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The prostate gland produces prostatic fluid, high in zinc and citrate and essential for the maintenance of spermatozoa. Prostate cancer is a common condition with limited treatment efficacy in castration-resistant metastatic disease, including with immune checkpoint inhibitors. Using single-cell RNA-sequencing to perform an unbiased assessment of the cellular landscape of human prostate, we identify a subset of tumor-enriched androgen receptor-negative luminal epithelial cells with increased expression of cancer-associated genes. We also find a variety of innate and adaptive immune cells in normal prostate that were transcriptionally perturbed in prostate cancer. An exception is a prostate-specific, zinc transporter-expressing macrophage population (MAC-MT) that contributes to tissue zinc accumulation in homeostasis but shows enhanced inflammatory gene expression in tumors, including T cell-recruiting chemokines. Remarkably, enrichment of the MAC-MT signature in cancer biopsies is associated with improved disease-free survival, suggesting beneficial antitumor functions., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Aim: To evaluate the effect of pre-biopsy magnetic resonance imaging (MRI) on cancer diagnostic times, and to report MRI-directed pathology outcomes., Materials and Methods: In total, 1483 patients were referred with prostate cancer suspicion during a 30-month period. Upfront MRI was performed in 745 patients: 332 MRIs in the 15 months prior to dedicated scanning slots (group 1), and 413 in the 15 months post-introduction (group 2). A further 88 patients had initial MRI following clinical assessment. Biopsy via the transrectal (TR) or transperineal (TP) approach was performed, with MRI/ultrasound fusion for MRI targets. Clinically significant cancer (csPCa) was defined as Gleason ≥3+4. Negative MRIs were defined as Likert 1-2. Per-case clinical decisions were taken to biopsy or not., Results: 44.4% of patients avoided biopsy. 484/833 (58.1%) MRIs were negative; 37.4% of these patients had biopsy with a negative predictive value (NPV) of 92.8% for Gleason ≥3+4 and 98.3% for ≥4+3. Overall prostate cancer prevalence was 34.3% (24.6% csPCa). In 323 MRI-positive cases, any cancer was present in 78.9% (csPCa 60.4%). Of the 1483 patients, 1232 (83.1%) completed all diagnostic tests within 28 days. Upfront MRI patients met this standard in 621/833 (74.5%), improving from 66.9% to 81.1% with reserved slots (group 2) with a reduced diagnostic time from median 25.5 to 20.9 days. Biopsy scheduling delayed the pathway in 69.7%, with MRI responsible in 22.3%, reducing to 10.3% in group 2. TP biopsies met the 28-day standard in significantly less cases (29.7%), compared to TR (67.4%, p<0.0001)., Conclusion: Reserved MRI slots reduces time-to-diagnosis, and upfront MRI safely avoids biopsy in a significant proportion of men, whilst maintaining expected csPCa detection rates., (Copyright © 2019 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Purpose: To evaluate sub-differentiation of PI-RADS-3 prostate lesions using pre-defined T2- and diffusion-weighted (DWI) MRI criteria, to aid the biopsy decision process., Methods: 143 patients with PIRADS-3 index lesions on MRI underwent targeted transperineal-MR/US fusion biopsy. Radiologists with 2 and 7-years experience performed blinded retrospective second-reads using set criteria and assigned biopsy recommendations. Inter-reader agreement, Gleason score (GS), positive (PPV) predictive values (±95% confidence intervals) were calculated and compared by Fisher's exact test with Bonferroni-Hom correction., Results: 43% (61/143) patients had GS 6-10 and 21% (30/143) GS≥3+4 cancer. For peripheral zone lesions, significant differences in any cancer detection were found for shape (0.26±0.13 geographical vs. 0.69±0.23 rounded; p=0.0055) and ADC (mild 0.21±0.12 vs marked 0.81±0.19; p=0.0001). For transition zone, significantly increased cancer detection was shown for location (anterior 0.63±0.15 vs. mid/posterior 0.31±0.14; p=0.0048), border (pseudo-capsule 0.32±0.14 vs. ill-defined 0.61±0.15; p=0.0092), and ADC (mild 0.35±0.12 vs marked restriction 0.68±0.17; p=0.0057). Biopsy recommendations had 62% inter-reader agreement (89/143). Experienced reader PPVs were significantly higher for any cancer with "biopsy-recommended" 0.61±0.11 vs. "no biopsy" 0.21±0.10 (p=0.0001), and for GS 7-10 cancers: 0.32±0.10 vs. 0.08±0.07, respectively (p=0.0003)., Conclusion: Identification of certain objective imaging criteria as well as a subjective biopsy recommendation from an experienced radiologist can help to increase the predictive value of equivocal prostate lesions and inform the decision making process of whether or not to biopsy., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objectives: To investigate the value of second-opinion evaluation of multiparametric prostate magnetic resonance imaging (MRI) by subspecialised uroradiologists at a tertiary centre for the detection of significant cancer in transperineal fusion prostate biopsy., Methods: Evaluation of prospectively acquired initial and second-opinion radiology reports of 158 patients who underwent MRI at regional hospitals prior to transperineal MR/untrasound fusion biopsy at a tertiary referral centre over a 3-year period. Gleason score (GS) 7-10 cancer, positive predictive value (PPV) and negative (NPV) predictive value (±95 % confidence intervals) were calculated and compared by Fisher's exact test., Results: Disagreement between initial and tertiary centre second-opinion reports was observed in 54 % of cases (86/158). MRIs had a higher NPV for GS 7-10 in tertiary centre reads compared to initial reports (0.89 ± 0.08 vs 0.72 ± 0.16; p = 0.04), and a higher PPV in the target area for all cancer (0.61 ± 0.12 vs 0.28 ± 0.10; p = 0.01) and GS 7-10 cancer (0.43 ± 0.12 vs 0.2 3 ± 0.09; p = 0.02). For equivocal suspicion, the PPV for GS 7-10 was 0.12 ± 0.11 for tertiary centre and 0.11 ± 0.09 for initial reads; p = 1.00., Conclusions: Second readings of prostate MRI by subspecialised uroradiologists at a tertiary centre significantly improved both NPV and PPV. Reporter experience may help to reduce overcalling and avoid overtargeting of lesions., Key Points: • Multiparametric MRIs were more often called negative in subspecialist reads (41 % vs 20 %). • Second readings of prostate mpMRIs by subspecialist uroradiologists significantly improved NPV and PPV. • Reporter experience may reduce overcalling and avoid overtargeting of lesions. • Greater education and training of radiologists in prostate MRI interpretation is advised.

Purpose: To compare histological outcomes in patients undergoing MRI-transrectal ultrasound fusion transperineal (MTTP) prostate biopsy and determine the incremental benefit of targeted cores., Methods: Seventy-six consecutive patients with 89 MRI-identified targets underwent MTTP biopsy. Separate targeted biopsies and background cores were obtained according to a standardized protocol. Target biopsies were considered of added diagnostic value if these cores showed a higher Gleason grade than non-targeted cores taken from the same sector (Group 1, n = 41). Conversely, where background cores demonstrated an equal or higher Gleason grade, target cores were considered to be non-beneficial (Group 2, n = 48)., Results: There was no significant difference in age, PSA, prostate volume, time-to-biopsy, and number of cores obtained between the groups. A greater proportion of target cores were positive for cancer (158/228; 69.3 %) compared to background (344/1881; 18.38 %). The median target volume was 0.54 cm(3) for Group 1 (range 0.09-2.79 cm(3)) and 1.65 cm(3) for Group 2 (0.3-9.07 cm(3)), p < 0.001. The targets in Group 1 had statistically lower diameters for short and long axes, even after correction for gland size. The highest area under the receiver operating characteristic curve was demonstrated when a lesion cutoff value of 1.0 cm in short axis was applied, resulting in a sensitivity of 83.3 % and a specificity of 82.9 %., Conclusions: When a combined systematic and targeted transperineal prostate biopsy is performed, there is limited benefit in acquiring additional cores from larger-volume targets with a short axis diameter >1.0 cm.

Genome-wide DNA sequencing was used to decrypt the phylogeny of multiple samples from distinct areas of cancer and morphologically normal tissue taken from the prostates of three men. Mutations were present at high levels in morphologically normal tissue distant from the cancer, reflecting clonal expansions, and the underlying mutational processes at work in morphologically normal tissue were also at work in cancer. Our observations demonstrate the existence of ongoing abnormal mutational processes, consistent with field effects, underlying carcinogenesis. This mechanism gives rise to extensive branching evolution and cancer clone mixing, as exemplified by the coexistence of multiple cancer lineages harboring distinct ERG fusions within a single cancer nodule. Subsets of mutations were shared either by morphologically normal and malignant tissues or between different ERG lineages, indicating earlier or separate clonal cell expansions. Our observations inform on the origin of multifocal disease and have implications for prostate cancer therapy in individual cases.