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New spatial molecular technologies are poised to transform our understanding and treatment of urological cancers. By mapping the spatial molecular architecture of tumours, these platforms uncover the complex heterogeneity within and around individual malignancies, offering novel insights into disease development, progression, diagnosis, and treatment. They enable tracking of clonal phylogenetics in situ and immune-cell interactions in the tumour microenvironment. A whole transcriptome/genome/proteome-level spatial analysis is hypothesis generating, particularly in the areas of risk stratification and precision medicine. Current challenges include reagent costs, harmonisation of protocols, and computational demands. Nonetheless, the evolving landscape of the technology and evolving machine learning applications have the potential to overcome these barriers, pushing towards a future of personalised cancer therapy, leveraging detailed spatial cellular and molecular data. PATIENT SUMMARY: Tumours are complex and contain many different components. Although we have been able to observe some of these differences visually under the microscope, until recently, we have not been able to observe the genetic changes that underpin cancer development. Scientists are now able to explore molecular/genetic differences using approaches such as "spatial transcriptomics" and "spatial proteomics", which allow them to see genetic and cellular variation across a region of normal and cancerous tissue without destroying the tissue architecture. Currently, these technologies are limited by high associated costs, and a need for powerful and complex computational analysis workflows. Future advancements and results through these new technologies may assist patients and their doctors as they make decisions about treating their cancer., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

For many years, transrectal ultrasound-guided (TRUS) prostate biopsies have been performed to establish a histological diagnosis of prostate cancer. This has been the recommended standard of care procedure, but has always carried risks, in particular the risk of post-procedural sepsis, and the associated antibiotic burden and risk of development of antibiotic resistance. Transperineal (TP) prostate biopsies performed under local anaesthetic (LA) have been proposed as a possible solution to these issues, with potentially lower infectious complications, and avoidance of need for antibiotic prophylaxis. The European Association of Urology produced guidance in 2023 with 'weak' recommendations in favour of LATP biopsy as a new standard of care, citing its safety profile. Both the National Institute for Health and Care Excellence in the UK, and the American Urological Association in the United States, have concluded for now that the body of evidence is inadequate and not offered a similar recommendation. We discuss the available evidence, pros and cons of each technique, and the status of current trials in the field. We believe that clinical equipoise remains necessary, given the disparity in national and international guidelines highlighting the need for large randomised controlled trials to answer the question: is LATP biopsy really better than TRUS biopsy?, (© 2024 The Authors. BJU International published by John Wiley & Sons Ltd on behalf of BJU International.)

Purpose: Prostate-specific membrane antigen (PSMA) is increasingly used to image prostate cancer in clinical practice. We sought to develop and test a humanised PSMA minibody IAB2M conjugated to the fluorophore IRDye 800CW-NHS ester in men undergoing robot-assisted laparoscopic radical prostatectomy (RARP) to image prostate cancer cells during surgery., Methods: The minibody was evaluated pre-clinically using PSMA positive/negative xenograft models, following which 23 men undergoing RARP between 2018 and 2020 received between 2.5 mg and 20 mg of IR800-IAB2M intravenously, at intervals between 24 h and 17 days prior to surgery. At every step of the procedure, the prostate, pelvic lymph node chains and extra-prostatic surrounding tissue were imaged with a dual Near-infrared (NIR) and white light optical platform for fluorescence in vivo and ex vivo. Histopathological evaluation of intraoperative and postoperative microscopic fluorescence imaging was undertaken for verification., Results: Twenty-three patients were evaluated to optimise both the dose of the reagent and the interval between injection and surgery and secure the best possible specificity of fluorescence images. Six cases are presented in detail as exemplars. Overall sensitivity and specificity in detecting non-lymph-node extra-prostatic cancer tissue were 100% and 65%, and 64% and 64% respectively for lymph node positivity. There were no side-effects associated with administration of the reagent., Conclusion: Intraoperative imaging of prostate cancer tissue is feasible and safe using IR800-IAB2M. Further evaluation is underway to assess the benefit of using the technique in improving completion of surgical excision during RARP., Registration: ISCRCTN10046036: https://www.isrctn.com/ISRCTN10046036 ., (© 2024. The Author(s).)

Background: The TRANSLATE (TRANSrectal biopsy versus Local Anaesthetic Transperineal biopsy Evaluation) trial assesses the clinical and cost-effectiveness of two biopsy procedures in terms of detection of clinically significant prostate cancer (PCa). This article describes the statistical analysis plan (SAP) for the TRANSLATE randomised controlled trial (RCT)., Methods/design: TRANSLATE is a parallel, superiority, multicentre RCT. Biopsy-naïve men aged ≥ 18 years requiring a prostate biopsy for suspicion of possible PCa are randomised (computer-generated 1:1 allocation ratio) to one of two biopsy procedures: transrectal (TRUS) or local anaesthetic transperineal (LATP) biopsy. The primary outcome is the difference in detection rates of clinically significant PCa (defined as Gleason Grade Group ≥ 2, i.e. any Gleason pattern ≥ 4 disease) between the two biopsy procedures. Secondary outcome measures are th eProBE questionnaire (Perception Part and General Symptoms) and International Index of Erectile Function (IIEF, Domain A) scores, International Prostate Symptom Score (IPSS) values, EQ-5D-5L scores, resource use, infection rates, complications, and serious adverse events. We describe in detail the sample size calculation, statistical models used for the analysis, handling of missing data, and planned sensitivity and subgroup analyses. This SAP was pre-specified, written and submitted without prior knowledge of the trial results., Discussion: Publication of the TRANSLATE trial SAP aims to increase the transparency of the data analysis and reduce the risk of outcome reporting bias. Any deviations from the current SAP will be described and justified in the final study report and results publication., Trial Registration: International Standard Randomised Controlled Trial Number ISRCTN98159689, registered on 28 January 2021 and registered on the ClinicalTrials.gov (NCT05179694) trials registry., (© 2024. The Author(s).)

Immune therapy is the new frontier of cancer treatment. Therapeutic radiation is a known inducer of immune response and can be limited by immunosuppressive mediators including cyclooxygenase-2 (COX2) that is highly expressed in aggressive triple negative breast cancer (TNBC). A clinical cohort of TNBC tumors revealed poor radiation therapeutic efficacy in tumors expressing high COX2. Herein, we show that radiation combined with adjuvant NSAID (indomethacin) treatment provides a powerful combination to reduce both primary tumor growth and lung metastasis in aggressive 4T1 TNBC tumors, which occurs in part through increased antitumor immune response. Spatial immunological changes including augmented lymphoid infiltration into the tumor epithelium and locally increased cGAS/STING1 and type I IFN gene expression were observed in radiation-indomethacin-treated 4T1 tumors. Thus, radiation and adjuvant NSAID treatment shifts "immune desert phenotypes" toward antitumor M1/TH1 immune mediators in these immunologically challenging tumors. Importantly, radiation-indomethacin combination treatment improved local control of the primary lesion, reduced metastatic burden, and increased median survival when compared with radiation treatment alone. These results show that clinically available NSAIDs can improve radiation therapeutic efficacy through increased antitumor immune response and augmented local generation of cGAS/STING1 and type I IFNs.

Cancer risk is associated with the widely debated measure body mass index (BMI). Fat mass and fat-free mass measurements from bioelectrical impedance may further clarify this association. The UK Biobank is a rare resource in which bioelectrical impedance and BMI data was collected on ~ 500,000 individuals. Using this dataset, a comprehensive analysis using regression, principal component and genome-wide genetic association, provided multiple levels of evidence that increasing whole body fat (WBFM) and fat-free mass (WBFFM) are both associated with increased post-menopausal breast cancer risk, and colorectal cancer risk in men. WBFM was inversely associated with prostate cancer. We also identified rs615029[T] and rs1485995[G] as associated in independent analyses with both PMBC (p = 1.56E-17 and 1.78E-11) and WBFFM (p = 2.88E-08 and 8.24E-12), highlighting splice variants of the intriguing long non-coding RNA CUPID1 (LINC01488) as a potential link between PMBC risk and fat-free mass., (© 2024. The Author(s).)

Background: Extension of prostate cancer beyond the primary site by local invasion or nodal metastasis is associated with poor prognosis. Despite significant research on tumour evolution in prostate cancer metastasis, the emergence and evolution of cancer clones at this early stage of expansion and spread are poorly understood. We aimed to delineate the routes of evolution and cancer spread within the prostate and to seminal vesicles and lymph nodes, linking these to histological features that are used in diagnostic risk stratification., Methods: We performed whole-genome sequencing on 42 prostate cancer samples from the prostate, seminal vesicles and lymph nodes of five treatment-naive patients with locally advanced disease. We spatially mapped the clonal composition of cancer across the prostate and the routes of spread of cancer cells within the prostate and to seminal vesicles and lymph nodes in each individual by analysing a total of > 19,000 copy number corrected single nucleotide variants., Results: In each patient, we identified sample locations corresponding to the earliest part of the malignancy. In patient 10, we mapped the spread of cancer from the apex of the prostate to the seminal vesicles and identified specific genomic changes associated with the transformation of adenocarcinoma to amphicrine morphology during this spread. Furthermore, we show that the lymph node metastases in this patient arose from specific cancer clones found at the base of the prostate and the seminal vesicles. In patient 15, we observed increased mutational burden, altered mutational signatures and histological changes associated with whole genome duplication. In all patients in whom histological heterogeneity was observed (4/5), we found that the distinct morphologies were located on separate branches of their respective evolutionary trees., Conclusions: Our results link histological transformation with specific genomic alterations and phylogenetic branching. These findings have implications for diagnosis and risk stratification, in addition to providing a rationale for further studies to characterise the genetic changes causally linked to morphological transformation. Our study demonstrates the value of integrating multi-region sequencing with histopathological data to understand tumour evolution and identify mechanisms of prostate cancer spread., (© 2024. The Author(s).)

Prostate cancer is typically of acinar adenocarcinoma type but can occasionally present as neuroendocrine and/or ductal type carcinoma. These are associated with clinically aggressive disease, and the former often arises on a background of androgen deprivation therapy, although it can also arise de novo. Two prostate cancer cases were sequenced by exome capture from archival tissue. Case 1 was de novo small cell neuroendocrine carcinoma and ductal adenocarcinoma with three longitudinal samples over 5 years. Case 2 was a single time point after the development of treatment-related neuroendocrine prostate carcinoma. Case 1 showed whole genome doubling in all samples and focal amplification of AR in all samples except the first time point. Phylogenetic analysis revealed a common ancestry for ductal and small cell carcinoma. Case 2 showed 13q loss (involving RB1) in both adenocarcinoma and small cell carcinoma regions, and 3p gain, 4p loss, and 17p loss (involving TP53) in the latter. By using highly curated samples, we demonstrate for the first time that small-cell neuroendocrine and ductal prostatic carcinoma can have a common ancestry. We highlight whole genome doubling in a patient with prostate cancer relapse, reinforcing its poor prognostic nature.

Objectives: To report a single centre's experience of the feasibility, safety and patient acceptability of same-day discharge robot-assisted laparoscopic prostatectomy (RALP)., Subjects/patients and Methods: Between June 2015 and December 2021, a total of 180 pre-selected consecutive patients underwent RALP with the intention to discharge on the same day as surgery. Cases were performed by two surgeons. An enhanced recovery after surgery (ERAS) programme was used. The feasibility of same-day discharge was analysed, along with the complication rate, oncological outcomes, and postoperative patient experience., Results: Of 180 patients, 169 (93.8%) were successfully discharged on the same day as surgery. The median (range) age was 63 ( 44-74) years. The median (range) console time was 97 (61-256) min and blood loss was 200 (20-800) mL. The resection specimen pathology results were: pT2 69.4%, pT3a 24.4% and pT3b 6.5%. With regard to Gleason Grade Group (GGG), 25.9% had GGG 1, 65.7% had GGG 2-3 and 8.4% had GGG 4-5 disease. Positive surgical margins were present in 25 cases (14.7%), 18 (15.5%) of which occurred in pT2 cases, and seven (13.4%) in pT3 cases. There were no early (<90 days) biochemical relapses (defined as prostate-specific antigen level >0.2 ng/mL). The 30-day readmission rate was 3%. A total of 13 early (0-30 days) complications were observed, five of which were Clavien-Dindo grade ≥3, however, none of these would have been avoided had the patient remained in hospital on the first postoperative night. Of 121 consecutive patients, 107 (88%) returned a satisfaction questionnaire, and 92% of responders stated they preferred recovery at home, with 94% stating they felt ready to go home., Conclusion: Robot-assisted laparoscopic prostatectomy combined with an ERAS programme allows patients to be safely discharged home on the same day of their surgery. This is a feasible option, well-liked by patients, with morbidity and oncological outcomes similar to non-day-case or 23 h stay RALP., (© 2023 BJU International.)

Objectives: Primary objectives: to determine whether local anaesthetic transperineal prostate (LATP) biopsy improves the detection of clinically significant prostate cancer (csPCa), defined as International Society of Urological Pathology (ISUP) Grade Group ≥2 disease (i.e., any Gleason pattern 4 disease), compared to transrectal ultrasound-guided (TRUS) prostate biopsy, in biopsy-naïve men undergoing biopsy based on suspicion of csPCa., Secondary Objectives: to compare (i) infection rates, (ii) health-related quality of life, (iii) patient-reported procedure tolerability, (iv) patient-reported biopsy-related complications (including bleeding, bruising, pain, loss of erectile function), (v) number of subsequent prostate biopsy procedures required, (vi) cost-effectiveness, (vii) other histological parameters, and (viii) burden and rate of detection of clinically insignificant PCa (ISUP Grade Group 1 disease) in men undergoing these two types of prostate biopsy., Patients and Methods: The TRANSLATE trial is a UK-wide, multicentre, randomised clinical trial that meets the criteria for level-one evidence in diagnostic test evaluation. TRANSLATE is investigating whether LATP biopsy leads to a higher rate of detection of csPCa compared to TRUS prostate biopsy. Both biopsies are being performed with an average of 12 systematic cores in six sectors (depending on prostate size), plus three to five target cores per multiparametric/bi-parametric magnetic resonance imaging lesion. LATP biopsy is performed using an ultrasound probe-mounted needle-guidance device (either the 'Precision-Point' or BK UA1232 system). TRUS biopsy is performed according to each hospital's standard practice. The study is 90% powered to detect a 10% difference (LATP biopsy hypothesised at 55% detection rate for csPCa vs 45% for TRUS biopsy). A total of 1042 biopsy-naïve men referred with suspected PCa need to be recruited., Conclusions: This trial will provide robust prospective data to determine the diagnostic ability of LATP biopsy vs TRUS biopsy in the primary diagnostic setting., (© 2023 The Authors. BJU International published by John Wiley & Sons Ltd on behalf of BJU International.)

Background: Between 1999 and 2009 in the United Kingdom, 82,429 men between 50 and 69 years of age received a prostate-specific antigen (PSA) test. Localized prostate cancer was diagnosed in 2664 men. Of these men, 1643 were enrolled in a trial to evaluate the effectiveness of treatments, with 545 randomly assigned to receive active monitoring, 553 to undergo prostatectomy, and 545 to undergo radiotherapy., Methods: At a median follow-up of 15 years (range, 11 to 21), we compared the results in this population with respect to death from prostate cancer (the primary outcome) and death from any cause, metastases, disease progression, and initiation of long-term androgen-deprivation therapy (secondary outcomes)., Results: Follow-up was complete for 1610 patients (98%). A risk-stratification analysis showed that more than one third of the men had intermediate or high-risk disease at diagnosis. Death from prostate cancer occurred in 45 men (2.7%): 17 (3.1%) in the active-monitoring group, 12 (2.2%) in the prostatectomy group, and 16 (2.9%) in the radiotherapy group (P = 0.53 for the overall comparison). Death from any cause occurred in 356 men (21.7%), with similar numbers in all three groups. Metastases developed in 51 men (9.4%) in the active-monitoring group, in 26 (4.7%) in the prostatectomy group, and in 27 (5.0%) in the radiotherapy group. Long-term androgen-deprivation therapy was initiated in 69 men (12.7%), 40 (7.2%), and 42 (7.7%), respectively; clinical progression occurred in 141 men (25.9%), 58 (10.5%), and 60 (11.0%), respectively. In the active-monitoring group, 133 men (24.4%) were alive without any prostate cancer treatment at the end of follow-up. No differential effects on cancer-specific mortality were noted in relation to the baseline PSA level, tumor stage or grade, or risk-stratification score. No treatment complications were reported after the 10-year analysis., Conclusions: After 15 years of follow-up, prostate cancer-specific mortality was low regardless of the treatment assigned. Thus, the choice of therapy involves weighing trade-offs between benefits and harms associated with treatments for localized prostate cancer. (Funded by the National Institute for Health and Care Research; ProtecT Current Controlled Trials number, ISRCTN20141297; ClinicalTrials.gov number, NCT02044172.)., (Copyright © 2023 Massachusetts Medical Society.)

BACKGROUND: Long-term patient-reported outcomes are needed to inform treatment decisions for localized prostate cancer. METHODS: Patient-reported outcomes of 1643 randomly assigned participants in the ProtecT (Prostate Testing for Cancer and Treatment) trial were evaluated to assess the functional and quality-of-life impacts of prostatectomy, radiotherapy with neoadjuvant androgen deprivation, and active monitoring. This article focuses on the outcomes of the randomly assigned participants from 7 to 12 years using mixed effects linear and logistic models. RESULTS: Response rates exceeded 80% for most measures. Among the randomized groups over 7 to 12 years, generic quality-of-life scores were similar. Among those in the prostatectomy group, urinary leakage requiring pads occurred in 18 to 24% of patients over 7 to 12 years, compared with 9 to 11% in the active monitoring group and 3 to 8% in the radiotherapy group. In the prostatectomy group, 18% reported erections sufficient for intercourse at 7 years, compared with 30% in the active monitoring and 27% in the radiotherapy groups; all converged to low levels of potency by year 12. Nocturia (voiding at least twice per night) occurred in 34% in the prostatectomy group compared with 48% in the radiotherapy group and 47% in the active monitoring group at 12 years. Fecal leakage affected 12% in the radiotherapy group compared with 6% in the other groups by year 12. The active monitoring group experienced gradual age-related declines in sexual and urinary function, avoiding radical treatment effects unless they changed management. CONCLUSIONS: ProtecT provides robust evidence about continued impacts of treatments in the long term. These data allow patients newly diagnosed with localized prostate cancer and their clinicians to assess the trade-offs between treatment harms and benefits and enable better informed and prudent treatment decisions. (Funded by the UK National Institute for Health and Care Research Health Technology Assessment Programme projects 96/20/06 and 96/20/99; ISRCTN number, ISRCTN20141297; ClinicalTrials.gov number, NCT02044172.)

Antitumor immune polarization is a key predictor of clinical outcomes to cancer therapy. An emerging concept influencing clinical outcome involves the spatial location of CD8 + T cells, within the tumor. Our earlier work demonstrated immunosuppressive effects of NOS2 and COX2 tumor expression. Here, we show that NOS2/COX2 levels influence both the polarization and spatial location of lymphoid cells including CD8 + T cells. Importantly, elevated tumor NOS2/COX2 correlated with exclusion of CD8 + T cells from the tumor epithelium. In contrast, tumors expressing low NOS2/COX2 had increased CD8 + T cell penetration into the tumor epithelium. Consistent with a causative relationship between these observations, pharmacological inhibition of COX2 with indomethacin dramatically reduced tumor growth of the 4T1 model of TNBC in both WT and Nos2 - mice. This regimen led to complete tumor regression in ∼20-25% of tumor-bearing Nos2 - mice, and these animals were resistant to tumor rechallenge. Th1 cytokines were elevated in the blood of treated mice and intratumoral CD4 + and CD8 + T cells were higher in mice that received indomethacin when compared to control untreated mice. Multiplex immunofluorescence imaging confirmed our phenotyping results and demonstrated that targeted Nos2/Cox2 blockade improved CD8 + T cell penetration into the 4T1 tumor core. These findings are consistent with our observations in low NOS2/COX2 expressing breast tumors proving that COX2 activity is responsible for limiting the spatial distribution of effector T cells in TNBC. Together these results suggest that clinically available NSAID's may provide a cost-effective, novel immunotherapeutic approach for treatment of aggressive tumors including triple negative breast cancer., Competing Interests: Declaration of competing interest The authors have no conflict of interests., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Objectives: To test the feasibility of randomisation to radical prostatectomy (RP) plus pelvic lymphadenectomy in addition to standard-of-care (SOC) systemic therapy in men with newly diagnosed oligo-metastatic prostate cancer., Patients and Methods: A prospective, randomised, non-blinded, feasibility clinical trial with an embedded QuinteT Recruitment Intervention (QRI) to optimise recruitment was conducted in nine nationwide tertiary care centres undertaking high-volume robotic surgery. We aimed to randomise 50 men with synchronous oligo-metastatic prostate cancer within an 18-month recruitment period to SOC systemic therapy vs SOC plus RP (intervention arm). The main outcome measures were: ability to randomise patients, optimised by a QRI; EuroQoL five Dimensions five Levels (EQ-5D-5L) questionnaires to capture quality-of-life (QoL) data at baseline and 3 months post-randomisation; routine clinicopathological assessment to capture adverse events and prostate-specific antigen in both arms, plus standard perioperative parameters in the surgical arm., Results: A total of 51 men were randomised within 14 months (one was subsequently deemed ineligible), with 60-83% accrual rate in centres that recruited at least two patients. All patients completed the trial follow-up; one patient in the intervention arm subsequently did not undergo the surgical intervention and one in the SOC arm refused all therapies. The QRI positively impacted recruitment. QoL data showed similarly high functioning in both study arms. Surgery for men with oligo-metastatic prostate cancer was found to be safe and had similar impact on early functional outcomes as surgery for standard indication., Conclusion: It is feasible to randomise men with synchronous oligo-metastatic prostate cancer to a surgical intervention in addition to standard systemic therapies. While surgery appeared safe with no substantial impact on QoL in this feasibility study, a large randomised controlled trial is now warranted to examine treatment effectiveness of this additional component in the multimodality management of oligo-metastatic prostate cancer., (© 2021 The Authors BJU International © 2021 BJU International.)

There has been particular interest in the deployment of digital pathology (DP) and artificial intelligence (AI) in the diagnosis of prostate cancer, but little is known about the views of the public on their use. Prostate Cancer UK supporters were invited to an online survey which included quantitative and qualitative questions exploring views on the use of DP and AI in histopathological assessment. A total of 1276 responses to the survey were analysed (response rate 12.5%). Most respondents were supportive of DP (87%, 1113/1276) and of testing AI in clinical practice as a diagnostic adjunct (83%, 1058/1276). Respondents saw DP as potentially increasing workflow efficiency, facilitating research, education/training and fostering clinical discussions between clinician and patient. Some respondents raised concerns regarding data security, reliability and the need for human oversight. Among those who were unsure about AI, information was requested regarding its performance and others wanted to defer the decision to use it to an expert. Although most are in favour of its use, some are unsure, and their concerns could be addressed with more information or better communication. A small minority (<1%) are not in favour of the testing of the use of AI in histopathology for reasons which are not easily addressed.

Objectives: To assess the feasibility of local anaesthetic transperineal (LATP) technique using a single-freehand transperineal (TP) access device, and report initial prostate cancer (PCa) detection, infection rates, and tolerability., Patients and Methods: Observational study of a multicentre prospective cohort, including all consecutive cases. LATP was performed in three settings: (i) first biopsy in suspected PCa, (ii) confirmatory biopsies for active surveillance, and (iii) repeat biopsy in suspected PCa. All patients received pre-procedure antibiotics according to local hospital guidelines. Local anaesthesia was achieved by perineal skin infiltration and periprostatic nerve block without sedation. Ginsburg protocol principles were followed for systematic biopsies including cognitive magnetic resonance imaging-targeted biopsies when needed using the PrecisionPoint™ TP access device. Procedure-related complications and oncological outcomes were prospectively and consecutively collected. A validated questionnaire was used in a subset of centres to collect data on patient-reported outcome measures (PROMs)., Results: Some 1218 patients underwent LATP biopsies at 10 centres: 55%, 24%, and 21% for each of the three settings, respectively. Any grade PCa was diagnosed in 816 patients (67%), of which 634 (52% of total) had clinically significant disease. Two cases of sepsis were documented (0.16%) and urinary retention was observed in 19 patients (1.6%). PROMs were distributed to 419 patients, with a 56% response rate (n = 234). In these men, pain during the biopsy was described as either 'not at all' or 'a little' painful by 64% of patients. Haematuria was the most common reported symptom (77%). When exploring attitude to re-biopsy, 48% said it would be 'not a problem' and in contrast 8.1% would consider it a 'major problem'. Most of the patients (81%) described the biopsy as a 'minor or moderate procedure tolerable under local anaesthesia', while 5.6% perceived it as a 'major procedure that requires general anaesthesia'., Conclusion: Our data suggest that LATP biopsy using a TP access system mounted to the ultrasound probe achieves excellent PCa detection, with a very low sepsis rate, and is safe and well tolerated. We believe a randomised controlled trial comparing LATP with transrectal ultrasound-guided biopsy (TRUS) to investigate the relative trade-offs between each biopsy technique would be helpful., (© 2021 The Authors BJU International © 2021 BJU International Published by John Wiley & Sons Ltd.)

Background: There is a need to improve the treatment of prostate cancer (PCa) and reduce treatment side effects. Vascular-targeted photodynamic therapy (VTP) is a focal therapy for low-risk low-volume localised PCa, which rapidly disrupts targeted tumour vessels. There is interest in expanding the use of VTP to higher-risk disease. Tumour vasculature is characterised by vessel immaturity, increased permeability, aberrant branching and inefficient flow. FRT alters the tumour microenvironment and promotes transient 'vascular normalisation'. We hypothesised that multimodality therapy combining fractionated radiotherapy (FRT) and VTP could improve PCa tumour control compared against monotherapy with FRT or VTP., Methods: We investigated whether sequential delivery of FRT followed by VTP 7 days later improves flank TRAMP-C1 PCa tumour allograft control compared to monotherapy with FRT or VTP., Results: FRT induced 'vascular normalisation' changes in PCa flank tumour allografts, improving vascular function as demonstrated using dynamic contrast-enhanced magnetic resonance imaging. FRT followed by VTP significantly delayed tumour growth in flank PCa allograft pre-clinical models, compared with monotherapy with FRT or VTP, and improved overall survival., Conclusion: Combining FRT and VTP may be a promising multimodal approach in PCa therapy. This provides proof-of-concept for this multimodality treatment to inform early phase clinical trials., (© 2021. The Author(s).)

Context: Studies characterising genomic changes in prostate cancer (PCa) during natural progression have greatly increased our understanding of the disease. A better understanding of the evolutionary history of PCa would allow advances in diagnostics, prognostication, and novel therapies that together will improve patient outcomes., Objective: To review the molecular heterogeneity of PCa and assess recent efforts to profile intratumoural heterogeneity and clonal evolution., Evidence Acquisition: We screened a total of 1313 abstracts from PubMed published between 2009 and 2020, of which we reviewed 84 full-text articles. We excluded 49, resulting in 35 studies for qualitative analysis., Evidence Synthesis: In studies of primary disease (16 studies, 4793 specimens), there is a lack of consensus regarding the monoclonal or polyclonal origin of primary PCa. There is no consistent mutation giving rise to primary PCa. Detailed clonal analysis of primary PCa has been limited by current techniques. By contrast, clonal relationships between PCa metastases and a potentiating clone have been consistently identified (19 studies, 732 specimens). Metastatic specimens demonstrate consistent truncal genomic aberrations that suggest monoclonal metastatic progenitors., Conclusions: The relationship between the clonal dynamics of PCa and clinical outcomes needs further investigation. It is likely that this will provide a biological rationale for whether radical treatment of the primary tumour benefits patients with oligometastatic PCa. Future studies on the mutational burden in primary disease at single-cell resolution should permit the identification of clonal patterns underpinning the origin of lethal PCa., Patient Summary: Prostate cancers arise in different parts of the prostate because of DNA mutations that occur by chance at different times. These cancer cells and their origin can be tracked by DNA mapping. In this review we summarise the state of the art and outline what further science is needed to provide the missing answers., (Crown Copyright © 2021. Published by Elsevier B.V. All rights reserved.)

Robot-assisted radical prostatectomy has become the standard of care for the removal of localized prostate cancer. Positive outcomes depend upon the precise removal of the prostate and associated tissue without damage to nearby structures. This process can be aided by fluorescence-guided surgery to enhance the visual contrast between different structures. Here the authors have conducted a systematic review using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines to identify ten investigations into the use of fluorescence-guided surgery in robot-assisted radical prostatectomy. These studies used fluorescent tracers to identify structures, including the prostate, neurovascular bundle and lymph nodes. These studies demonstrate the safe and effective use of fluorescence-guided surgery in robot-assisted radical prostatectomy and pave the way for further developments in this field.

Context: Ductal adenocarcinoma (DAC) is relatively rare, but is nonetheless the second most common subtype of prostate cancer. First described in 1967, opinion is still divided regarding its biology, prognosis, and outcome., Objectives: To systematically interrogate the literature to clarify the epidemiology, diagnosis, management, progression, and survival statistics of DAC., Materials and Methods: We conducted a literature search of five medical databases from inception to May 04 2020 according to PRISMA criteria using search terms "prostate ductal adenocarcinoma" OR "endometriod adenocarcinoma of prostate" and variations of each., Results: Some 114 studies were eligible for inclusion, presenting 2 907 170 prostate cancer cases, of which 5911 were DAC. [Correction added on 16 January 2021 after the first online publication: the preceding statement has been corrected in this current version.] DAC accounts for 0.17% of prostate cancer on meta-analysis (range 0.0837%-13.4%). The majority of DAC cases were admixed with predominant acinar adenocarcinoma (AAC). Median Prostate Specific Antigen at diagnosis ranged from 4.2 to 9.6 ng/mL in the case series.DAC was more likely to present as T3 (RR1.71; 95%CI 1.53-1.91) and T4 (RR7.56; 95%CI 5.19-11.01) stages, with far higher likelihood of metastatic disease (RR4.62; 95%CI 3.84-5.56; all P -values < .0001), compared to AAC. Common first treatments included surgery (radical prostatectomy (RP) or cystoprostatectomy for select cases) or radiotherapy (RT) for localized disease, and hormonal or chemo-therapy for metastatic disease. Few studies compared RP and RT modalities, and those that did present mixed findings, although cancer-specific survival rates seem worse after RP.Biochemical recurrence rates were increased with DAC compared to AAC. Additionally, DAC metastasized to unusual sites, including penile and peritoneal metastases. Where compared, all studies reported worse survival for DAC compared to AAC., Conclusion: When drawing conclusions about DAC it is important to note the heterogenous nature of the data. DAC is often diagnosed incidentally post-treatment, perhaps due to lack of a single, universally applied histopathological definition. As such, DAC is likely underreported in clinical practice and the literature. Poorer prognosis and outcomes for DAC compared to AAC merit further research into genetic composition, evolution, diagnosis, and treatment of this surprisingly common prostate cancer sub-type., Patient Summary: Ductal prostate cancer is a rare but important form of prostate cancer. This review demonstrates that it tends to be more serious at detection and more likely to spread to unusual parts of the body. Overall survival is worse with this type of prostate cancer and urologists need to be aware of the presence of ductal prostate cancer to alter management decisions and follow-up., (© 2021 The Authors. BJUI Compass published by John Wiley & Sons Ltd on behalf of BJU International Company.)

Background: Radiotherapy enhances innate and adaptive anti-tumour immunity. It is unclear whether this effect may be harnessed by combining immunotherapy with radiotherapy fractions used to treat prostate cancer. We investigated tumour immune microenvironment responses of pre-clinical prostate cancer models to radiotherapy. Having defined this landscape, we tested whether radiotherapy-induced tumour growth delay could be enhanced with anti-PD-L1., Methods: Hypofractionated radiotherapy was delivered to TRAMP-C1 and MyC-CaP flank allografts. Tumour growth delay, tumour immune microenvironment flow-cytometry, and immune gene expression were analysed. TRAMP-C1 allografts were then treated with 3 × 5 Gy ± anti-PD-L1., Results: 3 × 5 Gy caused tumour growth delay in TRAMP-C1 and MyC-CaP. Tumour immune microenvironment changes in TRAMP-C1 at 7 days post-radiotherapy included increased tumour-associated macrophages and dendritic cells and upregulation of PD-1/PD-L1, CD8 + T-cell, dendritic cell, and regulatory T-cell genes. At tumour regrowth post-3 × 5 Gy the tumour immune microenvironment flow-cytometry was similar to control tumours, however CD8 + , natural killer and dendritic cell gene transcripts were reduced. PD-L1 inhibition plus 3 × 5 Gy in TRAMP-C1 did not enhance tumour growth delay versus monotherapy., Conclusion: 3 × 5 Gy hypofractionated radiotherapy can result in tumour growth delay and immune cell changes in allograft prostate cancer models. Adjuncts beyond immunomodulation may be necessary to improve the radiotherapy-induced anti-tumour response.

Context: Prebiopsy multiparametric magnetic resonance imaging (mpMRI) is increasingly used in prostate cancer diagnosis. The reported negative predictive value (NPV) of mpMRI is used by some clinicians to aid in decision making about whether or not to proceed to biopsy., Objective: We aim to perform a contemporary systematic review that reflects the latest literature on optimal mpMRI techniques and scoring systems to update the NPV of mpMRI for clinically significant prostate cancer (csPCa)., Evidence Acquisition: We conducted a systematic literature search and included studies from 2016 to September 4, 2019, which assessed the NPV of mpMRI for csPCa, using biopsy or clinical follow-up as the reference standard. To ensure that studies included in this analysis reflect contemporary practice, we only included studies in which mpMRI findings were interpreted according to the Prostate Imaging Reporting and Data System (PIRADS) or similar Likert grading system. We define negative mpMRI as either (1) PIRADS/Likert 1-2 or (2) PIRADS/Likert 1-3; csPCa was defined as either (1) Gleason grade group ≥2 or (2) Gleason grade group ≥3. We calculated NPV separately for each combination of negative mpMRI and csPCa., Evidence Synthesis: A total of 42 studies with 7321 patients met our inclusion criteria and were included for analysis. Using definition (1) for negative mpMRI and csPCa, the pooled NPV for biopsy-naïve men was 90.8% (95% confidence interval [CI] 88.1-93.1%). When defining csPCa using definition (2), the NPV for csPCa was 97.1% (95% CI 94.9-98.7%). Calculation of the pooled NPV using definition (2) for negative mpMRI and definition (1) for csPCa yielded the following: 86.8% (95% CI 80.1-92.4%). Using definition (2) for both negative mpMRI and csPCa, the pooled NPV from two studies was 96.1% (95% CI 93.4-98.2%)., Conclusions: Multiparametric MRI of the prostate is generally an accurate test for ruling out csPCa. However, we observed heterogeneity in the NPV estimates, and local institutional data should form the basis of decision making if available., Patient Summary: The negative predictive values should assist in decision making for clinicians considering not proceeding to biopsy in men with elevated age-specific prostate-specific antigen and multiparametric magnetic resonance imaging reported as negative (or equivocal) on Prostate Imaging Reporting and Data System/Likert scoring. Some 7-10% of men, depending on the setting, will miss a diagnosis of clinically significant cancer if they do not proceed to biopsy. Given the institutional variation in results, it is of upmost importance to base decision making on local data if available., (Copyright © 2020 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Radiotherapy in combination with androgen deprivation therapy (ADT) is a standard treatment option for men with localized and locally advanced prostate cancer. However, emerging clinical evidence suggests that radiotherapy can be incorporated into multimodality therapy regimens beyond ADT, in combinations that include chemotherapy, radiosensitizing agents, immunotherapy and surgery for the treatment of men with localized and locally advanced prostate cancer, and those with oligometastatic disease, in whom the low metastatic burden in particular might be treatable with these combinations. This multimodal approach is increasingly recognized as offering considerable clinical benefit, such as increased antitumour effects and improved survival. Thus, radiotherapy is becoming a key component of multimodal therapy for many stages of prostate cancer, particularly oligometastatic disease.

Prostate cancer is a significant global health issue, and limitations to current patient management pathways often result in overtreatment or undertreatment. New ways to stratify patients are urgently needed. We conducted a feasibility study of such novel assessments, looking for associations between genomic changes and lymphocyte infiltration. An innovative workflow using an in-house targeted sequencing panel, immune cell profiling using an image analysis pipeline, RNA sequencing, and exome sequencing in select cases was tested. Gene fusions were profiled by RNA sequencing in 27 of 27 cases, and a significantly higher tumor-infiltrating lymphocyte (TIL) count was noted in tumors without a TMPRSS2:ERG fusion compared with those with the fusion (P = 0.01). Although this finding was not replicated in a larger validation set (n = 436) of The Cancer Genome Atlas images, there was a trend in the same direction. Differential expression analysis of TIL-high and TIL-low tumors revealed the enrichment of both innate and adaptive immune response pathways. Mutations in mismatch repair genes (MLH1 and MSH6 mutations in 1 of 27 cases) were identified. We describe a potential immune escape mechanism in TMPRSS2:ERG fusion-positive tumors. Detailed profiling, as shown herein, can provide novel insights into tumor biology. Likely differences with findings with other cohorts are related to methods used to define region of interest, but this warrants further study in a larger cohort., (Copyright © 2020 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Objective: To test the hypothesis that the baseline clinico-pathological features of the men with localized prostate cancer (PCa) included in the ProtecT (Prostate Testing for Cancer and Treatment) trial who progressed (n = 198) at a 10-year median follow-up were different from those of men with stable disease (n = 1409)., Patients and Methods: We stratified the study participants at baseline according to risk of progression using clinical disease stage, pathological grade and PSA level, using Cox proportional hazard models., Results: The findings showed that 34% of participants (n = 505) had intermediate- or high-risk PCa, and 66% (n = 973) had low-risk PCa. Of 198 participants who progressed, 101 (51%) had baseline International Society of Urological Pathology Grade Group 1, 59 (30%) Grade Group 2, and 38 (19%) Grade Group 3 PCa, compared with 79%, 17% and 5%, respectively, for 1409 participants without progression (P < 0.001). In participants with progression, 38% and 62% had baseline low- and intermediate-/high-risk disease, compared with 69% and 31% of participants with stable disease (P < 0.001). Treatment received, age (65-69 vs 50-64 years), PSA level, Grade Group, clinical stage, risk group, number of positive cores, tumour length and perineural invasion were associated with time to progression (P ≤ 0.005). Men progressing after surgery (n = 19) were more likely to have a higher Grade Group and pathological stage at surgery, larger tumours, lymph node involvement and positive margins., Conclusions: We demonstrate that one-third of the ProtecT cohort consists of people with intermediate-/high-risk disease, and the outcomes data at an average of 10 years' follow-up are generalizable beyond men with low-risk PCa., (© 2020 Crown copyright. BJU International published by John Wiley & Sons Ltd on behalf of BJU International.)

Introduction: Prostatic capsular incision (CapI) is an iatrogenic breach of the prostatic capsule during radical prostatectomy (RP) that can cause positive surgical margins (PSMs) in organ-confined (pT2) prostate cancer, or the retention of benign prostatic tissue. We systematically interrogated the literature in order to clarify the definition of CapI, and the implications of this event for rates of PSM and biochemical recurrence (BCR)., Methods: A literature search was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria using the search terms 'capsular incision' AND 'prostatectomy', and variations of each. In all, 18 studies were eligible for inclusion., Results: A total of 51 057 RP specimens were included. The incidence of CapI ranged from 1.3% to 54.3%. CapI definitions varied and included a breach of the prostatic capsule 'exposing both benign or malignant prostate cancer cells', 'malignant tissue only', or 'benign tissue only'. The incidence of PSMs due to CapI ranged from 2.8% to 71.7%. Our meta-analysis results found that when CapI was defined as 'exposing malignant tissue only in organ-confined prostate cancer' there was an increased risk of BCR compared to patients with pT2 disease and no CapI (relative risk 3.53, 95% confidence interval 2.82-4.41; P < 0.001)., Conclusions: The absolute impact of CapI on oncological outcomes is currently unclear due to inconsistent definitions. However, the data imply an association between CapI and PSMs and BCR. Reporting of possible areas of CapI on the operation note, or marking areas of concern on the specimen, are critical to assist CapI recognition by the pathologist., (© 2018 The Authors BJU International © 2018 BJU International Published by John Wiley & Sons Ltd.)

Importance: The current diagnostic pathway for patients with suspected prostate cancer (PCa) includes prostate biopsy. A large proportion of individuals who undergo biopsy have either no PCa or low-risk disease that does not require treatment. Unnecessary biopsies may potentially be avoided with prebiopsy imaging., Objective: To compare the performance of systematic transrectal ultrasonography-guided prostate biopsy vs prebiopsy biparametric or multiparametric magnetic resonance imaging (MRI) followed by targeted biopsy with or without systematic biopsy., Data Sources: MEDLINE, Embase, Cochrane, Web of Science, clinical trial registries, and reference lists of recent reviews were searched through December 2018 for randomized clinical trials using the terms "prostate cancer" and "MRI.", Study Selection: Randomized clinical trials comparing diagnostic pathways including prebiopsy MRI vs systematic transrectal ultrasonography-guided biopsy in biopsy-naive men with a clinical suspicion of PCa., Data Extraction and Synthesis: Data were pooled using random-effects meta-analysis. Risk of bias was assessed using the revised Cochrane tool. Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines were followed. All review stages were conducted by 2 reviewers., Main Outcomes and Measures: Detection rate of clinically significant and insignificant PCa, number of biopsy procedures, number of biopsy cores taken, and complications., Results: Seven high-quality trials (2582 patients) were included. Compared with systematic transrectal ultrasonography-guided biopsy alone, MRI with or without targeted biopsy was associated with a 57% (95% CI, 2%-141%) improvement in the detection of clinically significant PCa, a 33% (95% CI, 23%-45%) potential reduction in the number of biopsy procedures, and a 77% (95% CI, 60%-93%) reduction in the number of cores taken per procedure. One trial showed reduced pain and bleeding adverse effects. Systematic sampling of the prostate in addition to the acquisition of targeted cores did not significantly improve the detection of clinically significant PCa compared with systematic biopsy alone., Conclusions and Relevance: In this meta-analysis, prebiopsy MRI combined with targeted biopsy vs systematic transrectal ultrasonography-guided biopsy alone was associated with improved detection of clinically significant PCa, despite substantial heterogeneity among trials. Prebiopsy MRI was associated with a reduced number of individual biopsy cores taken per procedure and with reduced adverse effects, and it potentially prevented unnecessary biopsies in some individuals. This evidence supports implementation of prebiopsy MRI into diagnostic pathways for suspected PCa.

Background: Enhancer of zeste 2 (EZH2) promotes prostate cancer progression. We hypothesized that increased EZH2 expression is associated with postradiotherapy metastatic disease recurrence, and may promote radioresistance., Methods: EZH2 expression was investigated using immunohistochemistry in diagnostic prostate biopsies of 113 prostate cancer patients treated with radiotherapy with curative intent. Associations between EZH2 expression in malignant and benign tissue in prostate biopsy cores and outcomes were investigated using univariate and multivariate Cox regression analyses. LNCaP and PC3 cell radiosensitivity was investigated using colony formation and γH2AX assays following UNC1999 chemical probe-mediated EZH2 inhibition., Results: While there was no significant association between EZH2 expression and biochemical recurrence following radiotherapy, univariate analysis revealed that prostate cancer cytoplasmic and total EZH2 expression were significantly associated with metastasis development postradiotherapy (P = 0.034 and P = 0.003, respectively). On multivariate analysis, the prostate cancer total EZH2 expression score remained statistically significant (P = 0.003), while cytoplasmic EZH2 expression did not reach statistical significance (P = 0.053). No association was observed between normal adjacent prostate EZH2 expression and biochemical recurrence or metastasis. LNCaP and PC3 cell treatment with UNC1999 reduced histone H3 lysine 27 tri-methylation levels. Irradiation of LNCaP or PC3 cells with a single 2 Gy fraction with UNC1999-mediated EZH2 inhibition resulted in a statistically significant, though modest, reduction in cell colony number for both cell lines. Increased γH2AX foci were observed 24 hours after ionizing irradiation in LNCaP cells, but not in PC3, following UNC1999-mediated EZH2 inhibition vs controls., Conclusions: Taken together, these results reveal that high pretreatment EZH2 expression in prostate cancer in diagnostic biopsies is associated with an increased risk of postradiotherapy metastatic disease recurrence, but EZH2 function may only at most play a modest role in promoting prostate cancer cell radioresistance., (© 2019 The Authors. The Prostate Published by Wiley Periodicals, Inc.)

Purpose: We hypothesized that 1) introducing prebiopsy multiparametric magnetic resonance imaging would increase the diagnostic yield of transrectal prostate biopsy and 2) this would inform recommendations regarding systematic transrectal prostate biopsy in the setting of negative prebiopsy multiparametric magnetic resonance imaging., Materials and Methods: A total of 997 biopsy naïve patients underwent transrectal prostate biopsy alone to June 2016 (cohort 1) and thereafter 792 underwent transrectal prostate biopsy following prebiopsy multiparametric magnetic resonance imaging (cohort 2). Patients with lesions on prebiopsy multiparametric magnetic resonance imaging underwent cognitive targeted plus systematic transrectal prostate biopsy. Patients without lesions underwent systematic transrectal prostate biopsy., Results: Cohort 2 comprised younger men (age 68 vs 69 years, p = 0.01) with lower prostate specific antigen (7.6 vs 7.9 ng/ml, p = 0.024) and smaller prostate volume (56.1 vs 62 cc, p = 0.006). In cohort 2 vs cohort 1 there was no increase in overall prostate cancer detection (57.6% vs 56.7%, p = 0.701), the Gleason Grade Group or the number of positive cores (each p >0.05). Increased multifocal prostatic intraepithelial neoplasia, maximum prostate cancer core length (5 mm or greater vs less than 5 mm) and radical surgery/high intensity focused ultrasound (each p <0.05) were observed in cohort 2. For Gleason Grade Group 2-5 prostate cancer negative prebiopsy multiparametric magnetic resonance imaging had 88.1% sensitivity, 59.8% specificity, 67.8% positive predictive value and 84% negative predictive value. For negative prebiopsy multiparametric magnetic resonance images a prostate specific antigen density cutoff of 0.15 ng/ml 2 or greater increased clinically significant prostate cancer detection only if the latter was defined as Gleason Grade Group 3-5 disease and/or tumor length 6 mm or greater., Conclusions: Introducing prebiopsy multiparametric magnetic resonance imaging in our clinical setting increased the diagnostic yield of prostate cancer per biopsy core. Not performing a systematic transrectal prostate biopsy when prebiopsy multiparametric magnetic resonance imaging was negative would have led to under detection of 15.1% of Gleason Grade Group 2 or greater prostate cancer cases (approximately 1 in 6).

: Effective immunotherapy of stromal-rich tumors requires simultaneous targeting of cancer cells and immunosuppressive elements of the microenvironment. Here, we modified the oncolytic group B adenovirus enadenotucirev to express a stroma-targeted bispecific T-cell engager (BiTE). This BiTE bound fibroblast activation protein on cancer-associated fibroblasts (CAF) and CD3ε on T cells, leading to potent T-cell activation and fibroblast death. Treatment of fresh clinical biopsies, including malignant ascites and solid prostate cancer tissue, with FAP-BiTE-encoding virus induced activation of tumor-infiltrating PD1 + T cells to kill CAFs. In ascites, this led to depletion of CAF-associated immunosuppressive factors, upregulation of proinflammatory cytokines, and increased gene expression of markers of antigen presentation, T-cell function, and trafficking. M2-like ascites macrophages exhibited a proinflammatory repolarization, indicating spectrum-wide alteration of the tumor microenvironment. With this approach, we have actively killed both cancer cells and tumor fibroblasts, reversing CAF-mediated immunosuppression and yielding a potent single-agent therapeutic that is ready for clinical assessment. SIGNIFICANCE: An engineered oncolytic adenovirus that encodes a bispecific antibody combines direct virolysis with endogenous T-cell activation to attack stromal fibroblasts, providing a multimodal treatment strategy within a single therapeutic agent., (©2018 American Association for Cancer Research.)

Objectives: To determine whether replacement of protocol-driven repeat prostate biopsy (PB) with multiparametric magnetic resonance imaging (mpMRI) ± repeat targeted prostate biopsy (TB) when evaluating men on active surveillance (AS) for low-volume, low- to intermediate-risk prostate cancer (PCa) altered the likelihood of or time to treatment, or reduced the number of repeat biopsies required to trigger treatment., Patients and Methods: A total of 445 patients underwent AS in the period 2010-2016 at our institution, with a median (interquartile range [IQR]) follow-up of 2.4 (1.2-3.7) years. Up to 2014, patients followed a 'pre-2014' AS protocol, which incorporated PB, and subsequently, according to the 2014 National Institute for Health and Care Excellence (NICE) guidelines, patients followed a '2014-present' AS protocol that included mpMRI. We identified four groups of patients within the cohort: 'no mpMRI and no PB'; 'PB alone'; 'mpMRI ± TB'; and 'PB and mpMRI ± TB'. Kaplan-Meier plots and log-rank tests were used to compare groups., Results: Of 445 patients, 132 (30%) discontinued AS and underwent treatment intervention, with a median (IQR) time to treatment of 1.55 (0.71-2.4) years. The commonest trigger for treatment was PCa upgrading after mpMRI and TB (43/132 patients, 29%). No significant difference was observed in the time at which patients receiving a PB alone or receiving mpMRI ± TB discontinued AS to undergo treatment (median 1.9 vs 1.33 years; P = 0.747). Considering only those patients who underwent repeat biopsy, a greater proportion of patients receiving TB after mpMRI discontinued AS compared with those receiving PB alone (29/66 [44%] vs 32/87 [37%]; P = 0.003). On average, a single set of repeat biopsies was needed to trigger treatment regardless of whether this was a PB or TB., Conclusions: Replacing a systematic PB with mpMRI ±TB as part of an AS protocol increased the likelihood of re-classifying patients on AS and identifying men with clinically significant disease requiring treatment. mpMRI ±TB as part of AS thereby represents a significant advance in the oncological safety of the AS protocol., (© 2018 The Authors BJU International © 2018 BJU International Published by John Wiley & Sons Ltd.)

Internalization of ligand-activated type I IGF receptor (IGF1R) is followed by recycling to the plasma membrane, degradation or nuclear translocation. Nuclear IGF1R reportedly associates with clinical response to IGF1R inhibitory drugs, yet its role in the nucleus is poorly characterized. Here, we investigated the significance of nuclear IGF1R in clinical cancers and cell line models. In prostate cancers, IGF1R was predominantly membrane localized in benign glands, while malignant epithelium contained prominent internalized (nuclear/cytoplasmic) IGF1R, and nuclear IGF1R associated significantly with advanced tumor stage. Using ChIP-seq to assess global chromatin occupancy, we identified IGF1R-binding sites at or near transcription start sites of genes including JUN and FAM21 , most sites coinciding with occupancy by RNA polymerase II (RNAPol2) and histone marks of active enhancers/promoters. IGF1R was inducibly recruited to chromatin, directly binding DNA and interacting with RNAPol2 to upregulate expression of JUN and FAM21, shown to mediate tumor cell survival and IGF-induced migration. IGF1 also enriched RNAPol2 on promoters containing IGF1R-binding sites. These functions were inhibited by IGF1/II-neutralizing antibody xentuzumab (BI 836845), or by blocking receptor internalization. We detected IGF1R on JUN and FAM21 promoters in fresh prostate cancers that contained abundant nuclear IGF1R, with evidence of correlation between nuclear IGF1R content and JUN expression in malignant prostatic epithelium. Taken together, these data reveal previously unrecognized molecular mechanisms through which IGFs promote tumorigenesis, with implications for therapeutic evaluation of anti-IGF drugs. Significance: These findings reveal a noncanonical nuclear role for IGF1R in tumorigenesis, with implications for therapeutic evaluation of IGF inhibitory drugs. Cancer Res; 78(13); 3497-509. ©2018 AACR ., (©2018 American Association for Cancer Research.)

There is an unmet clinical need for adequate biomarkers to aid risk stratification and management of prostate cancer (PCa) patients. Even within the high-risk PCa category, not all patients will invariably have a poor prognosis, and improved stratification of this heterogeneous group is needed. In this context, components of the hedgehog (Hh) pathway may have promise as biomarkers, because the available evidence suggests increased Hh pathway activity may confer a poorer outcome in advanced and castrate-resistant PCa. In this study, potential associations between Hh pathway protein expression and clinicopathological factors, including time to biochemical recurrence (BCR), were investigated using a tissue microarray constructed from benign and malignant prostate samples from 75 predominantly high-risk PCa patients who underwent radical prostatectomy. Hh signaling activity was found to differ between benign and malignant prostate tissue, with a greater amount of active Hh signaling present in malignant than benign prostate epithelium. High expression of Patched 1 in malignant prostate epithelium was found to be an independent predictor of BCR in high-risk PCa patients. Glioma-associated oncogene 1 may potentially represent a clinically useful biomarker of an aggressive tumor phenotype. Evaluation of Hh signaling activity in PCa patients may be useful for risk stratification, and epithelial Patched 1 expression, in particular, may be a prognostic marker for BCR in high-risk PCa patients., (Copyright © 2018 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Background: Activated type 1 insulin-like growth factor receptors (IGF-1Rs) undergo internalisation and nuclear translocation, promoting cell survival. We previously reported that IGF-1R inhibition delays DNA damage repair, sensitising prostate cancer cells to ionising radiation. Here we tested the clinical relevance of these findings., Methods: We assessed associations between IGF-1R and clinical outcomes by immunohistochemistry in diagnostic biopsies of 136 men treated with 55-70 Gy external beam radiotherapy for prostate cancer, comparing results with publicly available transcriptional data in surgically treated patients., Results: Following radiotherapy, overall recurrence-free survival was shorter in patients whose tumours contained high total, cytoplasmic and internalised (nuclear/cytoplasmic) IGF-1R. High total IGF-1R associated with high primary Gleason grade and risk of metastasis, and cytoplasmic and internalised IGF-1R with biochemical recurrence, which includes patients experiencing local recurrence within the radiation field indicating radioresistance. In multivariate analysis, cytoplasmic, internalised and total IGF-1R were independently associated with risk of overall recurrence, and cytoplasmic IGF-1R was an independent predictor of biochemical recurrence post radiotherapy. Insulin-like growth factor receptors expression did not associate with biochemical recurrence after radical prostatectomy., Conclusions: These data reveal increased risk of post-radiotherapy recurrence in men whose prostate cancers contain high levels of total or cytoplasmic IGF-1R.

Background: Prostate cancer (PCa) is a heterogeneous disease with a variable natural history, genetics, and treatment outcome. The Hedgehog (Hh) signaling pathway is increasingly recognized as being potentially important for the development and progression of PCa. In this retrospective study, we compared the activation status of the Hh signaling pathway between benign and tumor tissue, and evaluated the clinical significance of Hh signaling in PCa., Methods: In this tissue microarray (TMA) study, the protein expression of several Hh signaling components and Hh target proteins, along with microvessel density, were compared between benign (n = 64) and malignant (n = 170) prostate tissue, and correlated with PCa clinicopathological characteristics and biochemical recurrence (BCR)., Results: The Hh signaling pathway appeared to be more active in PCa than in benign prostate tissue, as demonstrated by lower expression of the negative regulators PTCH1 and GLI3 in the tumor tissue compared to benign. In addition, high epithelial GLI2 expression correlated with higher pathological Gleason score. Overall, higher epithelial GLI3 expression in the tumor was shown to be an independent marker of a favorable prognosis., Conclusion: Hh signaling activation might reflect aggressive tumoral behavior, since high epithelial GLI2 expression positively correlates with a higher pathological Gleason score. Moreover, higher epithelial GLI3 expression is an independent marker of a more favorable prognosis.

Background: Tumour-specific radiosensitising treatments may enhance the efficacy of radiotherapy without exacerbating side effects. In this study we determined the radiation response following depletion or inhibition of TOPK, a mitogen-activated protein kinase kinase family Ser/Thr protein kinase that is upregulated in many cancers., Methods: Radiation response was studied in a wide range of cancer cell lines and normal cells using colony formation assays. The effect on cell cycle progression was assessed and the relationship between TOPK expression and therapeutic efficacy was studied in a cohort of 128 prostate cancer patients treated with radical radiotherapy., Results: TOPK knockdown did not alter radiation response in normal tissues, but significantly enhanced radiosensitivity in cancer cells. This result was recapitulated in TOPK knockout cells and with the TOPK inhibitor, OTS964. TOPK depletion altered the G 1 /S transition and G 2 /M arrest in response to radiation. Furthermore, TOPK depletion increased chromosomal aberrations, multinucleation and apoptotic cell death after irradiation. These results suggest a possible role for TOPK in the radiation-induced DNA damage checkpoints. These findings have clinical relevance, as elevated TOPK protein expression was associated with poorer clinical outcomes in prostate cancer patients treated with radical radiotherapy., Conclusions: This study demonstrates that TOPK disruption may cause tumour-specific radiosensitisation in multiple different tumour types.

Epithelial to mesenchymal transition (EMT) of cancer cells involves loss of epithelial polarity and adhesiveness, and gain of invasive and migratory mesenchymal behaviours. EMT occurs in prostate cancer (PCa) but it is unknown whether this is in specific areas of primary tumours. We examined whether any of eleven EMT-related proteins have altered expression or subcellular localisation within the extraprostatic extension component of locally advanced PCa compared with other localisations, and whether similar changes may occur in in vitro organotypic PCa cell cultures and in vivo PCa models. Expression profiles of three proteins (E-cadherin, Snail, and α-smooth muscle actin) were significantly different in extraprostatic extension PCa compared with intra-prostatic tumour, and 18/27 cases had an expression change of at least one of these three proteins. Of the three significantly altered EMT proteins in pT3 samples, one showed similar significantly altered expression patterns in in vitro organotypic culture models, and two in in vivo Pten-/- model samples. These results suggest that changes in EMT protein expression can be observed in the extraprostatic extension component of locally invasive PCa. The biology of some of these changes in protein expression may be studied in certain in vitro and in vivo PCa models.

Aims: Extraprostatic extension of prostate cancer in radical prostatectomy specimens significantly affects patient management. We evaluated the degree of interobserver variation between uropathologists at a tertiary referral teaching hospital in assessing the extraprostatic extension of prostate cancer in radical prostatectomy specimens., Methods: Histopathological data from a consecutive series of 293 radical prostatectomy specimens (January 2007-December 2012) were reviewed. A subset of 50 consecutive radical prostatectomy cases originally staged as tumours confined to the prostate (pT2) or tumours extending into periprostatic tissue (pT3a) during this period were reviewed by four specialist uropathologists., Results: Five consultant histopathologists reported these specimens with significant differences in the reported stage (p=0.0164) between pathologists. Double-blind review by 4 uropathologists of 50 consecutive radical prostatectomy cases showed a lack of consensus in 16/50 (32%) cases (κ score 0.58, moderate agreement). A consensus meeting was held, but consensus could still not be reached in 9/16 cases., Conclusions: Our findings highlight variability in the reporting of pT stage in radical prostatectomy specimens even by specialist uropathologists. Assessment of extraprostatic extension has important implications for patient management and there is a need for more precise guidance., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Background: Many men with elevated prostate-specific antigen (PSA) levels in serum do not have aggressive prostate cancer and undergo unnecessary biopsy. Retrospective studies using cryopreserved serum suggest that four kallikrein markers can predict biopsy outcome., Methods: Free, intact and total PSA, and kallikrein-related peptidase 2 were measured in cryopreserved blood from 6129 men with elevated PSA (≥3.0ng/mL) participating in the prospective, randomized trial Prostate Testing for Cancer and Treatment. Marker levels from 4765 men providing anticoagulated plasma were incorporated into statistical models to predict any-grade and high-grade (Gleason score ≥7) prostate cancer at 10-core biopsy. The models were corrected for optimism by 10-fold cross validation and independently validated using markers measured in serum from 1364 men. All statistical tests were two-sided., Results: The four kallikreins enhanced prostate cancer detection compared with PSA and age alone. Area under the curve (AUC) for the four kallikreins was 0.719 (95% confidence interval [CI] = 0.704 to 0.734) vs 0.634 (95% CI = 0.617 to 0.651, P < .001) for PSA and age alone for any-grade cancer, and 0.820 (95% CI = 0.802 to 0.838) vs 0.738 (95% CI = 0.716 to 0.761) for high-grade cancer. Using a 6% risk of high-grade cancer as an illustrative cutoff, for 1000 biopsied men with PSA levels of 3.0ng/mL or higher, the model would reduce the need for biopsy in 428 men, detect 119 high-grade cancers, and delay diagnosis of 14 of 133 high-grade cancers. Models exhibited excellent discrimination on independent validation among men with only serum samples available for analysis., Conclusions: A statistical model based on kallikrein markers was validated in a large prospective study and reduces unnecessary biopsies while delaying diagnosis of high-grade cancers in few men., (© The Author 2015. Published by Oxford University Press.)

This article updates advances in prostate cancer screening based on prostate-specific antigen, its derivatives, and human kallikrein markers. Many men are diagnosed with indolent disease not requiring treatment. Although there is evidence of a survival benefit from screening, the numbers needed to screen and treat remain high. There is risk of exposing men to the side effects of treatment for nonthreatening disease. A screening test is needed with sufficiently good performance characteristics to detect disease at an early stage so treatment may be offered with curative intent, while reducing the number of negative or unnecessary biopsies., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background and Purpose: The National Institute of Clinical Excellence published guidelines in 2010 recommending the use of cystoscopy to investigate profound lower urinary tract symptoms (pLUTS), recurrent urinary tract infection (rUTI), and pain in men. Currently, there are no equivalent guidelines for women. We aimed to examine the diagnostic performance of flexible cystoscopy (FC) when it is used in this context in both men and women., Patients and Methods: Results of all outpatient FCs undertaken in our department between April 2009 and March 2010 were examined retrospectively. Patients undergoing FC for the investigation of pLUTS, rUTI, or pain were included. Diagnostic performance was calculated, which was defined as the number of patients receiving a diagnosis of a clinically relevant abnormality at FC divided by the total number of patients undergoing FC for this indication., Results: Of the 1809 patients who underwent FC during the study period, 113 underwent FC to investigate pLUTS, rUTI, or pain. Diagnostic performance was 11.5% (n=13), being 11.4%, 19.2%, and 0% in those with pLUTS, rUTI, and pain, respectively. Bladder cancer was diagnosed in one (0.9%) patient who underwent FC to investigate pLUTS but also had nonvisible hematuria. Urethral stricture was diagnosed in nine (8.0%) cases and intravesical calculi in four (3.5%) cases., Conclusion: Clinically relevant abnormalities were found in 11.5% of patients with pLUTS, rUTI, or pain, supporting recently published NICE guidelines recommending cystoscopy in patients with pLUTS or rUTI. Of the 17 patients who were investigated for pain, none was found to have clinically relevant abnormalities; further studies are needed to define the clinical utility of FC in these cases.