TGF-ß signalling limits effector function capacity of NK cell anti-tumour immunity in human bladder cancer.

BACKGROUND: Natural killer (NK) cells are important innate immunity players and have unique abilities to recognize and eliminate cancer cells, particularly in settings of antibody-opsonization and antibody-dependant cellular cytotoxicity (ADCC). However, NK cell-based responses in bladder cancers to therapeutic antibodies are typically immunosuppressed, and these immunosuppressive mechanisms are largely unknown. METHODS: Single cell RNA sequencing (scRNA-seq) and high-dimensional flow cytometry were used to investigate the phenotype of tumour-infiltrating NK cells in patients with bladder cancer. Further, in vitro, and in vivo models of this disease were used to validate these findings. FINDINGS: NK cells within bladder tumours displayed reduced expression of FcγRIIIa/CD16, the critical Fc receptor involved in ADCC-mediated cytotoxicity, on both transcriptional and protein levels. Transcriptional signatures of transforming growth factor (TGF)-ß-signalling, a pleiotropic cytokine known for its immunosuppressive and tissue residency-inducing effects, were upregulated in tumour-infiltrating NK cells. TGF-ß mediated CD16 downregulation on NK cells, was further validated in vitro, which was accompanied by a transition into a tissue residency phenotype. This CD16 downregulation was also abrogated by TGF-ßR signalling inhibition, which could also restore the ADCC ability of NK cells subject to TGF-ß effects. In a humanized mouse model of bladder cancer, mice treated with a TGF-ß inhibitor exhibited increased ADCC activity compared to mice treated only with antibodies. INTERPRETATION: This study highlights how TGF-ß-rich bladder cancers inhibit NK cell-mediated ADCC by downregulating CD16. TGF-ß inhibition represents new avenues to reverse immunosuppression and enhance the tumoricidal capacity of NK cells in bladder cancer. FUNDING: The Guimaraes Laboratory is funded by a US Department of Defense-Breast Cancer Research Program-Breakthrough Award Level 1 (#BC200025), a grant (#2019485) awarded through the Medical Research Future Fund (MRFF, with the support of the Queensland Children's Hospital Foundation, Microba Life Sciences, Richie's Rainbow Foundation, Translational Research Institute (TRI) and UQ), and a grant (#RSS_2023_085) funded by a Metro South Health Research Support Scheme. J.K.M.W. is funded by a UQ Research Training Program PhD Scholarship and N.O. is funded by a NHMRC Postgraduate Scholarship (#2021932).

Systematic review and network meta-analysis of re-intervention rates of new surgical interventions for benign prostatic hyperplasia.

OBJECTIVE: To assess the re-intervention rates of new surgical benign prostatic hyperplasia (BPH) interventions, as the clinical durability of new surgical interventions for BPH is not widely known. METHODS: A critical review of new surgical BPH therapies namely 'UroLift®', 'Aquablation', 'Rezum', 'prostatic artery embolisation (PAE)' and 'temporary implantable nitinol device (iTIND)' was performed on PubMed, the Cochrane Library, and Embase databases between May 2010 and December 2022 according to the Preferred Reporting Items for Systematic Review and Meta-analyses (PRISMA) statement. All relevant articles were reviewed, and the risk of bias was evaluated using the Cochrane risk assessment tool and Newcastle-Ottawa Scale. RESULTS: Of the 32 studies included, there were 10 randomised controlled trials and 22 prospective observational cohorts. A total of 2400 participants were studied with a median patient age of 66 years, a median prostate volume of 51.9 mL, and a median International Prostate Symptom Score of 22. The lowest re-intervention rate at 12 months was for Aquablation at 0.01%, followed by Rezum at 0.02%, iTIND at 0.03%, and PAE at 0.05%. Network meta-analysis (NMA) showed that the best-ranked treatment at 12 months was transurethral resection of the prostate (TURP), followed by Aquablation, iTIND, Rezum, and UroLift. Re-intervention rates with these new BPH interventions are comparable, although some interventions reported better outcomes than TURP in the shorter term. CONCLUSIONS: While this systematic review and NMA showed that the re-intervention rate with these new surgical BPH interventions appears to be comparable to TURP in the short term, further studies are required to directly compare these various BPH procedures.

The Role of Prostate-specific Membrane Antigen Positron Emission Tomography/Computed Tomography in Primary Staging of Selected Renal Tumours: Initial Experience in a Multicentre Cohort.

BACKGROUND: Accurate primary staging of renal cancer with conventional imaging is challenging. Prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) may serve to improve the accuracy of renal cancer staging. OBJECTIVE: To determine clinicopathological and management differences for primary renal cancer staged with PSMA PET/CT in comparison to conventional imaging. DESIGN, SETTING, AND PARTICIPANTS: We conducted a retrospective cohort study of PSMA PET/CT scans performed for primary staging of renal cancer and incidental renal lesions at three sites in Brisbane, Australia between June 2015 and June 2020. Clinical characteristics, imaging, and histopathology were reviewed. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Clinicopathological and management differences according to staging modality (PSMA PET/CT, conventional imaging) were assessed. Descriptive statistics were used to report demographics and clinical parameters. Nonparametric methods were used for statistical analysis. Fisher's exact test was used for comparison of small-cell size categorical variables. RESULTS AND LIMITATIONS: From a total of 120 PSMA PET/CT scans, 61 were included (52 staging, 9 incidental) for predominantly males (74%) with a mean age of 65.1 yr (standard deviation 12.0). Most primary lesions (40/51) were clear-cell renal cell carcinoma (ccRCC; 98% PSMA-avid), eight were non-ccRCC (75% PSMA-avid), and three were non-RCC (oncocytoma; 67% PSMA-avid). PSMA PET identified a greater number of presumed metastatic lesions than conventional imaging (195 vs 160). A management change was observed for 32% of patients (20% major, 12% minor). Limitations include the retrospective design and selection bias, lack of blinding to PSMA reporting, and the use of different PSMA radiotracers. CONCLUSIONS: PSMA PET/CT detected more metastases than conventional imaging and most renal cancers were PSMA-avid, resulting in a management change for one-third of the patients. PATIENT SUMMARY: We looked at a newer type of scan called PSMA PET/CT for first staging of kidney cancer. We found that this detects more metastasis and helps in decisions on changes in treatment for some patients. This type of imaging is a useful addition to conventional scans in tricky cases and may help in better selection of suitable treatments, but more studies are required.

Bladder malignancy as a cause of spontaneous bladder rupture: A systematic review.

Objectives: To characterise cases of spontaneous rupture of the urinary bladder in the context of bladder cancer. Methods: A systematic review was performed to characterise cases of spontaneous bladder rupture in patients with bladder cancer. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) system was utilised, with databases being searched for relevant cases. Patient characteristics were extracted, including age, sex, presenting signs and symptoms, management modalities, tumour histology and mortality. Results: Thirty cases were included. Seventeen (57%) were male, and the median age of presentation was 59. Abdominal pain and peritonism were the most common presenting symptoms, in 80% and 60% of patients, respectively. Most patients (n = 16, 53%) had urothelial cell carcinoma. Nine patients (30%) died during their initial hospitalisation. Conclusion: Spontaneous bladder perforation in the context of bladder cancer is a rare cause of acute abdomen. The diagnosis is associated with high mortality, highlighting the aggressive nature of the malignancies that cause spontaneous bladder rupture. This raises important questions about the role of emergency cystectomy, the timing of systemic therapy and the appropriate involvement of palliative care.

Impact of the COVID-19 pandemic on delivery of prostate cancer care in Australia: An interrupted time series analysis.

The COVID-19 pandemic led to a major disruption to health services across the world. The aim of this population-based study was to assess the downstream effects of the pandemic on diagnostic tests and treatment activities related to prostate cancer (PC). The Australian Government Department of Health Medicare Benefits Schedule and the Pharmaceutical Benefits Scheme databases were queried from January 2010 to June 2022. Two interrupted time series were performed Pre-COVID (January 2010 to February 2020) and peri-COVID (March 2020 to June 2022). Temporal modeling was performed to account for seasonal variation. Pre-COVID-19, monthly prostate-specific antigen (PSA) testing showed a declining trend and testing decreased by 81 tests per 100 000 annually. A single-month 38% drop in PSA testing was observed in April 2020; this corresponded to Australia's first wave. No change was observed in the rate of prostate biopsies. Peri-COVID-19 outbreaks, there was a slight shift toward the use of long-acting androgen deprivation therapy (ADT) at 4% with a predilection still for short-acting agents. with no registered change in the overall volume of radiotherapy or surgery. There were no deficits in the number of diagnostic and treatment activities for men with PC. Aside from a slight shift toward long-acting ADT use during the pandemic, no other patterns were observed. The longer-term impact such as missed diagnosis or late presentation affecting chances of survival due to COVID-19 is yet to be ascertained.

A review of the objective cognitive function measurements in males receiving hormonal therapy for prostate cancer.

PURPOSE: Prostate cancer (PC) is more common in the older population and the use of hormonal therapy in PC can increase medical frailty and cognitive decline. This narrative review examines the impact of androgen deprivation therapies (ADTs) and next-generational hormonal therapies (NGHT) on cognitive function outcomes amongst patients with hormone-sensitive or castrate-resistant PC. MATERIALS AND METHODS: Six electronic databases were searched from January 2000 to June 2022 for quantitative studies to evaluate the impacts of hormonal therapies (ADT, combined androgen blockade, and NGHT) on cognitive functions in men with PC. RESULTS: Of the 36 studies identified, 20 studies reported no effect of hormonal therapies on any cognitive domain while 16 studies found possible declines in at least one domain. The domains assessed were highly variable and objective assessment measurements were not standardized or widely adopted. While the results have been inconsistent, a relationship between declining androgen levels and poorer performances in the visuospatial and visual memory domains has been highlighted. It was not possible to distinguish the degree of cognitive parameter changes between the populations of hormone-sensitive and castrate-resistant PC. CONCLUSIONS: While the exact impact of ADT and NGHT on cognitive function in men with PC remains controversial, appropriate care should be undertaken especially in older and frail individuals, specifically in those with progressive or established visuospatial or visual memory deficits.

Clinical impact of Prostate-Specific Membrane Antigen Positron Emission Tomography (PET) on intensification or deintensification of advanced renal cell carcinoma management.

PURPOSE: There is an emerging role of the use of Prostate-Specific Membrane Antigen (PSMA) Positron Emission Tomography (PET) in renal cell carcinoma. Herein, we report our experience in use of PSMA PET in recurrent or metastatic renal cell carcinoma (RCC). METHODS: A retrospective analysis of all patients who underwent PSMA PET for suspected recurrent or de-novo metastatic RCC between 2015 and 2020 at three institutions was performed. The primary outcome was change in management (intensification or de-intensification) following PSMA PET scan. Secondary outcomes included histopathological correlation of PSMA avid sites, comparison of sites of disease on PSMA PET to diagnostic CT and time to systemic treatment.

Weaponizing natural killer cells for solid cancer immunotherapy.

Enhancing natural killer (NK) cell-based innate immunity has become a promising strategy for immunotherapy against hard-to-cure solid cancers. Monoclonal antibody (mAb) therapy has been used to activate NK-cell-mediated antibody-dependent cellular cytotoxicity (ADCC) towards solid cancers. Cancer cells, however, can subvert immunosurveillance using multiple immunosuppressive mechanisms, which may hamper NK cell ADCC. Mechanisms to safely enhance ADCC by NK cells, such as utilizing temporary inhibition of receptor endocytosis to increase antibody presentation from target to effector cells can now be used to enhance NK-cell-mediated ADCC against solid tumors. This review summarizes and discusses the recent advances in the field and highlights current and potential future use of immunotherapies to maximize the therapeutic efficacy of innate anticancer immunity.

Trends in minimally invasive surgical therapies for overactive bladder management in Australia.

OBJECTIVE: To evaluate the national trends in minimally invasive surgical therapies (MIST) for overactive bladder (OAB) in Australia over the past decade. METHODS: Annual MIST data were extracted using the Australian Medicare Benefit Schedule (MBS) on intravesical botulinum toxin (BTX), sacral nerve modulators (SNM) and percutaneous tibial nerve stimulators (PTNS) performed between 2010 and 2021. Population-adjusted rates of these procedures were compared in relation to individual states and against the introduction of various OAB drugs during the intervening years. RESULTS: The overall national utilization of MIST for OAB has increased over the last decade. The data reflect a rapid uptake in PTNS over the last 2 years following its introduction compared to the relatively steady increase in BTX and SNM over the past decade. There was minimal difference in SNM lead and generator placement, suggesting perhaps the conversion of trial SNM to permanent SNM has been relatively stable across the years. In contrast, there was an increase in PTNS maintenance in the following years following the initial rise in the PTNS treatment initiation. The introduction of various OAB drugs in the market did not seem to significantly affect the pattern of MIST uptake. CONCLUSION: Despite the introduction of various OAB drugs, the overall MIST has increased steadily over the last decade, especially with PTNS. Further exploration into the motivators for specific MIST and cost-benefit analysis of these MIST for OAB is warranted.

Urgent nephrectomy for rapidly progressive disseminated metastatic Hypermucoid Klebsiella.

Few cases of Hypervirulent Klebsiella Pneumonia (HvKP) have been described. Even fewer cases with renal abscess and metastatic pulmonary spread are reported. Typically, prompt introduction of intravenous antibiotics leads to clinical resolution and more invasive measures of source control are rarely required. To date only one other case of disseminated metastatic HvKP requiring nephrectomy for infective source control is described. Here we present a rare case of metastatic HvKP refractory to intravenous antimicrobial therapy in an immunocompromised newly diagnosed diabetic patient. Specifically, we seek to illustrate the rapid effectiveness of surgical intervention following a poor response to initial treatment.

Characterization of tumor thrombus in renal cell carcinoma with prostate specific membrane antigen (PSMA) positron emission tomography (PET)/computed tomography (CT).

INTRODUCTION: Venous tumor thrombus (TT) occurs as part of the natural history of renal cell carcinoma (RCC) local progression in a small minority of cases. MRI is currently the most accurate imaging modality for determining TT extent. PSMA PET/CT may improve RCC staging and IVC TT characterization. The objective of this study was to investigate the role of PSMA PET/CT in defining superior extent of TT in RCC and TT IVC tributary vessel spread, with comparative accuracy vs. MRI, to assess suitability for resection and inform preoperative surgical planning. METHODS: Patients who underwent PSMA PET/CT for assessment of renal malignancy with TT from 2015 to 2020 at 3 tertiary hospitals in Brisbane, Australia, were retrospectively identified. TT extent was classified using Mayo Clinic levels and compared according to imaging modality. RESULTS: Fourteen patients were included, all of which were clear cell RCC. Ten patients also underwent MRI, 6 of which were concordant in extent according to MRI and PSMA PET. Discordant extent occurred in 4 patients, of which 2 patients had non-PSMA avid thrombus (Mayo level 0 and level 3 on MRI). Further discordance was seen in a patient with adrenal vein and lumbar vein TT only seen on MRI and PSMA PET/CT, respectively. Finally, discordant extent was seen in another patient with Mayo level 4 TT without lumbar vein involvement on MRI vs. level 3 on PSMA PET/CT with lumbar vein involvement. CONCLUSIONS: PSMA PET/CT can provide additional information about TT extent in RCC which may not be seen on MRI. Additional information from PSMA PET/CT in this setting may assist surgical planning, in addition to detection of metastatic disease.

Mixed connective tissue disease and idiopathic retroperitoneal fibrosis: A rare but important association.

Idiopathic Retroperitoneal fibrosis (RPF) is a fibro-inflammatory disease. In patients with known mixed connective tissue disease (MCTD) it has rarely been described. Our case illustrates a unique presentation of RPF in a patient with MCTD. We emphasise possible links between the two disease processes and the high level of clinical suspicion required to make a diagnosis.

Impact of Physical Exercise Program Interventions on Erectile Function and Cardiovascular Health in Males with Prostate Cancer.

Prostate cancer (PC) and its associated treatments can cause significant cardiovascular and sexual dysfunctions. While structured exercise interventions can induce positive outcomes in males with PC, there are limited data on its effects on cardiovascular health, erectile function, or the combination of these outcomes. It has been proposed that positive changes in biomarkers of cardiovascular health through physical exercise programs, can result in cardiovascular remodelling and improve penile haemodynamic and erectile function recovery in those with metabolic syndrome and/or cardiovascular diseases, although the data is accruing in males who are diagnosed and/or treated for PC. While the results of this review article support structured physical exercise interventions to effectively prevent and mitigate the development of both sexual and cardiovascular dysfunctions in males with PC, appropriate caution should be maintained and future clinical research should focus on the development of standardised and evidence-based exercise guidelines in the setting of PC survivorship.

The role of dual tracer PSMA and FDG PET/CT in renal cell carcinoma (RCC) compared to conventional imaging: A multi-institutional case series with intra-individual comparison.

PURPOSE: The objective of this study was to perform an intra-individual dual tracer comparison of Fluorodeoxyglucose (FDG) and Prostate Specific Membrane Antigen (PSMA) computed tomography (CT)/Positron Emission Tomography (PET) against standard of care (SOC) imaging for the characterisation, staging and restaging of renal cell carcinoma (RCC). METHODS: A multicentre retrospective cohort study was performed at 3 major tertiary referral institutions in Brisbane, Australia between 2015 and 2020. All patients who underwent both PSMA and FDG PET/CT following SOC imaging for investigation of RCC were identified. Clinical details, imaging characteristics and histopathology were collected prior to univariate statistical analysis. RESULTS: Eleven patients who underwent dual tracer PET/CT were included. Mean age was 65.5 years (SD 8.8). Most patients were male (64%) with clear cell morphology (91%). The indication for dual tracer PET was staging (36%) and restaging after radical/partial nephrectomy (64%). Primary tumour assessment showed mixed avidity patterns (concordant 40%, discordant favouring PSMA 20%, and FDG 40%). Metastatic disease assessment showed concordant avidity in 6 patients (55%), concordant negative in 3 (27%), and discordant uptake favouring PSMA. PET outperformed SOC imaging for assessment of metastatic disease in 5 patients (45%) and equivalent for the remainder. A change in management was noted in three cases (27%). CONCLUSION: Dual tracer FDG and PSMA PET/CT for assessment of primary and metastatic RCC were mostly concordant. PET imaging outperformed conventional imaging and led to a change in management for 1 in 4 patients. Further studies with larger samples sizes are required to validate these findings and identify characteristics to guide patient selection for selective or dual tracer use.

A Novel Liver-targeted Testosterone Therapy for Sarcopenia in Androgen Deprived Men With Prostate Cancer.

OBJECTIVE: Androgen deprivation therapy (ADT) reduces muscle and bone mass, increasing frailty in men with prostate cancer. The liver mediates the whole body anabolic effects of testosterone. Based on first-pass metabolism, liver-targeted testosterone treatment (LTTT) entails oral delivery of a small dose of testosterone that does not raise peripheral blood testosterone levels. LTTT reduces blood urea and stimulates protein anabolism in hypogonadal men and postmenopausal women. We investigated whether LTTT prevents loss of lean and bone mass during ADT. METHOD: A 6-month, double-blind, placebo-controlled study of testosterone 40 mg/day in 50 men. Primary outcome measures were lean mass and bone mineral content (BMC). Testosterone, urea and prostate-specific antigen (PSA) were monitored. Patients were withdrawn if PSA exceeded 4 ng/mL. RESULTS: 42 patients completed the study. Mean (95% CI) testosterone rose during LTTT but not placebo treatment [∆ 2.2 (1.3-3.0) vs -0.7 (-1.5 to 0.2) nmol/L; P < 0.01]. Mean PSA level did not change significantly during either treatment. Blood urea fell [∆ -0.4 (-0.9 to -0.1) mmol/L] during LTTT but not placebo [∆ 0.05 (-0.8 to 0.9) mmol/L]. BMC [∆ 49 (5 to 93) g; P < 0.02] and lean mass [∆ 0.8 (-0.1 to 1.7) kg; P = 0.04) increased compared to placebo. Five patients on LTTT withdrew from increased PSA levels, all returning to baseline levels. CONCLUSION: LTTT shows promise as a simple therapy for preventing sarcopenia and bone loss during ADT. LTTT may induce reversible PSA rise in some patients. Further studies are required to optimize LTTT dose in ADT. LTTT has potential application in other catabolic states in men and women.

Fumarate hydratase-deficient renal cell carcinoma presenting as pelvicalyceal filling defect: an unusual presentation of a rare disease.

A 75-year-old man was referred to our urology service with painless haematuria. The delayed phase on a subsequent computed tomography (CT) abdomen and pelvis showed a filling defect in the left renal pelvicalyceal system, suspicious for a transitional cell carcinoma. The patient underwent ureteroscopic biopsy suggestive of a papillary neoplasia, before progressing to a laparoscopic radical left nephrouretectomy. Final histology revealed a fumarate hydratase-deficient renal cell carcinoma with clear margins. The patient was subsequently referred for genetic counselling.

Bilateral renal haematuria and obstructive renal failure from acquired haemophilia A: a medical cause for a surgical problem.

A 55-year-old male presented to our emergency department with haematuria and abdominal pain. Investigations including a computed tomography (CT) scan revealed an intraluminal filling defect within the left collecting system, consistent in appearance with blood clot. With an initial working diagnosis of upper tract urothelial cell carcinoma, he was discharged with plans for an urgent cystoscopy and ureteroscopy. He subsequently represented with ongoing frank haematuria, anasarca, dropping haemoglobin and new right collecting system blood clot. Subsequent investigations showed that the patient had acquired haemophilia A resulting in the episodes of haematuria, highlighted after an elevated activated partial thromboplastic time prompted a thrombophilia screen. The patient was subsequently treated with factor eight inhibitor bypass activity, corticosteroids and cyclophosphamide.

PSMA-PET/CT-avid metastatic prostate cancer to the penis.

Penile metastases from prostate cancer (PC) are rarely reported in the literature. Most commonly diagnosed due to presentation with malignant priapism and other urinary symptoms or from findings on clinical examination, prognosis has been reported to be poor. The authors outline a case of penile metastasis from advanced PC. Initially treated with neoadjuvant androgen deprivation therapy for locally advanced PC, this patient displayed upfront castrate resistance, and subsequent prostate-specific membrane antigen positron emission tomography revealed penile metastatic deposits. The patient was treated with external beam radiotherapy, and worsening urethral stricture disease resulted in the placement of a suprapubic catheter.

The Use of MRI and PET Imaging Studies for Prostate Cancer Management: Brief Update, Clinical Recommendations, and Technological Limitations.

Multi-parametric magnetic resonance imaging (mpMRI) and positron emission tomography (PET) using prostate-specific membrane antigen (PSMA) targeting ligands have been adopted as a new standard of imaging modality in the management of prostate cancer (PCa). Technological advances with hybrid and advanced computer-assisted technologies such as MR/PET, MR/US, multi-parametric US, and robotic biopsy systems, have resulted in improved diagnosis and staging of patients in various stages of PCa with changes in treatment that may be considered "personalized". Whilst newer clinical trials incorporate these novel imaging modalities into study protocols and as long-term data matures, patients should be made aware of the potential benefits and harm related to these technologies. Published literature needs to report longer-term treatment efficacy, health economic outcomes, and adverse effects. False positives and negatives of these imaging modalities have the potential to cause harm and the limitations of these technologies should be appreciated. The role of a multi-disciplinary team (MDT) and a shared-decision-making model are important to ensure that all aspects of the novel imaging modalities are considered.

Metastatic plasmacytoid bladder cancer causing malignant priapism.

An 81-year-old man presented to medical services with pelvic pain and evolving urinary retention over 3 months. The patient was found to have a tense glans and penile shaft with surrounding induration consistent with malignant priapism. The extent of the induration included the suprapubic region, scrotum, left iliac region and left flank. A CT scan demonstrated an enhancing, pedunculated lesion arising from the anterior bladder wall measuring 30×31×20 mm. There were multiple enlarged left inguinal lymph nodes. Core biopsies of the subcutaneous tissue on the anterior abdominal wall demonstrated plasmacytoid urothelial carcinoma. The majority of patients with plasmacytoid variant of transitional cell carcinoma will present with >stage 3 bladder disease.