The SUB-urothelial DUrvalumab InjEction-1 (SUBDUE-1) trial: first-in-human trial in patients with bladder cancer.

OBJECTIVES: To assess the safety of sub-urothelial injection of durvalumab and examine the impact on tissue and circulating immune cell populations. PATIENTS AND METHODS: The patients were chemotherapy and immunotherapy naïve (bacille Calmette-Guérin allowed) with non-metastatic muscle-invasive bladder cancer or non-muscle-invasive bladder cancer planned for radical cystectomy (RC). The study was a Phase Ib 3 + 3 dose-escalation design with sub-urothelial injection of durvalumab at three pre-determined doses (25, 75, 150 mg) diluted in 25 mL normal saline, injected at 25 locations (25 × 1 mL injections), at least 2 weeks before RC. RESULTS: A total of 11 patients were recruited (10 male, one female). No significant changes were reported on American Urological Association Symptom Score or O'Leary Interstitial Cystitis Scale. In all, 14 adverse events (AEs) were reported (10 Grade 1, three Grade 2, one Grade 3), none considered immune-related. No Grade 4 or 5 AEs were recorded. All the patients underwent RC. Tissue immune populations changed following durvalumab injection (P = 0.012), with a statistically significant increase in M2-macrophage (CD163) when comparing the 25-150 mg dose (P = 0.021). Basal/mixed cancers showed a larger CD163 increase than luminal cancers (P = 0.033). CONCLUSION: Sub-urothelial injection of durvalumab is feasible and safe without immune-related AEs and shows local immunological effects.

A phase I open label dose-escalation study to evaluate the tolerability, safety and immunological efficacy of sub-urothelial durvalumab injection in adults with muscle-invasive or high-risk non-muscle-invasive bladder cancer (SUBDUE-1, SUB-urothelial DUrvalumab injection-1 study): clinical trial protocol.

OBJECTIVES: This article presents the clinical trial protocol for a phase I open label dose-escalation study to evaluate the tolerability, safety and immunological efficacy of sub-urothelial durvalumab injection in adults with muscle-invasive or high-risk non-muscle-invasive bladder cancer (NMIBC), the SUB-urothelial DUrvalumab injection-1 study (SUBDUE-1). The primary objectives of this study are to assess the safety of sub-urothelial injection of durvalumab using patient reported outcome measures and observed local or systemic adverse events. The secondary objectives are to examine the local immunological efficacy of sub-urothelial administration of durvalumab. PATIENTS AND METHODS: The SUBDUE-1 trial will include adult patients with either high-risk NMIBC or MIBC, who are scheduled for radical cystectomy or who have refused or are unsuitable for systemic neoadjuvant chemotherapy. Three fixed total dose levels of durvalumab (25, 75, 150 mg) will be studied to identify a dose suitable to be taken forward into phase II trials. The primary endpoint is to evaluate the safety and tolerability of the trial intervention in terms of the incidence and severity of adverse events and the potential establishment of dose-limiting toxicities. The secondary efficacy endpoints include rates of pT0 status at resection, lymph node status, as well as the change in distribution of tumour-infiltrating lymphocytes and tumour-activated macrophages between pre- and post-injection bladder biopsies. Translational studies will focus on bladder tumour molecular sub-typing, immune infiltrate characterisation, and immune checkpoint protein expression relative to efficacy end-points. OUTCOME AND SIGNIFICANCE: If proven safe and effective, this novel strategy comprising sub-urothelial durvalumab injections aimed at promoting an anti-tumour immune reaction, will provide additional treatment options for reducing tumour recurrence and progression in treatment-naïve patients with high-risk NMIBC or in patients with bacille Calmette-Guérin-refractory NMIBC. Local administration of durvalumab may be associated with a reduced rate of immunological side-effects and lower costs when compared to systemic delivery.

Adaptation of a MR imaging protocol into a real-time clinical biometric ultrasound protocol for persons with spinal cord injury at risk for deep tissue injury: A reliability study.

BACKGROUND: High strain in soft tissues that overly bony prominences are considered a risk factor for pressure ulcers (PUs) following spinal cord impairment (SCI) and have been computed using Finite Element methods (FEM). The aim of this study was to translate a MRI protocol into ultrasound (US) and determine between-operator reliability of expert sonographers measuring diameter of the inferior curvature of the ischial tuberosity (IT) and the thickness of the overlying soft tissue layers on able-bodied (AB) and SCI using real-time ultrasound. MATERIAL AND METHODS: Part 1: Fourteen AB participants with a mean age of 36.7 ± 12.09 years with 7 males and 7 females had their 3 soft tissue layers in loaded and unloaded sitting measured independently by 2 sonographers: tendon/muscle, skin/fat and total soft tissue and the diameter of the IT in its short and long axis. Part 2: Nineteen participants with SCI were screened, three were excluded due to abnormal skin signs, and eight participants (42%) were excluded for abnormal US signs with normal skin. Eight SCI participants with a mean age of 31.6 ± 13.6 years and all male with 4 paraplegics and 4 tetraplegics were measured by the same sonographers for skin, fat, tendon, muscle and total. Skin/fat and tendon/muscle were computed. RESULTS: AB between-operator reliability was good (ICC = 0.81-0.90) for 3 soft tissues layers in unloaded and loaded sitting and poor for both IT short and long axis (ICC = -0.028 and -0.01). SCI between-operator reliability was good in unloaded and loaded for total, muscle, fat, skin/fat, tendon/muscle (ICC = 0.75-0.97) and poor for tendon (ICC = 0.26 unloaded and ICC = -0.71 loaded) and skin (ICC = 0.37 unloaded and ICC = 0.10). CONCLUSION: A MRI protocol was successfully adapted for a reliable 3 soft tissue layer model and could be used in a 2-D FEM model designed to estimate soft tissue strain as a novel risk factor for the development of a PU.

Fremantle protocol: Multicenter clinical outcomes for a pragmatic protocol for intravesical bacillus Calmette-Guerin.

OBJECTIVES: To examine the utility and efficacy of a multifaceted protocol for the administration of intravesical bacillus Calmette-Guerin (BCG) for non-muscle-invasive bladder cancer (NMIBC). SUBJECTS AND METHODS: A multicenter retrospective review was conducted among 83 patients undergoing Fremantle protocol intravesical BCG for NMIBC within 4 major hospitals in Western Australia between January 2016 and December 2018. The Fremantle protocol consists of weekly BCG instillations for 6 weeks during the induction phase, followed by monthly BCG instillations for 10 months during the maintenance phase with integrated clearance-to-proceed algorithms for urine MSU checks, flexible cystoscopies performed at 3 monthly intervals during maintenance BCG, and repeat GA cystoscopies with four quadrant bladder biopsies routinely obtained following the completion of induction and maintenance treatment. RESULTS: For patients undergoing Fremantle protocol BCG, 98.8% (82/83) and 75.9% (63/83) of patients completed their induction and maintenance courses of BCG, respectively. Induction BCG was delivered over a median duration of 35 days (range 34-84 days), and maintenance BCG was delivered over a median duration of 266 days (range 1-682 days). The tumor recurrence rate was 10.8% (9/83) at the time of post-induction biopsies, 2.4% (2/83) during maintenance treatment, 0% (0/60) at the time of post-maintenance biopsies, and 8.8% (5/57) after a median further follow-up of 16 months (range 0-51 months). CONCLUSION: The Fremantle protocol appears to be a safe and effective BCG regimen with several advantages over other BCG protocols, including high completion rates, low recurrence rates, and being highly pragmatic.

Anterior pelvic exenteration and synchronous bilateral nephroureterectomy for BK polyoma virus induced urothelial carcinoma of the bladder: A case report.

BK polyoma virus (BKV) is a known risk factor for the development of urothelial carcinoma. There is currently limited data on the management of BKV-induced urothelial carcinoma (BUC) of the bladder, with available data limited to case reports. It remains debatable whether radical cystectomy (RC) with removal of the native urinary tract or RC alone is the most optimal management for BUC of the bladder. BKV-induced urothelial carcinoma is rare, and its management is challenging in immunocompromised patients such as that of post-transplant patients. This case report provides additional insight into a rare disease, the management of which still lacks established guidelines and remains debatable.

'One Stop Prostate Clinic': prospective analysis of 1000 men attending a public same-day prostate cancer assessment and/or diagnostic clinic.

BACKGROUND: This study reported the outcomes of the first 1000 men to attend the One Stop Prostate Clinic, a consultant-led same-day prostate cancer assessment and diagnostic clinic at a tertiary public hospital. METHODS: Prospective audit of demographic and clinical data between August 2011 and November 2017 was conducted for same-day urological assessment and/or trans-rectal ultrasound (TRUS)-guided prostate biopsies with peri-prostatic infiltration local anaesthetic (PILA) and antibiotic prophylaxis. RESULTS: A total of 466 (47%) rural and 534 (53%) metropolitan men attended. Rural mean (range) age was 63 years (38-86) and 65 years (37-89) for metro men (P = 0.006). Rural median (range) prostate specific antigen (PSA) level was 6.7 g/mL (0.2-450) and 7.3 ng/mL (0.5-860) for metro men (P = 0.011). Twenty-five men (2.5%) refused/could not tolerate TRUS-guided biopsy using PILA. One hundred and fifty-one (15%) men had multi-parametric magnetic resonance imaging prior to TRUS biopsy and 876 (88%) men had prostate biopsies, with a new cancer diagnostic rate of 51% (443 men). Clinically significant prostate cancer was detected in 339 (34%) men. The overall infective complication rate requiring hospital admission rose from 1.4% to 2.9% after the prophylactic antibiotic regimen changed from six doses of 500 mg ciprofloxacin to a single dose of 500 mg (P = 0.398). CONCLUSION: This is the largest single institution prospective TRUS prostate biopsy series in Australasia. Biopsies using PILA were well tolerated with low complication rates and diagnosed a high rate of clinically significant prostate cancer. The 'One Stop' pathway generates efficiencies with combined assessment and diagnostic process, lessens demand on outpatient clinic appointments and reduces travel time and costs for rural men.

Transrectal ultrasound biopsy of the prostate: does it still have a role in prostate cancer diagnosis?

Transrectal ultrasound (TRUS) guided biopsy of the prostate has been a standard diagnostic approach for prostate cancer over the past thirty years. Today, the role of TRUS biopsy is being challenged by transperineal (TP) prostate biopsy due to concerns over the safety and diagnostic yield of TRUS biopsy. TRUS biopsy still offers a convenient, reliable and accessible tool for diagnosing prostate cancer in the majority of patients. It continues to play a role in prostate cancer diagnosis, especially where hospital resource allocation is limited, including the public sector. TRUS biopsy has low rates of severe complications, although there remains room for improvement in current practice to improve the tolerability and reduce the incidence of post-biopsy infection.

Open partial nephrectomy for a collision renal cell carcinoma in a transplant kidney: A case report.

A collision tumour of the kidney is a very rare condition defined by two immediately adjacent but histologically distinct neoplasms that coexist within one organ without histological admixture. We present a collision tumour in a transplant kidney treated with open partial nephrectomy. This case also highlights key surgical principles the enhanced risk of oncogenesis in transplant recipients, and some key principles for surgical resection of a tumour in a transplant kidney.

Enhanced fluorescence emission using a programmable, reconfigurable LED-array based light source.

An array of up to 5 LEDs is presented to optimize the excitation signal that is transferred into a fluorescence analysis system. The array is varied by both type and drive current in order to broadly and narrowly tune the aggregate spectrum generated by the LED array to more closely match the desired excitation spectrum. Optimization results are shown for (a) a theoretical desired spectrum that clearly shows the increased flexibility of the LED array; (b) an experiment with AM1 bacteria demonstrating comparable emission output between a conventional Xenon lamp and an over driven LED array; and (c) an experiment with Rhodamine G that shows over a two-fold improvement in signal to noise ratio (or emission) obtainable using an optimized array over a non-optimized array. The flexibility of the LED array offers up to 3.2 million possibilities for aggregate spectra; without overdrive conditions, the 5-element array can only be configured into a maximum of 1020 different aggregate spectra.