NeuroSAFE frozen section during robot-assisted radical prostatectomy: peri-operative and histopathological outcomes from the NeuroSAFE PROOF feasibility randomized controlled trial.

OBJECTIVES: To report on the methods, peri-operative outcomes and histopathological concordance between frozen and final section from the NeuroSAFE PROOF feasibility study (NCT03317990). PATIENTS AND METHODS: Between May 2018 and March 2019, 49 patients at two UK centres underwent robot-assisted radical prostatectomy (RARP). Twenty-five patient were randomized to NeuroSAFE RARP (intervention arm) and 24 to standard RARP (control arm). Frozen section was compared to final paraffin section margin assessment in the 25 patients in the NeuroSAFE arm. Operation timings and complications were collected prospectively in both arms. RESULTS: Fifty neurovascular bundles (NVBs) from 25 patients in the NeuroSAFE arm were analysed. When analysed by each pathological section (n = 250, average five per side), we noted a sensitivity of 100%, a specificity of 99.2%, and an area under the curve (AUC) of 0.994 (95% confidence interval [CI] 0.985 to 1; P ≤0.001). On an NVB basis (n = 50), sensitivity was 100%, specificity was 92.7%, and the AUC was 0.963 (95% CI 0.914 to 1; P ≤0.001). NeuroSAFE RARP lasted a mean of 3 h 16 min (knife to skin to off table, 95% CI 3 h 2 min-3 h 30 min) compared to 2 h 4 min (95% CI 2 h 2 min-2 h 25 min; P ≤0.001) for standard RARP. There was no morbidity associated with the additional length of operating time on in the NeuroSAFE arm. CONCLUSION: This feasibility study demonstrates the safety, reproducibility and excellent histopathological concordance of the NeuroSAFE technique in the NeuroSAFE PROOF trial. Although the technique increases the duration of RARP, this does not cause short-term harm. Confirmation of feasibility has led to the opening of the fully powered NeuroSAFE PROOF randomized controlled trial, which is currently under way at four sites in the UK.

Cellular senescence as a possible link between prostate diseases of the ageing male.

Senescent cells accumulate with age in all tissues. Although senescent cells undergo cell-cycle arrest, these cells remain metabolically active and their secretome - known as the senescence-associated secretory phenotype - is responsible for a systemic pro-inflammatory state, which contributes to an inflammatory microenvironment. Senescent cells can be found in the ageing prostate and the senescence-associated secretory phenotype and can be linked to BPH and prostate cancer. Indeed, a number of signalling pathways provide biological plausibility for the role of senescence in both BPH and prostate cancer, although proving causality is difficult. The theory of senescence as a mechanism for prostate disease has a number of clinical implications and could offer opportunities for targeting in the future.

Clinical outcomes associated with prostate cancer conspicuity on biparametric and multiparametric MRI: a protocol for a systematic review and meta-analysis of biochemical recurrence following radical prostatectomy.

INTRODUCTION: There is an increasing body of evidence to suggest that visibility of prostate cancer on magnetic resonance (MRI) may be related to likelihood of adverse pathological outcomes. Biochemical recurrence (BCR) after radical prostatectomy remains a significant clinical challenge and a means of predicting likelihood of this prior to surgery could inform treatment choice. It appears that MRI could be a potential candidate strategy for BCR prediction, and as such, there is a need to review extant literature on the prognostic capability of MRI. Here, we describe a protocol for a systematic review and meta-analysis of the utility of biparametric MRI (bpMRI) and multiparametric MRI (mpMRI) in predicting BCR following radical prostatectomy for prostate cancer treatment. METHODS AND ANALYSIS: PubMed, MEDLINE, Embase and Cochrane databases will be searched and screening will be guided by the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. In order to meet the inclusion criteria, papers must be English-language articles involving patients who have had bpMRI or mpMRI for suspected prostate cancer and have undergone radical prostatectomy as definitive therapy. Patients must have had prostate-specific antigen monitoring before and after surgery. All relevant papers published from July 1977 to October 2020 will be eligible for inclusion. The Newcastle-Ottawa score will be used to determine the quality and bias of the studies. This protocol is written in-line with the PRISMA protocol 2015 checklist. ETHICS AND DISSEMINATION: There are no relevant ethical concerns. Dissemination of this protocol will be via peer-reviewed journals as well as national and international conferences. PROSPERO REGISTRATION NUMBER: CRD42020206074.

A Modified Newcastle-Ottawa Scale for Assessment of Study Quality in Genetic Urological Research.

Our modification of the traditional Newcastle-Ottawa scale enables urological researchers to effectively appraise and communicate the quality of genetic-based research in urology.

Genetic Landscape of Prostate Cancer Conspicuity on Multiparametric Magnetic Resonance Imaging: A Systematic Review and Bioinformatic Analysis.

CONTEXT: Multiparametric magnetic resonance imaging (mpMRI) detects most, but not all, clinically significant prostate cancer. The genetic basis of prostate cancer visibility and invisibility on mpMRI remains uncertain. OBJECTIVE: To systematically review the literature on differential gene expression between mpMRI-visible and mpMRI-invisible prostate cancer, and to use bioinformatic analysis to identify enriched processes or cellular components in genes validated in more than one study. EVIDENCE ACQUISITION: We performed a systematic literature search of the Medline, EMBASE, PubMed, and Cochrane databases up to January 2020 in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement. The primary endpoint was differential genetic features between mpMRI-visible and mpMRI-invisible tumours. Secondary endpoints were explanatory links between gene function and mpMRI conspicuity, and the prognostic value of differential gene enrichment. EVIDENCE SYNTHESIS: We retrieved 445 articles, of which 32 met the criteria for inclusion. Thematic synthesis from the included studies showed that mpMRI-visible cancer tended towards enrichment of molecular features associated with increased disease aggressivity, including phosphatase and tensin homologue (PTEN) loss and higher genomic classifier scores, such as Oncotype and Decipher. Three of the included studies had accompanying publicly available data suitable for further bioinformatic analysis. An over-representation analysis of these datasets revealed increased expression of genes associated with extracellular matrix components in mpMRI-visible tumours. CONCLUSIONS: Prostate cancer that is visible on mpMRI is generally enriched with molecular features of tumour development and aggressivity, including activation of proliferative signalling, DNA damage, and inflammatory processes. Additionally, there appears to be concordant cellular components and biological processes associated with mpMRI conspicuity, as highlighted by bioinformatic analysis of large genetic datasets. PATIENT SUMMARY: Prostate cancer that is detected by magnetic resonance imaging (MRI) tends to have genetic features that are associated with more aggressive disease. This suggests that MRI can be used to assess the likelihood of aggressive prostate cancer, based on tumour visibility.

Histopathological features of prostate cancer conspicuity on multiparametric MRI: protocol for a systematic review and meta-analysis.

INTRODUCTION: Multiparametric MRI (mpMRI) has improved risk stratification for men with suspected prostate cancer. Indeed, mpMRI-visible tumours tend to be larger and of higher pathological grade than mpMRI-invisible tumours; however, concern remains around significant cancer that is undetected by mpMRI. There has been considerable recent interest to investigate whether tumour conspicuity on mpMRI is associated with additional histopathological features (including cellular density, microvessel density and unusual prostate cancer subtypes), which may have important clinical implications in both diagnosis and prognosis. Furthermore, analysis of these features may help reveal the radiobiology that underpins the actual mechanisms of mpMRI visibility (and invisibility) of prostate tumours. Here, we describe a protocol for a systematic review of the histopathological basis of prostate cancer conspicuity on mpMRI. METHODS AND ANALYSIS: A systematic search of the MEDLINE, PubMed, Embase and Cochrane databases will be conducted. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines will be used to guide screening, thematic reporting and conclusions drawn from all eligible studies. Included papers will be full-text, English-language articles, comparing the histopathological characteristics of mpMRI-visible lesions and mpMRI-invisible tumours. All studies published between January 1950 and January 2020 will be eligible for inclusion. Studies using confirmatory immunohistochemistry for the identification of immune subsets or structural components will be included. Study bias and quality will be assessed using a modified Newcastle-Ottawa scale. To ensure methodological rigour, this protocol is written in accordance with the PRISMA Protocol 2015 checklist. If appropriate, a meta-analysis will be conducted comparing histopathological feature frequency between mpMRI-visible and mpMRI-invisible disease. ETHICS AND DISSEMINATION: No ethical approval will be required as this is an academic review of published literature. Findings will be disseminated through publications in peer-reviewed journals and presentations at national and international conferences. PROSPERO REGISTRATION NUMBER: CRD42020176049.

Exploring Patient Views and Acceptance of Multiparametric Magnetic Resonance Imaging for the Investigation of Suspected Prostate Cancer (the PACT Study): A Mixed-Methods Study Protocol.

BACKGROUND: The introduction of multiparametric magnetic resonance imaging (mpMRI) has improved the diagnosis of suspected prostate cancer, accurately risk-stratifying men before a biopsy. However, pre-biopsy mpMRI represents a significant deviation from the traditional approach of prostate specific antigen testing with subsequent systematic transrectal ultrasound-guided prostate biopsy and we have not yet explored the views of men who experience this new pathway. The purpose of the PACT study (PAtient views and aCceptance of mulTiparametric MRI) is to explore men's perceptions of mpMRI. METHODS: PACT will be conducted at teaching hospitals in which mpMRI is central to the prostate cancer diagnostic pathway using a two-phase, mixed-methods, quantitative and qualitative approach. In phase I, men referred with suspected prostate cancer will complete detailed surveys to explore their views on the mpMRI-directed pathway compared to the traditional pathway and on what constitutes 'significant' prostate cancer. In phase II, these themes will be expanded upon with in-depth, semi-structured interviews. Qualitative data will be transcribed and thematically analysed, and quantitative questionnaire responses will be analysed statistically. DISCUSSION: PACT will provide the first detailed insight into patient perceptions on the use and acceptability of mpMRI. Furthermore, results from PACT will help contribute to the resolution of outstanding controversies that surround this technology.

Five-year Outcomes of Magnetic Resonance Imaging-based Active Surveillance for Prostate Cancer: A Large Cohort Study.

BACKGROUND: Although the use of multiparametric magnetic resonance imaging (mpMRI) in active surveillance (AS) for prostate cancer is of increasing interest, existing data are derived from small cohorts. OBJECTIVE: We describe clinical, histological, and radiological outcomes from an established AS programme, where protocol-based biopsies were omitted in favour of MRI-led monitoring. DESIGN, SETTING, AND PARTICIPANTS: Data on 672 men enrolled in AS between August 2004 and November 2017 (inclusion criteria: Gleason 3 + 3 or 3 + 4 localised prostate cancer, presenting prostate-specific antigen <20 ng/ml, and baseline mpMRI) were collected from the University College London Hospital (UCLH) database. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Primary outcomes were event-free survival (EFS; event defined as prostate cancer treatment, transition to watchful waiting, or death) and treatment-free survival (TFS). Secondary outcomes included rates of all-cause or prostate cancer-related mortality, metastasis, and upgrading to Gleason ≥4 + 3. Data on radiological and histological progression were also collected. RESULTS AND LIMITATIONS: More than 3800 person-years (py) of follow-up were accrued (median: 58 mo; interquartile range 37-82 mo). Approximately 84.7% (95% confidence interval [CI]: 82.0-87.6) and 71.8% (95% CI: 68.2-75.6) of patients remained on AS at 3 and 5 yr, respectively. EFS and TFS were lower in those with MRI-visible (Likert 4-5) disease or secondary Gleason pattern 4 at baseline (log-rank test; p < 0.001). In total, 216 men were treated. There were 24 deaths, none of which was prostate cancer related (6.3/1000 py; 95% CI: 4.1-9.5). Metastases developed in eight men (2.1 events/1000 py; 95% CI: 1.0-4.3), whereas 27 men upgraded to Gleason ≥4 + 3 on follow-up biopsy (7.7 events/1000 py; 95% CI: 5.2-11.3). CONCLUSIONS: The rates of discontinuation, mortality, and metastasis in MRI-led surveillance are comparable with those of standard AS. MRI-visible disease and/or secondary Gleason grade 4 at baseline are associated with a greater likelihood of moving to active treatment at 5 yr. Further research will concentrate on optimising imaging intervals according to baseline risk. PATIENT SUMMARY: In this report, we looked at the outcomes of magnetic resonance imaging (MRI)-based surveillance for prostate cancer in a UK cohort. We found that this strategy could allow routine biopsies to be avoided. Secondary Gleason pattern 4 and MRI visibility are associated with increased rates of treatment. We conclude that MRI-based surveillance should be considered for the monitoring of small prostate tumours.

Genetic landscape of prostate cancer conspicuity on multiparametric MRI: a protocol for a systematic review and bioinformatic analysis.

INTRODUCTION: The introduction of multiparametric MRI (mpMRI) has enabled enhanced risk stratification for men at risk of prostate cancer, through accurate prebiopsy identification of clinically significant disease. However, approximately 10%-20% of significant prostate cancer may be missed on mpMRI. It appears that the genomic basis of lesion visibility or invisibility on mpMRI may have key implications for prognosis and treatment. Here, we describe a protocol for the first systematic review and novel bioinformatic analysis of the genomic basis of prostate cancer conspicuity on mpMRI. METHODS AND ANALYSIS: A systematic search of MEDLINE, PubMed, EMBASE and Cochrane databases will be conducted. Screening, data extraction, statistical analysis and reporting will be performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Included papers will be full text articles, written between January 1980 and December 2019, comparing molecular characteristics of mpMRI-visible lesions and mpMRI-invisible lesions at the DNA, DNA-methylation, RNA or protein level. Study bias and quality will be assessed using a modified Newcastle-Ottawa score. Additionally, we will conduct a novel bioinformatic analysis of supplementary material and publicly available data, to combine transcriptomic data and reveal common pathways highlighted across studies. To ensure methodological rigour, this protocol is written in accordance with the PRISMA Protocol 2015 checklist. ETHICS AND DISSEMINATION: Ethical approval will not be required, as this is an academic review of published literature. Findings will be disseminated through publications in peer-reviewed journals, and presentations at national and international conferences. PROSPERO REGISTRATION NUMBER: CRD42019147423.