The modified International Society of Urological Pathology system improves concordance between biopsy and prostatectomy tumour grade.

OBJECTIVES: To assess the concordance between biopsy and radical prostatectomy (RP) specimens using the 2005 Gleason score (GS) and the International Society of Urological Pathology (ISUP) 2014/World Health Organization 2016 modified system, accounting for the introduction of transperineal biopsy and pre-biopsy multiparametric magnetic resonance imaging (mpMRI). PATIENTS AND METHODS: Between 2002 and 2019, we identified 2431 patients with paired biopsy and RP histopathology from a prospectively recorded and maintained prostate cancer database. Biopsy specimens were graded according to the 2005 GS or ISUP 2014 modified system, according to the year of diagnosis. Multivariable logistic regression analysis was conducted to retrospectively assess the impact of prostate-specific antigen (PSA), PSA density, age, pre-biopsy mpMRI, and biopsy method, on the rate of upgraded disease. The kappa coefficient was used to establish the degree of change in concordance between groups. RESULTS: Overall, 24% of patients had upgraded disease and 8% of patients had downgraded disease when using the modified ISUP 2014 criteria. Agreement in the updated ISUP 2014 cohort was 68%, compared with 55% in the 2005 GS group, which was validated by a kappa coefficient that was good (k = 0.5 ± 0.4) and poor (k = 0.3 ± 0.1), respectively. In multivariable models, a change in grading system independently improved overall disease concordance (P = 0.02), and there were no other co-segregated patient or pathological factors such as PSA, total number of cores, maximum cancer length, biopsy route or the use of mpMRI that impacted this finding. CONCLUSION: The 2014 ISUP modifed system improves overall concordance between biopsy and surgical specimens, and thus allows more accurate prognostication and management in high-grade disease, independent of more extensive prostate sampling and the use of mpMRI.

Fractionated stereotactic body radiotherapy for up to five prostate cancer oligometastases: Interim outcomes of a prospective clinical trial.

Stereotactic body radiotherapy (SBRT) can delay escalation to systemic treatment in men with oligometastatic prostate cancer (PCa). However, large, prospective studies are still required to evaluate the efficacy of this approach in different patient groups. This is the interim analysis of a prospective, single institution study of men relapsing with up to five synchronous lesions following definitive local treatment for primary PCa. Our aim was to determine the proportion of patients not requiring treatment escalation following SBRT. In total, 199 patients were enrolled to receive fractionated SBRT (50 Gray in 10 fractions) to each visible lesion. Fourteen patients were castration resistant at enrolment. The proportion of patients not requiring treatment escalation 2 years following SBRT was 51.7% (95% CI: 44.1-59.3%). The median length of treatment escalation-free survival over the entire follow-up period was 27.1 months (95% CI; 21.8-29.4 months). Prior androgen deprivation therapy (ADT) predicted a significantly lower rate of freedom from treatment escalation at 2 years compared to no prior ADT (odds ratio = 0.21, 95% CI: 0.08-0.54, p = 0.001). There was no difference in the efficacy of SBRT when treating 4-5 vs. 1-3 initial lesions. A prostate-specific antigen (PSA) decline was induced in 75% of patients, with PSA readings falling to an undetectable level in six patients. No late grade three toxicities were observed. These interim results suggest that SBRT can be used to treat up to five synchronous PCa oligometastases to delay treatment escalation.

Late biochemical recurrence after radical prostatectomy is associated with a slower rate of progression.

OBJECTIVE: To characterise the pattern of late biochemical recurrence (BCR) in the largest contemporary cohort of patients with localised prostate cancer treated with radical prostatectomy (RP) in the active surveillance era. PATIENTS AND METHODS: Consecutive patients who underwent RP for localised prostate cancer between 2003 and 2017 were identified from a prospectively recorded, dedicated prostate cancer database. Patients who received neoadjuvant androgen-deprivation therapy were excluded. These patients were categorised into the following groups: no BCR, BCR at <12 months (early), BCR at 12-60 months (intermediate), and BCR at >60 months (late), after RP. Clinicopathological characteristics were analysed using the Student's t-test, Mann-Whitney U-test, or chi-squared test where appropriate. Multivariable binomial logistic regression models were used to assess predictors of BCR at various time-points. RESULTS: In all, 2312 patients were included in the final analysis with up to 12 years of follow-up data. The average patient had clinically localised prostate cancer, an elevated PSA level, and International Society of Urological Pathology (ISUP) Grade Group 2 on biopsy. In all, 88.7% of patients had ISUP Grade Group ≥2 at RP. A subgroup of 446 patients had undetectable PSA levels at 5 years after RP; 11.7% of them progressed to experience BCR. In this subgroup, late recurrers had significantly higher-grade tumours on ISUP and Gleason sum (P <0.001 and P = 0.001, respectively), higher rates of extraprostatic extension (P = 0.022), and larger tumour volumes (P = 0.032). Logistic regression showed that RP ISUP Grade Group was a significant predictor of BCR (odds ratio 2.14, 95% confidence interval 1.43-3.20; P <0.001). CONCLUSION: This study characterises the pattern of late BCR in the largest contemporary active surveillance era cohort. We have identified that RP ISUP Grade Group is a strong predictive indicator for late BCR. We also propose that timing of BCR resides on a continuum of risk and that the potential concept of dormant micrometastatic involvement requires further research and evaluation.

Routinely reported 'equivocal' lymphovascular invasion in prostatectomy specimens is associated with adverse outcomes.

OBJECTIVE: To evaluate the significance of routinely reported 'equivocal' lymphovascular invasion (LVI) in prostatectomy specimens of patients with clinically localized prostate cancer. MATERIALS AND METHODS: Prospectively collected data from men who underwent prostatectomy for clinically localized prostate cancer were retrospectively reviewed. Rates of adverse pathological features and biochemical recurrence (BCR) were compared between tumours positive, negative or 'equivocal' for LVI. Multivariable Cox regression analysis was performed to identify independent predictors of BCR. RESULTS: Of 1 310 consecutive cases, LVI was present definitively in 82 (6.3%) and equivocally in 43 (3.3%) cases. Similar to definitive LVI, equivocal LVI was significantly associated with other adverse pathological features, including advanced stage, higher Gleason grade and positive surgical margins. BCR occurred more frequently in patients with tumours that were equivocal (61%) or positive for LVI (71%) than in patients with negative results (14.7%). In addition, patients with both definitive and equivocal LVI had a significantly shorter BCR-free survival time compared with those with negative LVI. Multivariable Cox regression analysis indicated that the presence of either definitive or equivocal LVI were independent predictors of disease recurrence (hazard ratio [HR] 3.32, 95% confidence interval [CI] 2.3-4.8; P <0.001 vs HR 1.66, 95% CI 1.05-2.65; P = 0.032, respectively). CONCLUSION: In this single-institution study, equivocal LVI had a similar association with adverse pathological features and rate of BCR to that of definitive LVI. If our observations are validated in an independent cohort, consideration should be given to the inclusion of equivocal LVI as part of routine pathological reporting.

A prospective study of the short-term quality-of-life outcomes of patients undergoing transperineal prostate biopsy.

OBJECTIVE: To investigate in a prospective, observational study whether transperineal prostate biopsy (TPbx) results in patient-reported quality-of-life (QoL) changes from baseline in the first 3-months after TPbx. PATIENTS AND METHODS: Consenting patients completed the 26-item Expanded Prostate cancer Index Composite (EPIC-26), the Sexual Health Inventory for Men, the International Prostate Symptom Score, the Generalised Anxiety Disorder seven-item scale, the Patient Health Questionnaire nine-item scale, and a global question about willingness to have a repeat TPbx in a years' time. The instruments were scored using published scoring methods. Wilcoxon signed-rank tests and Mann-Whitney U-tests were used to investigate statistically significant differences. Clinically significant differences were also investigated defined by published minimal important differences for the EPIC-26 and changes in established categorical groups for the other instruments. RESULTS: In all, 53 patients consented to participate and completed the baseline questionnaire, in addition to at least one of the 1- or 3-month follow-up questionnaires. We found that most patients having a TPbx had no clinically significant change in QoL in the first 3 months after TPbx. However, 24% had clinically worse urinary function and 18% had worse sexual function at 1 month. At 3 months, 3% of patients had clinically worse urinary function and 25% continued to have worse sexual function compared with baseline. Patients who were subsequently diagnosed with cancer based on the results of the TPbx, had statistically significantly reduced QoL for the EPIC-26 urinary scales and reduced improvements in scores on the psychological scales at the 1-month follow-up compared with those who were not diagnosed with cancer. CONCLUSIONS: Most patients having a TPbx had no clinically significant change in QoL in the first 3 months after TPbx. However, patients should be advised that a quarter may have clinically worse urinary function and nearly 20% have clinically worse sexual function in the first month, and that sexual function deficits may continue up to 3 months. The results of this study provide a resource that the clinician can use when discussing TPbx with patients.

Are transrectal prostate biopsies routinely indicated in patients with incidentally diagnosed prostate cancer following transurethral resection of the prostate for benign disease?

OBJECTIVE: To determine the indication of routine transrectal ultrasound-guided needle biopsy (TRUSBx) of the prostate gland following incidental cancer diagnosis after transurethral resection of the prostate (TURP) for benign prostatic hyperplasia. MATERIALS AND METHODS: A multi-institutional search identified 63 patients with incidental TURP-diagnosed prostate cancer from 2001 to 2010, who underwent subsequent TRUSBx or radical prostatectomy (RP). The Gleason scores from TURP were compared to those from TRUSBx or RP. Whole mount maps from RP were analysed to provide an anatomical basis for the correlation observed. To determine the clinical impact of this problem, the incidence of TURP-diagnosed prostate cancer in the population was also determined. RESULTS: Of 22 patients who underwent TRUSBx, the rates of Gleason score concordance, upgrading and downgrading were 32, 14 and 54% respectively (Spearman correlation coefficient 0.20). Most cases of pathological downgrading consisted of benign cores at biopsy. Therefore, TRUSBx did not give additional Gleason score (GS) information in 86% of patients. Of 41 RP patients, the respective rates were 61, 22 and 17% (Spearman correlation coefficient 0.15). The majority of them retained a similar or lower GS between TURP and RP. Of 13 whole mount maps analysed, 6 (46%) were found with anterior/transitional zone (AZ/TZ) tumours, 6 (46%) with multifocal tumours and 1 (8%) with a large peripheral zone (PZ) tumour extending into the TZ. Regional population data show that despite a gradual reduction in the proportion of TURP-diagnosed cases over the past decade, they still account for 8.5-13% of all new cases. CONCLUSION: TURP-diagnosed prostate cancers represent predominantly AZ tumours. A TRUSBx does not give additional GS information in a majority of cases, and therefore is not routinely indicated. It may be selectively useful prior to active surveillance, but not in all pursuing radical treatment. These findings may help reduce unnecessary TRUSBx in the population.

Lymphovascular Invasion at the Time of Radical Prostatectomy Adversely Impacts Oncological Outcomes.

Lymphovascular invasion, whereby tumour cells or cell clusters are identified in the lumen of lymphatic or blood vessels, is thought to be an essential step in disease dissemination. It has been established as an independent negative prognostic indicator in a range of cancers. We therefore aimed to assess the impact of lymphovascular invasion at the time of prostatectomy on oncological outcomes. We performed a multicentre, retrospective cohort study of 3495 men who underwent radical prostatectomy for localised prostate cancer. Only men with negative preoperative staging were included. We assessed the relationship between lymphovascular invasion and adverse pathological features using multivariable logistic regression models. Kaplan-Meier curves and Cox proportional hazard models were created to evaluate the impact of lymphovascular invasion on oncological outcomes. Lymphovascular invasion was identified in 19% (n = 653) of men undergoing prostatectomy. There was an increased incidence of lymphovascular invasion-positive disease in men with high International Society of Urological Pathology (ISUP) grade and non-organ-confined disease (p < 0.01). The presence of lymphovascular invasion significantly increased the likelihood of pathological node-positive disease on multivariable logistic regression analysis (OR 15, 95%CI 9.7-23.6). The presence of lymphovascular invasion at radical prostatectomy significantly increased the risk of biochemical recurrence (HR 2.0, 95%CI 1.6-2.4). Furthermore, lymphovascular invasion significantly increased the risk of metastasis in the whole cohort (HR 2.2, 95%CI 1.6-3.0). The same relationship was seen across D'Amico risk groups. The presence of lymphovascular invasion at the time of radical prostatectomy is associated with aggressive prostate cancer disease features and is an indicator of poor oncological prognosis.

Robotic radical prostatectomy as the initial step in multimodal therapy for men with high-risk localised prostate cancer: initial experience of 160 men.

OBJECTIVES: • To report the outcome of robotic-assisted laparoscopic radical prostatectomy (RALP) for men with localised high-risk prostate cancer at diagnosis. • Although commonly managed by radiotherapy (RT) with prolonged androgen-deprivation therapy (ADT), we hypothesize that initiation of multimodal therapy with RALP is oncologically efficacious and may allow many men to avoid ADT. PATIENTS AND METHODS: • Between December 2003 and September 2010, 1480 men underwent RALP of whom 160 fulfilled the National Comprehensive Control Network criteria for high-risk disease (prostate-specific antigen (PSA) > 20 ng/mL and/or clinical stage, cT ≥ 3 and/or biopsy Gleason score ≥ 8). • Biochemical recurrence (postoperative PSA ≥ 0.2) was used to assess outcome after RALP monotherapy. • Treatment failure was defined as either a rising PSA level after salvage RT or the initiation of ADT. RESULTS: • The mean age ± standard deviation was 63.1 ± 6.3 years. Median PSA level was 9.95 ng/mL (interquartile range 6.0-21.4). • Analysis of prostatectomy specimen showed Gleason 8-10 cancers in 65 (41%), and extracapsular disease, pT ≥ 3, in 96 (60%) of which seminal vesicle invasion was evident in 36 (23%). Downgrading by prostatectomy occurred in 64 (40% of total group) and five (3%) were downstaged to pT2 disease. By contrast, any upgrading occurred in 29 (18% of total group) and upstaging occurred in 68 (43%). The overall positive surgical margin rate was 38%, correlating with stage pT2 (15%) or pT3 (53%). • With median follow-up of 26.2 months (interquartile range 5.5-37.3), two non-cancer-related deaths have occurred (overall survival 98.8%; cancer-specific survival 100%), and biochemical recurrence has occurred in 53 men (33%). RALP surgery has served as monotherapy (n= 117, 73%), or has been followed by salvage RT (n= 24, 15%) and/or ADT (n= 43, 27%). Overall 2-year and 3-year treatment failure was 31 and 41%, respectively. • Serum PSA level was the only independent predictor of overall treatment failure (hazard ratio [HR] 1.02, P= 0.001) although a strong trend was observed for both clinical stage (HR 1.22, P= 0.058) and the number of positive biopsy cores on transrectal biopsy (HR 1.06, P= 0.057). CONCLUSIONS: • RALP incorporating the use of postoperative RT is a good multimodal management strategy for men with this aggressive variant of prostate cancer. • At median follow-up in excess of 2 years, we found low rates of treatment failure enabling a high proportion of men to remain free of ADT.

Prostate weight is the preferred measure of prostate size in radical prostatectomy cohorts.

OBJECTIVE: To evaluate the accuracy of calculated prostate volume variables in a radical prostatectomy (RP) cohort, as many recent studies use these measures of prostate size instead of prostate weight. To determine whether this accuracy could be improved by modifying the mathematical model used in the volume estimation. PATIENTS AND METHODS: Patients who underwent RP for prostate cancer at our associated institutions had calculated specimen volumes and weights from RP specimens determined at one pathology institution and transrectal ultrasonography (TRUS) volumes were recorded preoperatively (n= 236). Correlation analysis was performed and errors were determined for calculated volume variables when compared with prostate weight. Bland-Altman plots were drawn and concordance coefficients calculated. Analysis was repeated with smaller prostates mathematically modelled as bullet-shaped rather than ellipsoid (n= 165). RESULTS: Although correlation was good for both TRUS and specimen volumes, they equally underestimated prostate weight with a large range of errors and poor concordance coefficients. Only 22% of TRUS volumes and 11% of calculated specimen volumes were within 10% of weight measurements. Application of a bullet-shaped mathematical model for prostates <55 g did not correct the large individual variation seen within these values. CONCLUSION: Calculated prostate volume variables are prone to a large range of individual error regardless of the mathematical model used and should be avoided in statistical studies involving RP cohorts, and the more accurate prostate weight variable should instead be used as a size variable or correction factor.

Phase 2 Study of Neoadjuvant FGFR Inhibition and Androgen Deprivation Therapy Prior to Prostatectomy.

BACKGROUND: Disease recurrence is common following prostatectomy in patients with localised prostate cancer with high-risk features. Although androgen deprivation therapy increases the rates of organ-confined disease and negative surgical margins, there is no significant benefit on disease recurrence. Multiple lines of evidence suggest that (Fibroblast Growth Factor/Fibroblast Growth Factor Receptor) FGF/FGFR-signalling is important in supporting prostate epithelial cell survival in hostile conditions, including acute androgen deprivation. Given the recent availability of oral FGFR inhibitors, we investigated whether combination therapy could improve tumour response in the neo-adjuvant setting. METHODS: We conducted an open label phase II study of the combination of erdafitinib (3 months) and androgen deprivation therapy (4 months) in men with localised prostate cancer with high-risk features prior to prostatectomy using a Simon's 2 stage design. The co-primary endpoints were safety and tolerability and pathological response in the prostatectomy specimen. The effect of treatment on residual tumours was explored by global transcriptional profiling with RNA-sequencing. RESULTS: Nine patients were enrolled in the first stage of the trial. The treatment combination was poorly tolerated. Erdafitinib treatment was discontinued early in six patients, three of whom also required dose interruptions/reductions. Androgen deprivation therapy for 4 months was completed in all patients. The most common adverse events were hyperphosphataemia, taste disturbance, dry mouth and nail changes. No patients achieved a complete pathological response, although patients who tolerated erdafitinib for longer had smaller residual tumours, associated with reduced transcriptional signatures of epithelial cell proliferation. CONCLUSIONS: Although there was a possible enhanced anti-tumour effect of androgen deprivation therapy in combination with erdafitnib in treatment naïve prostate cancer, the poor tolerability in this patient population prohibits the use of this combination in this setting.

Loss of SNAI2 in Prostate Cancer Correlates With Clinical Response to Androgen Deprivation Therapy.

PURPOSE: Androgen receptor (AR) signaling is important in prostate cancer progression, and therapies that target this pathway have been the mainstay of treatment for advanced disease for over 70 years. Tumors eventually progress despite castration through a number of well-characterized mechanisms; however, little is known about what determines the magnitude of response to short-term pathway inhibition. METHODS: We evaluated a novel combination of AR-targeting therapies (degarelix, abiraterone, and bicalutamide) and noted that the objective patient response to therapy was highly variable. To investigate what was driving treatment resistance in poorly responding patients, as a secondary outcome we comprehensively characterized pre- and post-treatment samples using both whole-genome and RNA sequencing. RESULTS: We find that resistance following short-term treatment differs molecularly from typical progressive castration-resistant disease, associated with transcriptional reprogramming, to a transitional epithelial-to-mesenchymal transition (EMT) phenotype rather than an upregulation of AR signaling. Unexpectedly, tolerance to therapy appears to be the default state, with treatment response correlating with the prevalence of tumor cells deficient for SNAI2, a key regulator of EMT reprogramming. CONCLUSION: We show that EMT characterizes acutely resistant prostate tumors and that deletion of SNAI2, a key transcriptional regulator of EMT, correlates with clinical response.

Ductal variant prostate carcinoma is associated with a significantly shorter metastasis-free survival.

BACKGROUND: Ductal adenocarcinoma is an uncommon prostate cancer variant. Previous studies suggest that ductal variant histology may be associated with worse clinical outcomes, but these are difficult to interpret. To address this, we performed an international, multi-institutional study to describe the characteristics of ductal adenocarcinoma, particularly focussing on the effect of presence of ductal variant cancer on metastasis-free survival. METHODS: Patients with ductal variant histology from two institutional databases who underwent radical prostatectomies were identified and compared with an independent acinar adenocarcinoma cohort. After propensity score matching, the effect of the presence of ductal adenocarcinoma on time to biochemical recurrence, initiation of salvage therapy and the development of metastatic disease was determined. Deep whole-exome sequencing was performed for selected cases (n = 8). RESULTS: A total of 202 ductal adenocarcinoma and 2037 acinar adenocarcinoma cases were analysed. Survival analysis after matching demonstrated that patients with ductal variant histology had shorter salvage-free survival (8.1 versus 22.0 months, p = 0.03) and metastasis-free survival (6.7 versus 78.6 months, p < 0.0001). Ductal variant histology was consistently associated with RB1 loss, as well as copy number gains in TAP1, SLC4A2 and EHHADH. CONCLUSIONS: The presence of any ductal variant adenocarcinoma at the time of prostatectomy portends a worse clinical outcome than pure acinar cancers, with significantly shorter times to initiation of salvage therapies and the onset of metastatic disease. These features appear to be driven by uncoupling of chromosomal duplication from cell division, resulting in widespread copy number aberration with specific gain of genes implicated in treatment resistance.

A Retrospective Comparison of Transrectal and Transperineal Prostate Biopsies: Experience of a Single Surgeon.

Background: Transrectal ultrasound-guided prostate biopsy (TRUS) is the gold standard for undertaking prostate biopsy, however, it has been associated with higher rates of post-biopsy sepsis than transperineal prostate biopsy (TP). Objective: To compare complication rates between transrectal prostate biopsy and TP for a single surgeon. Materials and Methods: Data were collected for all prostate biopsies undertaken by a single experienced urologist through his private rooms between February 2012 and March 2018. In total, 693 cases were included (560 individual men) in the final analysis (transrectal = 276 and transperineal = 417). All patients were followed up 2 weeks post-biopsy, and complications were recorded (sepsis, urinary tract infection [UTI], bleeding, and acute urinary retention [AUR]). Results: Complications occurred in 37 cases (transrectal = 3 and transperineal = 34). Sepsis occurred in one case following transrectal biopsy (0.36%) and two cases following TP (0.48%). UTI occurred in two cases following transrectal biopsy (0.72%) and two cases following transperineal (0.48%). Bleeding occurred in one case following TP (0.24%). The most common complication was AUR, which occurred in 28 cases following TP (6.71%). Conclusions: Data from this study compared complication rates for both transperineal and transrectal prostate biopsies in a single-surgeon study.

Prostatic nerve subtypes independently predict biochemical recurrence in prostate cancer.

OBJECTIVE: To describe nerve subtypes involved by perineural invasion (PNI) in prostate cancer and their relationship with clinicopathological parameters and recurrence risk. METHODS: 141 prostatectomy specimens from men with localized prostate cancer and known perineural invasion were analyzed. Index tumor blocks were stained for perineural invasion and sympathetic/parasympathetic markers. For 98 patients with complete staining, nerves from up to three hotspot regions of intraprostatic perineural invasion were classified according to autonomic subtype and perineural invasion status. Findings were correlated with prospectively collected clinicopathological data. Biochemical recurrence predictors were tested in univariable and multivariable models. RESULTS: Most intra-prostatic nerves contained sympathetic and parasympathetic fibres, irrespective of perineural invasion status. A fraction was purely sympathetic (5% PNI, 2% non-PNI) or double-negative (non-adrenergic, non-nitrergic; 1% PNI, 1% non-PNI). Perineural invasion nerve count was associated with higher pathological stage. Although total perineural invasion or non-perineural invasion nerve count did not predict biochemical recurrence, two subtypes were found to be independent predictors: pure sympathetic non-perineural invasion nerves (HR 6.79, p = 0.03) and non-adrenergic, non-nitrergic PNI nerves (HR 10.56, p < 0.005). CONCLUSIONS: Pure sympathetic nerve density without tumour invasion and perineural invasion specifically involving non-adrenergic, non-nitrergic fibres are independent predictors of biochemical recurrence post prostatectomy, supporting a role for the autonomic nervous system in prostate cancer progression.

Robotic-assisted radical cystectomy with intracorporeal urinary diversion versus open: early Australian experience.

BACKGROUND: The aim of this study was to describe our initial Australian single surgeon experience with robotic-assisted radical cystectomy (RARC) and intracorporeal urinary diversion (ICUD) and to compare the outcomes with open radical cystectomy (ORC). METHODS: Between January 2014 and June 2016, consecutive patients diagnosed with muscle invasive and high-risk non-muscle invasive bladder cancer undergoing radical cystectomy were included. Treatment modalities included either RARC with ICUD or ORC. ICUD consisted of either intracorporeal ileal conduit or orthotopic neobladder formation. Prospectively collected perioperative and oncological outcomes were analysed. RESULTS: Twenty-six RARC and 13 ORC were performed. Median operating times were 362 and 240 min for RARC and ORC, respectively (P < 0.001). Estimated blood loss for RARC was 300 mL compared with 500 mL for ORC (P = 0.01). Post-operative haemoglobin drop was less in the RARC cohort (20% versus 24%, P = 0.03). There was no statistical difference in overall 90-day complication rates (81% versus 62%, P = 0.25) and 90-day major complication rates (19% versus 23%, P = 0.67) between the RARC and ORC groups, respectively. Positive surgical margins for RARC were 4% and 8% for ORC (P = 1.0). CONCLUSION: Early results demonstrate that the safe introduction of RARC with ICUD in Australia is potentially feasible without compromising perioperative and oncological outcomes. Future randomized trial with larger numbers will be required for further analysis in the Australian setting.

Obesity suppresses tumor attributable PSA, affecting risk categorization.

Obesity is linked with more aggressive prostate cancer and higher rates of disease recurrence post treatment. It is unclear if this is due to specific tumor-promoting effects of obesity or diagnostic bias. Patients undergoing prostatectomy were categorized according to their body mass index (BMI). Expected prostate-specific antigen (PSA) levels were calculated for each patient based on tumor characteristics. The effect of obesity on the accuracy of pre-treatment risk categorization was determined, and mediation analysis was used to identify the contribution of biologic vs non-biologic mechanisms to the observed increased risk of biochemical recurrence. Residual tumor-promoting effects were estimated in a survival model controlling for diagnostic error. The following results were obtained. The analysis included 1587 patients. Despite similar rates of adverse pathological features at prostatectomy, biochemical recurrence rates were significantly higher in very obese patients, which persisted after adjustment for stage, grade and PSA. Tumor volume however correlated significantly with BMI (P = 0.004), and the difference in predicted and observed 'tumor-attributable' PSA (Delta-PSA) in very obese patients was greater than three times higher than that of healthy patients (P = 0.0067). Regression analysis indicated that the effect of BMI on tumor volume was fully mediated indirectly by its effect on PSA. Inclusion of this diagnostic error as a covariate in the survival analysis attenuated the effect of BMI on recurrence. In conclusion, being very obese suppresses tumor-associated PSA resulting in a diagnostic bias that is responsible for errors in risk classification, and potentially contributes to a delay in initial presentation.

Periprostatic fat tissue transcriptome reveals a signature diagnostic for high-risk prostate cancer.

Evidence suggests that altered adipose tissue homeostasis may be an important contributor to the development and/or progression of prostate cancer. In this study, we investigated the adipose transcriptional profiles of low- and high-risk disease to determine both prognostic potential and possible biological drivers of aggressive disease. RNA was extracted from periprostatic adipose tissue from patients categorised as having prostate cancer with either a low or high risk of progression based on tumour characteristics at prostatectomy and profiled by RNA sequencing. The expression of selected genes was then quantified by qRT-PCR in a cross-validation cohort. In the first phase, a total of 677 differentially transcribed genes were identified, from which a subset of 14 genes was shortlisted. In the second phase, a 3 gene (IGHA1, OLFM4, RERGL) signature was refined and evaluated using recursive feature selection and cross-validation, obtaining a promising discriminatory utility (area under curve 0.72) at predicting the presence of high-risk disease. Genes implicated in immune and/or inflammatory responses predominated. Periprostatic adipose tissue from patients with high-risk prostate cancer has a distinct transcriptional signature that may be useful for detecting its occult presence. Differential expression appears to be driven by a local immune/inflammatory reaction to more advanced tumours, than any specific adipose tissue-specific tumour-promoting mechanism. This signature is transferable into a clinically usable PCR-based assay, which in a cross-validation cohort shows diagnostic potential.

3D modelling of radical prostatectomy specimens: Developing a method to quantify tumor morphometry for prostate cancer risk prediction.

Prostate cancer displays a wide spectrum of clinical behaviour from biological indolence to rapidly lethal disease, but we remain unable to accurately predict an individual tumor's future clinical course at an early curable stage. Beyond basic dimensions and volume calculations, tumor morphometry is an area that has received little attention, as it requires the analysis of the prostate gland and tumor foci in three-dimensions. Previous efforts to generate three-dimensional prostate models have required specialised graphics units and focused on the spatial distribution of tumors for optimisation of biopsy strategies rather than to generate novel morphometric variables such as tumor surface area. Here, we aimed to develop a method of creating three-dimensional models of a prostate's pathological state post radical prostatectomy that allowed the derivation of surface areas and volumes of both prostate and tumors, to assess the method's accuracy to known clinical data, and to perform initial investigation into the utility of morphometric variables in prostate cancer prognostication. Serial histology slides from 21 prostatectomy specimens covering a range of tumor sizes and pathologies were digitised. Computer generated three-dimensional models of tumor and prostate space filling models were reconstructed from these scanned images using Rhinoceros 4.0 spatial reconstruction software. Analysis of three-dimensional modelled prostate volume correlated only moderately with weak concordance to that from the clinical data (r=0.552, θ=0.405), but tumor volume correlated well with strong concordance (r=0.949, θ=0.876). We divided the cohort of 21 patients into those with features of aggressive tumor versus those without and found that larger tumor surface area (32.7 vs 3.4cc, p=0.008) and a lower tumor surface area to volume ratio (4.7 vs 15.4, p=0.008) were associated with aggressive tumor biology.