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Bladder cancer is the 14th most common cause of cancer deaths worldwide and has a mean age of diagnosis of 73 years. Elderly people have fewer curative treatment options for muscle invasive bladder cancer. The aim of this study is to investigate how bladder cancer mortality has changed over the past forty years in different world regions to assess discrepancies between elderly and younger patients with bladder cancer.Bladder cancer mortality data were extracted from the World Health Organisation's GLOBOCAN database. Age-standardised mortality rates (ASMR) for bladder cancer were computed by year, sex, region and Human Development Index (HDI) using the world standard population.Overall ASMR in all available countries with data between 1986 and 2014 for men aged ≥ 75 has decreased from 101.2 to 89.9 per 100,000 (-11.2%). The decrease in ASMR for men 75 has been 0.3-2.0 per 100,000 (-39.4%). In women aged ≥ 75 ASMR has decreased from 26.9 to 22.5 per 100,000 (-16.4%) and in women 75 the ASMR has decreased from 0.76 to 0.56 per 100,000 (-26.4%). Correlation analysis showed a positive linear relationship between Human Development Index (HDI) and improvement in age-standardised mortality rate in all ages. Pearson's coefficient showed that correlation was strongest in the 60-74 age group (r = -0.61, p 0.001) and weakest in those aged ≥ 75 (r = -0.39, p = 0.01).Bladder cancer mortality is not improving in the elderly at the same rate as the rest of the population. Particular focus should be applied in future research to enhance and expand treatment options for bladder cancer that are appropriate for elderly patients.

Zinc inhibits replication of the SARS‐CoV virus. We aimed to evaluate the safety, feasibility, and biological effect of administering high‐dose intravenous zinc (HDIVZn) to patients with COVID‐19. We performed a Phase IIa double‐blind, randomized controlled trial to compare HDIVZn to placebo in hospitalized patients with COVID‐19. We administered trial treatment per day for a maximum of 7 days until either death or hospital discharge. We measured zinc concentration at baseline and during treatment and observed patients for any significant side effects. For eligible patients, we randomized and administered treatment to 33 adult participants to either HDIVZn (n = 15) or placebo (n = 18). We observed no serious adverse events throughout the study for a total of 94 HDIVZn administrations. However, three participants in the HDIVZn group reported infusion site irritation. Mean serum zinc on Day 1 in the placebo, and the HDIVZn group was 6.9 ± 1.1 and 7.7 ± 1.6 µmol/l, respectively, consistent with zinc deficiency. HDIVZn, but not placebo, increased serum zinc levels above the deficiency cutoff of 10.7 µmol/l (p

Background Ischaemia-reperfusion injury (IRI) is a major obstacle during liver transplantation and resection surgeries for cancer, with a need for effective and safe drugs to reduce IRI. Zinc preconditioning has been shown to protect against liver IRI in a partial (70%) ischaemia model. However, its efficacy against a clinically relevant Pringle manoeuvre that results in global liver ischaemia (100%) is unknown. Aims The aim of this study was to test the efficacy of zinc preconditioning in a rat model of global liver ischaemia. Methods Rats were preconditioned via subcutaneous injection of 10 mg/kg of ZnCl2, 24 h and 4 h before ischaemia. Total liver ischaemia (100%) was induced by placing a clamp across the portal triad for 30 min. Liver injury was assessed by serum alanine transaminase (ALT) and aspartate transaminase (AST) levels in blood taken before ischaemia (baseline) and at 1, 2, 4, 24, 48, 72, 96 and 120 hours after ischaemia. Animals were culled after 7 days, and the harvested livers were histologically analysed. Results On a two-way repeated-measures analysis of variance, there was a statistically significant (p = 0.025) difference in the mean ALT levels between saline- and ZnCl2-treated groups. Specifically at 24 h after ischaemia, the ALT (341 ± 99 U/L) and AST (606 ± 78 U/L) in the zinc-treated group were significantly less than the ALT (2863 ± 828 U/L) and AST (3591 ± 948 U/L) values in the saline-treated group. Zinc significantly reduced neutrophil infiltration and necrosis compared with the saline control. Conclusion Zinc preconditioning reduces the overall hepatocellular damage from IRI. These results lay the foundation to assess the benefit of zinc preconditioning for clinical applications.

Precise knowledge of each patient’s index cancer and surrounding anatomy is required for nerve-sparing robot-assisted radical prostatectomy (NS-RARP). Complementary to this, 3D printing has proven its utility in improving the visualisation of complex anatomy. This is the first systematic review to critically assess the potential of 3D printed patient-specific prostate cancer models in improving visualisation and the practice of NS-RARP. A literature search of PubMed and OVID Medline databases was performed using the terms “3D Printing”, “Robot Assisted Radical Prostatectomy” and related index terms as per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Eight articles were included; six were identified via database searches, to which a further two articles were located via a snowballing approach. Eight papers were identified for review. There were five prospective single centre studies, one case series, one technical report and one letter to the editor. Of these articles, five publications (62.5%) reported on the utility of 3D printed models for NS-RARP planning. Two publications (25%) utilised 3D printed prostate models for simulation and training, and two publications (25%) used the models for patient engagement. Despite the nascency of the field, 3D printed models are emerging in the uro-oncological literature as a useful tool in visualising complex anatomy. This has proven useful in NS-RARP for preoperative planning, simulation and patient engagement. However, best practice guidelines, the future regulatory landscape, and health economic considerations need to be addressed before this synergy of new technologies is ready for the mainstream.

Transfusion is a specific cause of acute kidney injury (AKI) after cardiac surgery. Whether there is an association between the composition of blood products and the onset of AKI is unknown. The present study suggests that the transfusion of packed red blood cells containing a high amount of myeloid-related protein 14 (MRP_14) could increase the incidence of AKI after cardiac surgery. In a mouse model, MRP_14 increased the influx of neutrophils in the kidney after ischemia-reperfusion and their ability to damage tubular cells. Higher concentrations of MRP_14 were found in packed red blood cells from female donors or prepared by whole blood filtration.

Ischaemia (interruption in the blood/oxygen supply) and subsequent damage induced by reperfusion (restoration of blood/oxygen supply) ultimately leads to cell death, tissue injury and permanent organ dysfunction. The impact of ischaemia reperfusion injury (IRI) is not limited to heart attack and stroke but can be extended to patients undergoing surgeries such as partial nephrectomy for renal cancer, liver resection for colorectal cancer liver metastasis, cardiopulmonary bypass, and organ transplantation. Unfortunately, there are no drugs that can protect organs against the inevitable peril of IRI. Recent data show that a protocol incorporating specific Zn formulation, dosage, number of dosages, time of injection, and mode of Zn delivery (intravenous) and testing of efficacy in a large preclinical sheep model of IRI strongly supports human trials of Zn preconditioning. No doubt, scepticism still exists among funding bodies and research fraternity on whether Zn, a naturally occurring metal, will work where everything else has failed. Therefore, in this article, we review the conflicting evidence on the promoter and protector role of Zn in the case of IRI and highlight factors that may help explain the contradictory evidence. Finally, we review the literature related to the knowledge of Zn's mechanism of action on ROS generation, apoptosis, HIF activation, inflammation, and signal transduction pathways, which highlight Zn's likelihood of success compared to various other interventions targeting IRI.

OBJECTIVES: To assess whether metformin reduces radio-resistance and increases survival in men undergoing external beam radiation therapy (EBRT) for prostate cancer (PCa), and to determine its effect on hypoxia inducible factor 1-α (HIF1α). PATIENTS AND METHODS: All patients treated with curative intent with EBRT for PCa at a major cancer centre between 2000 and 2007 were included in this study. The outcome measures of time to biochemical failure (BF), metastasis, PCa-specific mortality and overall survival (OS) were analysed in those taking metformin vs those not, using competing risk and Cox regression models. To determine metformin's effect on HIF1α expression and survival in vitro, PC3 cells with high basal HIF1α levels were subjected to increasing doses of metformin after H2 O2 -induced oxidative stress. RESULTS: A total of 2055 eligible cases, including 113 who were on metformin, were identified, with a median follow-up of 95.7 months. There were no differences in age, initial prostate-specific antigen level, Gleason score, T-stage, D'Amico risk class or duration of androgen deprivation therapy (ADT) between patients who were or were not on metformin. Treatment with metformin did not result in any apparent improvement in time to BF, time to metastasis detection or OS, but there was a 1.5-fold increase in PCa-specific deaths (P = 0.045) in patients on metformin and ADT when adjusted for cancer risk and comorbidities. When comparing patients on high-dose metformin (>1 g/d) with those on low-dose metformin (≤1 g), there was no difference in either time to metastases or time to BF. In vitro metformin at a high concentration of 100 μM did not reduce HIF1α expression, nor did metformin affect the PC3 cell survival when exposed to oxidative stress (H2 O2 ). CONCLUSIONS: No association was found between the use of metformin and time to metastasis detection, time to BF or OS in patients undergoing radiation therapy with or without ADT for PCa. In vitro, low therapeutic concentrations of metformin had no effect on HIF1α, and this observation could explain the conflicting evidence for the effectiveness of metformin in men undergoing EBRT for PCa. Higher, more toxic doses of metformin may be required to inhibit the mammalian target of rapamycin-HIF1α pathway in this patient group.

Acute kidney injury (AKI) as a result of ischaemia-reperfusion represents a major healthcare burden worldwide. Mortality rates from AKI in hospitalized patients are extremely high and have changed little despite decades of research and medical advances. In 1986, Murry et al. demonstrated for the first time the phenomenon of ischaemic preconditioning to protect against ischaemia-reperfusion injury (IRI). This seminal finding paved the way for a broad body of research, which attempted to understand and ultimately harness this phenomenon for human application. The ability of preconditioning to limit renal IRI has now been demonstrated in multiple different animal models. However, more than 30 years later, a safe and consistent method of protecting human organs, including the kidneys, against IRI is still not available. This review highlights agents which, despite strong preclinical data, have recently failed to reduce AKI in human trials. The multiple reasons which may have contributed to the failure to translate some of the promising findings to clinical therapies are discussed. Agents which hold promise in the clinic because of their recent efficacy in preclinical large animal models are also reviewed.

Partial nephrectomy (PN) is increasingly considered the gold standard treatment for localized renal cell carcinomas (RCCs) where technically feasible. The advantage of nephron-sparing surgery lies in preservation of parenchyma and hence renal function. However, this advantage is counterbalanced with increased surgical risk. In recent years with the popularization of minimally invasive partial nephrectomy (laparoscopic and robotic), the contemporary role of open PN (OPN) has changed. OPN has several advantages, particularly in complex patients such as those with a solitary kidney, multi-focal tumors, and significant surgical history, as well as providing improved application of renoprotective measures. As such, it is a technique that remains relevant in current urology practice. In this article we discuss the evidence, indications, operative considerations and surgical technique, along with the role of OPN in contemporary nephron-sparing surgery.

Introduction & Objectives. Contrast media (CM) causes renal injury through both direct cellular injury (cytotoxicity) and regional vascular changes (renal hypoxia) mediated by reactive oxygen species (ROS). Zinc may be able to provide protection against CM-induced cytotoxicity due to its indirect antioxidant properties and subsequent effect on ROS. We aimed to determine the protective role of zinc preconditioning against contrast-induced renal injury in vitro. Methods. Normal human proximal renal kidney cells (HK-2) were preconditioned with either increasing doses of ZnCl2 or control. Following this preconditioning, cells were exposed to increasing concentrations of Iohexol 300 mg I2/ml for four hours. Key outcome measures included cell survival (MTT colorimetric assay) and ROS generation (H2DCFDA fluorescence assay). Results. Contrast media induced a dose-dependent reduction in survival of HK-2 cells. Compared to control, contrast media at 150, 225, and 300 mg I2/ml resulted in 69.5% (SD 8.8%), 37.3% (SD 4.8%), and 4.8% (SD 6.6%) cell survival, respectively ( p < 0.001 ). Preconditioning with 37.5 μM and 50 μM ZnCl2 increased cell survival by 173% (SD 27.8%) ( p < 0.001 ) and 219% (SD 32.2%) ( p < 0.001 ), respectively, compared to control preconditioning. Zinc preconditioning resulted in a reduction of ROS generation. Zinc pre-conditioning with 37.5 μM μM ZnCl2 reduced ROS generation by 46% ( p < 0.001 ) compared to control pre-conditioning. Conclusions. Zinc preconditioning reduces oxidative stress following exposure to radiographic contrast media which in turn results in increased survival of renal cells. Translation of this in vitro finding in animal models will lay the foundation for future use of zinc preconditioning against contrast induced nephropathy.

Renal cell carcinoma (RCC) incidence has been increasing in recent years, and it now represents the sixth most common cancer diagnosis in men and the tenth in women. Although this is partly due to in-creased detection of incidental small renal masses on unrelated imaging, advanced RCC continues to be diagnosed in a significant portion of patients, with more than 15% presenting with distant metasta-ses. Biomarkers can be a cost-effective tool to identify high-risk patients and institute appropriate indi-vidualised therapies. While the literature in this field is nascent, this paper focuses on several bi-omarkers that have been extensively investigated in the diagnosis and prognosis of RCC, as well as in predicting its response to treatments, particularly the newer immuno-oncology drugs.

IntroductionSARS-CoV-2 (COVID-19) has caused an international pandemic of respiratory illness, resulting in significant healthcare and economic turmoil. To date, no robust vaccine or treatment has been identified. Elemental zinc has previously been demonstrated to have beneficial effects on coronaviruses and other viral respiratory infections due to its effect on RNA polymerase. Additionally, zinc has well-demonstrated protective effects against hypoxic injury—a clear mechanism of end-organ injury in respiratory distress syndrome. We aimed to assess the effect of high-dose intravenous zinc (HDIVZn) on SARS-CoV-2 infection. The end of study analyses will evaluate the reduction of impact of oxygen saturations or requirement of oxygen supplementation.Methods and analysisWe designed a double-blind randomised controlled trial of daily HDIVZn (0.5 mg/kg) versus placebo. Primary outcome measures are lowest oxygen saturation (or greatest level of supplemental oxygenation) for non-ventilated patients and worst PaO2/FiO2for ventilated patients. Following power calculations, 60 hospitalised patients and 100 ventilated patients will be recruited to demonstrate a 20% difference. The duration of follow-up is up to the point of discharge.Ethics and disseminationEthical approval was obtained through the independent Human Research Ethics Committee. Participant recruitment will commence in May 2020. Results will be published in peer-reviewed medical journals.Trial registration numberACTRN126200000454976.

OBJECTIVE. The purpose of this article is to prospectively compare image quality and diagnostic accuracy of clinically significant prostate cancer with and without endorectal coil (ERC) at 3 T using a combination of T2-weighted and diffusion-weighted MRI. SUBJECTS AND METHODS. Twenty-three patients with biopsy-proven prostate cancer underwent MRI with and without ERC at the same visit. Patients subsequently underwent radical prostatectomy. Specimens were assessed by whole-mount histopathologic examination. Two radiologists reviewed MR images for image quality (5-point scale) and disease using Prostate Imaging Reporting and Data Systems version 2 (PI-RADSv2). Sensitivity, specificity, and area under the ROC curve (AUC) were calculated with and without ERC. Additionally, apparent diffusion coefficient (ADC) was correlated with Gleason score and ADC values of each lesion were compared with and without ERC. RESULTS. Image quality was comparable with and without ERC (3.8 vs 3.5). Twenty-nine cancer foci larger than 0.5 cm in diameter were found in 23 patients on histopathologic examination; 18 tumors had a Gleason score of 7 or greater. Two radiologists recorded AUC for tumors with a Gleason score of 7 or greater as 0.96 and 0.96 with ERC and 0.88 and 0.91 without ERC. All 13 tumors with a Gleason score of 3 + 4 were detected with ERC, but only 9 were detected without ERC. One of five tumors with Gleason scores less than 3 + 4 was missed with and without ERC. ADC significantly correlated with Gleason score. There was no significant difference in the ADC of a lesion on MRI with and without an ERC. CONCLUSION. MRI with and without ERC was equally accurate at showing prostate cancers with Gleason scores of 4 + 3 or greater. However, MRI with ERC was superior at showing cancer with a Gleason score of 3 + 4. There was no significant difference in ADC values between scores acquired with or without an ERC.

Imparting the required psychomotor skills for trainees to become proficient in percutaneous nephrolithotomy (PCNL) and retrograde intrarenal surgery (RIRS) is tricky for surgical educators due to the challenging nature of the procedures and the lack of realistic simulators. The current COVID-19 pandemic has compounded these issues by reducing learning opportunities for trainees through reduced case numbers and the availability of surgical skills courses. To address these contemporaneous issues, the authors have developed 3D printed inexpensive combined RIRS and PCNL training models for both in-person and video conference skills training.

TPS602 Background: Adjuvant intravesical bacillus Calmette-Guérin (BCG) decreases disease recurrence and progression in people with high-risk, non-muscle invasive urothelial bladder cancer (NMIBC), however recurrence occurs in 30% despite optimal therapy. Recent meta-analyses evaluating addition of intravesical mitomycin (MM) to BCG showed lower rates of recurrence and cancer-specific mortality in people with NMIBC who received combination regimens. Good quality randomized trials to definitively test this combination are lacking. The BCGMM trial (NCT02948543) will be the largest study to date evaluating this approach in people with high-risk NMIBC. Methods: This open-label phase 3 trial aims to randomize 500 participants, stratified by stage, site of disease, and presence of carcinoma in-situ, to Arm A (BCG induction weekly x6 then monthly x10) or Arm B (BCG + MM weekly x9 then monthly x9). This study is powered to detect a 10% improvement in 2-year disease free survival (DFS) at 5% level of significance with 85% power. Stage 1 of this study, designed to recruit 130 patients to determine rates of treatment completion, activity reflected by cystoscopic findings at 3 months, adverse events, resource use, and health related quality of life, has completed enrolment and successfully established feasibility of this trial protocol. Stage 2, aiming for a further 370 patients, will inform on additional endpoints including differences in DFS, time to recurrence and progression, overall survival, and potential predictive biomarkers, is estimated to complete accrual in December 2020. Successful treatment completion, defined as 75% or more of planned treatment doses, has been achieved in 76% of patients treated in the experimental arm of Stage 1, compared to 60% in those allocated BCG alone. Clinical trial information: NCT02948543.

Ischaemia-reperfusion injury (IRI) during various surgical procedures, including partial nephrectomy for kidney cancer or renal transplantation, is a major cause of acute kidney injury and chronic kidney disease. Currently there are no drugs or methods for protecting human organs, including the kidneys, against the peril of IRI. The aim of this study was therefore to investigate the reno-protective effect of Zn2+ preconditioning in a clinically relevant large animal sheep model of IRI. Further the reno-protective effectiveness of Zn2+ preconditioning was tested on normal human kidney cell lines HK-2 and HEK293. Anaesthetised sheep were subjected to uninephrectomy and 60 min of renal ischaemia followed by reperfusion. Sheep were preconditioned with intravenous injection of zinc chloride prior to occlusion. Serum creatinine and urea were measured before ischaemia and for 7 days after reperfusion. HK-2 and HEK293 cells were subjected to in vitro IRI using the oxygen- and glucose-deprivation model. Zn2+ preconditioning reduced ischaemic burden determined by creatinine and urea rise over time by ~ 70% in sheep. Zn2+ preconditioning also increased the survival of normal human kidney cells subjected to cellular stress such as hypoxia, hydrogen peroxide injury, and serum starvation. Overall, our protocol incorporating specific Zn2+ dosage, number of dosages (two), time of injection (24 and 4 h prior), mode of Zn2+ delivery (IV) and testing of efficacy in a rat model, a large preclinical sheep model of IRI and cells of human origin has laid the foundation for assessment of the benefit of Zn2+ preconditioning for human applications.

Partial nephrectomy (open or minimally invasive) usually requires temporary renal arterial occlusion to limit intraoperative bleeding and improve access to intrarenal structures. This is a time-critical step due to the critical ischemia period of renal tissue. Prolonged renal ischemia may lead to irreversible nephron damage in the remaining tissue and, ultimately, chronic kidney disease. This is potentiated by the incompletely understood ischemia-reperfusion injury (IRI). A key mechanism in IRI prevention appears to be the upregulation of an intracellular transcription protein, Hypoxia-Inducible Factor (HIF). HIF mediates metabolic adaptation, angiogenesis, erythropoiesis, cell growth, survival, and apoptosis. Upregulating HIF-1α via ischemic preconditioning (IPC) or drugs that simulate hypoxia (hypoxia-mimetics) has been investigated as a method to reduce IRI. While many promising chemical agents have been trialed for the prevention of IRI in small animal studies, all have failed in human trials. The aim of this review is to highlight the techniques and drugs that target HIF-1α and ameliorate IRI associated with renal ischemia. Developing a technique or drug that could reduce the risk of acute kidney injury associated with renal IRI would have an immediate worldwide impact on multisystem surgeries that would otherwise risk ischemic tissue injury.

Background Following urological procedures, it is common for patients to receive written handouts containing pertinent post-operative information and advice. This study aims to assess the consistency of procedure-specific post-operative advice provided to patients in Australia. Methods Post-operative handouts for common urological procedures were obtained from a selection of Australian hospitals and practising urologists' websites. Handouts were examined for consistency with regard to post-operative advice and the Flesch–Kincaid grade level was calculated to determine readability. Results In total, 209 handouts were reviewed comprising seven urological procedures. The majority of handouts provided information regarding expected symptoms (88%) and when to seek medical attention (70.8%). Overall, 85.2% of handouts provided advice about which activities should and should not be performed. Instructions for return to work (32.1%), driving (45.5%), sex (32.1%) and physical activity (56%) were less universal. Infection, bleeding, pain and swelling were the principal reasons to seek medical attention. Duration of expected symptoms and timing for resuming normal activities were the most common sources of discordance between handouts. The mean Flesch–Kincaid grade level was 9.7 with a range of 6.7 to 13.6. Only 9.6% of patient information handouts had a grade level of 8 or less and no handouts were at or below the suggested grade 6 readability level. Conclusions There is a significant degree of variability in written post-operative advice provided to patients in Australia. Individual surgeons and hospitals should provide specific and tailored advice directly to their own patients, written at a grade level suitable for the majority to understand.

OBJECTIVE: To determine the expression and biology of the neuroendocrine growth factor gastrin-releasing peptide (GRP) and other proGRP-derived peptides in renal cancer. MATERIALS AND METHODS: Receptor binding studies, enzyme-linked immunosorbent assay (ELISA) and radioimmunoassay, were used to quantitate the presence of proGRP-derived peptide receptors and their ligands in renal cancer cell lines and human renal cancers. Biological activity of proGRP peptides was confirmed with proliferation, migration, and extracellular-signal-regulated kinases 1 and 2 (ERK1/2) activation assays in vitro. In vivo, ACHN renal cancer xenografts were treated with proGRP-derived peptides to assess tumour size and necrosis. hypoxia-inducible factor 1α (HIF1α) and vascular endothelial growth factor (VEGF) expression were investigated with Western blotting and ELISA respectively, to determine the possible contribution of the proGRP peptides to tumour viability. RESULTS: In ACHN cells that expressed both proGRP- and GRP-receptors, the expression of proGRP binding sites was 80-fold greater than the GRP-receptor (GRPR). C-terminal proGRP-derived peptides stimulated the activation of ERK1/2, but with a different time course to GRP, consistent with the suggestion that these peptides may have unique cellular functions. Both GRP and proGRP47-68 stimulated proliferation and migration of ACHN cells in vitro, but only GRP reduced the extent of tumour necrosis in ACHN xenografts. GRP, but not proGRP47-68, was able to induce HIF1α and VEGF expression in ACHN cells. This may account in part for the reduction in necrosis after GRP treatment. C-terminal proGRP-derived peptides were present in all three renal cancer cell lines and a panel of human renal cancers, but mature amidated GRP was absent. CONCLUSION: C-terminal proGRP peptides are more abundant in renal cancers and their cell lines than the more extensively studied amidated peptide, GRP. These results suggest that C-terminal proGRP-derived peptides may be a better target for novel renal cancer treatments.

To provide unencumbered real-time ultrasound image guidance during robot-assisted laparoscopic radical prostatectomy, we developed a robotic transrectal ultrasound system that tracks the da Vinci® Surgical System instruments. We describe our initial clinical experience with this system.After an evaluation in a canine model, 20 patients were enrolled in the study. During each procedure the transrectal ultrasound transducer was manually positioned using a brachytherapy stabilizer to provide good imaging of the prostate. Then the transrectal ultrasound was registered to the da Vinci robot by a previously validated procedure. Finally, automatic rotation of the transrectal ultrasound was enabled such that the transrectal ultrasound imaging plane safely tracked the tip of the da Vinci instrument controlled by the surgeon, while real-time transrectal ultrasound images were relayed to the surgeon at the da Vinci console. Tracking was activated during all critical stages of the surgery.The transrectal ultrasound robot was easy to set up and use, adding 7 minutes (range 5 to 14) to the procedure. It did not require an assistant or additional control devices. Qualitative feedback was acquired from the surgeons, who found transrectal ultrasound useful in identifying the urethra while passing the dorsal venous complex suture, defining the prostate-bladder interface during bladder neck dissection, identifying the seminal vesicles and their location with respect to the rectal wall, and identifying the distal prostate boundary at the apex.Real-time, registered robotic transrectal ultrasound guidance with automatic instrument tracking during robot-assisted laparoscopic radical prostatectomy is feasible and potentially useful. The results justify further studies to establish whether the approach can improve procedure outcomes.

Zinc ions (Zn2+) are known to influence cell survival and proliferation. However the homeostatic regulation of Zn2+ and their role in prostate cancer (PC) progression is poorly understood. Therefore the subcellular distribution and uptake of Zn2+ in PC cells were investigated. Inductively coupled plasma mass spectroscopy and fluorescent microscopy with the Zn2+-specific fluorescent probe FluoZin-3 were used to quantify total and free Zn2+, respectively, in the normal prostate epithelial cell line (PNT1A) and three human PC cell lines (PC3, DU145 and LNCaP). The effects of Zn2+ treatment on proliferation and survival were measured in vitro using MTT assays and in vivo using mouse xenografts. The ability of Zn2+ to protect against oxidative stress via a HIF1α-dependent mechanism was investigated using a HIF1α knock-down PC3 model. Our results demonstrate that the total Zn2+ concentration in normal PNT1A and PC cells is similar, but PC3 cells contain significantly higher free Zn2+ than PNT1A cells (p < 0.01). PNT1A cells can survive better in the presence of high concentrations of Zn2+ than PC3 cells. Exposure to 10 µM Zn2+ over 72 hours significantly reduces PC3 cell proliferation in vitro but not in vivo. Zn2+ increases PC3 cell survival up to 2.3-fold under oxidative stress, and this protective effect is not seen in PNT1A cells or in a HIF1α-KD PC3 cell model. A state of Zn2+ dyshomeostasis exists in PC. HIF1α is an integral component of a Zn2+-dependent protective mechanism present in PC3 cells. This pathway may be clinically significant through its contribution to castrate-resistant PC survival.

OBJECTIVE To assess, in men undergoing active surveillance (AS) for low-risk prostate cancer, whether saturation or transperineal biopsy altered oncological outcomes, compared with standard transrectal biopsy. PATIENTS AND METHODS Retrospective analysis of prospectively collected data from two cohorts with localised prostate cancer (1998-2012) undergoing AS. Prostate cancer-specific, metastasis-free and treatment-free survival, unfavourable disease and significant cancer at radical prostatectomy (RP) were compared for standard ( 12 core, median 16), and transrectal vs transperineal biopsy, using multivariate analysis. RESULTS In all, 650 men were included in the analysis with a median (mean) follow-up of 55 (67) months. Prostate cancer-specific, metastasis-free and biochemical recurrence-free survival were 100%, 100% and 99% respectively. Radical treatment-free survival at 5 and 10 years were 57% and 45% respectively (median time to treatment 7.5 years). On Kaplan-Meier analysis, saturation biopsy was associated with increased objective biopsy progression requiring treatment (log-rank P = 0.01). On multivariate Cox proportional hazards analysis, saturation biopsy (hazard ratio 1.68, P < 0.01) but not transperineal approach (P = 0.89) was associated with increased objective biopsy progression requiring treatment. On logistic regression analysis of 179 men who underwent RP for objective progression, transperineal biopsy was associated with lower likelihood of unfavourable RP pathology (odds ratio 0.42, P = 0.03) but saturation biopsy did not alter the likelihood (P = 0.25). Neither transperineal nor saturation biopsy altered the likelihood of significant vs insignificant cancer at RP (P = 0.19 and P = 0.41, respectively). CONCLUSIONS AS achieved satisfactory oncological outcomes. Saturation biopsy increased progression to treatment on AS; longer follow-up is needed to determine if this represents beneficial earlier detection of significant disease or over-treatment. Transperineal biopsy reduced the likelihood of unfavourable disease at RP, possibly due to earlier detection of anterior tumours.

Nearly three-quarters of all newly diagnosed urothelial cancers are non-muscle-invasive bladder cancers (NMIBCs). Although bladder-preserving surgery can be used to treat NMIBC, the rate of recurrence remains high. Intravesical chemotherapy has been shown to reduce the rate of NMIBC recurrence, and mitomycin C (MMC) has become the most commonly used intravesical cytotoxic agent. Despite the popularity of this agent in the treatment of NMIBCs, many questions regarding the optimal approach to MMC therapy remain unanswered. Strategies to enhance delivery of MMC have been well studied and multiple measures are recommended for implementation in routine clinical practice. In addition, less widely investigated techniques, such as hyperthermia and electromotive drug administration, have been shown to increase the efficacy of MMC therapy. Nevertheless, even when the current 'optimal' approaches to MMC administration are used, a large proportion of NMIBCs recur. This apparent treatment resistance might be overcome by combination of MMC with other agents that have different mechanisms of action and are unlikely to have cross-resistance. Study of the mechanisms of resistance is, therefore, important to identify key pathways underlying this phenomenon, which could be rationally targeted using specific combinations of drugs. Knowledge of these mechanisms might also reveal markers of responsiveness to therapy that could be used for patient selection.

Gastrin-releasing peptide (GRP) acts as an important regulatory peptide in several normal physiological processes and as a growth factor in certain cancers. In this review we provide a comprehensive overview of the current state of knowledge of GRP in urological tissues under both normal and cancerous conditions. GRP and its receptor, GRP-R, are expressed in the normal kidney and renal cancers. GRP can stimulate the growth of renal cancer cells. GRP and GRP-R are expressed in prostate cancer and GRP can stimulate the growth of prostate cancer cell lines. Importantly, GRP is a key neuroendocrine peptide, which may be involved in the progression of advanced prostate cancer and in the neuroendocrine differentiation of prostate cancer. Recent animal studies have shown that GRP and GRP-R are an integral part of male sexual function and play a crucial role in spinal control of erections and ejaculation.

To compare the immediate postoperative outcomes of patients with benign prostatic hyperplasia undergoing Holmium laser enucleation of the prostate (HOLEP) with and without full anticoagulation or antiplatelet therapy at the time of surgery.A retrospective review was performed on a series of consecutive patients undergoing HOLEP at our institution by a single surgeon from February 2004 to September 2010. Demographic, surgical, pathological and outcome data were collected. Two cohorts were identified on the basis of antithrombotic therapy at the time of surgery. Patients who continued on aspirin, aspirin/dipyridamole, clopidogrel and warfarin throughout the surgery were included in the antithrombotic cohort. Univariate analysis was performed to determine differences in outcomes between the 2 cohorts.Total 125 consecutive patients underwent HOLEP with 52 patients on antithrombotic therapy at the time of surgery and 73 patients were not on antithrombotic therapy during surgery. Patients in the antithrombotic group were older (75.1 ±7.5 vs. 71.7 ± 8.3 years; p = 0.02) and had a higher median ASA physical status (3 (3-3) vs. 2 (2-3), p0.0001). The mean operating time and median specimen volume were not significantly different between the 2 cohorts. The median length of stay (2 (1-3) vs. 1 (1-2) d, p = 0.014) was longer in the antithrombotic cohort. The transfusion rate (7.7 vs. 0%, p = 0.028) was predictably higher in the antithrombotic cohort. No patients required re-operation for bleeding.The use of HOLEP in patients on antithrombotic therapy is safe despite the higher surgical risk profile of that particular patient population and the potential increased risk for significant bleeding.

Heat shock proteins (HSPs) and clusterin (another chaperone protein with HSP-like properties) are present in normal cells and are upregulated by cellular stressors such as hyperthermia, hypoxia, and cytotoxic agents. HSPs are overexpressed in a wide range of cancers. Cancer cells are in a constant state of proteotoxic stress and exploit the HSPs to protect themselves against the toxic effects of aberrant oncoproteins, genomic instability, hypoxia, and acidosis. In many patients with cancer, high levels of HSPs are associated with poor prognosis and treatment resistance as these proteins protect tumour cells from therapeutic stressors such as androgen or oestrogen withdrawal, radiation, and cytotoxic chemotherapy. Differences in the expression levels of HSPs in bladder cancers compared with normal urothelium have led to HSPs being investigated as diagnostic and prognostic biomarkers. Evidence suggests that HSPs are important modulators of the immune system and have a role in BCG-stimulated regression of urothelial cancers. New bladder cancer treatment strategies that target HSPs are being investigated and could have a synergistic role with modern radiotherapy and chemotherapy regimens. A combination of OGX-427 (an antisense oligonucleotide that targets HSP27), gemcitabine, and cisplatin is currently being investigated in a phase II trial of patients with advanced bladder cancer.

One consistent finding in the studies regarding treating men with prostate cancer is that men with high-risk disease have the most to gain from treatment with curative intent. Men with high-risk or locally-advanced prostate cancer require treat- ment to the primary cancer or risk dying prematurely from their disease. Increasingly, combined androgen deprivation therapy + radiation treatment is seen as the standard treatment as a result of prospective studies in this space, and the perceived increased morbidity of radical prostatectomy in the setting of a "low" cure rate as monotherapy. In the absence of a well-conducted randomized trial, there is no definite evidence that one treatment is superior to the other. The advantages of radical prostatectomy are that it provides excellent local control of the primary tumor without an increase in morbidity, accurately stages the disease to guide further therapy, and removes benign sources of prostate-specific antigen so that failures can be promptly identified and subsequent treatment can be initiated in a timely manner. Although several guidelines recommend radiation treatment over radical prostatectomy as first-line treatment, there is no evi- dence that surgery is inferior and radical prostatectomy should remain part of any informed discussion regarding treatment options for men with high-risk prostate cancer.

Objectives Ischemia-reperfusion injury (IRI) is a major cause of acute kidney injury and chronic kidney disease. Two promising preconditioning methods for the kidney, intermittent arterial clamping (IC) and treatment with the hypoxia mimetic cobalt chloride, have never been directly compared. Furthermore, the protective efficacy of the chemically related transition metal Zn2+ against renal IRI is unclear. Although Co2+ ions have been shown to protect the kidney via hypoxia inducible factor (HIF), the effect of Zn2+ ions on the induction of HIF1α, HIF2α and HIF3α has not been investigated previously. Materials and methods The efficacy of different preconditioning techniques was assessed using a Sprague-Dawley rat model of renal IRI. Induction of HIF proteins following Zn2+ treatment of the human kidney cell lines HK-2 (immortalized normal tubular cells) and ACHN (renal cancer) was measured using Western Blot. Results Following 40 minutes of renal ischemia in rats, cobalt preconditioning offered greater protection against renal IRI than IC as evidenced by lower peak serum creatinine and urea concentrations. ZnCl2 (10 mg/kg) significantly lowered the creatinine and urea concentrations compared to saline-treated control rats following a clinically relevant 60 minutes of ischemia. Zn2+ induced expression of HIF1α and HIF2α but not HIF3α in HK-2 and ACHN cells. Conclusion ZnCl2 preconditioning protects against renal IRI in a dose-dependent manner. Further studies are warranted to determine the possible mechanisms involved, and to assess the benefit of ZnCl2 preconditioning for clinical applications.