Introduction of Androgen Receptor Targeting shRNA Inhibits Tumor Growth in Patient-Derived Prostate Cancer Xenografts.

Patient-derived xenograft (PDX) models have been established as important preclinical cancer models, overcoming some of the limitations associated with the use of cancer cell lines. The utility of prostate cancer PDX models has been limited by an inability to genetically manipulate them in vivo and difficulties sustaining PDX-derived cancer cells in culture. Viable, short-term propagation of PDX models would allow in vitro transfection with traceable reporters or manipulation of gene expression relevant to different studies within the prostate cancer field. Here, we report an organoid culture system that supports the growth of prostate cancer PDX cells in vitro and permits genetic manipulation, substantially increasing the scope to use PDXs to study the pathobiology of prostate cancer and define potential therapeutic targets. We have established a short-term PDX-derived in vitro cell culture system which enables genetic manipulation of prostate cancer PDXs LuCaP35 and BM18. Genetically manipulated cells could be re-established as viable xenografts when re-implanted subcutaneously in immunocompromised mice and were able to be serially passaged. Tumor growth of the androgen-dependent LuCaP35 PDX was significantly inhibited following depletion of the androgen receptor (AR) in vivo. Taken together, this system provides a method to generate novel preclinical models to assess the impact of controlled genetic perturbations and allows for targeting specific genes of interest in the complex biological setting of solid tumors.

Sodium glucose-linked transport protein 2 inhibitors: An overview of genitourinary and perioperative implications.

Sodium glucose-linked transport protein 2 inhibitors are relatively novel drugs, used for the treatment of type 2 diabetes mellitus. Their use since Pharmaceutical Benefits Scheme approval in Australia has increased drastically, possibly due to the low risk of hypoglycemic events and their advertised cardiovascular mortality benefits. However, as with any novel drug, adverse effects regarding their use require medical practitioner awareness for optimal patient outcomes. This paper aims to cover the major urological implications, including those pertinent perioperatively, that concern this class of drugs. There is a clear risk of developing genital mycotic infections with the use of sodium glucose-linked transport protein 2 inhibitors, including serious infections such as Fournier's gangrene. Evidence for developing urinary tract infections has been mixed. Sodium glucose-linked transport protein 2 inhibitor-induced lower urinary tract symptoms may have impacts on quality of life via pollakiuria and nocturia, of which there are increased reports. Perioperative use increases the risk of euglycemic diabetic ketoacidosis. It is recommended that sodium glucose-linked transport protein 2 inhibitors be ceased perioperatively.

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.

Culture of Bladder Cancer Organoids as Precision Medicine Tools.

Current in vitro therapeutic testing platforms lack relevance to tumor pathophysiology, typically employing cancer cell lines established as two-dimensional (2D) cultures on tissue culture plastic. There is a critical need for more representative models of tumor complexity that can accurately predict therapeutic response and sensitivity. The development of three-dimensional (3D) ex vivo culture of patient-derived organoids (PDOs), derived from fresh tumor tissues, aims to address these shortcomings. Organoid cultures can be used as tumor surrogates in parallel to routine clinical management to inform therapeutic decisions by identifying potential effective interventions and indicating therapies that may be futile. Here, this procedure aims to describe strategies and a detailed step-by-step protocol to establish bladder cancer PDOs from fresh, viable clinical tissue. Our well-established, optimized protocols are practical to set up 3D cultures for experiments using limited and diverse starting material directly from patients or patient-derived xenograft (PDX) tumor material. This procedure can also be employed by most laboratories equipped with standard tissue culture equipment. The organoids generated using this protocol can be used as ex vivo surrogates to understand both the molecular mechanisms underpinning urological cancer pathology and to evaluate treatments to inform clinical management.

Overactive bladder syndrome: Management and treatment options.

BACKGROUND: Overactive bladder (OAB) is a common syndrome in the community characterised by unstable bladder contractions, resulting in urinary urgency, frequency and nocturia in the absence of detectable disease. Large studies suggest that >10% of the general population is symptomatic. OBJECTIVE: The aim of this article is to summarise the stepwise treatment for OAB that seeks to improve patient quality of life and reduce patient and health system costs. DISCUSSION: OAB is a diagnosis of exclusion that begins with a targeted history and examination of the urogenital system with the aim of assessing the burden of disease on the patient. First-line treatment comprises conservative measures including weight reduction, a decrease in exposure to bladder stimulants, fluid optimisation and pelvic floor exercises. Pharmacological treatments for OAB include anticholinergic medications such as oxybutynin. If the patient is unresponsive to pharmacological treatment, a review by a urology specialist is appropriate. Recommendations may include minimally invasive procedures such as intravesical botulinum toxin A injections, reserving the invasive procedures for patients in specific circumstances.

Challenges, applications and future directions of precision medicine in prostate cancer - the role of organoids and patient-derived xenografts.

OBJECTIVE: To provide a clinically relevant outline of various current precision medicine principles and available evidence on the application and potential for a precision medicine approach in prostate cancer. METHODS: Narrative review of the current literature in the field. CONCLUSION: Precision medicine is the concept of individualising patient management based on specific tumour characteristics and biology, rather than traditional histological subtypes. The overall aim is to personalise management to individual patients, to provide the right cancer treatment, to the right patient, at the right time. While the approach aims to improve clinical outcomes, decrease morbidity and improve survival in men with advanced prostate cancer, its clinical application is in its infancy. It does however show great promise in this and other cancers, and will continue to be an area of active research and clinical investigation.

Exploratory cost-effectiveness analysis of 68Gallium-PSMA PET/MRI-based imaging in patients with biochemical recurrence of prostate cancer.

Men treated for prostate cancer with curative intent face a recurrence rate of up to 53% at 10 years. 68Ga-PSMA imaging is a new technique that can more accurately stage cancer recurrences and facilitate personalised treatment. We evaluated the cost-effectiveness of 68Ga-PSMA PET/MRI for staging men with prostate cancer biochemical recurrence. A cost-effectiveness analysis using a decision-analytic model with Markov chains was constructed. 68Ga-PSMA PET/MRI was compared with usual care in staging of men with suspected prostate cancer recurrence. Men with biochemical recurrence from a study in Brisbane, Australia (n = 30) provided key estimates for the model. The primary outcomes were health system costs and years of life (survival) over 10 years. Deterministic and probabilistic sensitivity analyses were undertaken to address uncertainty in model estimates. On average, a strategy of 68Ga-PSMA was expected to cost AU$56 961(US$39 426) and produce 7.48 life years compared with AU$64 499 (US$44 667) and 7.41 life years in usual care. Therefore, 68Ga-PSMA was potentially cost saving (- AU$7 592 95% UI - $24 846, $7 825) (- US$5 258) and slightly more effective 0.07 life years (95% UI - 0.01, 0.16). The likelihood that 68Ga-PSMA strategy was cost-effective at acceptable thresholds was 87%. The findings were sensitive to the lesion detection rate of the 68Ga-PSMA strategy (52-75%) and the cost of follow up in usual care (AU$1 947 to $2 635). In this exploratory economic evaluation, using 68Ga-PSMA PET/MRI to detect prostate cancer recurrence appears to be cost-effective relative to usual care.

Open retropubic radical prostatectomy.

Radical prostatectomy (RP) is a common treatment choice for localized prostate cancer. While there is increasing utilisation of robotic assisted RP in some centres, open RP (ORP) remains well established and commonly performed in many parts of the world. The goals of modern ORP are to remove the prostate en-bloc with negative surgical margins, while minimising blood loss and preserving urinary continence and erectile function. We present a technical review of ORP incorporating contemporary techniques for control of the deep venous complex, additional haemostatic measures, nerve-sparing and vesicourethral reconstruction.

Declining use of radical prostatectomy and pelvic lymphadenectomy despite more robotics: National population data over 15 years.

AIM: To describe national surgical patterns of prostate cancer (PCa) care considering radical prostatectomy with or without pelvic lymphadenectomy and consideration of robotic-assisted techniques. METHODS: Retrospective analysis of publicly accessible Medicare claims data was performed for the period 2001-2016 and included patients undergoing radical prostatectomy with or without pelvic lymphadenectomy relative to total and PCa-specific populations among men aged 45-84 years. Proportion of cases performed robotically was considered. RESULTS: Total procedures performed increased from 2001, peaked in 2009 and subsequently decreased until 2016. Since 2009, the age-specific rate of surgery in men aged 75-84 increased by 2.3-fold, whereas the rates for men aged 55-64 and 45-54 reduced by 44% and 55%, respectively. Rates of concurrent pelvic lymphadenectomy fell until 2009 with subsequent stabilization (ratio 1.05-1.14) through to 2016. Significant regional practice patterns were observed, as was an increasing trend toward a robotic-assisted laparoscopic approach, comprising more than 80% of radical prostatectomies in 2016. CONCLUSION: Since the peak in 2009, radical prostatectomy is performed less in men <65 years and more in men ≥65 years. An increasing proportion of cases omit concurrent pelvic lymphadenectomy and are performed robotically.

Retained neonatal ureteral stent post-ureteric reimplantation: a 26-year saga.

Ureteral stents are an essential tool in modern day adult and paediatric urology. They are usually placed with the intention of removal or replacement after a specific time but may occasionally be forgotten or unintentionally retained. We present the case of a young man who presented with symptoms caused by a retained ureteric stent placed 26 years earlier during reconstructive ureteric surgery as an infant.

A contemporary, nationwide analysis of surgery and radiotherapy treatment for prostate cancer.

OBJECTIVE: To characterize national clinical practice trends in the treatment of prostate cancer (PCa) in Australia. PATIENTS AND METHODS: Population-level data were extracted from existing Medicare Benefits Schedule data for radical prostatectomy (RP) and brachytherapy (2002-2016), as well as external beam radiotherapy (EBRT; 2012-2016). Treatment rates were calculated relative to whole and PCa populations among privately treated patients. Overall age-related and geographical trends were analysed. RESULTS: The use of RP and low-dose-rate (LDR) brachytherapy increased between 2002 and 2009, but subsequently decreased to 124 and 6.9 per 100 000 men, respectively, in 2016. More dramatic decreases were observed for men aged <65 years. From 2012, rates of RP (15% drop) and LDR brachytherapy (58% drop) decreased, while the use of EBRT remained steady, falling by 5% to 42 per 100 000 men in 2016. Overall treatment increased in the age group 75-84 years, with the rate of RP increasing by 108%. CONCLUSION: National claims data indicate there has been a reduction in PCa treatment since 2009, which is mostly attributable to a reduction in the treatment of younger patients and reduced use of brachytherapy. RP is most commonly used and its use is rising in men aged >65 years.

A Review of Prostate-Specific Membrane Antigen (PSMA) Positron Emission Tomography (PET) in Renal Cell Carcinoma (RCC).

Metastatic renal cell carcinoma (mRCC) is a disease that portends poor prognosis despite an increasing number of novel systemic treatment options including new targeted therapies and immunotherapy. Ablative intervention directed at oligometastatic RCC has demonstrated survival benefit. Consequently, developing techniques for improved staging of mRCC on contemporary imaging modalities including X-ray computed tomography (CT), magnetic resonance imaging (MRI) and/or bone scan (BS) is a clinical priority. This is relevant for metastatic deposits too small to characterize or lymph nodes within physiological normality. Prostate-specific membrane antigen (PSMA) is a type II transmembrane glycoprotein highly expressed on prostate cancer epithelial cells. Recently, small molecules targeting the PSMA receptor, linked to radioactive isotopes have been developed for use with positron emission tomography (PET). Despite its nomenclature, PSMA has also been found to be expressed in the neovasculature of non-prostate cancers such as renal cell carcinoma (RCC) and hence PSMA PET/CT imaging has been proposed as an alternative staging modality. Preliminary small studies involving the use of PSMA PET/CT imaging in mRCC have been encouraging with evidence of improved staging sensitivity which has directly led to change in management in some cases. Given these early encouraging reports, we performed a comprehensive narrative review on the available evidence, including the scientific basis for PSMA expression in RCC, the role of PSMA PET/CT imaging with potential clinical implications in mRCC, its limitations and future opportunities.

Optimising assessment of kidney function when managing localised renal masses.

Increased early and incidental detection, improved surgical techniques and technological advancement mean that the management of renal mass lesions is constantly evolving. The treatment of choice for renal mass lesions has historically been radical nephrectomy. Partial nephrectomy is now recommended for localised renal masses, owing to favourable renal functional outcomes. Ablative renal surgery confers a significant risk of chronic kidney disease. There are few studies assessing long term outcomes of nephrectomy on renal outcomes, and virtually no studies assessing long term outcomes for less invasive therapies such as ablation. Unless a renal mass is clearly benign on imaging, management decisions will be made with an assumption of malignancy. The content of this review applies to both benign and malignant renal mass lesions. We advocate for improved strategies for kidney function assessment and risk stratification, early targeted referral, and regular screening for chronic kidney disease for all patients after surgery.

Incidental Malignancies Identified During Staging for Prostate Cancer With 68Ga Prostate-specific Membrane Antigen HBED-CC Positron Emission Tomography Imaging.

The rapid uptake of 68Ga prostate-specific membrane antigen HBED-CC positron emission tomography (PSMA PET) imaging for prostate cancer staging has led to concerns regarding its specificity, with uptake in both malignant and nonmalignant tissues. We describe 3 separate malignancies identified on PSMA PET imaging. The misnomer "prostate-specific membrane antigen" is demonstrated by this case and highlights the importance of continued investigation of the potential role of PSMA PET in other malignancies.