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The coronavirus disease 2019 (COVID-19) pandemic necessitated using telehealth to bridge the clinical gap, but could increase health disparities. This article reports on a chart review of diabetes telehealth visits occurring before COVID-19, during shelter-in-place orders, and during the reopening period. Visits for children with public insurance and for those who were non-English speaking were identified. Telehealth visits for children with public insurance increased from 26.2% before COVID-19 to 37.3% during shelter-in-place orders and 34.3% during reopening. Telehealth visits for children who were non-English speaking increased from 3.5% before COVID-19 to 17.5% during shelter-in-place orders and remained at 15.0% during reopening. Pandemic-related telehealth expansion included optimization of workflows to include patients with public insurance and those who did not speak English. Increased participation by those groups persisted during the reopening phase, indicating that prioritizing inclusive telehealth workflows can reduce disparities in access to care.

Objectives The Prostate Imaging Quality (PI-QUAL) score assesses the quality of multiparametric MRI (mpMRI). A score of 1 means all sequences are below the minimum standard of diagnostic quality, 3 implies that the scan is of sufficient diagnostic quality, and 5 means that all three sequences are of optimal diagnostic quality. We investigated the inter-reader reproducibility of the PI-QUAL score in patients enrolled in the NeuroSAFE PROOF trial. Methods We analysed the scans of 103 patients on different MR systems and vendors from 12 different hospitals. Two dedicated radiologists highly experienced in prostate mpMRI independently assessed the PI-QUAL score for each scan. Interobserver agreement was assessed using Cohen’s kappa with standard quadratic weighting (κw) and percent agreement. Results The agreement for each single PI-QUAL score was strong (κw = 0.85 and percent agreement = 84%). A similar agreement (κw = 0.82 and percent agreement = 84%) was observed when the scans were clustered into three groups (PI-QUAL 1–2 vs PI-QUAL 3 vs PI-QUAL 4–5). The agreement in terms of diagnostic quality for each single sequence was highest for T2-weighted imaging (92/103 scans; 89%), followed by dynamic contrast-enhanced sequences (91/103; 88%) and diffusion-weighted imaging (80/103; 78%). Conclusion We observed strong reproducibility in the assessment of PI-QUAL between two radiologists with high expertise in prostate mpMRI. At present, PI-QUAL offers clinicians the only available tool for evaluating and reporting the quality of prostate mpMRI in a systematic manner but further refinements of this scoring system are warranted. Key Points • Inter-reader agreement for each single Prostate Imaging Quality (PI-QUAL) score (i.e., PI-QUAL 1 to PI-QUAL 5) was strong, with weighted kappa = 0.85 (95% confidence intervals: 0.51 – 1) and percent agreement = 84%. • Interobserver agreement was strong when the scans were clustered into three groups according to the ability (or not) to rule in and to rule out clinically significant prostate cancer (i.e., PI-QUAL 1-2 vs PI-QUAL 3 vs PI-QUAL 4–5), with weighted kappa = 0.82 (95% confidence intervals: 0.68 – 0.96) and percent agreement = 84%. • T2-weighted acquisitions were the most compliant with the Prostate Imaging Reporting and Data System (PI-RADS) v. 2.0 technical recommendations and were the sequences of highest diagnostic quality for both readers in 95/103 (92%) scans, followed by dynamic contrast enhanced acquisition with 81/103 (79%) scans and lastly by diffusion-weighted imaging with 79/103 (77%) scans.

We determined the early efficacy of bipolar radiofrequency ablation with a coil design for focal ablation of clinically significant localized prostate cancer visible at multiparametric magnetic resonance imaging.A prospective IDEAL phase 2 development study (Focal Prostate Radiofrequency Ablation, NCT02294903) recruited treatment-naïve patients with a single focus of significant localized prostate cancer (Gleason 7 or 4 mm or more of Gleason 6) concordant with a lesion visible on multiparametric magnetic resonance imaging. Intervention was a focal ablation with a bipolar radiofrequency system (Encage™) encompassing the lesion and a predefined margin using nonrigid magnetic resonance imaging-ultrasound fusion. Primary outcome was the proportion of men with absence of significant localized disease on biopsy at 6 months. Trial followup consisted of serum prostate specific antigen, multiparametric magnetic resonance imaging at 1 week, and 6 and 12 months post-ablation. Validated patient reported outcome measures for urinary, erectile and bowel functions, and adverse events monitoring system were used. Analyses were done on a per-protocol basis.Of 21 patients recruited 20 received the intervention. Baseline characteristics were median age 66 years (IQR 63-69) and preoperative median prostate specific antigen 7.9 ng/ml (5.3-9.6). A total of 18 patients (90%) had Gleason 7 disease with median maximum cancer 7 mm (IQR 5-10), for a median of 2.8 cc multiparametric magnetic resonance imaging lesions (IQR 1.4-4.8). Targeted biopsy of the treated area (median number of cores 6, IQR 5-8) showed absence of significant localized prostate cancer in 16/20 men (80%), concordant with multiparametric magnetic resonance imaging. There was a low profile of side effects at patient reported outcome measures analysis and there were no serious adverse events.Focal therapy of significant localized prostate cancer associated with a magnetic resonance imaging lesion using bipolar radiofrequency showed early efficacy to ablate cancer with low rates of genitourinary and rectal side effects.

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.

Background: The pathogenesis of penile intraepithelial neoplasia (PeIN) is unclear but human papillomavirus (HPV) infection and polymorphisms in human leucocyte antigen (HLA). Objectives: To examine the prevalence of HPV DNA and HLA in PeIN. Methods: Adult Caucasian men with a clinical and histological diagnosis of PeIN, that is, Bowenoid papulosis (BP), Bowen’s disease of penis (BDP) and erythroplasia of Queyrat (EQ) were selected and phenotyped from the clinical records. DNA was extracted from blood and paraffin-embedded sections for HLA and HPV typing, respectively. Human leucocyte antigen allele frequencies were compared with those derived from the UK–based Caucasian population. Results: Seventy-two cases of PeIN (20 BP, 34 BDP and 18 EQ) were studied. Human papillomavirus DNA was identified in 65/72 (90.2%) PeIN; Alphapapillomavirus types were detected in 62/72 (85%) followed by Betapapillomavirus types in 9/72 (12.5%) and cutaneous types in 7/72 (9.7%); HPV16 was the most prevalent genotype at 35/72 (48.6%) followed by HPV33 at 7/72 (9.7%); multiple infections were seen in 18/72 (25%) PeIN. HLA-C*15 (Bonferroni corrected p = 0.049) confers susceptibility to PeIN, whereas HLA-DQA1*01 (corrected p = 0.02) protects against PeIN. HPV16-associated PeIN cases showed no statistically significant association with HLA genotype after multiple corrections. Conclusion: Human papillomavirus is involved in the pathogenesis of PeIN. Immunogenotype may play a role in the pathogenesis of PeIN.

Background False positive multiparametric magnetic resonance imaging (mpMRI) phenotypes prompt unnecessary biopsies. The Prostate MRI Imaging Study (PROMIS) provides a unique opportunity to explore such phenotypes in biopsy-naïve men with raised prostate-specific antigen (PSA) and suspected cancer. Objective To compare mpMRI lesions in men with/without significant cancer on transperineal mapping biopsy (TPM). Design, setting, and participants PROMIS participants (n = 235) underwent mpMRI followed by a combined biopsy procedure at University College London Hospital, including 5-mm TPM as the reference standard. Patients were divided into four mutually exclusive groups according to TPM findings: (1) no cancer, (2) insignificant cancer, (3) definition 2 significant cancer (Gleason ≥3 + 4 of any length and/or maximum cancer core length ≥4 mm of any grade), and (4) definition 1 significant cancer (Gleason ≥4 + 3 of any length and/or maximum cancer core length ≥6 mm of any grade). Outcome measurements and statistical analysis Index and/or additional lesions present in 178 participants were compared between TPM groups in terms of number, conspicuity, volume, location, and radiological characteristics. Results and limitations Most lesions were located in the peripheral zone. More men with significant cancer had two or more lesions than those without significant disease (67% vs 37%; p, Take Home Message Significant cancer-associated magnetic resonance imaging lesions in biopsy-naïve men with suspected prostate cancer are larger, more conspicuous, and more diffusion restricted than false positives. Prostate-specific antigen density and apparent diffusion coefficient are predictors of significant disease, and could help guide decisions to biopsy men with indeterminate phenotypes.

Background Multiparametric magnetic resonance imaging (MP-MRI) is established in the diagnosis of prostate cancer, but the need for enhanced sequences has recently been questioned. Objective To assess whether dynamic contrast-enhanced imaging (DCE) improves accuracy over T2 and diffusion sequences. Design, setting, and participants PROMIS was a multicentre, multireader trial, with, in this part, 497 biopsy-naive men undergoing standardised 1.5T MP-MRI using T2, diffusion, and DCE, followed by a detailed transperineal prostate mapping (TPM) biopsy at 5 mm intervals. Likert scores of 1–5 for the presence of a significant tumour were assigned in strict sequence, for (1) T2 + diffusion and then (2) T2 + diffusion + dynamic contrast-enhanced images. Outcome measurements and statistical analysis For the primary analysis, the primary PROMIS outcome measure (Gleason score ≥4 + 3 or ≥6 mm maximum cancer length) on TPM was used, and an MRI score of ≥3 was considered positive. Results and limitations Sensitivity without and with DCE was 94% and 95%, specificity 37% and 38%, positive predictive value 51% and 51%, and negative predictive value 90% and 91%, respectively (p > 0.05 in each case). The number of patients avoiding biopsy (scoring 1–2) was similar (123/497 vs 121/497, p = 0.8). The number of equivocal scores (3/5) was slightly higher without DCE (32% vs 28% p = 0.031). The proportion of MRI equivocal (3/5) and positive (4–5) cases showing significant tumours were similar (23% and 71% vs 20% and 69%). No cases of dominant Gleason 4 or higher were missed with DCE, compared with a single case with T2 + diffusion-weighted imaging. No attempt was made to correlate lesion location on MRI and histology, which may be considered a limitation. Radiologists were aware of the patient’s prostate-specific antigen. Conclusions Contrast adds little when MP-MRI is used to exclude significant prostate cancer. Patient summary An intravenous injection of contrast may not be necessary when magnetic resonance imaging is used as a test to rule out significant tumours in the prostate.

Pre‐biopsy multiparametric magnetic resonance imaging (mpMRI) has transformed the risk stratification and diagnostic approach for suspected prostate cancer. The majority of clinically significant prostate cancers are visible on pre‐biopsy mpMRI, however, there are a subset of significant tumors that are not detected by mpMRI. The radiobiological mechanisms underpinning mpMRI‐visibility and invisibility of these cancers remain uncertain. Emerging evidence suggests that mpMRI‐visible tumors are enriched with molecular features associated with increased disease aggressivity and poor clinical prognosis, which is supported by short‐term endpoints, such as biochemical recurrence following surgery. Furthermore, at the histopathological level, mpMRI‐visible tumors appear to exhibit increased architectural and vascular density compared to mpMRI‐invisible disease. It seems probable that the genomic, pathological, radiological, and clinical features of mpMRI‐visible and mpMRI‐invisible prostate cancers are interrelated. Here, we propose a novel cross‐disciplinary theory that links genomic and molecular evidence with cellular and histopathological appearances, elucidating both the mpMRI visibility and clinical status of significant prostate cancer.

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, Take Home Message We report excellent clinical outcomes from one of the largest imaging-based active surveillance cohorts to date. Magnetic resonance imaging (MRI)-visible cancer at baseline, along with 3 + 4 Gleason grade, predicts a greater likelihood of treatment at five years. MRI-visible lesions appear to have a distinct clinical trajectory from less conspicuous ones.

Objective: Technical skills in robot-assisted radical prostatectomy (RARP) are not mandated by the Intercollegiate Surgical Curriculum Programme. The European Association of Urology Robotic Urology Section (ERUS) developed a structured curriculum; however, surgeons’ outcomes data from subsequent independent practice are limited. We describe the initial post-ERUS curriculum RARP outcomes for a United Kingdom (UK)-based surgeon. Patients and methods: This was a prospective single surgeon cohort study of 272 patients who underwent RARP between February 2016 and October 2019 in a high-volume UK centre and who were followed up at approximately 3 and 12 months. Positive surgical margins (PSMs), and 3- and 12-month continence rates were obtained and used to generate learning curves, with point of plateau estimated from logarithmic trendlines. Results: Overall (⩾3 mm) PSM rate for pT2 was 14.9% (5.4%) and pT3 was 22.6% (3.2%). Where data were available, 70.5% (of n=251) and 95.5% (of n=154) patients achieved social continence (0–1 pads) at 3 and 12 months, respectively. PSM and 3-month social continence rates plateaued at ~175 and ~100 cases, respectively. Conclusion: Following completion of the ERUS RARP curriculum, early oncological and functional outcomes consistent with published standards are rapidly achievable in independent practice. These data exemplify the potential value of a standardised RARP training curriculum to mitigate possible compromises in outcomes. Level of evidence: IV

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., Take Home Message The genomic evidence surrounding multiparametric magnetic resonance imaging (mpMRI) visibility is varied and often discordant; however, the literature suggests that tumour mpMRI visibility correlates with aggressive genomic features.

Objective To determine the additional diagnostic value of diffusion-weighted imaging (DWI) and dynamic contrast-enhanced imaging (DCE) in men requiring a repeat biopsy within the PICTURE study. Patients and methods PICTURE was a paired-cohort confirmatory study in which 249 men who required further risk stratification after a previous non-magnetic resonance imaging (MRI)-guided transrectal ultrasonography-guided biopsy underwent a 3-Tesla (3T) multiparametic (mp)MRI consisting of T2-weighted imaging (T2W), DWI and DCE, followed by transperineal template prostate mapping biopsy. Each mpMRI was reported using a LIKERT score in a sequential blinded manner to generate scores for T2W, T2W+DWI and T2W+DWI+DCE. Area under the receiver-operating characteristic curve (AUROC) analysis was performed to compare the diagnostic accuracy of each combination. The threshold for a positive mpMRI was set at a LIKERT score ≥3. Clinically significant prostate cancer was analysed across a range of definitions including UCL/Ahmed definition 1 (primary definition), UCL/Ahmed definition 2, any Gleason ≥3 + 4 and any Gleason ≥4 + 3. Results Of 249 men, sequential MRI reporting was available for 246. There was a higher rate of equivocal lesions (44.6%) using T2W alone compared to the addition of DWI (23.9%) and DCE (19.8%). Using the primary definition of clinically significant disease, there was no significant difference in the overall accuracy between T2W, with an AUROC of 0.74 (95% confidence interval [CI] 0.68-0.80), T2W+DWI at 0.76 (95% CI 0.71-0.82), and T2W+DWI+DCE, with an AUROC of 0.77 (95% CI 0.71-0.82; P = 0.55). The AUROC values remained comparable using other definitions of clinically significant disease including UCL/Ahmed definition 2 (P = 0.79), Gleason ≥3 + 4 (P = 0.53) and Gleason ≥4 + 3 (P = 0.53). Conclusions Using 3T MRI, a high level of diagnostic accuracy can be achieved using T2W as a single parameter in men with a prior biopsy; however, such a strategy can lead to a higher rate of equivocal lesions.

Penile mucosal melanoma is an aggressive and rare genital malignancy. The aim of the present study was to review the management and outcomes of a homogenous cohort of patients with histologically confirmed penile mucosal melanoma, at a single specialist centre. A retrospective review of an institutional database identified patients with penile mucosal melanoma over a 10-year period. Patient demographics, histopathological characteristics, type of primary surgery, recurrence, presence of metastatic disease and molecular markers were evaluated. The management of the patients was initially based on the European Association of Urology (EAU) penile cancer guidelines which are primarily for squamous cell carcinoma with inputs from a melanoma multidisciplinary team. Twelve patients with penile mucosal melanoma were analysed. Median [interquartile range (IQR)] age was 69.5 (67.25-81) years. The overall median follow-up (IQR) was 69.5 (20-114) months, while median follow-up for cancer-specific survival (CSS) was 11.5 (8-37) months. Location of the primary tumour was glans penis (n = 7), urethra (n = 2) and inner prepuce (n = 3). The CSS at 1, 2 and 5 years after primary surgery was 33%, 16.7% and 0%, respectively. The recurrence-free survival at 1, 3 and 5 months after the primary surgery was 90%, 67% and 56%, respectively. All patients with metastatic disease or with inguinal lymph node invasion at presentation, died within 25 months of the primary diagnosis. Management based on the modified EAU penile cancer guidelines still led to poor outcomes. We present a management diagram based on our experience.

INTRODUCTION AND OBJECTIVE: Robot-assisted Radical Prostatectomy (RARP) is an effective cure for organ confined prostate cancer but is associated with considerable post-operative functional toxicity. The NeuroSAFE technique (intra-operative frozen section analysis of the neurovascular structure adjacent margin) may help improve functional outcomes by promoting safe nerve-sparing (NS) RARP without compromising on oncological outcomes. NeuroSAFE technique has reported favourably in retrospective, single-centre studies but has never been evaluated prospectively by a randomised study. The NeuroSAFE PROOF Feasibility Study has succeeded in demonstrating feasibility and has facilitated opening of the full-scale, definitively powered NeuroSAFE Randomized Controlled Trial (RCT) (NCT03317990). We report on the design and progress of the full NeuroSAFE PROOF RCT. METHODS: Potent men (IIEF-5>21) with localised prostate cancer at 4 regional uro-oncology centres in the UK (UCLH, Bristol, Sheffield and Glasgow) are eligible. Participants are randomised 1:1 to RARP with NS decision guided by standard of care (clinical information, DRE and pre-operative mpMRI surgical plan) vs. RARP with NS decision guided by standard of care information and the NeuroSAFE technique. The primary outcome is erectile function recovery assessed by IIEF-5 score >15 at 12-months. Important secondary outcomes include detailed peri-operative outcomes, histological outcomes, post-operative complications, biochemical recurrence rates, urinary continence (assessed by ICIQ), and health related quality of life (assessed by Rand-36 and EQ-5D-5L). Aiming to demonstrate a difference of 15% in erectile function recovery rates between the arms, a total of 404 men will need to be randomised and treated. Patients will continue to be followed for outcomes until 5 years after treatment. RESULTS: At the time of writing, 159 men have been recruited and treated with RARP as per random allocation at the 4 participating sites. The independent DMC has met thrice to ensure the oncological safety of the trial and will continue to review the data at intervals. Covid-19 has led to significant challenges, including suspension of recruitment and difficulties performing follow-up. The trial team have developed new methods of recruitment, consent and follow-up to ensure conduct of the study remains in line with the highest standards of trial conduct. CONCLUSIONS: The NeuroSAFE technique has been reported as a method to optimise outcomes for men undergoing RARP for over a decade, but, in the absence of level 1 evidence, equipoise remains. We hope that our full trial (the first RCT of the NeuroSAFE technique in the world) will provide the evidence to establish whether what has long been a promising technique truly improves outcomes for men undergoing RP.

INTRODUCTION AND OBJECTIVE:Not all significant cancers are detected by multiparametric magnetic resonance imaging (mpMRI), when risk stratifying for suspected prostate cancer in both biopsy-naive m...

Objectives: The aim of this study was to evaluate the changes in lesion volume on serial multiparametric magnetic resonance (mpMRI) during active surveillance for prostate cancer. Methods: A total of 160 patients with a targeted biopsy-confirmed visible lesion on mpMRI, stratified by low- and intermediate-risk disease (Gleason Grade Group 1 vs Gleason Grade Group 2), were analysed. The % change per year was calculated using the formula: [(final volume/initial volume) exp (1/interval between scans in years)]-1. Results: There was no significant difference in the annual median percentage change between Gleason Grade Group 1 (18%) and Gleason Grade Group 2 (23%) disease (p = 0.16), and between ≤ 10% (23%) and > 10% (22%) of Gleason pattern 4 (p = 0.78). Assuming a spherical lesion, these changes corresponded to annual increases in mean tumour diameter of 6% and 7% for Gleason Grade Group 1 and Gleason Grade Group 2 respectively, which may be less than the interscan variability of serial mpMRI. Conclusion: In an active surveillance cohort, we did not see a significant difference in the annual growth rate of Gleason Grade Group 1 and 2 tumours. Advances in knowledge: In patients on active surveillance, the measured growth rates for visible tumours in Gleason Grade Groups 1 and 2 were similar. The annual growth rate was small in most cases and this may have implications for the MRI follow-up interval in active surveillance.

Multiparametric magnetic resonance imaging (mpMRI) has enhanced the risk stratification for men with suspected prostate cancer 1\ud and inevitable implementation challenges around pathway modification, capacity and quality control are well rehearsed. 2\ud Use of pre-biopsy prostate mpMRI is now well-established following publication of multiple Level 1 evidence trials, 1\ud however, views of men undergoing this pathway have not yet been explored, in-depth.

CGM use is associated with improvements in A1c. We hypothesized that initiation of CGM in the 1st month after T1D diagnosis would improve A1c. Youth with newly diagnosed T1D from July 2018 to May 2020 (pilot cohort, n=122) were offered CGM initiation in the 1st month after T1D diagnosis (119 started CGM). We compared A1c outcomes in the pilot cohort with those diagnosed from 2014-2016 (controls, n=272) who were not offered early CGM. We visualized A1c trajectories using locally estimated scatter plot smoothing (Fig). We and assessed for differences in A1c trajectory by cohort via interaction terms in a linear mixed model adjusted for baseline characteristics (age, sex, race and insurance type). The mean A1c at diagnosis was higher in the pilot cohort (12.2 vs. 10.7%). The median age of diagnosis was 9.5 years [6.8, 13.3], 64% male, 38% non-Hispanic White, and 76% with private insurance in the pilot cohort. In this pilot, 89% initiated CGM in the first 30 days after diagnosis compared to 2% in the control cohort. After adjusting for baseline characteristics, the mean A1c of the pilot cohort was lower at 6 months (-0.81, p = 0.019), 9 months (-1.43, p = 0.013), and 12 months (-2.05, p = 0.012) post-diagnosis compared to the historic cohort. Early initiation of CGM was associated with a lower A1c compared to those in a historic cohort. These data support early initiation of CGM as standard of care in youth with T1D. Disclosure P. Prahalad: None. J. Senaldi: None. A. Freeman: None. A. Addala: None. D. P. Zaharieva: None. K. K. Hood: Consultant; Self; Cecelia Health, Cercacor, LifeScan Diabetes Institute. D. Scheinker: Advisory Panel; Self; Carta Healthcare. M. Desai: None. D. M. Maahs: Advisory Panel; Self; Abbott Diabetes, Dompe, Eli Lilly and Company, Medtronic, Novo Nordisk, Consultant; Self; aditxt. V. Ding: None. B. Leverenz: None. J. Hooper: None. A. Chmielewski: None. B. P. Conrad: Advisory Panel; Self; Abbott Diabetes. J. Leverenz: None. A. Martinez-singh: None. P. Sagan: None. Funding National Institutes of Health (R18DK122422, P30DK116074)

Previous studies have shown that CGM use and frequent contact with the care team is associated with improved A1c. We hypothesized that youth with new onset T1D started on CGM with weekly CGM data review by a CDE would have improved outcomes compared to those on CGM alone. Youth with newly diagnosed T1D from 7/2018 to 3/2019 were started on CGM alone (control, n=46) while those from 3/2019 to 5/2020 were started on CGM with weekly data review by a CDE (GluVue, n=76). Dose adjustments were made via secure messaging. We visualized A1c trajectories using locally estimated scatter plot smoothing (Fig) and assessed for differences in A1c trajectory by GluVue status via cohort*time and cohort*time2 interaction terms in a linear mixed model regression adjusted for baseline characteristics (age, sex, race and insurance type). The mean (SD) A1c at diagnosis was 12.0% (1.8) in the control group and 12.3% (2.3) in the GluVue group. Baseline characteristics of control vs. GluVue: male 25% vs. 39%, Non-Hispanic White 41.3% vs. 35.5%, private insurance 80.4% vs. 73.7%. Mean A1c of the GluVue cohort was lower at 6 months (-0.45%), 9 months (-0.07%), and 12 months (-0.52%) post-diagnosis. A1c trajectories were significantly different between groups via regression analysis (p=0.004). Early initiation of CGM with remote monitoring was associated with lower A1c compared to CGM alone. These data support early CGM initiation plus care team contact in youth with T1D. Disclosure P. Prahalad: None. K. K. Hood: Consultant; Self; Cecelia Health, Cercacor, LifeScan Diabetes Institute. D. Scheinker: Advisory Panel; Self; Carta Healthcare. M. Desai: None. D. M. Maahs: Advisory Panel; Self; Abbott Diabetes, Dompe, Eli Lilly and Company, Medtronic, Novo Nordisk, Consultant; Self; aditxt. V. Ding: None. B. Leverenz: None. J. Hooper: None. J. Leverenz: None. P. Sagan: None. A. Martinez-singh: None. A. Freeman: None. D. P. Zaharieva: None. Funding National Institutes of Health (P30DK116074, R18DK122422)

Background and ObjectivesBladder tumours are rare in young patients. Consequently, the literature is sparse and studies provide con-flicting reports on clinicopathological data and patient outcomes. This study examines, to our knowledge, the largest UK series of patients aged less than 40 years diagnosed with bladder cancer, and examines their risks and outcomes.Material and MethodsA prospectively recorded database (2008-2018) was used to identify patients aged under 40 years diagnosed with bladder cancer. Data were retrospectively analyzed. Patients were then sub-divided into 2 groups based on age: group 1 was aged below 20 years and group 2 was aged 20–39 years.ResultsA total of 27 patients were identified with a median age of 34 years (range 14–39). Male to female ratio was 2.86:1. Median follow-up was 41.5 months (range 3–108). 61.9% presented with visible hematuria and 54.2% had one or more risk factors such as cigarette smoking. A total of 96.3% of patients had urothelial carcinoma and 92.3% of these were non-muscle invasive tumours. 7.7% presented with muscle invasive disease with 3.8% having positive nodes at diagnosis. Patients with non-muscle invasive urothelial tumours were risk-stratified according to the EAU-Guidelines Panel risk grouping with 39.1% low-risk, 4.3% intermediate-risk and 56.5% high-risk of recurrence and/or progression. During follow-up 30.4% recurred and 4.3% progressed to invasive disease. 23.1% underwent cystectomy and overall 11.5% died during follow-up, all due to metastatic disease. Patients in group one showed a statistically significant incidence of lower-grade disease at diagnosis with lower risk-group stratification but there was no significant difference in other parameters.ConclusionThe majority of young patients in our series presented with non-muscle invasive urothelial bladder tumours but a significant proportion of these had high-risk disease. Some patients presented with aggressive, muscle invasive bladder cancer and consequently bladder cancer remains an important differential diagnosis in symptomatic patients regardless of age.

Bladder cancer is a heterogeneous group of tumours with at least 40 histological subgroups. Patients with localized disease can be cured with surgical resection or radiotherapy, but such curative options are limited in the setting of recurrent disease or distant spread, in which case systemic therapy is used to control disease and palliate symptoms. Cytotoxic chemotherapy has been the mainstay of treatment for advanced bladder cancer, but high-quality evidence is lacking to inform the management of rare subgroups that are often excluded from studies. Advances in molecular pathology, the development of targeted therapies and the resurgence of immunotherapy have led to the reclassification of bladder cancer subgroups and rigorous efforts to define predictive biomarkers for cancer therapies. In this Review, we present the current evidence for the management of conventional, variant and divergent urothelial cancer subtypes, as well as non-urothelial bladder cancers, and discuss how the integration of genomic, transcriptomic and proteomic characterization of bladder cancer could guide future therapies.

Objective The purpose of this study was: To test whether machine learning classifiers for transition zone (TZ) and peripheral zone (PZ) can correctly classify prostate tumors into those with/without a Gleason 4 component, and to compare the performance of the best performing classifiers against the opinion of three board-certified radiologists. Methods A retrospective analysis of prospectively acquired data was performed at a single center between 2012 and 2015. Inclusion criteria were (i) 3-T mp-MRI compliant with international guidelines, (ii) Likert ≥ 3/5 lesion, (iii) transperineal template ± targeted index lesion biopsy confirming cancer ≥ Gleason 3 + 3. Index lesions from 164 men were analyzed (119 PZ, 45 TZ). Quantitative MRI and clinical features were used and zone-specific machine learning classifiers were constructed. Models were validated using a fivefold cross-validation and a temporally separated patient cohort. Classifier performance was compared against the opinion of three board-certified radiologists. Results The best PZ classifier trained with prostate-specific antigen density, apparent diffusion coefficient (ADC), and maximum enhancement (ME) on DCE-MRI obtained a ROC area under the curve (AUC) of 0.83 following fivefold cross-validation. Diagnostic sensitivity at 50% threshold of specificity was higher for the best PZ model (0.93) when compared with the mean sensitivity of the three radiologists (0.72). The best TZ model used ADC and ME to obtain an AUC of 0.75 following fivefold cross-validation. This achieved higher diagnostic sensitivity at 50% threshold of specificity (0.88) than the mean sensitivity of the three radiologists (0.82). Conclusions Machine learning classifiers predict Gleason pattern 4 in prostate tumors better than radiologists. Key Points • Predictive models developed from quantitative multiparametric magnetic resonance imaging regarding the characterization of prostate cancer grade should be zone-specific. • Classifiers trained differently for peripheral and transition zone can predict a Gleason 4 component with a higher performance than the subjective opinion of experienced radiologists. • Classifiers would be particularly useful in the context of active surveillance, whereby decisions regarding whether to biopsy are necessitated.

OBJECTIVE: To investigate whether patients with Gleason 3 + 4 cancer on transrectal biopsy are upgraded after undergoing transperineal magnetic resonance imaging (MRI)-targeted biopsy and whether this has implications for current clinical practice. PATIENTS AND METHODS: In this retrospective analysis we examined 107 consecutive patients presenting at a single tertiary referral centre (July 2012 to July 2016) with prostate cancer of Gleason score 3 + 4 on transrectal ultrasonography (TRUS)-guided systematic non-targeted biopsy who then underwent a multiparametric MRI followed by MRI-targeted transperineal prostate biopsy for accurate risk stratification and localization. RESULTS: The patients' mean (sd) age was 67.0 (8.0) years, and they had a median (interquartile range) PSA concentration of 6.2 (4.7-9.6) ng/mL. Of the 107 patients, 84 (78.5%) had Gleason 3 + 4 on both transrectal systematic biopsy and transperineal MRI-targeted biopsy. Nineteen patients (17.8%) were upgraded to Gleason 4 + 3, three patients (3.0%) to Gleason 4 + 4 and one patient (1.0%) to Gleason 4 + 5. These differences were significant (P = 0.0006). Likewise, 23/107 patients (22%) had higher-risk disease based on their targeted biopsies. CONCLUSION: The use of targeted biopsy in men with impalpable cancer, ultimately upgraded one in five patients from favourable-intermediate- to unfavourable-intermediate-risk disease or worse. This has significant clinical implications for men considering active surveillance or radical treatment. Our risk calculators must now be validated using these data from targeted biopsy as the technique becomes widely adopted.

We describe the pathological characteristics of recurrence following high intensity focused ultrasound partial ablation in men treated with salvage robot-assisted radical prostatectomy. We assessed the sensitivity of magnetic resonance imaging before salvage robot-assisted radical prostatectomy in these men.A total of 35 men underwent salvage robot-assisted radical prostatectomy after high intensity focused ultrasound partial ablation from 2012 to 2018. We compared clinicopathological characteristics before ultrasound and before salvage prostatectomy after ultrasound to histopathology on salvage prostatectomy. We assessed infield recurrence, out of field disease, positive surgical margins and magnetic resonance imaging sensitivity before salvage robot-assisted radical prostatectomy.Before high intensity focused ultrasound 55.9% of men had multifocal disease and 47.1% had Gleason 3 + 3 disease outside the treatment field. Median time to salvage prostatectomy was 16 months (IQR 11-26). Indications for salvage prostatectomy were infield recurrence in 55.8% of cases, out of field recurrence in 20.6%, and infield and out of field recurrence in 23.5%. On salvage prostatectomy histopathology revealed significant cancer, defined as ISUP (International Society of Urological Pathology) 2 or greater, infield in 97.1% of cases, out of field in 81.3%, and infield and out of field in 79.4%. Of the cases 82.4% were adversely reclassified at salvage prostatectomy compared to 67.6% before ultrasound. The positive surgical margin rate was 40.0%. Of the positive margins 84.6% were in the region of previous ultrasound despite wide excision, including pT2 in 28.6%, pT3 in 47.6% and size 3 mm or greater, pT3 or multifocal (ie significant) in 31.4%. After ultrasound the sensitivity of magnetic resonance imaging for infield and out of field recurrence was 81.8% and 60.7%, respectively.Salvage robot-assisted radical prostatectomy may confer a higher risk of positive surgical margins, upgrading and up-staging than primary robot-assisted radical prostatectomy. High intensity focused ultrasound carries a risk of recurrence inside and outside the ablation zone. This information may inform salvage surgical planning and patient counseling regarding the choice of initial therapy and salvage treatment after high intensity focused ultrasound.

Clinical trials rely on multidisciplinary teams for successful delivery. Pathologists should be involved in clinical trial design from the outset to ensure that protocols are optimised to deliver maximum data collection and translational research opportunities. Clinical trials must be performed according to the principles of Good Clinical Practice (GCP) and the trial sponsor has an obligation to ensure that all of the personnel involved in the trial have undergone training relevant to their role. Pathologists who are involved in the delivery of clinical trials are often required to undergo formal GCP training and may additionally undergo Good Clinical Laboratory Practice training if they are involved in the laboratory analysis of trials samples. Further training can be provided via trial‐specific investigator meetings, which may be either multidisciplinary or discipline‐specific events. Pathologists should also ensure that they undertake External Quality Assurance schemes relevant to the area of diagnostic practice required in the trial. The level of engagement of pathologists in academia and clinical trials research has declined in the United Kingdom over recent years. This paper recommends the optimal training and accreditation for pathologists undertaking clinical trials activities with the aim of facilitating increased engagement. Clinical trials training should ideally be provided to all pathologists through centrally organised educational events, with additional training provided to pathologists in training through local postgraduate teaching. Pathologists in training should also be strongly encouraged to undertake GCP training. It is hoped that these recommendations will increase the number of pathologists who take part in clinical trials research in order to ensure a high level and standard of data collection and to maximise the translational research opportunities.

Background Multiparametric magnetic resonance imaging (mp-MRI) is becoming an increasingly important diagnostic tool for prostate cancer. So far there has been little focus on management for indeterminate mp-MRI results. Objective To describe outcomes for a cohort of men rated as having an indeterminate mp-MRI result. Design, setting, and participants Patients were identified retrospectively from a single UK centre between October 2010 and January 2015. Patients were included if they had a Likert score of 3/5 on a first MRI scan without any prior prostate biopsy. Patients were offered one of two initial management strategies. Strategy 1 was an immediate targeted biopsy of the MRI lesion. Strategy 2 was a surveillance process comprising prostate-specific antigen monitoring and/or mp-MRI at intervals of 6–12 mo, with biopsy on a for-cause basis. Outcome measurements and statistical analysis Cancer detection and treatment outcomes were compared for the two strategies. Results and limitations Of 168 patients, 73 (43%) chose strategy 1 and 95 (57%) chose strategy two. The overall proportion of men with clinically significant cancer detected was 14% (23/168). The risk profile for cancer identified in the initial surveillance group was similar to that identified in the immediate biopsy group. Limitations of the study include the short follow-up. Conclusions Men with indeterminate mp-MRI were willing to forego immediate biopsy for a strategy of surveillance involving PSA measurement and/or mp-MRI repeated at intervals. The risk profile of the cancers identified by both strategies appeared similar, but many men in the surveillance group avoided the risks, complications, and costs of biopsy. Long-term results are awaited. Patient summary This report compares two approaches for an uncertain magnetic resonance imaging result for clinically important prostate cancer: immediate biopsy versus surveillance with delayed biopsy if required. Delayed biopsy did not result in identification of cancer with adverse features, and many men benefited from avoiding a biopsy and its complications.

We evaluated the detection of clinically significant prostate cancer using magnetic resonance imaging targeted biopsies and compared visual estimation to image fusion targeting in patients requiring repeat prostate biopsies.The prospective, ethics committee approved PICTURE trial (ClinicalTrials.gov NCT01492270) enrolled 249 consecutive patients from January 11, 2012 to January 29, 2014. Men underwent multiparametric magnetic resonance imaging and were blinded to the results. All underwent transperineal template prostate mapping biopsies. In 200 men with a lesion this was preceded by visual estimation and image fusion targeted biopsies. As the primary study end point clinically significant prostate cancer was defined as Gleason 4 + 3 or greater and/or any grade of cancer with a length of 6 mm or greater. Other definitions of clinically significant prostate cancer were also evaluated.Mean ± SD patient age was 62.6 ± 7 years, median prostate specific antigen was 7.17 ng/ml (IQR 5.25-10.09), mean primary lesion size was 0.37 ± 1.52 cc with a mean of 4.3 ± 2.3 targeted cores per lesion on visual estimation and image fusion combined, and a mean of 48.7 ± 12.3 transperineal template prostate mapping biopsy cores. Transperineal template prostate mapping biopsies detected 97 clinically significant prostate cancers (48.5%) and 85 insignificant cancers (42.5%). Overall multiparametric magnetic resonance imaging targeted biopsies detected 81 clinically significant prostate cancers (40.5%) and 63 insignificant cancers (31.5%). In the 18 cases (9%) of clinically significant prostate cancer on magnetic resonance imaging targeted biopsies were benign or clinically insignificant on transperineal template prostate mapping biopsy. Clinically significant prostate cancer was detected in 34 cases (17%) on transperineal template prostate mapping biopsy but not on magnetic resonance imaging targeted biopsies and approximately half was present in nontargeted areas. Clinically significant prostate cancer was found on visual estimation and image fusion in 53 (31.3%) and 48 (28.4%) of the 169 patients (McNemar test p = 0.5322). Visual estimation missed 23 clinically significant prostate cancers (13.6%) detected by image fusion. Image fusion missed 18 clinically significant prostate cancers (10.8%) detected by visual estimation.Magnetic resonance imaging targeted biopsies are accurate for detecting clinically significant prostate cancer and reducing the over diagnosis of insignificant cancers. To maximize detection visual estimation as well as image fusion targeted biopsies are required.

IntroductionThere 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 analysisPubMed, 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 disseminationThere are no relevant ethical concerns. Dissemination of this protocol will be via peer-reviewed journals as well as national and international conferences.PROSPERO registration numberCRD42020206074.

Introduction The implications of tumour location on mpMRI conspicuity are not fully understood. Identifying topographical correlates that influence conspicuity may improve outcomes. Here, we present the first systematic review and meta-analysis describing the effect of tumour location on prostate cancer conspicuity on mpMRI. Methods Medline, PubMed, EMBASE and Cochrane databases were systematically searched and results were assessed as per the PRISMA statement. Differential tumour conspicuity on mpMRI was compared between cancers in the peripheral zone (PZ), transitional zone (TZ), base, apex, anterior and posterior. Meta-analysis was conducted to compare diagnostic odds ratios (DOR) of mpMRI detection for tumours in the PZ and TZ. PROSPERO registration: CRD42021228087. Results Thematic synthesis showed apical and basal tumours had reduced conspicuity compared to mid-gland tumours. Cancer in the TZ demonstrated increased conspicuity on T2-weighted imaging, whilst PZ cancers had higher conspicuity on diffusion-weighted and dynamic contrast enhancement imaging. mpMRI had better diagnostic accuracy for PZ lesions, albeit higher specificity for TZ lesions. Meta-analysis showed an increased DOR for PZ tumours (OR: 7.206 [95% CI: 4.991;10.403], compared to TZ (OR: 5.310 [95% CI: 3.082; 9.151]). However, the test for subgroup differences was not significant (p = 0.2743). Conclusions Cancer in the apex or base of the prostate may be less conspicuous than mid-gland tumours. Similarly, TZ cancer appears to have reduced conspicuity compared to PZ cancer, however, meta-analysis did not show a significant difference between DOR. Future larger studies with prospective datasets are required to clarify the relationship between tumour position and conspicuity.

Objectives: To assess the clinical outcomes of mpMRI before biopsy and evaluate the space remaining for novel biomarkers. Methods: The INNOVATE study was set up to evaluate the validity of novel fluidic biomarkers in men with suspected prostate cancer who undergo pre-biopsy mpMRI. We report the characteristics of this clinical cohort, the distribution of clinical serum biomarkers, PSA and PSA density (PSAD), and compare the mpMRI Likert scoring system to the Prostate Imaging–Reporting and Data System v2.1 (PI-RADS) in men undergoing biopsy. Results: 340 men underwent mpMRI to evaluate suspected prostate cancer. 193/340 (57%) men had subsequent MRI-targeted prostate biopsy. Clinically significant prostate cancer (csigPCa), i.e., overall Gleason ≥ 3 + 4 of any length OR maximum cancer core length (MCCL) ≥4 mm of any grade including any 3 + 3, was found in 96/195 (49%) of biopsied patients. Median PSA (and PSAD) was 4.7 (0.20), 8.0 (0.17), and 9.7 (0.31) ng/mL (ng/mL/mL) in mpMRI scored Likert 3,4,5 respectively for men with csigPCa on biopsy. The space for novel biomarkers was shown to be within the group of men with mpMRI scored Likert3 (178/340) and 4 (70/350), in whom an additional of 40% (70/178) men with mpMRI-scored Likert3, and 37% (26/70) Likert4 could have been spared biopsy. PSAD is already considered clinically in this cohort to risk stratify patients for biopsy, despite this 67% (55/82) of men with mpMRI-scored Likert3, and 55% (36/65) Likert4, who underwent prostate biopsy had a PSAD below a clinical threshold of 0.15 (or 0.12 for men aged &lt, 50 years). Different thresholds of PSA and PSAD were assessed in mpMRI-scored Likert4 to predict csigPCa on biopsy, to achieve false negative levels of ≤5% the proportion of patients whom who test as above the threshold were unsuitably high at 86 and 92% of patients for PSAD and PSA respectively. When PSA was re tested in a sub cohort of men repeated PSAD showed its poor reproducibility with 43% (41/95) of patients being reclassified. After PI-RADS rescoring of the biopsied lesions, 66% (54/82) of the Likert3 lesions received a different PI-RADS score. Conclusions: The addition of simple biochemical and radiological markers (Likert and PSAD) facilitate the streamlining of the mpMRI-diagnostic pathway for suspected prostate cancer but there remains scope for improvement, in the introduction of novel biomarkers for risk assessment in Likert3 and 4 patients, future application of novel biomarkers tested in a Likert cohort would also require re-optimization around Likert3/PI-RADS2, as well as reproducibility testing.

Cribriform, from the Latin for 'sieve-like,' describes an aggressive prostate cancer pattern associated with poor prognosis, including biochemical recurrence after prostatectomy [1]. Following progressive integration of multiparametric magnetic resonance imaging (mpMRI) into risk stratification for suspected prostate cancer, there has been understandable concern that particular morphologies (including, intraductal, mucinous and cribriform) may have reduced visibility on mpMRI [2]. If undetected, mpMRI-invisible pathology may avoid biopsy interrogation, resulting in delayed presentation, management, and adverse clinical outcome. However, evidence surrounding mpMRI conspicuity of cribriform disease is contradictory, and given the clinical importance of this phenomenon, warrants discussion.

International audience; Senescent cells accumulate with age in all tissues. Although senescent cells undergo cell-cycle arrest, these cells remain metabolically active and their secretomeknown as senescence-associated secretory phenotype (SASP)-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 SASP and can be linked to benign prostatic hyperplasia 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 targetting in the future.

Background\ud Predict Prostate is a freely available online personalised risk communication tool for men with nonmetastatic prostate cancer. Its accuracy has been assessed in multiple validation studies, but its clinical impact among patients has not hitherto been assessed.\ud \ud Objective\ud To assess the impact of the tool on patient decision-making and disease perception.\ud \ud Design, setting, and participants\ud A multicentre randomised controlled trial was performed across eight UK centres among newly diagnosed men considering either active surveillance or radical treatment. A total of 145 patients were included between 2018 and 2020, with median age 67 yr (interquartile range [IQR] 61–72) and prostate-specific antigen 6.8 ng/ml (IQR 5.1–8.8).\ud \ud Intervention\ud Participants were randomised to either standard of care (SOC) information or SOC and a structured presentation of the Predict Prostate tool.\ud \ud Outcome measurements and statistical analysis\ud Validated questionnaires were completed by assessing the impact of the tool on decisional conflict, uncertainty, anxiety, and perception of survival.\ud \ud Results and limitations\ud Mean Decisional Conflict Scale scores were 26% lower in the Predict Prostate group (mean = 16.1) than in the SOC group (mean = 21.7; p = 0.027). Scores on the “support”, “uncertainty”, and “value clarity” subscales all favoured Predict Prostate (all p < 0.05). There was no significant difference in anxiety scores or final treatment selection between the two groups. Patient perception of 15-yr prostate cancer–specific mortality (PCSM) and overall survival benefit from radical treatment were considerably lower and more accurate among men in the Predict Prostate group (p < 0.001). In total, 57% of men reported that the Predict Prostate estimates for PCSM were lower than expected, and 36% reported being less likely to select radical treatment. Over 90% of patients in the intervention group found it useful and 94% would recommend it to others.\ud \ud Conclusions\ud Predict Prostate reduces decisional conflict and uncertainty, and shifts patient perception around prognosis to be more realistic. This randomised trial demonstrates that Predict Prostate can directly inform the complex decision-making process in prostate cancer and is felt to be useful by patients. Future larger trials are warranted to test its impact upon final treatment decisions.\ud \ud Patient summary\ud In this national study, we assessed the impact of an individualised risk communication tool, called Predict Prostate, on patient decision-making after a diagnosis of localised prostate cancer. Men were randomly assigned to two groups, which received either standard counselling and information, or this in addition to a structured presentation of the Predict Prostate tool. Men who saw the tool were less conflicted and uncertain in their decision-making, and recommended the tool highly. Those who saw the tool had more realistic perception about their long-term survival and the potential impact of treatment upon this.\ud \ud Take Home Message\ud The use of an individualised risk communication tool, such as Predict Prostate, reduces patient decisional conflict and uncertainty when deciding about treatment for nonmetastatic prostate cancer. The tool leads to more realistic perceptions about survival outcomes and prognosis.

Background Multiparametric magnetic resonance imaging (mpMRI) has improved risk stratification for suspected prostate cancer in patients following prior biopsy. However, not all significant cancers are detected by mpMRI. The PICTURE study provides the ideal opportunity to investigate cancer undetected by mpMRI owing to the use of 5 mm transperineal template mapping (TTPM) biopsy. Objective To summarise attributes of cancers systematically undetected by mpMRI in patients with prior biopsy. Design, setting, and participants PICTURE was a paired-cohort confirmatory study in which men requiring repeat biopsy underwent mpMRI followed by TTPM biopsy. Outcome measurements and statistical analysis Attributes were compared between cancers detected and undetected by mpMRI at the patient level. Four predefined histopathological thresholds were used as the target condition for TTPM biopsy. Application of prostate-specific antigen density (PSAD) was explored. Results and limitations When nonsuspicious mpMRI was defined as Likert score 1–2, 2.9% of patients (3/103; 95% confidence interval [CI] 0.6–8.3%) with definition 1 disease (Gleason ≥ 4 + 3 of any length or maximum cancer core length [MCCL] ≥ 6 mm of any grade) had their cancer not detected by mpMRI. This proportion was 6.5% (11/168; 95% CI 3.3–11%) for definition 2 disease (Gleason ≥ 3 + 4 of any length or MCCL ≥ 4 mm of any grade), 4.8% (7/146; 95% CI 2.0–9.6%) for any amount of Gleason ≥ 3 + 4 cancer, and 9.3% (20/215; 95% CI 5.8–14%) for any cancer. Definition 1 cancers undetected by mpMRI had lower overall Gleason score (p = 0.02) and maximum Gleason score (p = 0.01) compared to cancers detected by mpMRI. Prostate cancers undetected by mpMRI had shorter MCCL than cancers detected by mpMRI for every cancer threshold: definition 1, 6 versus 8 mm (p = 0.02); definition 2, 5 versus 6 mm (p = 0.04); any Gleason ≥ 3 + 4, 5 versus 6 mm (p = 0.03); and any cancer, 3 versus 5 mm (p = 0.0009). A theoretical PSAD threshold of 0.15 ng/ml/ml reduced the proportion of patients with undetected disease on nonsuspicious mpMRI to 0% (0/105; 95% CI 0–3.5%) for definition 1, 0.58% (1/171; 95% CI 0.01–3.2%) for definition 2, and 0% (0/146) for any Gleason ≥ 3 + 4. Conclusions Few significant cancers are undetected by mpMRI in patients requiring repeat prostate biopsy. Undetected tumours are of lower overall and maximum Gleason grade and shorter cancer length compared to cancers detected by mpMRI. Patient summary In patients with a previous prostate biopsy, magnetic resonance imaging (MRI) overlooks few prostate cancers, and these tend to be smaller and less aggressive than cancer that is detected., Take Home Message In men with previous prostate biopsy, few prostate cancers are not detected by multiparametric magnetic resonance imaging (mpMRI), and these are lower in size and grade than prostate cancer that is detected by mpMRI. This further reinforces the role that mpMRI should play in assessment of suspected prostate cancer.

PIM and PI3K/mTOR pathways are often dysregulated in prostate cancer, and may lead to decreased survival, increased metastasis and invasion. The pathways are heavily interconnected and act on a variety of common effectors that can lead to the development of resistance to drug inhibitors. Most current treatments exhibit issues with toxicity and resistance. We investigated the novel multikinase PIM/PI3K/mTOR inhibitor, AUM302, versus a combination of the PIM inhibitor, AZD-1208, and the PI3K/mTOR inhibitor BEZ235 (Dactolisib) to determine their impact on mRNA and phosphoprotein expression, as well as their functional efficacy. We have determined that around 20% of prostate cancer patients overexpress the direct targets of these drugs, and this cohort are more likely to have a high Gleason grade tumour (≥ Gleason 8). A co-targeted inhibition approach offered broader inhibition of genes and phosphoproteins in the PI3K/mTOR pathway, when compared to single kinase inhibition. The preclinical inhibitor AUM302, used at a lower dose, elicited a comparable or superior functional outcome compared with combined AZD-1208 + BEZ235, which have been investigated in clinical trials, and could help to reduce treatment toxicity in future trials. We believe that a co-targeting approach is a viable therapeutic strategy that should be developed further in pre-clinical studies.

Background The pathogenesis of male genital lichen sclerosus (MGLSc) is controversial. Incriminated factors include infection with human papillomavirus (HPV) and autoimmunity (e.g. Human Leukocyte Antigen [HLA]). To address the roles of HLA and HPV in MGLSc we studied adult Caucasian males with a clinical and histological diagnosis of MGLSc. The men in the study attended two specialised Male Genital Dermatoses Clinics between July 2011 and September 2012 and were selected and phenotyped from the clinical records. DNA was extracted from blood and paraffin-embedded biopsy sections, for HLA and HPV typing, respectively. HLA allele frequencies were compared with those derived from the UK-based Caucasian population. Eighty-eight cases of MGLSc were identified. HPV DNA was detected in 33/88 (37.5%) cases of MGLSc. HPV16 was the most prevalent type found: 11/88 (12.5%) MGLSc. No statistically significant HLA associations were established but HLA-B*35, -B*51, -C*15, -DRB1*04, -DRB1*10 (predisposition) and -DQA1*01 (protection) were revealed as alleles of interest. HPV16-associated MGLSc cases showed no statistically significant association with HLA genotype. The relationship between HPV and MGLSc suggests a passenger effect rather than a pathogenic role. HLA is not associated with MGLSc nor co-existent HPV16.

Gleason score 7 prostate cancer with a higher proportion of pattern 4 (G4) has been linked to genomic heterogeneity and poorer patient outcome. The current assessment of G4 proportion uses estimation by a pathologist, with a higher proportion of G4 more likely to trigger additional imaging and treatment over active surveillance. This estimation method has been shown to have inter-observer variability. Fifteen patients with Prostate Grade Group (GG) 2 (Gleason 3 + 4) and fifteen patients with GG3 (Gleason 4 + 3) disease were selected from the PROMIS study with 192 haematoxylin and eosin-stained slides scanned. Two experienced uropathologists assessed the maximum cancer core length (MCCL) and G4 proportion using the current standard method (visual estimation) followed by detailed digital manual annotation of each G4 area and measurement of MCCL (planimetric estimation) using freely available software by the same two experts. We aimed to compare visual estimation of G4 and MCCL to a pathologist-driven digital measurement. We show that the visual and digital MCCL measurement differs up to 2 mm in 76.6% (23/30) with a high degree of agreement between the two measurements; Visual gave a median MCCL of 10 ± 2.70 mm (IQR 4, range 5–15 mm) compared to digital of 9.88 ± 3.09 mm (IQR 3.82, range 5.01–15.7 mm) (p = 0.64) The visual method for assessing G4 proportion over-estimates in all patients, compared to digital measurements [median 11.2% (IQR 38.75, range 4.7–17.9%) vs 30.4% (IQR 18.37, range 12.9–50.76%)]. The discordance was higher as the amount of G4 increased (Bias 18.71, CI 33.87–48.75, r 0.7, p

PIM and PI3K/mTOR pathways are often dysregulated in prostate cancer, and may lead to decreased survival, increased metastasis and invasion. The pathways are heavily interconnected and act on a variety of common effectors that can lead to the development of resistance to drug inhibitors. Most current treatments exhibit issues with toxicity and resistance. We investigated the novel multikinase PIM/PI3K/mTOR inhibitor, AUM302, versus a combination of the PIM inhibitor, AZD-1208, and the PI3K/mTOR inhibitor BEZ235 (Dactolisib) to determine their impact on mRNA and phosphoprotein expression, as well as their functional efficacy. We have determined that around 20% of prostate cancer patients overexpress the direct targets of these drugs, and this cohort are more likely to have a high Gleason grade tumour (≥ Gleason 8). A co-targeted inhibition approach offered broader inhibition of genes and phosphoproteins in the PI3K/mTOR pathway, when compared to single kinase inhibition. The preclinical inhibitor AUM302, used at a lower dose, elicited a comparable or superior functional outcome compared with combined AZD-1208 + BEZ235, which have been investigated in clinical trials, and could help to reduce treatment toxicity in future trials. We believe that a co-targeting approach is a viable therapeutic strategy that should be developed further in pre-clinical studies.