Patients' Preferences for Cytoreductive Treatments in Newly Diagnosed Metastatic Prostate Cancer: The IP5-MATTER Study.

Background And Objective: Cytoreductive treatments for patients diagnosed with de novo synchronous metastatic hormone-sensitive prostate cancer (mHSPC) confer incremental survival benefits over systemic therapy, but these may lead to added toxicity and morbidity. Our objective was to determine patients' preferences for, and trade-offs between, additional cytoreductive prostate and metastasis-directed interventions.

Methods: A prospective multicentre discrete choice experiment trial was conducted at 30 hospitals in the UK between December 3, 2020 and January 25, 2023 (NCT04590976).

Focal therapy versus radical prostatectomy and external beam radiotherapy as primary treatment options for non-metastatic prostate cancer: results of a cost-effectiveness analysis.

Aims: Focal therapy treats individual areas of tumour in non-metastatic prostate cancer in patients unsuitable for active surveillance. The aim of this work was to evaluate the cost-effectiveness of focal therapy versus prostatectomy and external beam radiotherapy (EBRT).

Materials And Methods: A Markov cohort health state transition model with four health states (stable disease, local recurrence, metastatic disease and death) was created, evaluating costs and utilities over a 10-year time horizon for patients diagnosed with non-metastatic prostate cancer.

Re-evaluating the diagnostic efficacy of PSA as a referral test to detect clinically significant prostate cancer in contemporary MRI-based image-guided biopsy pathways.

Introduction: Modern image-guided biopsy pathways at diagnostic centres have greatly refined the investigations of men referred with suspected prostate cancer. However, the referral criteria from primary care are still based on historical prostate-specific antigen (PSA) cut-offs and age-referenced thresholds. Here, we tested whether better contemporary pathways and biopsy methods had improved the predictive utility value of PSA referral thresholds.

Evaluation of Outcomes Following Focal Ablative Therapy for Treatment of Localized Clinically Significant Prostate Cancer in Patients >70 Years: A Multi-institute, Multi-energy 15-Year Experience.

Purpose: In older patients who do not wish to undergo watchful waiting, focal therapy could be an alternative to the more morbid radical treatment. We evaluated the role of focal therapy in patients 70 years and older as an alternative management modality.

Materials And Methods: A total of 649 patients across 11 UK sites receiving focal high-intensity focused ultrasound or cryotherapy between June 2006 and July 2020 reported within the UK-based HEAT (HIFU Evaluation and Assessment of Treatment) and ICE (International Cryotherapy Evaluation) registries were evaluated.

Reducing the Frequency of Follow-up Cystoscopy in Low-grade pTa Non-muscle-invasive Bladder Cancer Using the ADXBLADDER Biomarker.

Background: Non-muscle-invasive bladder cancer (NMIBC) is one of the most expensive cancers owing to frequent follow-up cystoscopies for detection of recurrence.

Objective: To assess if the noninvasive ADXBLADDER urine test could permit a less intensive surveillance schedule for patients with low-grade (LG) pTa tumor without carcinoma in situ (CIS) at the previous diagnosis.

Design, Setting, And Participants: In a prospective, double-blind, multicenter study, 629 patients underwent follow-up cystoscopy, transurethral resection of bladder tumor/biopsy of suspect lesions, and ADXBLADDER testing.

Clinical Impact of the Predict Prostate Risk Communication Tool in Men Newly Diagnosed with Nonmetastatic Prostate Cancer: A Multicentre Randomised Controlled Trial.

Background: Predict Prostate is a freely available online personalised risk communication tool for men with nonmetastatic prostate cancer. Its accuracy has been assessed in multiple validation studies, but its clinical impact among patients has not hitherto been assessed.

Objective: To assess the impact of the tool on patient decision-making and disease perception.

Feasibility of Comparative Health Research Outcome of Novel Surgery in prostate cancer (IP4-CHRONOS): statistical analysis plan for the randomised feasibility phase of the CHRONOS study.

Background: Randomised controlled trials (RCTs) for surgical interventions have often proven difficult with calls for innovative approaches. The Imperial Prostate (IP4) Comparative Health Research Outcomes of Novel Surgery in prostate cancer (IP4-CHRONOS) study aims to deliver level 1 evidence on outcomes following focal therapy which involves treating just the tumour rather than whole-gland surgery or radiotherapy. Our aim is to test the feasibility of two parallel RCTs within an overarching strategy that fits with existing patient and physician equipoise and maximises the chances of success and potential benefit to patients and healthcare services.

Conventional radical versus focal treatment for localised prostate cancer: a propensity score weighted comparison of 6-year tumour control.

Background: For localised prostate cancer, focal therapy offers an organ-sparing alternative to radical treatments (radiotherapy or prostatectomy). Currently, there is no randomised comparative effectiveness data evaluating cancer control of both strategies.

Methods: Following the eligibility criteria PSA < 20 ng/mL, Gleason score ≤ 7 and T-stage ≤ T2c, we included 830 radical (440 radiotherapy, 390 prostatectomy) and 530 focal therapy (cryotherapy, high-intensity focused ultrasound or high-dose-rate brachytherapy) patients treated between 2005 and 2018 from multicentre registries in the Netherlands and the UK.

Additional Treatments to the Local tumour for metastatic prostate cancer-Assessment of Novel Treatment Algorithms (IP2-ATLANTA): protocol for a multicentre, phase II randomised controlled trial.

Introduction: Survival in men diagnosed with synchronous metastatic prostate cancer has increased following the use of upfront systemic treatment, using chemotherapy and other novel androgen receptor targeted agents, in addition to standard androgen deprivation therapy (ADT). Local cytoreductive and metastasis-directed interventions are hypothesised to confer additional survival benefit. In this setting, IP2-ATLANTA will explore progression-free survival (PFS) outcomes with the addition of sequential multimodal local and metastasis-directed treatments compared with standard care alone.

Focal therapy compared to radical prostatectomy for non-metastatic prostate cancer: a propensity score-matched study.

Introduction: Focal therapy (FT) ablates areas of prostate cancer rather than treating the whole gland. We compared oncological outcomes of FT to radical prostatectomy (RP).

Methods: Using prospective multicentre databases of 761 FT and 572 RP cases (November/2005-September/2018), patients with PSA < 20 ng/ml, Gleason  View Article and Find Full Text PDF

A Comparison of Prostate Cancer Detection between Visual Estimation (Cognitive Registration) and Image Fusion (Software Registration) Targeted Transperineal Prostate Biopsy.

Purpose: We compared clinically significant prostate cancer detection by visual estimation and image fusion targeted transperineal prostate biopsy.

Materials And Methods: This multicenter study included patients with multiparametric magnetic resonance imaging lesions undergoing visual estimation or image fusion targeted transperineal biopsy (April 2017-March 2020). Propensity score matching was performed using demographics (age and ethnicity), clinical features (prostate specific antigen, prostate volume, prostate specific antigen density and digital rectal examination), multiparametric magnetic resonance imaging variables (number of lesions, PI-RADS® score, index lesion diameter, whether the lesion was diffuse and radiological T stage) and biopsy factors (number of cores, operator experience and anesthetic type).

Comparison of the performances of the ADXBLADDER test and urinary cytology in the follow-up of non-muscle-invasive bladder cancer: a blinded prospective multicentric study.

Objective: To compare directly the performance of the ADXBLADDER test with that of cytology in the detection of non-muscle-invasive bladder cancer (NMIBC) recurrences.

Background: ADXBLADDER is a urine test based on the detection of MCM5, a DNA licensing factor expressed in all cells capable of dividing. Expression is usually restricted to the basal stem cell compartment; however, in malignancy, MCM5-expressing cells can be found throughout the epithelium.

IKBKE activity enhances AR levels in advanced prostate cancer via modulation of the Hippo pathway.

Resistance to androgen receptor (AR) targeting therapeutics in prostate cancer (PC) is a significant clinical problem. Mechanisms by which this is accomplished include AR amplification and expression of AR splice variants, demonstrating that AR remains a key therapeutic target in advanced disease. For the first time we show that IKBKE drives AR signalling in advanced PC.

Diagnostic Accuracy of MCM5 for the Detection of Recurrence in Nonmuscle Invasive Bladder Cancer Followup: A Blinded, Prospective Cohort, Multicenter European Study.

Purpose: Detection of MCM5 containing cells in urine has been shown to be indicative of the presence of a bladder tumor on primary diagnosis. In this study we evaluate diagnostic performance of ADXBLADDER in patients undergoing cystoscopic surveillance in nonmuscle invasive bladder cancer followup.

Materials And Methods: A multicenter prospective blinded study was performed at 21 European centers with patients undergoing cystoscopy for nonmuscle invasive bladder cancer surveillance, diagnosed in the preceding 2 years.

Comparative Healthcare Research Outcomes of Novel Surgery in prostate cancer (IP4-CHRONOS): A prospective, multi-centre therapeutic phase II parallel Randomised Control Trial.

Introduction: Focal therapy (FT) targets individual areas of cancer within the prostate, providing oncological control with minimal side-effects. Early evidence demonstrates encouraging short-medium-term outcomes. With no randomized controlled trials (RCT) comparing FT to radical therapies, Comparative Healthcare Research Outcomes of Novel Surgery in prostate cancer (CHRONOS) will compare the cancer control of these two strategies.

Clinical utility and cost modelling of the phi test to triage referrals into image-based diagnostic services for suspected prostate cancer: the PRIM (Phi to RefIne Mri) study.

Background: The clinical pathway to detect and diagnose prostate cancer has been revolutionised by the use of multiparametric MRI (mpMRI pre-biopsy). mpMRI however remains a resource-intensive test and is highly operator dependent with variable effectiveness with regard to its negative predictive value. Here we tested the use of the phi assay in standard clinical practice to pre-select men at the highest risk of harbouring significant cancer and hence refine the use of mpMRI and biopsies.

A Novel, non-invasive Test Enabling Bladder Cancer Detection in Urine Sediment of Patients Presenting with Haematuria-A Prospective Multicentre Performance Evaluation of ADXBLADDER.

Bladder cancer is the sixth most commonly diagnosed cancer in the European Union. Here, we evaluate the performance of a novel, commercially available enzyme-linked immunosorbent assay utilising MCM5 antibodies (ADXBLADDER; Arquer Diagnostics Ltd, Sunderland, UK) for the detection of bladder cancer, in a blinded, prospective study of 856 patients, across seven centres, presenting with haematuria. The results were compared with the patients' clinical data and final diagnosis as defined by the results of the imaging and cystoscopy, with a prevalence of bladder cancer of 8.

A novel CRISPR-engineered prostate cancer cell line defines the AR-V transcriptome and identifies PARP inhibitor sensitivities.

Resistance to androgen receptor (AR)-targeted therapies in prostate cancer (PC) is a major clinical problem. A key mechanism of treatment resistance in advanced PC is the generation of alternatively spliced forms of the AR termed AR variants (AR-Vs) that are refractory to targeted agents and drive tumour progression. Our understanding of how AR-Vs function is limited due to difficulties in distinguishing their discriminate activities from full-length AR (FL-AR).

Culture and Lentiviral Transduction of Benign Prostatic Hyperplasia (BPH) Samples.

To assess oncogenic potential, classical transformation assays are based on cell line models. However, cell line based models do not reflect the complexity of human tissues. We thus developed an inducible expression system for gene expression in human tissues, which maintain native tissue architecture, such as epithelia and stroma.

Molecular mechanism of the TP53-MDM2-AR-AKT signalling network regulation by USP12.

The TP53-MDM2-AR-AKT signalling network plays a critical role in the development and progression of prostate cancer. However, the molecular mechanisms regulating this signalling network are not completely defined. By conducting transcriptome analysis, denaturing immunoprecipitations and immunopathology, we demonstrate that the TP53-MDM2-AR-AKT cross-talk is regulated by the deubiquitinating enzyme USP12 in prostate cancer.

Human ex vivo prostate tissue model system identifies ING3 as an oncoprotein.

Background: Although the founding members of the INhibitor of Growth (ING) family of histone mark readers, ING1 and ING2, were defined as tumour suppressors in animal models, the role of other ING proteins in cellular proliferation and cancer progression is unclear.

Methods: We transduced ex vivo benign prostate hyperplasia tissues with inducible lentiviral particles to express ING proteins. Proliferation was assessed by H3S10 immunohistochemistry (IHC).

Ubiquitin-specific protease 12 interacting partners Uaf-1 and WDR20 are potential therapeutic targets in prostate cancer.

Unlabelled: The androgen receptor (AR) is a key transcription factor in the initiation and progression of prostate cancer (PC) and is a major therapeutic target for the treatment of advanced disease. Unfortunately, current therapies are not curative for castration resistant PC and a better understanding of AR regulation could identify novel therapeutic targets and biomarkers to aid treatment of this disease. The AR is known to be regulated by a number of post-translational modifications and we have recently identified the deubiquitinating enzyme Usp12 as a positive regulator of AR.