Lessons from a population-based bladder cancer registry: exploring why survival is not improving.

OBJECTIVE: To explore the causes of the decrease in bladder cancer survival that has occurred over the past four decades. METHODS: We extracted data from the South Australian Cancer Registry. Data from the period 1 January 1977 to 31 December 2020 were extracted to explore changes in incidence and survival among a total of 8356 patients diagnosed with ≥pT1 disease. Invasive bladder cancer was defined as ≥pT1 in this study. RESULTS: Invasive bladder cancer age-standardized incidence decreased from 7.20 cases per 100 000 people in 1977 to 5.85 cases per 100 000 in 2020. The mean age at diagnosis increased from 68 years to 76 years. The crude incidence for patients aged 80 years and over increased by 3.3% per year (95% confidence interval [CI] 2.1 to 4.6). Overall survival decreased over the study period (hazard ratio [HR] 1.22 [95% CI 1.09 to 1.35]), however, survival increased after adjusting for age at diagnosis (HR 0.80 [95% CI 0.76 to 0.94]). Despite a decrease in non-bladder cancer-specific deaths in older people, there was no change in the bladder cancer-specific death rate in older people (HR 0.94 [95% CI 0.70 to 1.26]). Male sex was associated with higher survival (HR 0.87 [95% CI 0.83 to 0.92]), whereas socioeconomic advantage was not. CONCLUSIONS: Invasive bladder cancer survival has decreased over the past 40 years, with the age structure of the population being a significant contributing factor. PATIENT SUMMARY: We looked at why bladder cancer survival is decreasing using a large cancer registry with information from 1977 to 2020. We found that people are now more likely to be diagnosed at an older age. Older people often live for a shorter time with bladder cancer compared to younger people. Bladder cancer survival has decreased because there are more older people with the disease than previously.

Fluoroquinolone resistance in urinary tract infections: Epidemiology, mechanisms of action and management strategies.

Background: Fluoroquinolone resistance is an issue of concern amongst physicians worldwide. In urology, fluoroquinolones are often used in the treatment of acute pyelonephritis and prostatitis, as well as infections caused by multidrug-resistant pathogens. Aims: We aim to highlight the importance of antimicrobial stewardship and the need for ongoing biomedical research to discover novel agents in our losing battle against resistant pathogens. Materials and methods: In this review, we survey the literature and summarise fluoroquinolone resistance as it pertains to pyelonephritis and prostatitis, as well as alternative treatment strategies and prevention of multidrug resistance. Results: The rise of fluoroquinolone resistance in bacteria has reduced the available treatment options, often necessitating hospital admission for intravenous antibiotics, which places an additional burden on both patients and the healthcare system. Many countries such as Australia have attempted to limit fluoroquinolone resistance by imposing strict prescribing criteria, though these efforts have not been entirely successful. Solutions to overcome resistance include prevention, combination therapy and the development of novel antimicrobial agents. Conclusions: Prevention of the proliferation of resistant organisms by antimicrobial stewardship is paramount, and urologists are obliged to be aware of responsible prescribing practices such as referring to local guidelines when prescribing. By reserving fluoroquinolones for infections in which they are truly indicated and by prescribing based on both patient and local environmental factors, we can preserve this effective resource for future use.

Near-infrared spectroscopy as a novel method of ex vivo bladder cancer tissue characterisation.

OBJECTIVE: To evaluate near-infrared (NIR) spectroscopy in differentiating between benign and malignant bladder pathologies ex vivo immediately after resection, including the grade and stage of malignancy. PATIENTS AND METHODS: A total of 355 spectra were measured on 71 bladder specimens from patients undergoing transurethral resection of bladder tumour (TURBT) between April and August 2022. Scan time was 5 s, undertaken using a portable NIR spectrometer within 10 min from excision. Specimens were then sent for routine histopathological correlation. Machine learning models were applied to the spectral dataset to construct diagnostic algorithms; these were then tested for their ability to predict the histological diagnosis of each sample using its NIR spectrum. RESULTS: A two-group algorithm comparing low- vs high-grade urothelial cancer demonstrated 97% sensitivity, 99% specificity, and the area under the receiver operating characteristic curve (AUC) was 0.997. A three-group algorithm predicting stages Ta vs T1 vs T2 achieved 97% sensitivity, 92% specificity, and the AUC was 0.996. CONCLUSIONS: This first study evaluating the diagnostic potential of NIR spectroscopy in urothelial cancer shows that it can be accurately used to assess tissue in an ex vivo setting immediately after TURBT. This offers point-of-care assessment of bladder pathology, with potential to influence the extent of resection, reducing both the need for re-resection where invasive disease may be suspected, and also the potential for complications where extent of diagnostic resection can be limited. Further studies utilising fibre-optic probes offer the potential for in vivo assessment.

A novel two-stage approach to the treatment of renal cell carcinoma with intra-cardiac tumour extension and Budd-Chiari syndrome.

OBJECTIVE: To present the early results of a new technique for the treatment of renal cell carcinoma with intra-cardiac tumour extension and Budd-Chiari syndrome. PATIENTS AND METHODS: The first stage involves transdiaphragmatic debulking of the right heart, inferior vena cava (IVC) and hepatic veins via median sternotomy, followed by a purse-string suture placed in the IVC below the hepatic veins. The second stage is performed separately and involves en bloc resection of the affected kidney, and IVC and vascular reconstruction via an abdominal incision. RESULTS: Three of five patients presented with clinical Budd-Chiari syndrome; two had radiological features only. The median time between surgical procedures was 12 days (IQR 13 days). Four of the five patients had a R0 resection. While all five patients successfully completed both operative stages, one patient died 22 days after the second stage. Of the remaining four, all survive with no disease recurrence. CONCLUSION: While we continue to compile longer-term data for a larger follow-up series, these preliminary findings show the feasibility of this technique and support the development of this programme of surgery.

Clinical Trial Protocol for PRIMARY2: A Multicentre, Phase 3, Randomised Controlled Trial Investigating the Additive Diagnostic Value of [68Ga]Ga-PSMA-11 Positron Emission Tomography/Computed Tomography in Men with Negative or Equivocal Multiparametric Magnetic Resonance Imaging for the Diagnosis of Clinically Significant Prostate Cancer.

BACKGROUND: Multiparametric magnetic resonance imaging (mpMRI) has an established role for the diagnosis of clinically significant prostate cancer (sPCa). The PRIMARY trial demonstrated that [68Ga]Ga-PSMA-11 positron emission tomography/computed tomography (PET/CT) was associated with a significant improvement in sensitivity and negative predictive value for sPCa detection. OBJECTIVE: To demonstrate that addition of prostate-specific membrane antigen (PSMA) radioligand PET/CT will enable some men to avoid transperineal prostate biopsy without missing sPCa, and will facilitate biopsy targeting of PSMA-avid sites. DESIGN, SETTING, AND PARTICIPANTS: This multicentre, two-arm, phase 3, randomised controlled trial will recruit 660 participants scheduled to undergo biopsy. Eligible participants will have clinical suspicion of sPCa with a Prostate Imaging-Reporting and Data System (PI-RADS) score of 2 and red flags, or a PI-RADS score of 3 on mpMRI (PI-RADS v2). Participants will be randomised at a 1:1 ratio in permuted blocks stratified by centre. The trial is registered on ClinicalTrials.gov as NCT05154162. INTERVENTION: In the experimental arm, participants will undergo pelvic PSMA PET/CT. Local and central reviewers will interpret scans independently using the PRIMARY score. Participants with a positive result will undergo targeted transperineal prostate biopsies, whereas those with a negative result will undergo prostate-specific antigen monitoring alone. In the control arm, all participants undergo template transperineal prostate biopsies. Participants will be followed for subsequent clinical care for up to 2 yr after randomisation. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: sPCa is defined as Gleason score 3 + 4 (≥10%) = 7 disease (grade group 2) or higher on transperineal prostate biopsy. Avoidance of transperineal prostate biopsy will be measured at 6 mo from randomisation. The primary endpoints will be analysed on an intention-to-treat basis. CONCLUSIONS: Patient enrolment began in March 2022, with recruitment expected to take 36 mo. PATIENT SUMMARY: For patients with suspected prostate cancer who have nonsuspicious or unclear MRI (magnetic resonance imaging) scan findings, a different type of scan (called PSMA PET/CT; prostate-specific membrane antigen positron emission tomography/computed tomography) may identify men who could avoid an invasive prostate biopsy. This type of scan could also help urologists in better targeting of samples from suspicious lesions during prostate biopsies.

Immuno-oncology therapy associated thromboembolic events in metastatic renal cell carcinoma.

The relationship between thromboembolic events (TEs) and immune-oncology (IO) agents in patients with metastatic renal cell carcinoma (mRCC) with inferior-vena-cava (IVC) thrombus has not been explored despite conferring significant morbidity. A late 30s female is diagnosed with mRCC with a level-II IVC thrombus after presenting with back pain. Two weeks post initiation of immunotherapy, she re-presented with bilateral sub-massive pulmonary emboli requiring IVC and pulmonary thrombectomy. This case exposes a potential relationship between mRCC and IVC thrombus with IO agents that creates a critically hypercoagulable state. This issue requires further investigation given the apparent under-reporting of TEs in these patients.

Postoperative complications and hospital costs following open radical cystectomy: A retrospective study.

OBJECTIVES: To evaluate primarily the relationship between postoperative complications and hospital costs, and secondarily the relationship between postoperative complications and mortality, following radical cystectomy. METHODS: Postoperative complications were retrospectively examined for 147 patients undergoing radical cystectomy at a university hospital between January 2012 and July 2021. Complications were defined and graded using the Clavien-Dindo classification system. In-hospital cost was calculated using an activity-based costing methodology. Regression modelling was used to investigate the relationships among a priori selected perioperative variables, complications, and costs. The effect of complications on postoperative mortality was ascertained using time-dependent coefficients in a Cox proportional hazards regression model. RESULTS: 135 (92%) patients experienced one or more postoperative complications. The medians of hospital cost for patients who experienced no complications and those who experienced complications were $42,796.3 (29,222.9-53,532.5) and $81,050.1 (49,614.8-122,533.6) respectively, p < 0.001. Hospital costs were strongly associated with complication severity: Clavien-Dindo grade II complications increased costs by 45.2% (p < 0.001, 95% CI 19.1%-76.6%), and Clavien-Dindo grade III to V complications increased costs by 107.5% (p < 0.001, 95% CI 52.4%-181.8%). Each additional count of complication and increase in Clavien-Dindo complication grade increased the risk of mortality 1.28-fold (RR = 1.28, p = 0.006, 95% CI 1.08-1.53) and 2.50-fold (RR = 2.50, p = 0.012 95% CI 1.23-5.07) respectively. CONCLUSIONS: These findings demonstrate a high prevalence of complications following cystectomy and significant associated increases in hospital costs and mortality. Postoperative complications are a key target for cost-containment strategies. TRIAL REGISTRATION: Trial Registration: Australian New Zealand Clinical Trials Registry (ACTRN:12622000057785.

3D printed patient-specific prostate cancer models to guide nerve-sparing robot-assisted radical prostatectomy: a systematic review.

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.

Global changes in bladder cancer mortality in the elderly.

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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.

Role of PSMA PET-guided metastases-directed therapy in oligometastatic recurrent prostate cancer.

Oligometastatic prostate cancer (OMPC) has been proposed as an intermediary state between localised disease and widespread metastases, with varying definitions including 1, 3, or ≤5 visceral or bone metastasis. Traditional definitions of OMPC are based on staging with conventional imaging, such as computerised tomography (CT) and whole-body bone scan (WBBS). Novel imaging modalities such as prostate-specific membrane antigen positron emission tomography (PSMA PET) have improved diagnostic utility in detecting early metastatic prostate cancer (PC) metastases compared with conventional imaging. Specifically, meta-analytical data suggest that PSMA PET is sensitive in detecting oligometastatic disease in patients with biochemical recurrence (BCR) post-radical treatment of PC. Recent trials have evaluated PSMA PET-guided metastases-directed therapy (MDT) in oligometastatic recurrent disease, typically with salvage surgery or radiotherapy (RT). To date, these preliminary studies demonstrate promising results, potentially delaying the need for systemic therapy. We aim to report a comprehensive, multidisciplinary review of PSMA-guided MDT in OMPC. In this review, we highlight the utility of PMSA PET in biochemically recurrent disease and impact of PSMA PET on the definition of oligometastatic disease and outline data pertaining to PSMA-guided MDT.

Transfusion-Related Renal Dysfunction After Cardiac Surgery: The Role of Myeloid-Related Protein_14 in Neutrophil-Mediated Tubular Damage.

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.

Case Report: Reversal of Hyaluronic Acid Rectal Wall Infiltration with Hyaluronidase.

Peri-rectal spacers provide protection to the rectum for patients receiving radiation therapy treating prostate cancers. Commonly used hydrogel spacers hold the disadvantage that they cannot be readily reversed should inadvertent injection outside of the target area occurs, potentially leading to ischemia of the rectal mucosa leading to severe pain and ulceration, which can then lead to superinfection and pelvic abscess formation, and subsequently recto-prostatic fistulas. This could require major surgical intervention. New hyaluronic acid spacers are readily reversible with hyaluronidase and provide a valuable means to correct any misinjected spacer. We present a patient with prostate cancer who was planned for radiation therapy and required a rectal spacer. The hyaluronic acid rectal spacer was injected in part into the rectal wall. The patient was asymptomatic, and a sigmoidoscopy confirms healthy bowel mucosa only. The misinjected hyaluronic acid was successfully treated with targeted injection of hyaluronidase into only the rectal wall portion. Serial follow-up imaging demonstrated rapid dissolution of the misinjected hyaluronic acid with the well-positioned hyaluronic acid remaining. The patient did not experience any side effects of the hyaluronidase.

Zinc Preconditioning Provides Cytoprotection following Iodinated Contrast Media Exposure in In Vitro Models.

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.

Zinc supplementation as an adjunct therapy for COVID-19: Challenges and opportunities.

An outbreak of a novel coronavirus (COVID-19 or 2019-CoV) infection has posed significant threats to international health and the economy. Patients with COVID-19 are at risk of cytokine storm, acute respiratory distress syndrome (ARDS), reduced blood oxygenation, mechanical ventilation, and a high death rate. Although recent studies have shown remdesivir and dexamethasone as treatment options, there is an urgent need to find a treatment to inhibit virus replication and to control the progression of the disease. Essential biometal zinc has generated a lot of excitement as one of the promising candidates to reduce the severity of COVID-19 infection. Several published observations outlined in the review are the reasons why there is a global enthusiasm that zinc therapy could be a possible therapeutic option. However, the biggest challenge in realising the therapeutic value of zinc is lack of optimal treatment modalities such as dose, duration of zinc supplementation and the mode of delivery. In this review, we discuss the regulatory mechanism that hinges upon the bioavailability of zinc. Finally, we propose that intravenous zinc could circumvent the confounding factors affecting the bioavailability of zinc and allow zinc to achieve its therapeutic potential. If successful, due to advantages such as lack of toxicity, low cost and ease of availability, intravenous zinc could be rapidly implemented clinically.

A pilot double-blind safety and feasibility randomized controlled trial of high-dose intravenous zinc in hospitalized COVID-19 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 < .001) on Day 6. Our study did not reach its target enrollment because stringent public health measures markedly reduced patient hospitalizations. Hospitalized COVID-19 patients demonstrated zinc deficiency. This can be corrected with HDIVZn. Such treatment appears safe, feasible, and only associated with minimal peripheral infusion site irritation. This pilot study justifies further investigation of this treatment in COVID-19 patients.

Randomised controlled trial for high-dose intravenous zinc as adjunctive therapy in SARS-CoV-2 (COVID-19) positive critically ill patients: trial protocol.

INTRODUCTION: SARS-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 ANALYSIS: We 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/FiO2 for 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 DISSEMINATION: Ethical 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 NUMBER: ACTRN126200000454976.

The Protective Effect of Zinc Against Liver Ischaemia Reperfusion Injury in a Rat Model of Global Ischaemia.

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.