intensity was recorded by two independent observers using a four-tired semi-quantitative grading system (0, 1+, 2+, 3+) converted into H-scores. Interobserver agreement was calculated by linear weighted kappa statistics. The association between staining intensity and BR was analysed using the Kaplan-Meier estimator and uni- and multiple Cox proportional hazard regression models. RESULTS: Significantly higher staining intensity was found in PCa glands compared to benign glands (p < 0.001). The concordance rate in TRPM4 staining intensities for benign, PIN and PCa tissue ranged from 86.0 to 91.5 %, corresponding to linear weighted kappa values of 0.566-0.789. After adjusting for patient and tumour characteristics, patients with a higher staining intensity in PCa glands compared to matched benign glands and an H-score equal to or above the median had an increased risk of BR (HR 1.79-2.62; p = 0.01-0.03 for the two observers) when compared to patients with a lower staining intensity. CONCLUSIONS: TRPM4 protein expression is widely expressed in benign and cancerous prostate tissue, with highest staining intensities found in PCa. Overexpression of TRPM4 in PCa (combination of high staining intensity and a high H-score) is associated with increased risk of BR after RP.

ERG protein expression over time: from diagnostic biopsies to radical prostatectomy specimens in clinically localised prostate cancer.

AIMS: We evaluated the consistency in ERG protein expression from diagnostic specimens through rebiopsies to radical prostatectomies in patients with clinically localised prostate cancer to investigate the validity of ERG status in biopsies. METHODS: ERG expression was assessed by immunohistochemistry (IHC) in 625 biopsy sets and 86 radical prostatectomy specimens from 265 patients with prostate cancer managed on active surveillance. For IHC, a rabbit monoclonal primary antibody was used (clone: EPR3864). TMPRSS2-ERG fluorescence in situ hybridisation (FISH) analyses were performed in 74 biopsies using the FISH ZytoLight TriCheck Probe (SPEC ERG/TMPRSS2). FISH results were correlated with IHC findings. RESULTS: The concordance between FISH and IHC was 97.3% and IHC demonstrated a sensitivity and specificity for ERG rearrangement of 100% and 95.5%, respectively. Applying IHC, 38.1% of patients were ERG-positive, 53.6% were ERG-negative and 8.3% showed both ERG-positive and negative tumour foci (ERG heterogeneous) at diagnosis. When ERG status was dichotomised (ERG-positive or heterogeneous vs ERG-negative), 95.6%-97.1% of patients did not experience ERG reclassification during the first two rounds of rebiopsies. The concordance in ERG status between biopsies and surgical specimen was 89.5%-94.2% depending on the number of rebiopsies included. Sampling bias was assumed to explain most (81.3%) of the mismatches in ERG status. CONCLUSIONS: Consistency in ERG status ranged from 90% to 95% for patients undergoing serial biopsies and radical prostatectomy. This indicates that biopsies can be used reliably to investigate ERG's prognostic and predictive value.