'Pain-free TRUS B': a phase 3 double-blind placebo-controlled randomized trial of methoxyflurane with periprostatic local anaesthesia to reduce the discomfort of transrectal ultrasonography-guided prostate biopsy (ANZUP 1501).

OBJECTIVE: To determine whether the addition of inhaled methoxyflurane to periprostatic infiltration of local anaesthetic (PILA) during transrectal ultrasonography-guided prostate biopsies (TRUSBs) improved pain and other aspects of the experience. PATIENTS AND METHODS: We conducted a multicentre, placebo-controlled, double-blind, randomized phase 3 trial, involving 420 men undergoing their first TRUSB. The intervention was PILA plus a patient-controlled device containing either 3 mL methoxyflurane, or 3 mL 0.9% saline plus one drop of methoxyflurane to preserve blinding. The primary outcome was the pain score (0-10) reported by the participant after 15 min. Secondary outcomes included ratings of other aspects of the biopsy experience, willingness to undergo future biopsies, urologists' ratings, biopsy completion, and adverse events. RESULTS: The mean (SE) pain scores 15 min after TRUSB were 2.51 (0.22) in those assigned methoxyflurane vs 2.82 (0.22) for placebo (difference 0.31, 95% confidence interval [CI] -0.75 to 0.14; P = 0.18). Methoxyflurane was associated with better scores for discomfort (difference -0.48, 95% CI -0.92 to -0.03; P = 0.035, adjusted [adj.] P = 0.076), whole experience (difference -0.50, 95% CI -0.92 to -0.08; P = 0.021, adj. P = 0.053), and willingness to undergo repeat biopsies (odds ratio 1.67, 95% CI 1.12-2.49; P = 0.01) than placebo. Methoxyflurane resulted in higher scores for drowsiness (difference +1.64, 95% CI 1.21-2.07; P < 0.001, adj. P < 0.001) and dizziness (difference +1.78, 95% CI 1.31-2.24; P < 0.001, adj. P < 0.001) than placebo. There was no significant difference in the number of ≥ grade 3 adverse events. CONCLUSIONS: We found no evidence that methoxyflurane improved pain scores at 15 min, however, improvements were seen in patient-reported discomfort, overall experience, and willingness to undergo repeat biopsies.

The MURAL collection of prostate cancer patient-derived xenografts enables discovery through preclinical models of uro-oncology.

Preclinical testing is a crucial step in evaluating cancer therapeutics. We aimed to establish a significant resource of patient-derived xenografts (PDXs) of prostate cancer for rapid and systematic evaluation of candidate therapies. The PDX collection comprises 59 tumors collected from 30 patients between 2012-2020, coinciding with availability of abiraterone and enzalutamide. The PDXs represent the clinico-pathological and genomic spectrum of prostate cancer, from treatment-naïve primary tumors to castration-resistant metastases. Inter- and intra-tumor heterogeneity in adenocarcinoma and neuroendocrine phenotypes is evident from bulk and single-cell RNA sequencing data. Organoids can be cultured from PDXs, providing further capabilities for preclinical studies. Using a 1 x 1 x 1 design, we rapidly identify tumors with exceptional responses to combination treatments. To govern the distribution of PDXs, we formed the Melbourne Urological Research Alliance (MURAL). This PDX collection is a substantial resource, expanding the capacity to test and prioritize effective treatments for prospective clinical trials in prostate cancer.

High dose rate brachytherapy boost for prostate cancer: Biochemical control and the impact of transurethral resection of the prostate and hydrogel spacer insertion on toxicity outcomes.

INTRODUCTION: To examine the long-term outcomes of high dose rate brachytherapy boost (HDR-BT) combined with external beam radiotherapy (EBRT) for intermediate and high-risk prostate cancer patients. METHODS: Data from 95 patients who underwent combined EBRT (50.4 Gy) and HDR-BT to the prostate between 2010 and 2017 were retrospectively analysed. Biochemical progression free survival (bPFS), local recurrence free survival (LRFS), metastatic free survival (MFS) and overall survival (OS) were estimated using Kaplan-Meier method. Regression analysis was conducted to identify important predictors of outcomes. RESULTS: A total of 24 patients received an initial HDR-BT dose of 18 Gy in three fractions, with the remaining 71 patients receiving 16 Gy in two fractions as per departmental protocol changes. Most patients (88%) received androgen deprivation therapy. A transurethral resection of the prostate (TURP) was performed in 14 patients and hydrogel spacers (HS) were used in 30 patients. Median follow-up was 58 months. The 5-year bPFS, LRFS, MFS and OS were 92%, 100%, 92% and 88%. Univariate regression revealed no statistical association between patient characteristics and time to relapse (all P > 0.1). Late > grade 2 genitourinary (GU) toxicity was 6.3%. The use of HS or prior TURP had no impact on late GU toxicity. Late Grade 1 gastrointestinal (GI) toxicity was 5.3%. CONCLUSION: The combined HDR-BT with EBRT resulted in excellent bPFS. The cumulative risk of late GU and GI toxicity was low and can be further improved with preventative strategies such as a pre-emptive TURP and/or HS insertion.

Fiducial markers: can the urologist do better?

INTRODUCTION: Radiotherapy to the bladder has a risk of toxicity to pelvic structures, which can be reduced by using fiducial markers for targeting. Injectable contrast offers an alternative marker to gold seeds, which may fall out or exacerbate scarring. Combining contrast agents with tissue glue can minimize dispersion through tissue, enhancing its utility. We evaluated combinations of contrast agents and tissue glue using porcine bladder, for feasibility and utility as fiducial markers to aid image-guided radiotherapy. METHODS: Different contrast agents (Lipiodol ultra or Urografin) were combined with different tissue glues (Histoacryl, Tisseal or Glubran2). The mixtures were endoscopically injected into porcine bladder submucosa to identify the area of interest with multiple fiducial markers. The porcine bladders were imaged within a phantom porcine pelvis using standard radiation therapy imaging modalities. The feasibility as an injectable fiducial marker and visibility of each fiducial marker on imaging were scored as binary outcomes by two proceduralists and two radiation therapists, respectively. RESULTS: Lipiodol-glue combinations were successfully administered as multiple fiducials that were evident on CT and CBCT. Lipiodol with Histoacryl or Glubran2 was visible on kV imaging. The Lipiodol Glubran2 combination was deemed subjectively easiest to use at delivery, and a better fiducial on KV imaging. CONCLUSION: This study demonstrates the feasibility of mixing contrast medium Lipiodol with Histoacryl or Glubran2 tissue glue, which, injected endoscopically, provides discrete and visible fiducial markers to aid image-guided radiotherapy. Although promising, further study is required to assess the durability of these markers through a course of radiotherapy.

Pelvic lymph node dissection during radical cystectomy for muscle-invasive bladder cancer.

Radical cystectomy is the gold-standard treatment option for muscle-invasive and metastatic bladder cancer. At the time of cystectomy, up to 25% of patients harbour metastatic lymph node deposits. These deposits most frequently occur in the obturator fossa, but can be as proximal as the interaortocaval region. Thus, the use of concurrent pelvic lymph node dissection (PLND) with cystectomy has been increasingly reported. Data from studies including many patients suggest substantial oncological benefit in PLND cohorts versus non-PLND cohorts, irrespective of pathological nodal status. Additionally, PLND provides useful prognostic information, including disease burden, lymph node density, and extracapsular extension of metastatic lymph nodes. Accordingly, the National Comprehensive Cancer Network guidelines advocate the use of PLND during radical cystectomy for muscle-invasive bladder cancer. Despite this recommendation, a lack of consensus exists regarding the optimal PLND template. Comparative series suggest that extended PLND provides improved recurrence-free survival and cancer-specific survival compared with more limited PLND templates. More extensive templates (such as super-extended PLND) provide no additional survival benefit at the potential cost of increased operative time and patient morbidity. In addition to extended PLND templates, increased nodal harvest confers an oncological benefit in patients with node-positive disease or in patients with node-negative disease. Accordingly, recommendations for a minimum nodal yield have been proposed. Despite the growing body of evidence, formal recommendations by oncological and urological authoritative bodies have been limited owing to the lack of randomized data and level I evidence.

Interpolation to define clinical tumor stage in prostate cancer using clinical description of digital rectal examination.

AIM: This study aims to assess characteristics of patients with prostate cancer for whom clinical T stage category (cT) was not documented in the medical record and assess whether specialists had concordant conclusions regarding cT based on digital rectal examination (DRE) notes. METHODS: Data from the Prostate Cancer Outcome Registry - Victoria (PCOR-Vic) were interrogated. Four specialists independently assigned cT to DRE notes. Words, or part thereof, associated with agreement between clinicians were identified. RESULTS: Of the 10 587 men, cT was documented in 8758 (82.7%) cases. Multivariate analysis indicated that poor cT documentation was associated with older patient age (odds ratio [OR] 0.80, 95% confidence interval [CI] 0.66-0.99 if 75.1-85 years; OR 0.50, 95%CI 0.36-0.72 if >85 years); diagnosis via transperineal compared to transrectal ultrasound-guided biopsy (TRUS) (OR 0.68, 95%CI 0.51-0.91); diagnosed in a private hospital (OR 0.85, 95%CI 0.75-0.96); and a diagnostic Gleason score of >8 compared to ≤6 (OR 0.59, 95%CI = 0.48-0.73). cT was more likely documented in men diagnosed via transurethral resection of prostate (OR 2.06, 95%CI 1.64-2.58) compared to TRUS and/or if receiving treatment in a radiotherapy center (OR 3.44, 95%CI 2.80-4.23 for external beam radiotherapy; OR 3.57 95%CI 2.44-5.23 for brachytherapy and OR 1.34, 95%CI 1.06-1.69 for combination surgery and radiotherapy) compared to those undergoing radical prostatectomy. Agreement in cT assignment ranged from kappa of 0.158 to 0.582. Stem word components in DRE notes associated with poorest level of agreement were "abnorm," "hard," "nodul" and those with highest level of agreement were terms "benign" and "smooth." CONCLUSIONS: Mode of diagnosis/subsequent treatment, and cancer characteristics were associated with cT documentation. Third party interpretation of clinical notes is problematic.

Trends in the surgical treatment of benign prostatic hyperplasia in a tertiary hospital.

BACKGROUND: To assess current treatment trends and perioperative outcomes of transurethral resection of the prostate (TURP) and photoselective vaporization of the prostate (PVP) in a tertiary institution. METHODS: We prospectively collected a database of all patients undergoing TURP and PVP for benign prostatic hyperplasia (BPH) at a tertiary hospital between January 2011 and December 2013. Patient characteristics such as length of stay, readmission, anticoagulation status, American Society of Anesthesiologists (ASA) score and need for blood transfusion were recorded and analysed. RESULTS: In total, 560 cases were included: 204 (36.4%) underwent TURP and 356 (63.6%) PVP. Patients undergoing PVP had higher ASA scores (P < 0.001) and were more frequently on continuing anticoagulant therapy (P < 0.001). With regards to non-aspirin/asasantin coagulation therapy, 61 (17.1%) patients underwent PVP with their anticoagulants continued while no patients who received TURP continued anticoagulation. Blood transfusion percentages were similar at 1.0% for TURP and 1.7% for PVP but readmission proportions were higher after PVP (32 patients, 9.0%) compared to TURP (10 patients, 4.9%). These differences were attenuated when excluding patients continuing anticoagulation during the procedure. CONCLUSION: At our institution, the use of PVP has been increasing on a year-by-year basis. The results of the current study demonstrated that PVP is safe in patients with increased anaesthetic risk or on active anticoagulation when compared to traditional TURP. While this makes PVP an attractive alternative to TURP in high-risk anticoagulated patients, these patients may have complex post-discharge issues that should be addressed during the informed consent process.

The role of cystectomy in elderly patients - a multicentre analysis.

INTRODUCTION: Life expectancy in developed countries is continuously increasing. Hence elderly patients are becoming more common in our clinical practice. Currently, one of the greatest challenges of medicine is balancing the life expectancy of elderly patients against aggressive treatments that carry significant risks. OBJECTIVE: To outline the complications and survival in surgical patients 80 years and over undergoing radical cystectomy for bladder cancer. PATIENTS AND METHODS: A review of a radical cystectomy in elderly recorded in four different institutional prospective databases during the period between 1991 and 2014. Clinical and pathologic features, complications and survival were evaluated. RESULTS: A total of 111 patients were available. Median (range) age 82.2 (80-89) years. Seventeen women and 94 men. Regarding the ASA score, 6 patients were ASA I, 47 patients were ASA II, 49 patients ASA III and 9 ASA IV. Prior to surgery, 48 patients had hydronephrosis. The median (range) creatinine series was 1.1 (0.71-11.1) ng/dL. In 88 cases an ileal conduit was performed, 17 a cutaneous ureterostomy diversion, 5 neobladders and 1 ureterosigmoidostomy case. The median (range) operative time was 230 (120-420) min and a total of 97 patients required blood transfusion. The median (range) hospital stay was 14 (7-126) days. The early and late complication rates were 50.4% and 32%, respectively. A total of 14 patients (12.6%) required surgical reintervention. Eight patients (7.2%) died in the immediate postoperative period. The readmission rate of the series was 27.2%. The mean follow-up of the series was 18 (0.27-134.73) months. During this period 66 patients died, 52 of them due to the tumor. Twelve month tumour progression free survival was 83.9% for ≤pT1, 70.2% for pT2 and 36% for ≥pT3, respectively. Twelve month cancer specific survival was 85.6% for ≤pT1, 75.1% for pT2 and 42.5% for ≥pT3, respectively. CONCLUSION: Radical cystectomy in elderly population is an aggressive surgical treatment with a significant complication rate, hospital readmission and perioperative mortality rate. Careful selection of patients is essential in order to minimize the complications of this surgery and balance benefits against risks in the elderly population. Tumour progression and cancer specific survival are poor for patients with ≥pT3 disease. Alternatives such as tri-modality therapy need to be considered within a multi-disciplinary approach. More data is required to determine which sub-groups of elderly patients would benefit from a complication, survival and quality of life perspective.