Feasibility of aspirin and/or vitamin D3 for men with prostate cancer on active surveillance with Prolaris® testing.

Objectives: To test the feasibility of a randomised controlled trial (RCT) of aspirin and/or vitamin D3 in active surveillance (AS) low/favourable intermediate risk prostate cancer (PCa) patients with Prolaris® testing. Patients and Methods: Newly-diagnosed low/favourable intermediate risk PCa patients (PSA ≤ 15 ng/ml, International Society of Urological Pathology (ISUP) Grade Group ≤2, maximum biopsy core length <10 mm, clinical stage ≤cT2c) were recruited into a multi-centre randomised, double-blind, placebo-controlled study (ISRCTN91422391, NCT03103152). Participants were randomised to oral low dose (100 mg), standard dose (300 mg) aspirin or placebo and/or vitamin D3 (4000 IU) versus placebo in a 3 × 2 factorial RCT design with biopsy tissue Prolaris® testing. The primary endpoint was trial acceptance/entry rates. Secondary endpoints included feasibility of Prolaris® testing, 12-month disease re-assessment (imaging/biochemical/histological), and 12-month treatment adherence/safety. Disease progression was defined as any of the following (i) 50% increase in baseline PSA, (ii) new Prostate Imaging-Reporting and Data System (PI-RADS) 4/5 lesion(s) on multi-parametric MRI where no previous lesion, (iii) 33% volume increase in lesion size, or radiological upstaging to ≥T3, (iv) ISUP Grade Group upgrade or (v) 50% increase in maximum cancer core length. Results: Of 130 eligible patients, 104 (80%) accepted recruitment from seven sites over 12 months, of which 94 patients represented the per protocol population receiving treatment. Prolaris® testing was performed on 76/94 (81%) diagnostic biopsies. Twelve-month disease progression rate was 43.3%. Assessable 12-month treatment adherence in non-progressing patients to aspirin and vitamin D across all treatment arms was 91%. Two drug-attributable serious adverse events in 1 patient allocated to aspirin were identified. The study was not designed to determine differences between treatment arms. Conclusion: Recruitment of AS PCa patients into a multi-centre multi-arm placebo-controlled RCT of minimally-toxic adjunctive oral drug treatments with molecular biomarker profiling is acceptable and safe. A larger phase III study is needed to determine optimal agents, intervention efficacy, and outcome-associated biomarkers.

Comparing an Imaging-guided Pathway with the Standard Pathway for Staging Muscle-invasive Bladder Cancer: Preliminary Data from the BladderPath Study.

Transurethral resection of bladder tumour (TURBT) is central to the diagnosis of muscle-invasive bladder cancer (MIBC). With the oncological safety of TURBT unknown, staging inaccuracies commonplace, and correct treatment of MIBC potentially delayed, multiparametric magnetic resonance imaging (mpMRI) may offer rapid, accurate, and noninvasive diagnosis of MIBC. BladderPath is a randomised trial comparing risk-stratified (5-point Likert scale) image-directed care with TURBT for patients with newly diagnosed BC. To date, we have screened 279 patients and randomised 113. Here we report on the first 100 participants to complete staging: 48 in pathway 1 (TURBT) and 52 in pathway 2 (mpMRI for possible MIBC, Likert 3-5). Fifty of 52 participants designated Likert 1-2 (probable NMIBC) from both pathways were confirmed as having NMIBC (96%). Ten of 11 cases diagnosed as NMIBC by mpMRI have been pathologically confirmed as NMIBC, and 10/15 cases diagnosed as MIBC by mpMRI have been treated as MIBC (5 participants underwent TURBT). The specificity of mpMRI for identification of MIBC remains a limitation. These initial experiences indicate that it is feasible to direct possible MIBC patients to mpMRI for staging instead of TURBT. Furthermore, a 5-point Likert scale accurately identifies patients with low risk of MIBC (Likert 1-2), and flexible cystoscopy biopsies appear sufficient for diagnosing BC. PATIENT SUMMARY: We are conducting a clinical trial to assess whether some bladder tumour surgery can be replaced by magnetic resonance imaging scans to determine the stage of the cancer in patients whose tumours appear to be invasive. Our early data suggest that this approach is feasible. The data also show that using a visual score ('Likert scale') can help to identify bladder tumours that are very unlikely to be invasive, and that taking a biopsy in the outpatient clinic when first inspecting the bladder via a camera (diagnostic flexible cystoscopy) is useful for confirming bladder cancer.

Low serum 25-hydroxyvitamin D is associated with increased bladder cancer risk: A systematic review and evidence of a potential mechanism.

The development of some cancers is associated with vitamin D deficiency. We suggest that reduced conversion of 25-hydroxyvitamin D (25(OH)D) to 1,25-dihydroxyvitamin D (1,25(OH)2D) and the resulting modification of tissue specific immune responses may be key. Non-muscle-invasive bladder cancer is highly immunoresponsive and stimulation of an inflammatory response by intravesical bacillus Calmette-Guerin (BCG) treatment prevents recurrence. To assess the relationship between serum 25(OH)D and bladder cancer risk we conducted a systematic review. To test our hypothesis, the synthesis of 1,25(OH)2D by human bladder epithelial cell lines (T24/83 and RT4) was examined. Studies were identified from Medline, Web of Science, Embase and Cochrane library (limited to English language, humans and 1990-2018). After removal of duplicates, title and abstract review 6 full papers were appraised. Low vitamin D levels were associated with bladder cancer risk in 5/6 of the studies. Both cell lines express the vitamin D receptor, 25-hydroxyvitamin D 1α-hydroxylase (1α-OHase) and 24-hydroxylase (24-OHase) mRNA, which was induced by 1,25(OH)2D. 24-OHase mRNA was also increased by 25(OH)D indicating 1α-OHase activity. Both cell types expressed TLR1,2,4 and the TLR partners MyD88 and CD14mRNA. Cathelicidin mRNA was undetectable in both cell lines but was induced by 1,25(OH)2D and 25(OH)D in RT4 cells. The systematic review demonstrated that bladder cancer risk correlates with serum 25(OH)D levels. In addition, we have shown that transitional epithelial cells express functional vitamin D signaling and can synthesize sufficient 1,25(OH)2D to stimulate a local immune response. We suggest that in order to maintain optimal immune surveillance within the bladder adequate levels of serum 25(OH)D are required for direct synthesis of 1,25(OH)2D by bladder epithelial cells.

Effects of Initiating or Switching to a Six-Monthly Triptorelin Formulation on Prostate Cancer Patient-Healthcare Interactions and Hospital Resource Use: a Real-World, Retrospective, Non-Interventional Study.

INTRODUCTION: Luteinising hormone-releasing hormone agonist (LHRHa) injections are currently used in the treatment of advanced prostate cancer, but the frequency of injections may represent a burden to patients and healthcare services. The aim of this study was to collect real-world evidence about clinical and practical outcomes for patients with prostate cancer initiating six-monthly triptorelin, or switching from shorter-acting formulations to six-monthly triptorelin, in hospitals in the DEcapeptyl SERVice Evaluation project. METHODS: Up to 2 years of data were collected retrospectively by physicians from records of 88 patients receiving six-monthly triptorelin at three centres. The primary outcome measure was the change in the number of patient-healthcare interactions (patient reviews, prostate-specific antigen (PSA) tests, and LHRHa injections) over a 24-month treatment period. RESULTS: This analysis included 47 patients newly initiated on six-monthly triptorelin and 41 who received 12 months of a one- or three-monthly LHRHa before switching to six-monthly triptorelin. After switching to six-monthly triptorelin, there was a statistically significant reduction in patient reviews (46.8%), injections (46.8%), and PSA tests (26.6%; all P < 0.0001). The total number of patient-healthcare interactions was significantly reduced (41.5%; P < 0.0001). Based upon cost of these interactions only, the cost reduction of switching to six-monthly triptorelin was £10,214.85 (£249.14 per patient) over 12 months. At 12 months, median PSA was 1.30 ng/mL (23.50 ng/mL at diagnosis) for newly treated patients and 0.24 ng/mL (0.35 ng/mL at switch) for patients who had switched treatment. No safety issues were identified. CONCLUSION: Switching from one- or three-monthly LHRHa to six-monthly triptorelin significantly reduced patient-healthcare interactions and associated costs while maintaining PSA control over a 12-month treatment period. This not only translates into healthcare savings but may release men from the restriction of repeated healthcare interactions and thus improve the overall patient experience as the population of long-term prostate cancer survivors continues to increase. FUNDING: Ipsen Limited.

'Special k' and a loss of cell-to-cell adhesion in proximal tubule-derived epithelial cells: modulation of the adherens junction complex by ketamine.

Ketamine, a mild hallucinogenic class C drug, is the fastest growing 'party drug' used by 16-24 year olds in the UK. As the recreational use of Ketamine increases we are beginning to see the signs of major renal and bladder complications. To date however, we know nothing of a role for Ketamine in modulating both structure and function of the human renal proximal tubule. In the current study we have used an established model cell line for human epithelial cells of the proximal tubule (HK2) to demonstrate that Ketamine evokes early changes in expression of proteins central to the adherens junction complex. Furthermore we use AFM single-cell force spectroscopy to assess if these changes functionally uncouple cells of the proximal tubule ahead of any overt loss in epithelial cell function. Our data suggests that Ketamine (24-48 hrs) produces gross changes in cell morphology and cytoskeletal architecture towards a fibrotic phenotype. These physical changes matched the concentration-dependent (0.1-1 mg/mL) cytotoxic effect of Ketamine and reflect a loss in expression of the key adherens junction proteins epithelial (E)- and neural (N)-cadherin and ß-catenin. Down-regulation of protein expression does not involve the pro-fibrotic cytokine TGFß, nor is it regulated by the usual increase in expression of Slug or Snail, the transcriptional regulators for E-cadherin. However, the loss in E-cadherin can be partially rescued pharmacologically by blocking p38 MAPK using SB203580. These data provide compelling evidence that Ketamine alters epithelial cell-to-cell adhesion and cell-coupling in the proximal kidney via a non-classical pro-fibrotic mechanism and the data provides the first indication that this illicit substance can have major implications on renal function. Understanding Ketamine-induced renal pathology may identify targets for future therapeutic intervention.

Introduction of an enhanced recovery protocol for radical cystectomy.

OBJECTIVE: To describe and assess an enhanced recovery protocol (ERP) for the peri-operative management of patients undergoing radical cystectomy (RC), which was started at our institution on 1 October 2005, as RC is associated with increased morbidity and longer inpatient stays than other major urological procedures. PATIENTS AND METHODS: An ERP was introduced in our institution that focused on reduced bowel preparation, and standardized feeding and analgesic regimens. In all, 112 consecutive patients were compared, i.e. 56 before implementing the ERP and 56 since introducing the ERP. The primary outcome measures were duration of total inpatient stay and interval from surgery to discharge, and the morbidity and mortality. Data were analysed retrospectively from cancer network and hospital records. RESULTS: The demographics of the two groups showed no significant difference in age, gender distribution, American Society of Anesthesiologists grade, or type of urinary diversion. Re-admission, mortality and morbidity rates showed no statistically significant difference between the groups. The median (interquartile range) duration of hospital stay was 17 (15-23) days in the no-ERP group, and 13 (11-17) days in the ERP group (significantly different, P < 0.001, Wilcoxon rank-sum test). The median duration of recovery after RC was 15 (13-21) days in the no-ERP group and 12 (10-15) days in the ERP group (significantly different, P = 0.001, Wilcoxon rank-sum test). CONCLUSION: The introduction of an ERP was associated with significantly reduced hospital stay, with no deleterious effect on morbidity or mortality.

Hereditary urological cancer syndromes.

Hereditary urological cancer syndromes are rare, but it is important that they are recognized because they have important prognostic implications; prompt diagnosis can dramatically improve patient outcomes. The urologist or urological oncologist should, therefore, ascertain which tumors of the many seen in clinical practice warrant referral for the opinion of a clinical geneticist. Despite the aggressive natural history of most inherited urological cancer syndromes, organ-preserving treatments are desirable because these syndromes predispose affected patients to the formation of multifocal and metachronous tumors. Identification of the molecular mechanisms that underlie carcinogenesis in both familial and sporadic urological cancers has, in some cases, resulted in novel and specifically targeted approaches to therapy. Patients who present with early-onset or multiple tumors should be carefully investigated for the presence of a hereditary cancer syndrome, and once a diagnosis is made, appropriate screening should be instigated for family members to enable early detection of tumors both within and outside the urogenital tract.