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Background: Immunotherapy has demonstrated limited activity in prostate cancer to date. This likely reflects an immune suppressive tumor microenvironment (TME), with previous studies suggesting low PD-L1 expression and a sparse immune cell infiltrate. We aimed to further characterise the immune TME in primary prostate cancer and correlate immune subset densities with clinical outcomes. Methods: Two distinct cohorts of patients treated with radical prostatectomy were identified, based on the development of biochemical recurrence (BCR), one subgroup with high International Society of Urological Pathologists (ISUP) grade group, recurrent disease and a second with low grade, non-recurrent disease. A prostate immunohistochemical (IHC) antibody cocktail was used to differentiate tumor and peritumoral benign tissue. Specific CD8+, CD4+, FoxP3+, CD20+ and CD68+ cell subsets were identified using IHC staining of consecutive slides. PD-L1 and CD8/PD-L1 dual staining were also performed. Cell subset densities were quantified within tumor and peritumoral regions. We used descriptive statistics to report cell subset densities and T-tests to compare groups by age, grade and the development of BCR. Univariable and multivariable logistic regression were used to analyse risk factors for BCR and the development of metastatic disease. Results: A total of 175 patients were included, with a median age of 63 years and median pre-operative PSA of 8.2ng/ml. BCR occurred in 115 patients (66%) and 56 (32%) developed metastatic disease. CD68+ cells were the most abundant (median 648.8/mm2 intratumoral, 247.6/mm2 peritumoral), while PD-L1+ and PD-L1/CD8+ cell density was low overall (PD-L1+ median 162.4/mm2 intratumoral, 141.7/mm2 peritumoral; PD-L1/CD8+ (median 5.52/mm2 intratumoral, 3.41/mm2 peritumoral). Overall, grade group and T-stage were independently associated with BCR and metastatic disease. Higher density of peritumoral PD-L1+ cells was an independent risk factor for BCR (OR 5.33, 95%CI 1.31–21.61, p = 0.019).Although higher densities of CD8+ and CD4+ cells were observed in higher grade group 3–5 tumors, these were not associated with the development of BCR or metastasis. Conclusions: In our cohort of prostate cancer patients who underwent radical prostatectomy, higher grade group and T-stage were independent predictors of BCR and metastasis. Despite higher grade group being associated with higher CD8+ cell density, PD-L1+ and PD-L1/CD8+ cell densities were low overall, suggesting lower T cell receptor recognition of tumor antigens. Further understanding of this phenomenon would influence development of future immunotherapeutic strategies in prostate cancer. [ABSTRACT FROM AUTHOR] more...

Simple Summary: In this study, we investigated the impact of lymphovascular invasion at the time of prostatectomy on oncological outcomes in patients with prostate cancer. We found that 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. Therefore, lymphovascular invasion status could be used as a factor to identify patients that have underlying disseminated disease and may benefit from systemic treatment intensification, especially those with high-risk disease. Further prospective studies need to be conducted to validate these findings. 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. [ABSTRACT FROM AUTHOR] more...

Objective: To assess the long‐term safety of nerve‐sparing radical prostatectomy (NSRP) in men with high‐risk prostate cancer (PCa) by comparing survival outcomes, disease recurrence, the need for additional therapy, and perioperative outcomes of patients undergoing NSRP to those having non‐NSRP. Patients and methods: We included consecutive patients at a single, academic centre who underwent open RP for high‐risk PCa, defined as preoperative prostate‐specific antigen level of > 20 ng/mL and/or postoperative International Society of Urological Pathology Grade Group 4 or 5 (i.e., Gleason score ≥ 8) and/or ≥pT3 and/or pN1 assessing the RP and lymph node specimen. We calculated a propensity score and used inverse probability of treatment weighting to match baseline characteristics of patients with high‐risk PCa who underwent NSRP vs non‐NSRP. We analysed oncological outcome as time‐to‐event and calculated hazard ratios (HRs). Results: A total of 726 patients were included in this analysis of which 84% (n = 609) underwent NSRP. There was no evidence for the positive surgical margin rate being different between the NSRP and non‐NSRP groups (47% vs 49%, P = 0.64). Likewise, there was no evidence for the need for postoperative radiotherapy being different in men who underwent NSRP from those who underwent non‐NSRP (HR 0.78, 95% confidence interval [CI] 0.53–1.15). NSRP did not impact the risk of any recurrence (HR 0.99, 95% CI 0.73–1.34, P = 0.09) and there was no evidence for survival being different in men who underwent NSRP to those who underwent non‐NSRP (HR 0.65, 95% CI 0.39–1.08). There was also no evidence for the cancer‐specific survival (HR 0.56, 95% CI 0.29–1.11) or progression‐free survival (HR 0.99, 95% CI 0.73–1.34) being different between the groups. Conclusion: In patients with high‐risk PCa, NSRP can be attempted without compromising long‐term oncological outcomes provided a comprehensive assessment of objective (e.g., T Stage) and subjective (e.g., intraoperative appraisal of tissue planes) criteria are conducted. [ABSTRACT FROM AUTHOR] more...

Simple Summary: In this study, we investigated the functional and oncological outcomes of low and intermediate risk compared to high risk prostate cancer patients undergoing radical prostatectomy with attempted neurovascular bundle preservation. We found that satisfactory urinary continence and erectile function recovery is possible without compromising oncological outcomes. Therefore, preservation of the neurovascular bundle should be considered in carefully selected patients with high risk disease. Future studies should develop risk stratification tools to identify which high risk prostate cancer cases are suitable for nerve sparing. Nerve sparing (NS) is a surgical technique to optimize functional outcomes of radical prostatectomy (RP). However, it is not recommended in high risk (HR) cases because of the risk of a positive surgical margin that may increase the risk of cancer recurrence. In the last two decades there has been a change of perspective to the effect that in well-selected cases NS could be an oncologically safe option with better functional outcomes. Therefore, we aim to compare the functional outcomes and oncological safety of NS during RP in men with HR disease. A total of 1340 patients were included in this analysis, of which 12% (n = 158) underwent non-NSRP and 39% (n = 516) and 50% (n = 666) uni- and bilateral NSRP, respectively. We calculated a propensity score and used inverse probability of treatment weighting (IPTW) to balance the baseline characteristics of Pca patients undergoing non-NSRP and those having uni- and bilateral NSRP, respectively. NS improved functional outcomes; after IPTW, only 3% of patients having non-NSRP reached complete erectile function recovery (without erectile aid) at 24 months, whereas 22% reached erectile function recovery (with erectile aid), while 87% were continent. Unilateral NS increased the probability of functional recovery in all outcomes (OR 1.1 or 1.2, respectively), bilateral NS slightly more so (OR 1.1 to 1.4). NSRP did not impact the risk of any recurrence (HR 0.99, 95%CI 0.73–1.34, p = 0.09), and there was no difference in survival for men who underwent NSRP (HR 0.65, 95%CI 0.39–1.08). There was no difference in cancer-specific survival (0.56, 95%CI 0.29–1.11). Our study found that NSRP significantly improved functional outcomes and can be safely performed in carefully selected patients with HR-PCa without compromising long term oncological outcomes. [ABSTRACT FROM AUTHOR] more...

Background: The introduction of robotic surgical systems has significantly impacted urological surgery, arguably more so than other surgical disciplines. The focus of our study was length of hospital stay ‐ patients have traditionally been discharged day 1 post‐robot‐assisted radical prostatectomy (RARP), however, during the ongoing COVID‐19 pandemic and consequential resource limitations, our centre has facilitated a cohort of same‐day discharges with initial success. Methods: We conducted a prospective tertiary single‐centre cohort study of a series of all patients (n = 28) – undergoing RARP between January and April 2021. All patients were considered for a day zero discharge pathway which consisted of strict inclusion criteria. At follow‐up, each patient's perspective on their experience was assessed using a validated post‐operative satisfaction questionnaire. Data were reviewed retrospectively for all those undergoing RARP over the study period, with day zero patients compared to overnight patients. Results: Overall, 28 patients 20 (71%) fulfilled the objective criteria for day zero discharge. Eleven patients (55%) agreed pre‐operatively to day zero discharge and all were successfully discharged on the same day as their procedure. There was no statistically significant difference in age, BMI, ASA, Charlson score or disease volume. All patients indicated a high level of satisfaction with their procedure. Median time from completion of surgery to discharge was 426 min (7.1 h) in the day zero discharge cohort. Conclusion: Day zero discharge for RARP appears to deliver high satisfaction, oncological and safety outcomes. Therefore, our study demonstrates early success with unsupported same‐day discharge in carefully selected and pre‐counselled patients. [ABSTRACT FROM AUTHOR] more...

Objectives: To estimate the lifetime health and economic outcomes of selecting active surveillance (AS), radical prostatectomy (RP), or radiation therapy (RT) as initial management for low- or favorable-risk localized prostate cancer.Methods: A discrete-event simulation model was developed using evidence from published randomized trials. Health outcomes were measured in life-years and quality-adjusted life-years (QALYs). Costs were included from a public payer perspective in Australian dollars. Outcomes were discounted at 5% over a lifetime horizon. Probabilistic and scenario analyses quantified parameter and structural uncertainty.Results: A total of 60% of patients in the AS arm eventually received radical treatment (surgery or radiotherapy) compared with 90% for RP and 91% for RT. Although AS resulted in fewer treatment-related complications, it led to increased clinical progression (AS 40.7%, RP 17.6%, RT 19.9%) and metastatic disease (AS 13.4%, RP 6.1%, RT 7.0%). QALYs were 10.88 for AS, 11.10 for RP, and 11.13 for RT. Total costs were A$17 912 for AS, A$15 609 for RP, and A$15 118 for RT. At a willingness to pay of A$20 000/QALY, RT had a 61.4% chance of being cost-effective compared to 38.5% for RP and 0.1% for AS.Conclusions: Although AS resulted in fewer and delayed treatment-related complications, it was not found to be a cost-effective strategy for favorable-risk localized prostate cancer over a lifetime horizon because of an increase in the number of patients developing metastatic disease. RT was the dominant strategy yielding higher QALYs at lower cost although differences compared with RP were small. [ABSTRACT FROM AUTHOR] more...

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. [ABSTRACT FROM AUTHOR] more...

• Autonomic nerve subtypes predict cancer recurrence after prostatectomy. • Our results support a regulatory role for the autonomic nervous system in prostate cancer. • These findings may contribute to risk stratification and future therapeutic targets. To describe nerve subtypes involved by perineural invasion (PNI) in prostate cancer and their relationship with clinicopathological parameters and recurrence risk. 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. 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). 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. [ABSTRACT FROM AUTHOR] more...

Erectile dysfunction after radical prostatectomy for prostate cancer remains a significant morbidity for a large group of patients. A large body of work suggests that disrupting the cavernosal nerves is central as a causative factor. Extensive research has focused on ways to increase potency rates after surgery, either by preserving neuro-integrity, or attempting to restore it using various approaches. Herein we discuss the neurophysiology of nerve injury and regeneration, and review the work to date on cavernosal nerve regeneration. [ABSTRACT FROM AUTHOR] more...

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. [ABSTRACT FROM AUTHOR] more...

Context The aetiology of urinary incontinence following radical prostatectomy (RP) is incompletely understood. In particular, it is unclear whether there is a relationship between neurovascular bundle (NVB) sparing and post-RP urinary continence. Objective To review systematically the association of NVB sparing in RP with postoperative urinary continence outcomes and synthesise the results in a meta-analysis. Evidence acquisition This study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analysis statement. PubMed, Medline, and Cochrane Central Register of Controlled Trials were searched (December 2013), yielding 3413 unique records. A total of 27 longitudinal cohort studies were selected for inclusion. Studies were evaluated using a predefined criteria adapted from the Cochrane Tool to Assess Risk of Bias in Cohort Studies. Evidence synthesis Data from 13 749 participants in 27 studies were synthesised in a meta-analysis. An assessment of the study methodology revealed a high risk of bias due to differences in baseline characteristics, outcome assessment, and the likely presence of unreported confounding factors such as meticulous apical dissection. Meta-analysis demonstrated that nerve sparing (NS) compared with non–nerve sparing (NNS) resulted in improved early urinary continence rates up to 6 mo postoperatively. Beyond this time, no significant difference was observed. This effect was seen most clearly for bilateral NS compared with NNS. A sensitivity analysis of prospective cohort studies revealed consistent results. Conclusions This analysis demonstrates an association between NS and improved urinary continence outcomes up to 6 mo postoperatively. NS in men with poor preoperative erectile function should be considered in the context of oncologic risk stratification because it may improve time to continence recovery. The underlying cause of the relationship between NS and continence is unknown. It may represent preservation of the intrapelvic somatic nerves supplying the rhabdosphincter or the influence of other confounding factors. Future research should be directed towards improving understanding of the anatomy of urinary continence and the pathophysiology of post-RP incontinence. Patient summary We found that avoiding damage to the nerves around the prostate improves urinary continence in the first 6 mo after surgery. After this time, there is no difference in continence between men who had these nerves removed and those who had them saved. This finding could be due to a true effect of saving these nerves or to a number of other factors affecting the research. [ABSTRACT FROM AUTHOR] more...