The prevalence of human leucocyte antigen and human papillomavirus DNA in penile intraepithelial neoplasia in England 2011-2012.

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.

Primary Squamous Cell Carcinoma of the Male Proximal Urethra: Outcomes from a Single Centre.

BACKGROUND: Primary squamous cell carcinoma (SCC) of the male proximal urethra is an aggressive and rare urogenital malignancy. OBJECTIVE: To review the surgical management and outcomes for male proximal urethral SCCs within a single centre and to suggest an algorithm for the surgical management of these rare tumours. DESIGN, SETTING, AND PARTICIPANTS: This was a retrospective study of patients undergoing surgery for male proximal urethral SCC within a single tertiary academic centre managing rare genital tumours. Ten patients with a histological diagnosis of proximal urethral SCC were identified from an institutional database over a period of 10 yr with a median follow-up of 22.5 mo (standard deviation±25.77 mo). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Pathological staging, surgical treatment, and neoadjuvant and adjuvant treatment were recorded. Complications according to the Clavien-Dindo classification and overall survival rates were recorded. Kaplan-Meier curves were used for overall survival. RESULTS AND LIMITATIONS: A total of 10 patients were identified of whom eight underwent panurethrectomy and radical prostatectomy. Radical inguinal lymphadenectomy was performed in five patients, which confirmed bilateral metastatic disease. Perioperative complications were reported in six patients (Clavien I and II). Within 6 mo of surgery, 90% of patients developed distant metastatic disease. Nine patients died of urethra cancer during the follow-up. One patient is still on follow-up. The median overall follow-up was 13.92 mo (range: 5-91 mo). At 5 yr, cancer-specific/overall survival was 10%. A limitation of this study is the retrospective design, which is unavoidable for such a rare disease. CONCLUSIONS: Radical surgery allows local disease control, but despite neo/adjuvant treatment, proximal urethral SCC is associated with poor survival outcomes and progression to distant metastatic disease within 6 mo. PATIENT SUMMARY: Proximal urethral squamous cell carcinoma is a rare cancer in men which is often detected late. Patients often present with problems such as voiding, urethral bleeding, or a palpable mass. Aggressive surgery allows local control, but despite this the overall survival is poor. Adjuvant and neoadjuvant radiochemotherapy can improve survival. Multicentric randomised trials are needed to identify the correct treatment modality.

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.

Author Correction: Co-targeting PIM and PI3K/mTOR using multikinase inhibitor AUM302 and a combination of AZD-1208 and BEZ235 in prostate cancer.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Immunogenetics and human papillomavirus (HPV) in male genital lichen sclerosus (MGLSc).

BackgroundThe 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.

Co-targeting PIM and PI3K/mTOR using multikinase inhibitor AUM302 and a combination of AZD-1208 and BEZ235 in 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.

Additional Value of Dynamic Contrast-enhanced Sequences in Multiparametric Prostate Magnetic Resonance Imaging: Data from the PROMIS Study.

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-naïve 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.

A Multicentre Analysis of the Detection of Clinically Significant Prostate Cancer Following Transperineal Image-fusion Targeted and Nontargeted Systematic Prostate Biopsy in Men at Risk.

BACKGROUND: Prostate biopsy guided by magnetic resonance imaging (MRI) is increasingly used to obtain tissue from men with suspected prostate cancer (PC). OBJECTIVE: To report a multicentre series of image-fusion transperineal prostate biopsies and compare the diagnostic yield of clinically significant PC (csPC) between targeted and nontargeted biopsies. DESIGN, SETTING, AND PARTICIPANTS: The study included 640 consecutive patients with elevated prostate specific antigen (PSA) presenting for first biopsy or following a previous negative transrectal biopsy under the care of 13 urologists in 11 centres in the UK (April 2014-June 2017). INTERVENTION: Multiparametric MRI was carried out in 61 approved prostate MRI centres with transperineal targeted alone (n=283) or targeted plus nontargeted (n=357) transperineal rigid image-fusion targeted biopsy (MIM-Symphony-DX). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Rates of csPC and insignificant cancer detection in targeted and nontargeted biopsies were measured using a number of thresholds to define clinical significance. The primary definition was Gleason≥4+3 or any grade ≥6mm. RESULTS AND LIMITATIONS: The mean age, median PSA, and median prostate volume for the cohort were 63.8yr (standard deviation [SD] 8.4), 6.3 ng/ml (SD 5.8), and 42.0cm3 (SD 24.7), respectively. Overall, 276/640 men (43.1%) were diagnosed with csPC. csPC was detected from targeted biopsies alone in 263/640 cases (41.1%). Of the 357 men who underwent nontargeted biopsies, three (0.8%) had csPC exclusively in nontargeted cores, with no evidence of cancer in targeted cores. Overall, 32/357 (9.0%) had csPC in nontargeted biopsies regardless of the targeted biopsy findings. Clinically insignificant disease in nontargeted biopsies was detected in 93/357 men (26.1%). Our findings were consistent across all other thresholds of clinical significance. Limitations include the lack of nontargeted biopsies in all men. CONCLUSIONS: In this large multicentre series, nontargeted prostate biopsy cores had a low yield of csPC and a high yield of clinically insignificant PC. An image-fusion targeted-biopsy-only approach maintains high detection for csPC and low detection of clinically insignificant cancers. PATIENT SUMMARY: In this report, we found that following prostate multiparametric magnetic resonance imaging and targeted transperineal biopsies of suspicious areas, the clinical value of performing additional extensive unguided biopsies of nonsuspicious areas is limited and can often find insignificant cancers that do not need treatment.

Targeted biopsy of the prostate: does this result in improvement in detection of high-grade cancer or the occurrence of the Will Rogers phenomenon?

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.

Medium-term oncological outcomes in a large cohort of men treated with either focal or hemi-ablation using high-intensity focused ultrasonography for primary localized prostate cancer.

OBJECTIVE: To report medium-term oncological outcomes in men receiving primary focal treatment with high-intensity focused ultrasonography ( HIFU) for prostate cancer (PCa). PATIENTS AND METHODS: Consecutive patients with PCa treated with primary focal HIFU at two centres by six treating clinicians were assessed. Patients were submitted to either focal ablation or hemi-ablation using HIFU (Sonablate 500). The primary objective of the study was to assess medium-term oncological outcomes, defined as overall survival, freedom from biopsy failure, freedom from any further treatment and freedom from radical treatment after focal HIFU. The secondary objective was to evaluate the changes in pathological features among patients treated with focal HIFU over time. We also assessed the relationship between year of surgery and 5-year retreatment probability. RESULTS: A total of 1032 men treated between November 2005 and October 2017 were assessed. The median age was 65 years and median prostate-specific antigen level was 7 ng/mL. The majority of patients had a Gleason score of 3 + 4 or above (80.3%). The median (interquartile range) follow-up was 36 (14-64) months. The overall survival rates at 24, 60 and 96 months were 99%, 97% and 97%, respectively. Freedom from biopsy failure, defined as absence of Gleason 3 + 4 disease, was 84%, 64% and 54% at 24, 60 and 96 months. Freedom from any further treatment was 85%, 59% and 46% at 24, 60 and 96 months, respectively. Approximately 70% of patients who were retreated received a second focal treatment. Freedom from radical treatment was 98%, 91% and 81% at 24, 60 and 96 months. During the study period, we observed an increase in the proportion of patients undergoing focal HIFU with Gleason 3 + 4 disease and with T2 stage disease as defined by multiparametric magnetic resonance imaging. Finally, there was a reduction over time in the proportion of patients undergoing re-treatment within 5 years of first treatment. CONCLUSIONS: Focal HIFU for PCa is a feasible therapeutic strategy, with acceptable survival and oncological results and a reduction in the 5-year retreatment rates over the last decade. Re-do focal treatment is a feasible technique whose functional and oncological outcomes have still to be evaluated.

PEOPLE: PatiEnt prOstate samPLes for rEsearch, a tissue collection pathway utilizing magnetic resonance imaging data to target tumor and benign tissue in fresh radical prostatectomy specimens.

BACKGROUND: Over 1 million men are diagnosed with prostate cancer each year worldwide, with a wide range of research programs requiring access to patient tissue samples for development of improved diagnoses and treatments. A random sampling of prostate tissue is sufficient for certain research studies; however, there is growing research need to target areas of the aggressive tumor as fresh tissue. Here we set out to develop a new pathway "PEOPLE: PatiEnt prOstate samPLes for rEsearch" to collect high-quality fresh tissue for research use, using magnetic resonance imaging (MRI) to target areas of tumor and benign tissue. METHODS: Prostate tissue was sampled following robotic radical prostatectomy, using MRI data to target areas of benign and tumor tissue. Initially, 25 cases were sampled using MRI information from clinical notes. A further 59 cases were sampled using an optimized method that included specific MRI measurements of tumor location along with additional exclusion criteria. All cases were reviewed in batches with detailed clinical and histopathological data recorded. For one subset of samples, DNA was extracted and underwent quality control. Ex vivo culture was carried out using the gelatin sponge method for an additional subset. RESULTS: Tumor was successfully fully or partially targeted in 64% of the initial cohort and 70% of the optimized cohort. DNA of high quality and concentration was isolated from 39 tumor samples, and ex vivo culture was successfully carried out in three cases with tissue morphology, proliferation, and apoptosis remaining comparable before and after 72 hours culture. CONCLUSION: Here we report initial data from the PEOPLE pathway; using a method for targeting areas of tumor within prostate samples using MRI. This method operates alongside the standard clinical pathway and minimizes additional input from surgical, radiological, and pathological teams, while preserving surgical margins and diagnostic tissue.

Prostate Imaging Compared to Transperineal Ultrasound-guided biopsy for significant prostate cancer Risk Evaluation (PICTURE): a prospective cohort validating study assessing Prostate HistoScanning.

BACKGROUND: Men with negative prostate biopsies or those diagnosed with low-risk or low-volume intermediate-risk prostate cancers often require a second prostate biopsy prior to a treatment decision. Prostate HistoScanning (PHS) is an ultrasound imaging test that might inform prostate biopsy in such men. METHODS: PICTURE was a prospective, paired-cohort validating trial to assess the diagnostic accuracy of imaging in men requiring a further biopsy (clinicaltrials.gov, NCT01492270) (11 January 2012-29 January 2014). We enrolled 330 men who had undergone a prior TRUS biopsy but where diagnostic uncertainty remained. All eligible men underwent PHS and transperineal template prostate mapping (TTPM) biopsy (reference standard). Men were blinded to the imaging results until after undergoing TTPM biopsies. We primarily assessed the ability of PHS to rule out clinically significant prostate (negative predictive value [NPV] and sensitivity) for a target histological condition of Gleason ≥4+3 and/or a cancer core length (MCCL) ≥6 mm. We also assessed the role of visually estimated PHS-targeted biopsies. RESULTS: Of the 330 men enrolled, 249 underwent both PHS and TTPM biopsy. Mean (SD) age was 62 (7) years, median (IQR) PSA 6.8 (4.98-9.50) ng/ml, median (IQR) number of previous biopsies 1 (1-2) and mean (SD) gland size 37 (15.5) ml. One hundred and forty six (59%) had no clinically significant cancer. PHS classified 174 (70%) as suspicious. Sensitivity was 70.3% (95% CI 59.8-79.5) and NPV 41.3% (95% CI 27.0-56.8). Specificity and positive predictive value (PPV) were 14.7% (95% CI 9.1-22.0) and 36.8% (95% CI 29.6-44.4), respectively. In all, 213/220 had PHS suspicious areas targeted with targeting sensitivity 13.6% (95% CI 7.3-22.6), specificity 97.6% (95% CI 93.1-99.5), NPV 61.6% (95% CI 54.5-68.4) and PPV 80.0% (95% CI 51.9-95.7). CONCLUSIONS: PHS is not a useful test in men seeking risk stratification following initial prostate biopsy.

Prostate cancer diagnostic pathway: Is a one-stop cognitive MRI targeted biopsy service a realistic goal in everyday practice? A pilot cohort in a tertiary referral centre in the UK.

OBJECTIVES: To evaluate the feasibility of a novel multiparametric MRI (mpMRI) and cognitive fusion transperineal targeted biopsy (MRTB) led prostate cancer (PCa) diagnostic service with regard to cancer detection and reducing time to diagnosis and treatment. DESIGN: Consecutive men being investigated for possible PCa under the UK 2-week wait guidelines. SETTING: Tertiary referral centre for PCa in the UK. PARTICIPANTS: Men referred with a raised prostate-specific antigen (PSA) or abnormal digital rectal examination between February 2015 and March 2016 under the UK 2-week rule guideline. INTERVENTIONS: An mpMRI was performed prior to patients attending clinic, on the same day. If required, MRTB was offered. Results were available within 48 hours and discussed at a specialist multidisciplinary team meeting. Patients returned for counselling within 7 days PRIMARY AND SECONDARY OUTCOME MEASURES: Outcome measures in this regard included the time to diagnosis and treatment of patients referred with a suspicion of PCa. Quality control outcome measures included clinically significant and total cancer detection rates. RESULTS: 112 men were referred to the service. 111 (99.1%) underwent mpMRI. Median PSA was 9.4 ng/mL (IQR 5.6-21.0). 87 patients had a target on mpMRI with 25 scoring Likert 3/5 for likelihood of disease, 26 4/5 and 36 5/5.57 (51%) patients received a local anaesthetic, Magnetic resonance imaging targeted biopsy (MRTB). Cancer was detected in 45 (79%). 43 (96%) had University College London definition 2 disease or greater. The times to diagnosis and treatment were a median of 8 and 20 days, respectively. CONCLUSIONS: This approach greatly reduces the time to diagnosis and treatment. Detection rates of significant cancer are high. Similar services may be valuable to patients with a potential diagnosis of PCa.

Immunohistochemical biomarker validation in highly selective needle biopsy microarrays derived from mpMRI-characterized prostates.

INTRODUCTION: Diagnosing prostate cancer routinely involves tissue biopsy and increasingly image guided biopsy using multiparametric MRI (mpMRI). Excess tissue after diagnosis can be used for research to improve the diagnostic pathway and the vertical assembly of prostate needle biopsy cores into tissue microarrays (TMAs) allows the parallel immunohistochemical (IHC) validation of cancer biomarkers in routine diagnostic specimens. However, tissue within a biopsy core is often heterogeneous and cancer is not uniformly present, resulting in needle biopsy TMAs that suffer from highly variable cancer detection rates that complicate parallel biomarker validation. MATERIALS AND METHODS: The prostate cores with the highest tumor burden (in terms of Gleason score and/or maximum cancer core length) were obtained from 249 patients in the PICTURE trial who underwent transperineal template prostate mapping (TPM) biopsy at 5 mm intervals preceded by mpMRI. From each core, 2 mm segments containing tumor or benign tissue (as assessed on H&E pathology) were selected, excised and embedded vertically into a new TMA block. TMA sections were then IHC-stained for the routinely used prostate cancer biomarkers PSA, PSMA, AMACR, p63, and MSMB and assessed using the h-score method. H-scores in patient matched malignant and benign tissue were correlated with the Gleason grade of the original core and the MRI Likert score for the sampled prostate area. RESULTS: A total of 2240 TMA cores were stained and IHC h-scores were assigned to 1790. There was a statistically significant difference in h-scores between patient matched malignant and adjacent benign tissue that is independent of Likert score. There was no association between the h-scores and Gleason grade or Likert score within each of the benign or malignant groups. CONCLUSION: The construction of highly selective TMAs from prostate needle biopsy cores is possible. IHC data obtained through this method are highly reliable and can be correlated with imaging. IHC expression patterns for PSA, PSMA, AMACR, p63, and MSMB are distinct in malignant and adjacent benign tissue but did not correlate with mpMRI Likert score.

Accuracy of Transperineal Targeted Prostate Biopsies, Visual Estimation and Image Fusion in Men Needing Repeat Biopsy in the PICTURE Trial.

PURPOSE: 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. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Predictive factors for local recurrence after glansectomy and neoglans reconstruction for penile squamous cell carcinoma.

OBJECTIVES: To investigate predictive pathological factors for local recurrence (LR) after glansectomy for penile squamous cell carcinoma (SCC) and to develop a risk score for prediction of LR after glansectomy. PATIENTS AND METHODS: In this retrospective study, we analyzed 117 patients operated between February 2005 and January 2016 in a supraregional penile cancer center in the UK for LR after glansectomy and glans reconstruction. Univariate and multivariate Cox proportional hazards regression was used to identify 4 prognostic indicators for LR. The hazard ratio (HR) of LR was estimated in Kaplan-Meier analysis, and based on these data, we designed a postoperative model for prediction of LR based on 3 risk groups. RESULTS: Median follow-up period was 33.7 (95% CI: 26.8-40.3) months; 12.8% of the patients experienced LR. Univariate Cox proportional hazards regression revealed that the risk factors for recurrence were the presence of perineural invasion, carcinoma in situ, positive margin on definitive pathology, and high-grade disease. Based on Kaplan-Meier analysis stratified by number of factors present, we defined 3 risk groups for LR: low (0,1 risk factors) as reference, intermediate (2,3 risk factors) with HR of 13.9 (95% CI: 1.81-107.04, P = 0.0115), or high risk (all 4 risk factors present) with a HR of 34.2 (95% CI: 3.07-381.81, P = 0,0041). Limitations include the retrospective design and low number of events inherent to the rare nature of penile SCC. CONCLUSIONS: Perineural invasion, carcinoma in situ, positive definitive margins, and the presence of high-grade SCC predict LR following glansectomy. These factors can be used to stratify patients into low-, intermediate-, and high-risk groups for recurrence which may be used to tailor follow-up.

The CADMUS trial - Multi-parametric ultrasound targeted biopsies compared to multi-parametric MRI targeted biopsies in the diagnosis of clinically significant prostate cancer.

OBJECTIVE: To compare the proportion of clinically significant prostate cancers (PCa) found in lesions detected by multiparametric MRI (mpMRI) with that found in lesions detected by multiparametric ultrasound (mpUSS), in men at risk. PATIENTS AND METHODS: CADMUS (Cancer Detection by Multiparametric Ultrasound of the prostate) is a prospective, multi-centre paired cohort diagnostic utility study with built-in randomisation of order of biopsies. The trial is registered ISRCTN38541912. All patients will undergo the index test under evaluation (mpUSS±biopsies), as well as the standard test (mpMRI±biopsies). Eligible men will be those at risk of harbouring prostate cancer usually recommended for prostate biopsy, either for the first time or as a repeat, who have not had any prior treatment for prostate cancer. Men in need of repeat biopsy will include those with prior negative results but ongoing suspicion, and those with an existing prostate cancer diagnosis but a need for accurate risk stratification. Both scans will be reported blind to the results of the other and the order in which the targeted biopsies derived from the two different imaging modalities are taken will be randomised. Comparison will be drawn between biopsy results of lesions detected by mpUSS with those lesions detected by mpMRI. Agreement over position between the two imaging modalities will be studied. DISCUSSION: CADMUS will provide level one evidence on the performance of mpUSS derived targeted biopsies in the identification of clinically significant prostate cancer in comparison to mpMRI targeted biopsies. Recruitment is underway and expected to complete in 2018.

Prostate cancer detection using quantitative T2 and T2 -weighted imaging: The effects of 5-alpha-reductase inhibitors in men on active surveillance.

BACKGROUND: T2 -weighted imaging (T2 -WI) information has been used in a qualitative manner in the assessment of prostate cancer. Quantitative derivatives (T2 relaxation time) can be generated from T2 -WI. These outputs may be useful in helping to discriminate clinically significant prostate cancer from background signal. PURPOSE/HYPOTHESIS: To investigate changes in quantitative T2 parameters in lesions and noncancerous tissue of men on active surveillance for prostate cancer taking dutasteride 0.5 mg or placebo daily for 6 months. STUDY TYPE: Retrospective. POPULATION/SUBJECTS: Forty men randomized to 6 months of daily dutasteride (n = 20) or placebo (n = 20). FIELD STRENGTH/SEQUENCE: Multiparametric 3T MRI at baseline and 6 months. This included a multiecho MR sequence for quantification of the T2 relaxation times, in three regions of interest (index lesion, noncancerous peripheral [PZ] and transitional [TZ] zones). A synthetic signal contrast (T2 Q contrast) between lesion and noncancerous tissue was assessed using quantitative T2 values. Signal contrast was calculated using the T2 -weighted sequence (T2 W contrast). ASSESSMENT: Two radiologists reviewed the scans in consensus according to Prostate Imaging Reporting and Data System (PI-RADS v. 2) guidelines. STATISTICAL TESTS: Wilcoxon and Mann-Whitney U-tests, Spearman's correlation. RESULTS: When compared to noncancerous tissue, shorter T2 values were observed within lesions at baseline (83.5 and 80.5 msec) and 6 months (81.5 and 81.9 msec) in the placebo and dutasteride arm, respectively. No significant differences for T2 W contrast at baseline and after 6 months were observed, both in the placebo (0.40 [0.29-0.49] vs. 0.43 [0.25-0.49]; P = 0.881) and dutasteride arm (0.35 [0.24-0.47] vs. 0.37 [0.22-0.44]; P = 0.668). There was a significant, positive correlation between the T2 Q contrast and the T2 W contrast values (r = 0.786; P < 0.001). DATA CONCLUSION: The exposure to antiandrogen therapy did not significantly influence the T2 contrast or the T2 relaxation values in men on active surveillance for prostate cancer. LEVEL OF EVIDENCE: 4 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:1646-1653.

MRI findings in men on active surveillance for prostate cancer: does dutasteride make MRI visible lesions less conspicuous? Results from a placebo-controlled, randomised clinical trial.

OBJECTIVES: To investigate changes in the Apparent Diffusion Coefficient (ADC) using diffusion-weighted imaging (DWI) in men on active surveillance for prostate cancer taking dutasteride 0.5 mg or placebo. METHODS: We analysed 37 men, randomised to 6 months of daily dutasteride (n = 18) or placebo (n = 19), undergoing 3T multi-parametric Magnetic Resonance Imaging (mpMRI) scans at baseline and 6 months. Images were reviewed blind to treatment allocation and clinical information. Mean ADC of peripheral (PZ) and transition (TZ) zones, and MR-suspicious lesions were compared between groups over 6 months. Conspicuity was defined as the PZ divided by tumour ADC, and its change over 6 months was assessed. RESULTS: A decrease in mean conspicuity in the dutasteride group (but not the controls) was seen over 6 months (1.54 vs 1.38; p = 0.025). Absolute changes in ADC and conspicuity were significantly different between placebo and dutasteride groups at 6 months: (-0.03 vs 0.08, p = 0.033) and (0.11 vs -0.16, p = 0.012), as were percentage changes in the same parameters: (-2.27% vs 8.56% p = 0.048) and (9.25% vs -9.89% p = 0.013). CONCLUSIONS: Dutasteride was associated with increased tumour ADC and reduced conspicuity. A lower threshold for triggering biopsy might be considered in men on dutasteride undergoing mpMRI for prostate cancer. KEY POINTS: • Dutasteride increases ADC and reduces conspicuity in small mpMRI-visible prostate cancers. • Knowledge of dutasteride exposure is important in the interpretation of prostate mpMRI. • A lower threshold for triggering biopsy may be appropriate on dutasteride.