Reproducibility and Accuracy of the PRIMARY Score on PSMA PET and of PI-RADS on Multiparametric MRI for Prostate Cancer Diagnosis Within a Real-World Database.

The PRIMARY score is a 5-category scale developed to identify clinically significant intraprostate malignancy (csPCa) on 68Ga-prostate-specific membrane antigen (PSMA)-11 PET/CT (68Ga-PSMA PET) using a combination of anatomic site, pattern, and intensity. Developed within the PRIMARY trial, the score requires evaluation in external datasets. This study aimed to assess the reproducibility and diagnostic accuracy of the PRIMARY score in a cohort of patients who underwent multiparametric MRI (mpMRI) and 68Ga-PSMA PET before prostate biopsy for the diagnosis of prostate cancer. Methods: In total, data from 242 men who had undergone 68Ga-PSMA PET and mpMRI before transperineal prostate biopsy were available for this ethics-approved retrospective study. 68Ga-PSMA PET and mpMRI data were centrally collated in a cloud-based deidentified image database. Six experienced prostate-focused nuclear medicine specialists were trained (1 h) in applying the PRIMARY score with 30 sample images. Six radiologists experienced in prostate mpMRI read images as per the Prostate Imaging-Reporting and Data System (PI-RADS), version 2.1. All images were read (with masking of clinical information) at least twice, with discordant findings sent to a masked third (or fourth) reader as necessary. Cohen κ was determined for both imaging scales as 5 categories and then collapsed to binary (negative and positive) categories (score 1 or 2 vs. 3, 4, or 5). Diagnostic performance parameters were calculated, with an International Society of Urological Pathology grade group of at least 2 (csPCa) on biopsy defined as the gold standard. Combined-imaging-positive results were defined as any PI-RADS score of 4 or 5 or as a PI-RADS score of 1-3 with a PRIMARY score of 3-5. Results: In total, 227 patients with histopathology, 68Ga-PSMA PET, and mpMRI imaging before prostate biopsy were included; 33% had no csPCa, and 67% had csPCa. Overall interrater reliability was higher for the PRIMARY scale (κ = 0.70) than for PI-RADS (κ = 0.58) when assessed as a binary category (benign vs. malignant). This was similar for all 5 categories (κ = 0.65 vs. 0.48). Diagnostic performance to detect csPCa was comparable between PSMA PET and mpMRI (sensitivity, 86% vs. 89%; specificity, 76% vs. 74%; positive predictive value, 88% vs. 88%; negative predictive value, 72% vs. 76%). Using combined imaging, sensitivity was 94%, specificity was 68%, positive predictive value was 86%, and negative predictive value was 85%. Conclusion: The PRIMARY score applied by first-user nuclear medicine specialists showed substantial interrater reproducibility, exceeding that of PI-RADS applied by mpMRI-experienced radiologists. Diagnostic performance was similar between the 2 modalities. The PRIMARY score should be considered when interpreting intraprostatic PSMA PET images.

High-dose vitamin D supplementation to prevent prostate cancer progression in localised cases with low-to-intermediate risk of progression on active surveillance (ProsD): protocol of a phase II randomised controlled trial.

INTRODUCTION: Active surveillance (AS) for patients with prostate cancer (PC) with low risk of PC death is an alternative to radical treatment. A major drawback of AS is the uncertainty whether a patient truly has low risk PC based on biopsy alone. Multiparametric MRI scan together with biopsy, appears useful in separating patients who need curative therapy from those for whom AS may be safe. Two small clinical trials have shown short-term high-dose vitamin D supplementation may prevent PC progression. There is no substantial evidence for its long-term safety and efficacy, hence its use in the care of men with PC on AS needs assessment. This protocol describes the ProsD clinical trial which aims to determine if oral high-dose vitamin D supplementation taken monthly for 2 years can prevent PC progression in cases with low-to-intermediate risk of progression. METHOD AND ANALYSIS: This is an Australian national multicentre, 2:1 double-blinded placebo-controlled phase II randomised controlled trial of monthly oral high-dose vitamin D supplementation (50 000 IU cholecalciferol), in men diagnosed with localised PC who have low-to-intermediate risk of disease progression and are being managed by AS. This trial will assess the feasibility, efficacy and safety of supplementing men with an initial oral loading dose of 500 000 IU cholecalciferol, followed by a monthly oral dose of 50 000 IU during the 24 months of AS. The primary trial outcome is the commencement of active therapy for clinical or non-clinical reason, within 2 years of AS. ETHICS AND DISSEMINATION: This trial is approved by Bellberry Ethics Committee (2016-06-459). All results will be reported in peer-reviewed journals. TRIAL REGISTRATION NUMBER: ACTRN12616001707459.

Association between ureteric stent dwell time and urinary tract infection.

BACKGROUND: Ureteric stone obstruction commonly presents to the emergency department, with definitive management often involving ureteroscopy and laser lithotripsy. Insertion of a ureteric stent prior to staged lithotripsy is commonly performed in the public healthcare system. Foreign bodies in the urinary tract are also known to increase urinary tract infection (UTI) risk. This study aims to evaluate the association between stent dwell time and UTI prior to lithotripsy. METHODS: The medical records of all patients who were treated for ureteric stones with initial stent insertion and staged lithotripsy, from 1 January 2018 to 30 June 2019 at a single tertiary centre, by eight urologists were retrospectively reviewed. Demographic features, disease factors and urine culture data were collected and analysed. RESULTS: Of the 172 patients (median age 56.7 years) identified, one-third had a positive pre-stent urine culture. Twenty-three percent had a positive pre-lithotripsy urine culture with 38% of females compared with 15% of males having a positive culture (P = 0.001). Only 4.3% of patients had a pre-lithotripsy UTI when the stent dwell time was less than 1 month compared with 26.2% when ureteric stents were in situ for longer than 1 month (P = 0.021). The correlation between ureteric stent dwell time and pre-lithotripsy UTI was not linear. Patient comorbidities, stone size, burden and location were not statistically correlated to pre-lithotripsy UTI. CONCLUSION: In delayed two-staged surgical management of acute urolithiasis, optimal ureteric stent dwell time is less than 1 month to reduce pre-lithotripsy UTI. Female gender is an independent risk factor for pre-lithotripsy UTI.

Protocol for the PRIMARY clinical trial, a prospective, multicentre, cross-sectional study of the additive diagnostic value of gallium-68 prostate-specific membrane antigen positron-emission tomography/computed tomography to multiparametric magnetic resonance imaging in the diagnostic setting for men being investigated for prostate cancer.

OBJECTIVES: Primary objectives: To determine the additive value of gallium-68 prostate-specific membrane antigen (PSMA) positron emission topography (PET)/computed tomography (CT) when combined with multiparametric magnetic resonance imaging (mpMRI) detecting clinically significant prostate cancer (csPCa) in men undergoing initial biopsy for suspicion of PCa, and to determine the proportion of men who could have avoided prostate biopsy with positive mpMRI (PI-RADS ≥3) but negative PSMA-PET/CT. Secondary objectives: To determine the proportion of men who had csPCa detected only by PSMA-PET/CT or only by systematic prostate biopsy; to compare index lesions by template biopsies vs targeted lesions identified on mpMRI or PSMA-PET/CT; to assess whether there may be health economic benefit or harm if PSMA-PET/CT is incorporated into the diagnostic algorithm; and to develop a nomogram which combines clinical, imaging and biomarker data to predict the likelihood of csPCa. PATIENTS AND METHODS: The PRIMARY trial is a multicentre, prospective, cross-sectional study that meets the criteria for level 1 evidence in diagnostic test evaluation. PRIMARY will investigate if a limited (pelvic-only) PSMA-PET/CT in combination with routine mpMRI can reliably discriminate men with csPCa from those without csPCa. We conducted a power calculation based on pilot data and will recruit up to 600 men who will undergo PSMA-PET/CT (the index test), mpMRI (standard test) and transperineal template + targeted (PSMA-PET/CT and/or mpMRI) biopsies (reference test). The conduct and reporting of the mpMRI and PSMA-PET/CT will be blinded to each other. RESULTS: The PRIMARY trial will measure and compare sensitivity, specificity, positive predictive value and negative predictive value of both mpMRI and PSMA-PET/CT vs targeted prostrate biopsy. The results will be used to determine the proportion of men who could safely avoid biopsy without compromising detection of csPCa. Furthermore, we will assess whether there is a health economic benefit in incorporating PSMA-PET/CT into the diagnostic algorithm. CONCLUSIONS: This trial will provide robust prospective data to determine the diagnostic ability of PSMA-PET/CT used in addition to mpMRI. It will establish if certain patients can avoid biopsy in the investigation of PCa.

Results of a Prospective Dose Escalation Study of Linear Accelerator-Based Virtual Brachytherapy (BOOSTER) for Prostate Cancer; Virtual HDR Brachytherapy for Prostate Cancer.

PURPOSE: To demonstrate feasibility and toxicity of linear accelerator-based stereotactic radiation therapy boost (SBRT) for prostate cancer, mimicking a high-dose-rate brachytherapy boost. METHODS AND MATERIALS: A phase 1 sequential dose escalation study of SBRT compared 20 Gy, 22 Gy, and 24 Gy to the prostate and 25 Gy, 27.5 Gy, and 30 Gy to the gross tumor volume in 2 fractions, combined with 46 Gy in 23 fractions of external beam radiation. Feasibility of dose escalation (volume receiving 125% and 150% of the dose) while meeting organ-at-risk dose constraints, grade 2 acute and late gastrointestinal and genitourinary toxicity, and freedom from biochemical failure were secondary endpoints. RESULTS: Thirty-six men with intermediate- and high-risk prostate cancer were enrolled with a median follow-up of 24 months. Sixty-four percent of patients had high-risk features. Nine men were enrolled to dose level 1, 6 to level 2, and 6 to level 3. Another 15 patients were treated at dose level 3 on the continuation study. Dose level 3 achieved superior 125% (23.75 Gy) and 150% (28.5 Gy) dose compared to dose levels 1 and 2, with minimal differences in organ-at-risk doses. Kaplan-Meier estimate of freedom from biochemical failure at 3 years was 93.3%. There were no late grade 2 or 3 gastrointestinal events. The late grade 2 genitourinary toxicity at 2 years was 19.3%. Prostate-specific membrane antigen positron emission tomography was performed at 2 years with no local recurrences. CONCLUSIONS: We have shown that a linear accelerator-based SBRT boost for prostate cancer is feasible and can achieve doses comparable to high-dose-rate boost up to the 150% isodose volumes. Rectal, bladder, and urethral doses remained low, and long-term toxicity was the same as or better than previous reports from high-dose-rate or low-dose-rate boost protocols.

Dataset for the reporting of prostate carcinoma in radical prostatectomy specimens: updated recommendations from the International Collaboration on Cancer Reporting.

The International Collaboration on Cancer Reporting (ICCR) was formed in 2011 to harmonise the datasets, protocols and checklists for pathological reporting of various cancers and develop internationally agreed upon, evidence-based datasets. A dataset for prostate cancer in radical prostatectomy specimens was developed in 2011-2012 as part of a pilot project; however, it required substantial revision following the ISUP Consensus Conference on Gleason Grading in 2014, the publication of the World Health Organisation (WHO) Classification of Tumours of the Urinary System and Male Genital Organs in 2016, and the 8th edition of the Tumour-Node-Metastasis (TNM) staging system in late 2016. This article presents the up-to-date, evidence-based ICCR dataset and associated commentary for reporting prostate cancer in radical prostatectomy specimens. PubMed and Google search engines were used to review the published literature on the subject, and the dataset was developed in line with the previously published ICCR framework for the development of cancer datasets. Substantial changes have been incorporated into the second edition of the ICCR prostate cancer (radical prostatectomy) dataset. These include revisions to prostate cancer grading, reporting of intraductal carcinoma of prostate and surgical margins, among others. Up-to-date cancer datasets underpin structured reporting and facilitate the production of consistent and accurate pathological data for patient care as well as comparisons between different cohorts and populations internationally.

An analysis of a multiple biomarker panel to better predict prostate cancer metastasis after radical prostatectomy.

A plethora of individual candidate biomarkers for predicting biochemical relapse in localized prostate cancer (PCa) have been proposed. Combined biomarkers may improve prognostication, and ensuring validation against more clinically relevant endpoints are required. The Australian PCa Research Centre NSW has contributed to numerous studies of molecular biomarkers associated with biochemical relapse. In the current study, these biomarkers were re-analyzed for biochemical relapse, metastatic relapse and PCa death with extended follow-up. Biomarkers of significance were then used to develop a combined prognostic model for clinical outcomes and validated in a large independent cohort. The discovery cohort (n = 324) was based on 12 biomarkers with a median follow-up of 16 years. Seven biomarkers were significantly associated with biochemical relapse. Three biomarkers were associated with metastases: AZGP1, Ki67 and PML. Only AZGP1 was associated with PCa death. In their individual and combinational forms, AZGP1 and Ki67 as a dual BM signature was the most robust predictor of metastatic relapse (AUC 0.762). The AZPG1 and Ki67 signature was validated in an independent cohort of 347 PCa patients. The dual BM signature of AZGP1 and Ki67 predicted metastasis in the univariable (HR 7.2, 95% CI, 1.6-32; p = 0.01) and multivariable analysis (HR 5.4, 95% CI, 1.2-25; p = 0.03). The dual biomarker signature marginally improved risk prediction compared to AZGP1 alone (AUC 0.758 versus 0.738, p < 0.001). Our findings indicate that biochemical relapse is not an adequate surrogate for metastasis or PCa death. The dual biomarker signature of AZGP1 and Ki67 offers a small benefit in predicting metastasis over AZGP1 alone.

Dataset for the reporting of prostate carcinoma in core needle biopsy and transurethral resection and enucleation specimens: recommendations from the International Collaboration on Cancer Reporting (ICCR).

The International Collaboration on Cancer Reporting (ICCR) is a project which issues datasets and guidelines for international standardisation of cancer reporting. This review summarises the required and recommended elements of the datasets for prostate core needle biopsies and transurethral resection (TURP) and enucleation specimens of the prostate. To obtain as much information as possible from needle biopsies there should be only one core in each specimen jar with the exception of saturation biopsies. The gross description of the specimens should include core lengths of needle biopsies and weight of resection specimens. The tumours should be classified according to the 4th World Health Organization (WHO) classification and graded both by Gleason scores and the grouping of these in International Society of Urological Pathology (ISUP) grades (Grade groups). Percent high-grade cancer is an optional component of the report. Tumour extent in needle biopsies should be reported both by number of cores positive for cancer and the linear extent measured in either millimetre or percent core involvement by tumour. In needle biopsies where low-grade cancer is discontinuous and seen in few cores, it is recommended that the tumour extent should be reported both by including and subtracting intervening benign tissue. For resection specimens, the percentage of the tissue area (or percentage of number of TURP chips) involved with cancer should be estimated. Extraprostatic extension should be reported when seen, while the reporting of perineural, seminal vesicle/ejaculatory duct and lymphovascular invasion is only recommended. Intraductal carcinoma of the prostate (IDC-P) should be reported when present, because of its strong link with aggressive cancer. The current recommendation is that the IDC-P component should not be graded. The structured and standardised reporting of prostate cancer contributes to safer and more efficient patient care and facilitates the compilation and understanding of multiparametric diagnostic and prognostic data.

A multiparametric magnetic resonance imaging-based risk model to determine the risk of significant prostate cancer prior to biopsy.

OBJECTIVE: To develop and externally validate a predictive model for detection of significant prostate cancer. PATIENTS AND METHODS: Development of the model was based on a prospective cohort including 393 men who underwent multiparametric magnetic resonance imaging (mpMRI) before biopsy. External validity of the model was then examined retrospectively in 198 men from a separate institution whom underwent mpMRI followed by biopsy for abnormal prostate-specific antigen (PSA) level or digital rectal examination (DRE). A model was developed with age, PSA level, DRE, prostate volume, previous biopsy, and Prostate Imaging Reporting and Data System (PIRADS) score, as predictors for significant prostate cancer (Gleason 7 with >5% grade 4, ≥20% cores positive or ≥7 mm of cancer in any core). Probability was studied via logistic regression. Discriminatory performance was quantified by concordance statistics and internally validated with bootstrap resampling. RESULTS: In all, 393 men had complete data and 149 (37.9%) had significant prostate cancer. While the variable model had good accuracy in predicting significant prostate cancer, area under the curve (AUC) of 0.80, the advanced model (incorporating mpMRI) had a significantly higher AUC of 0.88 (P < 0.001). The model was well calibrated in internal and external validation. Decision analysis showed that use of the advanced model in practice would improve biopsy outcome predictions. Clinical application of the model would reduce 28% of biopsies, whilst missing 2.6% significant prostate cancer. CONCLUSIONS: Individualised risk assessment of significant prostate cancer using a predictive model that incorporates mpMRI PIRADS score and clinical data allows a considerable reduction in unnecessary biopsies and reduction of the risk of over-detection of insignificant prostate cancer at the cost of a very small increase in the number of significant cancers missed.

Superior quality of life and improved surgical margins are achievable with robotic radical prostatectomy after a long learning curve: a prospective single-surgeon study of 1552 consecutive cases.

BACKGROUND: Comparative studies suggest functional and perioperative superiority of robot-assisted radical prostatectomy (RARP) over open radical prostatectomy (ORP). OBJECTIVE: To determine whether high-volume experienced open surgeons can improve their functional and oncologic outcomes with RARP and, if so, how many cases are required to surpass ORP outcomes and reach the learning curve plateau. DESIGN, SETTING, AND PARTICIPANTS: A prospective observational study compared two surgical techniques: 1552 consecutive men underwent RARP (866) or ORP (686) at a single Australian hospital from 2006 to 2012, by one surgeon with 3000 prior ORPs. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Demographic and clinicopathologic data were collected prospectively. The Expanded Prostate Cancer Index Composite quality of life (QoL) questionnaire was administered at baseline, 1.5, 3, 6, 12, and 24 mo. Multivariate linear and logistic regression modelled the difference in QoL domains and positive surgical margin (PSM) odds ratio (OR), respectively, against case number. RESULTS AND LIMITATIONS: A total of 1511 men were included in the PSM and 609 in the QoL analysis. RARP sexual function scores surpassed ORP scores after 99 RARPs and increased to a mean difference at 861st case of 11.0 points (95% confidence interval [CI], 5.9-16.1), plateauing around 600-700 RARPs. Early urinary incontinence scores for RARP surpassed ORP after 182 RARPs and increased to a mean difference of 8.4 points (95% CI, 2.1-14.7), plateauing around 700-800 RARPs. The odds of a pT2 PSM were initially higher for RARP but became lower after 108 RARPs and were 55% lower (OR: 0.45; 95% CI, 0.22-0.92) by the 866th RARP. The odds of a pT3/4 PSM were initially higher for RARP but decreased, plateauing around 200-300 RARPs with an OR of 1.15 (0.68-1.95) at the 866th RARP. Limitations include single-surgeon data and residual confounding. CONCLUSIONS: RARP had a long learning curve with inferior outcomes initially, and then showed progressively superior sexual, early urinary, and pT2 PSM outcomes and similar pT3 PSM and late urinary outcomes. Learning RARP was worthwhile for this high-volume surgeon, but the learning curve may not be justifiable for late-career/low-volume surgeons; further studies are needed.

High-dose rate brachytherapy compared with open radical prostatectomy for the treatment of high-risk prostate cancer: 10 year biochemical freedom from relapse.

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

High Gleason grade carcinoma at a positive surgical margin predicts biochemical failure after radical prostatectomy and may guide adjuvant radiotherapy.

UNLABELLED: Study Type - Prognosis (case series) Level of Evidence 4 What's known on the subject? and What does the study add? Only 30-35% of patients with positive surgical margins after radical prostatectomy develop recurrent disease. Adjuvant radiotherapy reduces the rate of biochemical relapse or metastasis and improves overall survival after radical prostatectomy. Various pathological factors, such as location and extent of positive margins, have been proposed as possible prognostic factors in men with margin-positive prostate cancer, however, the recent International Society of Urological Pathology consensus meeting in Boston noted that there is limited data on the significance of Gleason grade of the carcinoma at a positive margin. The present study shows that the presence of high grade prostate cancer, i.e. Gleason pattern 4 or 5, at a positive surgical margin is an independent predictor of biochemical recurrence after radical prostatectomy. Moreover, patients with lower grade carcinoma at the margin have a similar prognosis to men with negative margins. Hence, assessment of Gleason grade at the site of positive margin may aid optimal selection of patients for adjuvant radiotherapy. OBJECTIVE: • To establish predictors of biochemical recurrence by analysing the pathological characteristics of positive surgical margins (PSMs), including Gleason grade of the carcinoma at the involved margin. PATIENTS AND METHODS: • Clinicopathological and outcome data on 940 patients who underwent radical prostatectomy (RP) between 1997 and 2003 were collected. • Of these, 285 (30.3%) patients with PSMs were identified for pathological review, including assessment of location of margin, linear extent, number of PSMs, plane of margin and Gleason grade (3 vs 4 or 5) at the margin. RESULTS: • At a median follow-up of 82 months, the biochemical recurrence rate of the PSM cohort was 29%. • On univariate analysis, the presence of Gleason grade 4 or 5 at the margin (34.4% of cases) was significantly associated with biochemical recurrence (hazard ratio [HR] 2.80, 95% confidence interval [CI]= 1.82-4.32, P < 0.001) compared with the presence of Gleason grade 3. • Linear extent of margin involvement was also associated with recurrence (P= 0.009). • Single vs multiple margin involvement, location, and plane of the involved margin were not significant predictors of recurrence. • On multivariate analysis, Gleason grade 4 or 5 at the margin remained an independent predictor of recurrence (HR 2.14, 95% CI = 1.29-4.03, P= 0.003). CONCLUSION: • The Gleason grade at the site of a PSM identifies patients at increased risk of biochemical recurrence and should aid stratification of patients for adjuvant radiation therapy.

The impact of nerve sparing on incidence and location of positive surgical margins in radical prostatectomy.

OBJECTIVE: • To examine whether nerve-sparing surgery (NSS) is a risk factor for positive surgical margins (PSMs) in patients with either organ-confined prostate cancer or extracapsular extension (ECE). PATIENTS AND METHODS: • Clinicopathological outcome data on 945 consecutive patients treated with radical prostatectomy (RP) were prospectively collected. • All patients underwent RP (bilateral, unilateral or non-NSS) by one surgeon between 2002 and 2007. • Risk of PSMs and their locations with respect to NSS was determined by multivariate logistic regression analysis adjusting for preoperative risk factors for PSMs within pT2, pT3a and pT3b tumours. RESULTS: • Overall a PSM was identified in 19.6% of patients in an unscreened population with mean prostate-specific antigen (PSA) level of 8.1 ng/mL. • There was no significant difference in rates of PSMs between NSS groups on multivariate analysis (P= 0.147). • There was no significant difference in pT2 (P= 0.880), pT3a (P= 0.175) or pT3b (P= 0.354) tumours. • The only significant predictor of PSMs was preoperative PSA level (risk ratio 1.289, P= 0.006). • There was no significant difference in the location of PSMs except for the pT3a group, where the patients that had bilateral NSS were at higher risk of a posterolateral PSM (P= 0.028). CONCLUSIONS: • With appropriate selection of patients, NSS does not increase the risk of PSMs, whether the cancer is organ confined or ECE is present. • The adverse impact of the NSS procedure in the hands of an experienced surgeon is minimal and is a realistic compromise to obtain the increase in health-related quality of life offered by NSS.

Low AZGP1 expression predicts for recurrence in margin-positive, localized prostate cancer.

BACKGROUND: Men with positive margins after radical prostatectomy (RP) for localized prostate cancer (PC) have a 40-50% biochemical relapse rate at 5 years. Adjuvant radiotherapy improves biochemical progression-free and overall survival in men with positive margins, but is associated with increased toxicity. There is an urgent need to identify new prognostic markers to define the group of patients who would benefit from multimodality therapy. METHODS: Nuclear ß-catenin, membranous secreted frizzled-related protein 4 (sFRP4), zinc-alpha 2-glycoprotein (AZGP1), and macrophage inhibitory cytokine-1 (MIC-1) have previously been identified as molecular markers of outcome in localized PC. From these published studies, we identified a subset of patients with positive margins. The aim of this study was to assess the association between these four molecular markers and outcome in men with margin-positive, localized PC. RESULTS: We identified 186 men with positive margins from 330 men with localized PC; 53% had preoperative PSA >10 ng/ml, 72% extraprostatic extension (EPE), 24% seminal vesicles involvement (SVI), and 57% RP Gleason score ≥ 7. AZGP1 (P = 0.009), membranous sFRP4 (P = 0.03) and MIC-1 (P = 0.04) expression predicted for biochemical relapse on univariate analysis. Only absent/low AZGP1 expression (P = 0.01) was an independent predictor of recurrence in margin-positive, localized PC when modeled with preoperative PSA (P = 0.2), EPE (P = 0.2), SVI (P = 0.4), Gleason score ≥ 7 (P = 0.5) and adjuvant treatment (P = 0.4). Furthermore, there was an association between absent/low AZGP1 expression and clinical recurrence (P = 0.007). CONCLUSIONS: AZGP1 is a potential molecular marker for biochemical relapse in men with margin-positive, localized PC. Routine assessment of this biomarker may lead to better selection of patients who will benefit from post-RP radiotherapy.

Stage migration in localized prostate cancer has no effect on the post-radical prostatectomy Kattan nomogram.

OBJECTIVE: To investigate the effect of prostate-specific antigen (PSA) testing on stage migration in an Australian population, and its consequences on the prognostic accuracy of the post-radical prostatectomy (RP) Kattan nomogram, as in North America widespread PSA testing has resulted in prostate cancer stage migration, questioning the utility of prognostic nomograms in this setting. PATIENTS AND METHODS: The study comprised 1008 men who had consecutive RP for localized prostate cancer between 1991 and 2001 at one institution. Two groups were assessed, i.e. those treated in 1991-96 (group 1, the early PSA era), and 1997-2001 (group 2, the contemporary PSA era). Differences in clinicopathological features between the groups were analysed by chi-squared testing and survival modelling. Individual patient data were entered into the post-RP Kattan nomogram and the efficacy assessed by receiver- operating characteristic curve analysis. RESULTS: Patients in group 2 had lower pathological stage disease (P = 0.01) and fewer cancers with Gleason score > or =8 (P < 0.001) than group 1. Multivariate analysis identified preoperative serum PSA level (P < 0.01) and Gleason score (P < 0.01) as strong predictors of biochemical relapse in both groups. In group 2 pathological stage was not significant, but margin involvement became highly significant (P = 0.004). There was no difference in the predictive accuracy of the Kattan nomogram between the groups (P = 0.253). CONCLUSIONS: These findings show a downward stage migration towards organ-confined disease after the introduction of widespread PSA testing in an Australian cohort. Despite this, the Kattan nomogram remains a robust prognostic tool in clinical practice.

HSD17B4 overexpression, an independent biomarker of poor patient outcome in prostate cancer.

Steroid hormones and their metabolising enzymes have been studied extensively for their potential role in prostate cancer, with more recent interest in the androgen/estrogen inactivating enzyme 17beta-hydroxysteroid dehydrogenase type 4 (HSD17B4). Gene expression profiling showed HSD17B4 to be significantly overexpressed in prostate cancer compared to matched-benign epithelium. We therefore hypothesized that altered HSD17B4 expression may contribute to prostate cancer progression via altered hormone balance. In this study, HSD17B4 mRNA and protein expression were assessed by in situ hybridisation (ISH) and immunohistochemistry (IHC), respectively, in tissue arrays of prostate tissue from 172 patients treated by radical prostatectomy. Overexpression of HSD17B4 mRNA and protein was associated with prostate cancer (P<0.0001) and multivariate Cox proportional hazards analysis, adjusted for known prognostic indicators, demonstrated HSD17B4 mRNA and high protein expression were significant independent predictors of poor patient outcome as measured by time until PSA relapse (mRNA: hazards ratio [HR]=1.90, 95% confidence interval [CI]=1.15-3.12; P<0.0001; and protein: HR=2.09, 95% CI=1.31-3.33; P=0.0026). Here we provide strong evidence that both mRNA and protein overexpression of HSD17B4 is not only associated with the presence of prostate cancer, but is also a significant independent predictor of poor patient outcome.

Aberrant neuropeptide Y and macrophage inhibitory cytokine-1 expression are early events in prostate cancer development and are associated with poor prognosis.

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

The propeptide mediates formation of stromal stores of PROMIC-1: role in determining prostate cancer outcome.

The extracellular matrix (ECM) is a reservoir of cellular binding proteins and growth factors that are critical for normal cell behavior, and aberrations in the ECM invariably accompany malignancies such as prostate cancer. Carcinomas commonly overexpress macrophage inhibitory cytokine 1 (MIC-1), a proapoptotic and antitumorigenic transforming growth factor-beta superfamily cytokine. Here we show that MIC-1 is often secreted in an unprocessed propeptide containing form. It is variably processed intracellularly, with unprocessed forms being secreted from several tumor lines, including prostate carcinoma lines, PC-3 and LNCaP. Once secreted, only unprocessed proMIC-1 binds ECM, demonstrating for the first time the occurrence of extracellular stores of MIC-1. The propeptide mediates this association via its COOH-terminal 89 amino acids. Xenograft models bearing tumors secreting various engineered forms of MIC-1 show that the propeptide regulates the balance between ECM stores and circulating serum levels of mature MIC-1 in vivo. The absence of propeptide results in approximately 20-fold increase in serum MIC-1 levels. The significance of stromal MIC-1 stores was evaluated in prostate cancer tissue cores, which show major variation in stromal levels of MIC-1. Stromal MIC-1 levels are linked to prostate cancer outcome following radical prostatectomy, with decreasing stromal levels providing an important independent predictor of disease relapse. In low-grade localized prostate cancer (Gleason sum score < or = 6), the level of MIC-1 stromal stores was the best predictor of future relapse when compared with all other clinicopathologic variables. The secretion and ECM association of unprocessed proMIC-1 is likely to play a central role in modulating local bioavailability of MIC-1 which can affect patient outcome in prostate cancer and other epithelial tumors.