Stereotactic ablative body radiotherapy for primary kidney cancer (TROG 15.03 FASTRACK II): a non-randomised phase 2 trial.

BACKGROUND: Stereotactic ablative body radiotherapy (SABR) is a novel non-invasive alternative for patients with primary renal cell cancer who do not undergo surgical resection. The FASTRACK II clinical trial investigated the efficacy of SABR for primary renal cell cancer in a phase 2 trial. METHODS: This international, non-randomised, phase 2 study was conducted in seven centres in Australia and one centre in the Netherlands. Eligible patients aged 18 years or older had biopsy-confirmed diagnosis of primary renal cell cancer, with only a single lesion; were medically inoperable, were at high risk of complications from surgery, or declined surgery; and had an Eastern Cooperative Oncology Group performance status of 0-2. A multidisciplinary decision that active treatment was warranted was required. Key exclusion criteria were a pre-treatment estimated glomerular filtration rate of less than 30 mL/min per 1·73 m2, previous systemic therapies for renal cell cancer, previous high-dose radiotherapy to an overlapping region, tumours larger than 10 cm, and direct contact of the renal cell cancer with the bowel. Patients received either a single fraction SABR of 26 Gy for tumours 4 cm or less in maximum diameter, or 42 Gy in three fractions for tumours more than 4 cm to 10 cm in maximum diameter. The primary endpoint was local control, defined as no progression of the primary renal cell cancer, as evaluated by the investigator per Response Evaluation Criteria in Solid Tumours (version 1.1). Assuming a 1-year local control of 90%, the null hypothesis of 80% or less was considered not to be worthy of proceeding to a future randomised controlled trial. All patients who commenced trial treatment were included in the primary outcome analysis. This trial is registered with ClinicalTrials.gov, NCT02613819, and has completed accrual. FINDINGS: Between July 28, 2016, and Feb 27, 2020, 70 patients were enrolled and initiated treatment. Median age was 77 years (IQR 70-82). Before enrolment, 49 (70%) of 70 patients had documented serial growth on initial surveillance imaging. 49 (70%) of 70 patients were male and 21 (30%) were female. Median tumour size was 4·6 cm (IQR 3·7-5·5). All patients enrolled had T1-T2a and N0-N1 disease. 23 patients received single-fraction SABR of 26 Gy and 47 received 42 Gy in three fractions. Median follow-up was 43 months (IQR 38-60). Local control at 12 months from treatment commencement was 100% (p<0·0001). Seven (10%) patients had grade 3 treatment-related adverse events, with no grade 4 adverse events observed. Grade 3 treatment-related adverse events were nausea and vomiting (three [4%] patients), abdominal, flank, or tumour pain (four [6%]), colonic obstruction (two [3%]), and diarrhoea (one [1%]). No treatment-related or cancer-related deaths occurred. INTERPRETATION: To our knowledge, this is the first multicentre prospective clinical trial of non-surgical definitive therapy in patients with primary renal cell cancer. In a cohort with predominantly T1b or larger disease, SABR was an effective treatment strategy with no observed local failures or cancer-related deaths. We observed an acceptable side-effect profile and renal function after SABR. These outcomes support the design of a future randomised trial of SABR versus surgery for primary renal cell cancer. FUNDING: Cancer Australia Priority-driven Collaborative Cancer Research Scheme.

Role of diverting colostomy and reconstruction in managing Fournier's gangrene-a narrative review.

OBJECTIVE: To examine the role of bowel diversion and reconstructive surgeries in managing Fournier's gangrene (FG) to facilitate multidisciplinary collaboration between urologists, colorectal and plastic surgery teams. METHODS: A review of the literature was conducted using the databases Medline, Embase, PubMed in June 2023. The review included studies that evaluated the outcomes of FG following reconstructive surgeries or diverting colostomies. RESULTS: The existing evidence suggests that bowel diversion and colostomy formation could reduce the need for further debridement, shorten the time to wound healing, and facilitate skin graft or flap uptake in patients with FG. Additionally, the psychological impact of a stoma was shown not to be a major concern for patients. However, stoma carries a risk of perioperative complications and therefore may prolong the length of hospital stay. In reviewing the evidence for reconstruction in FG, large and deep defects seem to benefit from skin grafts or flaps. Noticeably, burial of testicles in thigh pockets has grown out of favour due to concerns regarding the thermoregulation of the testicles and the psychological impact on patients. CONCLUSION: The use of bowel diversion and reconstructive surgeries in managing FG is case dependent. Therefore, it is important to have close discussions with colorectal and plastic surgery teams when managing FG.

The CONFIRM trial protocol: the utility of prostate-specific membrane antigen positron emission tomography/computed tomography in active surveillance for prostate cancer.

OBJECTIVES: Primary objectives: To determine the additive value of prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) in the risk stratification of men with newly diagnosed prostate cancer (PCa) who would have otherwise been deemed suitable for active surveillance (AS). Specifically, we aim to determine if PSMA PET/CT can detect a cohort of men on AS that are in fact high risk and likely to experience unfavourable outcomes should they remain on their current treatment pathway. SECONDARY OBJECTIVES: to determine the additive value of PSMA PET/CT to repeat multiparametric magnetic resonance imaging (mpMRI) of the prostate and explore whether a confirmatory biopsy may be avoided in men with a negative PSMA PET/CT and a negative repeat mpMRI of the prostate (Prostate Imaging-Reporting and Data System score of <3). Furthermore, to develop a nomogram combining clinical, imaging and biomarker data to predict the likelihood of failure on AS in men with high-risk features. Also, a blood sample will be taken to perform a Prostate Health Index test at the time of confirmatory biopsy. Furthermore, a portion of this blood will be stored at a biobank for up to 5 years if a follow-up study on molecular biomarkers and genetic assays in this cohort of men is indicated, based on the results from the CONFIRM trial. PATIENTS AND METHODS: The CONFIRM trial is a prospective, multicentre, pre-test/post-test, cohort study across Victoria, Australia, involving men with newly diagnosed low-risk PCa with high-risk features, considered suitable for AS and undergoing confirmatory biopsy. The trial's goal is to provide high-quality evidence to establish whether PSMA PET/CT has a role in risk-stratifying men deemed suitable for AS despite having high-risk feature(s). RESULTS: The CONFIRM trial will measure the proportion of men deemed unsuitable for ongoing AS based on pathological upgrading and multidisciplinary team recommendation due to PSMA PET/CT scan and PSMA-targeted confirmatory biopsy. Additionally, the positive and negative predictive values, sensitivity, and specificity of PSMA PET/CT will be calculated in isolation and combined with repeat mpMRI of the prostate. CONCLUSIONS: This trial will provide robust prospective data to determine if PSMA-PET/CT and standard of care (prostate biopsy ± repeat mpMRI) can improve diagnostic certainty in men undergoing confirmatory biopsy for low-grade PCa with high-risk features.

Barriers and enablers of active surveillance for prostate cancer: a qualitive study of clinicians.

OBJECTIVES: To identify and explore barriers to, and enablers of, active surveillance (AS) in men with low-risk prostate cancer (LRPCa), as perceived by PCa clinicians. PATIENTS AND METHODS: Urologists and radiation oncologists in Australia and New Zealand were purposively sampled for a cross-section on gender and practice setting (metropolitan/regional; public/private). Using a grounded theory approach, semi-structed interviews were conducted with participants. Interviews were coded independently by two researchers using open, axial, and selective coding. A constant comparative approach was used to analyse data as it was collected. Thematic saturation was reached after 18 interviews, and a detailed model of barriers to, and enablers of, AS for LRPCa, as perceived by clinicians was developed. RESULTS: A model explaining what affects clinician decision making regarding AS in LRPCa emerged. It was underpinned by three broad themes: (i) clinician perception of patients' barriers and enablers; (ii) clinician perception of their own barriers and enablers; and (iii) engagement with healthcare team and resource availability. CONCLUSIONS: Clinicians unanimously agree that AS is an evidence-based approach for managing LRPCa. Despite this many men do not undergo AS for LRPCa, which is due to the interplay of patient and clinician factors, and their interaction with the wider healthcare system. This study identifies strategies to mitigate barriers and enhance enablers, which could increase access to AS by patients with LRPCa.

Cardiovascular disease risk assessment and multidisciplinary care in prostate cancer treatment with ADT: recommendations from the APMA PCCV expert network.

PURPOSE: Androgen deprivation therapy (ADT) is the mainstay approach for prostate cancer (PCa) management. However, the most commonly used ADT modality, gonadotropin-releasing hormone (GnRH) agonists, has been associated with an increased risk of cardiovascular disease (CVD). METHODS: The PCa Cardiovascular (PCCV) Expert Network, consisting of multinational urologists, cardiologists and oncologists with expertise in managing PCa, convened to discuss challenges to routine cardiovascular risk assessment in PCa management, as well as how to mitigate such risks in the current treatment landscape. RESULTS: The experts identified several barriers, including lack of awareness, time constraints, challenges in implementing risk assessment tools and difficulties in establishing multidisciplinary teams that include cardiologists. The experts subsequently provided practical recommendations to improve cardio-oncology care for patients with PCa receiving ADT, such as simplifying cardiovascular risk assessment, individualising treatment based on CVD risk categories, establishing multidisciplinary teams and referral networks and fostering active patient engagement. A streamlined cardiovascular risk-stratification tool and a referral/management guide were developed for seamless integration into urologists' practices and presented herein. The PCCV Expert Network agreed that currently available evidence indicates that GnRH antagonists are associated with a lower risk of CVD than that of GnRH agonists and that GnRH antagonists are preferred for patients with PCa and a high CVD risk. CONCLUSION: In summary, this article provides insights and guidance to improve management for patients with PCa undergoing ADT.

Spontaneous (idiopathic) rupture of the urinary bladder: a systematic review of case series and reports.

OBJECTIVES: To perform a systematic review of all cases of spontaneous rupture of the urinary bladder (SRUB) and to describe the demographic data, associated comorbidities, clinical presentation, diagnosis, relevant laboratory findings, associated factors, management, morbidity and mortality associated with the presentation of SRUB. METHODS: The study protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO). A search was carried out across the following electronic databases: PubMed, Web of Science, Scopus, Google Scholar and the Cochrane Database of Systematic Reviews. Full texts of selected studies were analysed, and data extracted. The review was reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). RESULTS: A total of 278 articles comprising 240 case reports and 38 case series, with a total of 351 patients were included. The median (interquartile range [IQR]) age of all included patients was 47.5 (33-65) years. The median (IQR) time to presentation was 48 (24-96) h, with the major presenting symptom being abdominal pain (76%). In patients in whom the diagnosis was made prior to any intervention, the condition was misdiagnosed in 64% of cases. The diagnosis was confirmed during explorative open surgery in 42% of cases. Pelvic radiation (13%) and alcohol intoxication (11%) were the most common associated factors. Intraperitoneal rupture (89%) was much more common, with the dome of the bladder being most frequently involved (55%). The overall mortality was 15%. CONCLUSION: This review identified a number of key factors that appear to be associated with an increased incidence of SRUB. It also emphasized the high rate of misdiagnosis and challenge in confirming the diagnosis. Overall, it highlighted the importance of the need for increased awareness and maintaining a high index of suspicion for this condition.

Guidelines of guidelines: focal therapy for prostate cancer, is it time for consensus?

OBJECTIVE: To provide a summary and discussion of international guidelines, position statements and consensus statements in relation to focal therapy (FT) for prostate cancer (PCa). METHODS: The European Association of Urology-European Association of Nuclear Medicine-European Society for Radiotherapy and Oncology-European Society of Urogential Radiology-International Society of Urological Pathology-International Society of Geriatric Oncology and American Urological Association-American Society for Radiation Oncology-Society of Urologic Oncology guidelines were interrogated for recommendations for FT. PubMed and Ovid Medline were searched for consensus statements. Only studies in English since 2015 were included. Reference lists of the included articles were also interrogated and a manual search for studies was also performed. RESULTS: Our results showed a lack of long-term randomised data for FT. International Urological guidelines emphasised the need for more high-quality clinical trials with robust oncological and toxicity outcomes. Consensus and positions statements were heterogenous. CONCLUSION: A globally accepted guideline for FT planning, technique and follow-up are still yet to be determined. Well-designed studies with long-term follow-up and robust clinical and toxicity endpoints are needed to improve our understanding of FT and create uniform guidelines to streamline management and follow-up.

Decade-long trends in prostate cancer biopsy grade groups and treatment within a population-based registry.

OBJECTIVE: To assess changes in diagnosis prostate cancer (PCa) grade, biopsy and treatment approach over a decade (2011-2020) at a population level within a clinical quality cancer registry. PATIENTS AND METHODS: Patients diagnosed by prostate biopsy between 2011 and 2020 were retrieved from the Victorian Prostate Cancer Outcomes Registry, a prospective, state-wide clinical quality registry in Australia. Distributions of each grade group (GG) proportion over time were modelled with restricted cubic splines, separately by biopsy technique, age group and subsequent treatment method. RESULTS: From 2011 to 2020, 24 308 men were diagnosed with PCa in the registry. The proportion of GG 1 disease declined from 36-23%, with commensurate rises in GG 2 (31-36%), GG 3 (14-17%) and GG 5 (9.3-14%) disease. This pattern was similar for men diagnosed by transrectal ultrasonography or transperineal biopsy. Patients aged <55 years had the largest absolute reduction in GG 1 PCa, from 56-35%, compared to patients aged 55-64 (41-31%), 65-74 (31-21%), and ≥75 years (12-10%). The proportion of prostatectomies performed for patients with GG 1 disease fell from 28% to 7.1% and, for primary radiation therapy, the proportion fell from 22% to 3.5%. CONCLUSION: From 2011 to 2020, there has been a substantial decrease in the proportion of GG 1 PCa diagnosed, particularly in younger men. The percentage of interventional management performed in GG 1 disease has fallen to very low levels. These results reflect the implementation of major changes to diagnostic and treatment guidelines and inform the future allocation of treatment methods.

Salvage irreversible electroporation for radio-recurrent prostate cancer - the prospective FIRE trial.

OBJECTIVES: To prospectively assess the safety, functional- and oncological-outcomes of irreversible electroporation (IRE) as salvage therapy for radio-recurrent focal prostate cancer in a multicenter setting. PATIENTS AND METHODS: Men with focal recurrent PCa after external beam radiation or brachytherapy without metastatic disease on staging imaging and co-registration between mpMRI and biopsies were prospectively included in this multicenter trial. Adverse events were reported following the Clavien-Dindo classification. Validated questionnaires were used for patient-reported functional outcomes. Follow-up consisted of 3 monthly prostate specific antigen (PSA) levels, a 6-month mpMRI and standardised transperineal template mapping biopsies at 12-months. Thereafter follow-up was guided by MRI and/or PSMA-PET/CT and PSA. Local recurrence was defined as any ISUP score ≥2 on biopsies. RESULTS: 37 patients were analysed with a median (interquartile range (IQR)) follow up of 29 (22-43) months. Median age was 71 (53-83), median PSA was 3.5 ng/mL (2.7-6.1). 28 (75.5%) patients harboured intermediate risk and 9 patients (24.5%) high risk PCa. Seven patients (19%) reported self-limiting urgency, frequency, or hematuria (grade 1-2). Seven patients (19%) developed a grade 3 AE; urethral sludge requiring transurethral resection. At 12 months post treatment 93% of patients remained continent and erectile function sufficient for intercourse deteriorated from 35% to 15% (4/27). Local control was achieved in 29 patients (78%) and 27 patients (73%) were clear of local and systemic disease. Four (11%) patients had local recurrence only. Six (16%) patients developed metastatic disease with a median time to metastasis of 8 months. CONCLUSION: The FIRE trial shows that salvage IRE after failed radiation therapy for localised PCa is safe with minimal toxicity, and promising functional and oncological outcomes. Salvage IRE can offer a possible solution for notoriously difficult to manage radio recurrent prostate tumours.

Synchronous vs independent reading of prostate-specific membrane antigen positron emission tomography (PSMA-PET) and magnetic resonance imaging (MRI) to improve diagnosis of prostate cancer.

OBJECTIVES: To identify whether synchronous reading of multiparametric magnetic resonance imaging (mpMRI) and 68 Ga-PSMA-11 positron emission tomography (PET)/computed tomography (prostate-specific membrane antigen [PSMA-PET]) images can improve diagnostic performance and certainty compared with mpMRI/PSMA-PET reported independently and synthesized, while also assessing concordance between imaging modalities and agreement with histopathology. METHODS: This was a retrospective analysis of 100 patients randomly selected from the PRIMARY trial, a prospective Phase II multicentre imaging trial. Three dual-trained radiologist/nuclear medicine physicians re-reported the mpMRI and PSMA-PET both independently and synchronously for the same patients in random order, blinded to previous results. Diagnostic performance was assessed for mpMRI/PSMA-PET images read synchronously or independently and then synthesized. Agreement between imaging results and histopathology was examined. 'Concordance' between imaging modalities was defined as overlapping lesions. Reporting certainty was evaluated by the individual reporters for each modality. RESULTS: International Society of Urological Pathology Grade Group ≥2 cancer was present in 60% of patients on biopsy. Synchronous reading of mpMRI/PSMA-PET increased sensitivity compared to mpMRI or PSMA-PET alone (93% vs 80% vs 88%, respectively), although specificity was not improved (63% vs 58% vs 78%, respectively). No significant difference in diagnostic performance was noted between mpMRI/PSMA-PET read synchronously and mpMRI or PSMA-PET reported independently and then synthesized. Most patients had concordant imaging (60%), while others had discordant lesions only (28%) or a mixture (concordant and discordant lesions; 12%). When mpMRI/PSMA-PET findings were concordant and positive, 95% of patients had clinically significant prostate cancer (csPCa). When PSMA-PET alone was compared to synchronous PSMA-PET/MRI reads, there was an improvement in reader certainty in 20% of scans. CONCLUSION: Synchronous mpMRI/PSMA-PET reading improves reader certainty and sensitivity for csPCa compared to mpMRI or PSMA-PET alone. However, synthesizing the results of independently read PSMA-PET and mpMRI reports provided similar diagnostic performance to synchronous PSMA-PET/MRI reads. This may provide greater flexibility for urologists in terms of referral patterns, reducing healthcare system costs and improving efficiencies in prostate cancer diagnosis.

Investigating PSMA-PET/CT to resolve prostate MRI PIRADS4-5 and negative biopsy discordance.

BACKGROUND: To determine the utility of diagnostic 18F-DCPyL PSMA-PET/CT to aid management of men with highly suspicious multiparametric MRI prostate (PIRAD 4-5 lesions) and discrepant negative prostate biopsy. METHODS: A multicentre prospective consecutive case series was conducted (2018-2021), recruiting men with prior mpMRI prostate PIRADS 4-5 lesions and negative prostate biopsy. All men had 18F-DCPyL PSMA-PET/CT with subsequent management based on the concordance between MRI and PET: (1) Concordant lesions were biopsied using in-bore MRI targeting; (2) PSMA-PET/CT avidity without MRI correlate were biopsied using cognitive/software targeting with ultrasound guidance and (3) Patients with negative PET/CT were returned to standard of care follow-up. RESULTS: 29 patients were recruited with 48% (n = 14) having concordant MRI/PET abnormalities. MRI targeted biopsy found prostate cancer in six patients, with grade groups GG3 (n = 1), GG2 (n = 1), GG1 (n = 4) found. Of the 20 men who PSMA-PET/CT avidity and biopsy, analysis showed higher SUVmax (20.1 vs 6.8, p = 0.036) predicted prostate cancer. Of patients who had PSMA-PET avidity without MRI correlate, and those with no PSMA-PET avidity, only one patient was subsequently found to have prostate cancer (GG1). The study is limited by small size and short follow-up of 17 months (IQR 12.5-29.9). CONCLUSIONS: PSMA-PET/CT is useful in this group of men but requires further investigation. Avidity (higher SUVmax) that correlates to the mpMRI prostate lesion should be considered for targeted biopsy.

Recent developments in the diagnosis and management of N1 penile cancer.

PURPOSE OF REVIEW: This article presents a critical review of the current literature to provide a brief update on the contemporary advances in diagnosing and managing N1 penile cancer. RECENT FINDINGS: Penile squamous cell carcinoma (pSCC) has evolved from being an orphan field for cancer innovation. Advances in the understanding tumour biology have enabled sophisticated diagnostics and predictive modelling to better characterize inguinal disease. Minimally invasive inguinal lymph node dissection is emerging as a technique that reduces morbidity while maintaining oncological safety. Furthermore, robust clinical trials are underway ,which will provide level one evidence to guide treatment decisions. Exciting advances in the field of immune-oncology offer promise as adjuvant therapies. International collaboration and centralisation of care will be essential to driving translational research and equitable evidence-based care. SUMMARY: Improving outcomes for men with pSCC remains a global challenge. Radical inguinal lymph node dissection remains the gold standard for diagnosing and curing N1 disease. Although many promising developments are on the horizon, high-level evidence is required to guide therapy.

Molecular classification of hormone-sensitive and castration-resistant prostate cancer, using nonnegative matrix factorization molecular subtyping of primary and metastatic specimens.

BACKGROUND: Despite the rapidly evolving therapeutic landscape, immunotherapy has demonstrated limited activity in prostate cancer. A greater understanding of the molecular landscape, particularly the expression of immune-related pathways, will inform future immunotherapeutic strategies. Consensus nonnegative matrix factorization (cNMF) is a novel model of molecular classification analyzing gene expression data, focusing on biological interpretation of metagenes and selecting meaningful clusters. OBJECTIVE: We aimed to identify molecular subtypes of prostate cancer using cNMF and correlate these with existing biomarkers to inform future immunotherapeutic strategies. METHODS: A cohort of archival tumor specimens from hormone-sensitive and castration-resistant disease was studied. Whole transcriptomic profiles were generated using TruSeq RNA Access technology and subjected to cNMF. Comprehensive genomic profiling was performed with the FoundationOne assay. NMF subtypes were characterized by gene expression pathways, genomic alterations and correlated with clinical data, then applied to The Cancer Genome Atlas data set. RESULTS: We studied 164 specimens, including 52 castration-resistant and 13 paired primary/metastatic specimens. cNMF identified four distinct subtypes. NMF1 (19%) is enriched for immune-related and stromal-related pathways with transforming growth factor ß (TGFß) signature. NMF2 (36%) is associated with FOXO-mediated transcription signature and AKT signaling, NMF3 (26%) is enriched for ribosomal RNA processing, while NMF4 (19%) is enriched for cell cycle and DNA-repair pathways. The most common gene alterations included TMPRSS22 (42%), TP53 (23%), and DNA-repair genes (19%), occurring across all subtypes. NMF4 is significantly enriched for MYC and Wnt-signaling gene alterations. TMB, CD8 density, and PD-L1 expression were low overall. NMF1 and NMF4 were NMF2 was associated with superior overall survival. CONCLUSIONS: Using cNMF, we identified four molecularly distinct subtypes which may inform treatment selection. NMF1 demonstrates the most inflammatory signature with asuppressive TGFß signature, suggesting potential benefit with immunotherapy combination strategies targeting TGFß and PD-(L)1. Prospective studies are required to evaluate the use of this novel model to molecularly stratify patients for optimal treatment selection.

Online urological educational material for medical students: can search engines be trusted?

OBJECTIVES: To determine the credibility of online urological information that medical students are likely to encounter, determine possible discrepancies between the credibility of information pertaining to different areas within urology (especially those less relevant to patients), and assess trends in the sponsorship of online urological educational material. MATERIALS AND METHODS: Health on the Net (HON) principles were used as a validated benchmark to assess the reliability of websites that appeared in the first 150 results of a search using the Google search engine. A variety of urological search terms were used, grouped into three broad categories with varying relevance to patients and medical students. Further analysis focussed on the sponsorship of assessed websites. RESULTS: A total of 5400 websites were assessed for validation over a set of 36 search terms. Only 843/5400 (15.6%) of these were HONcode accredited, indicating a large proportion of unverified and potentially unreliable information. Search engine rankings usually favoured accredited websites (P = 0.009), and accreditation peaked at 51.1% (184/360) in the first page of results, but sorting became weaker outside the highest search results. The percentage of accredited websites varied significantly between different subcategories of search terms such as conditions (18.3% [329/1800], P = 0.003) and procedures (13.5% [243/1800], P = 0.043). Governmental/educational and commercial sources supported the majority of websites assessed for sponsorship (21% [31/150] and 33% [49/150], respectively), and the former were more likely to rank highly in search results. CONCLUSION: Online urological information frequently lacks validation and is often of indeterminate credibility. There is a marked decrease in the proportion of accredited websites beyond the highest-ranked results and when considering search categories more relevant to students and less relevant to patients. Students cannot necessarily rely on free online sources for accurate information and could benefit from the development of more rigorous novel tools and platforms.

Adjuvant therapies for non-muscle-invasive bladder cancer: advances during BCG shortage.

Non-muscle-invasive bladder cancer (NMIBC) represents a significant global therapeutic challenge, particularly in the era of Bacillus Calmette-Guérin (BCG) shortage. High-risk NMIBC can progress to muscle invasive or metastatic disease in 25% of patients. Optimal treatment selection, according to risk stratification, is imperative. International guidelines slightly differ in their categorisation of low, intermediate and high-risk NMIBC. Nonetheless, a single post-operative instillation of chemotherapy with Mitomycin C (MMC) or Gemcitabine improves relapse-free survival (RFS) in low-risk NMIBC. Induction and maintenance intravesical BCG remains the historical gold standard for patients with intermediate or high-risk NMIBC. However, clinicians may be forced to consider alternatives given the current BCG shortage. Both intravesical MMC and Gemcitabine have been associated with similar efficacy to BCG, albeit in smaller studies. MMC may also be manipulated using a variety of methods to potentiate its effects. BCG treatment delivery may also be modified without affecting efficacy through dose reduction and abbreviation or omission of maintenance therapy. Preliminary data also highlight that directly proceeding to radical cystectomy may not adversely affect long-term quality of life measures. Access to new systemic and intravesical therapies must be prioritised for patients with BCG recurrent or unresponsive disease. When used in conjunction with molecularly defined biomarkers, these agents herald the potential for improved survival outcomes and alleviation of the current BCG shortage.

A comparative study of peri-operative outcomes for 100 consecutive post-chemotherapy and primary robot-assisted and open retroperitoneal lymph node dissections.

PURPOSE: To describe and compare differences in peri-operative outcomes of robot-assisted (RA-RPLND) and open (O-RPLND) retroperitoneal lymph node dissection performed by a single surgeon where chemotherapy is the standard initial treatment for Stage 2 or greater non-seminomatous germ cell tumour. METHODS: Review of a prospective database of all RA-RPLNDs (28 patients) and O-RPLNDs (72 patients) performed by a single surgeon from 2014 to 2020. Peri-operative outcomes were compared for patients having RA-RPLND to all O-RPLNDs and a matched cohort of patients having O-RPLND (20 patients). Further comparison was performed between all patients in the RA-RPLND group (21 patients) and matched O-RPLND group (18 patients) who had previous chemotherapy. RA-RPLND was performed for patients suitable for a unilateral template dissection. O-RPLND was performed prior to the introduction of RA-RPLND and for patients not suitable for RA-RPLND after its introduction. RESULTS: RA-RPLND showed improved peri-operative outcomes compared to the matched cohort of O-RPLND-median blood loss (50 versus 400 ml, p < 0.00001), operative duration (150 versus 195 min, p = 0.023) length-of-stay (1 versus 5 days, p < 0.00001) and anejaculation (0 versus 4, p = 0.0249). There was no statistical difference in complication rates. RA-RPLND had lower median lymph node yields although not significant (9 versus 13, p = 0.070). These improved peri-operative outcomes were also seen in the post-chemotherapy RA-RPLND versus O-RPLND analysis. There were no tumour recurrences seen in either group with median follow-up of 36 months and 60 months, respectively. CONCLUSIONS: Post-chemotherapy RA-RPLND may have decreased blood loss, operative duration, hospital length-of-stay and anejaculation rates in selected cases and should, therefore, be considered in selected patients. Differences in oncological outcomes require longer term follow-up.

Self-reported lack of energy or feeling depressed 12 months after treatment in men diagnosed with prostate cancer within a population-based registry.

OBJECTIVE: Feeling depressed and lethargic are common side effects of prostate cancer (PCa) and its treatments. We examined the incidence and severity of feeling depressed and lack of energy in patients in a population based PCa registry. METHODS: We included men diagnosed with PCa between 2015 and 2019 in Victoria, Australia, and enrolled in the Prostate Cancer Outcomes Registry. The primary outcome measures were responses to two questions on the Expanded Prostate Cancer Index Composite (EPIC-26) patient reported instrument: problems with feeling depressed and problems with lack of energy 12 months following treatment. We evaluated associations between these and age, cancer risk category, treatment type, and urinary, bowel, and sexual function. RESULTS: Both outcome questions were answered by 9712 out of 12,628 (77%) men. 981 patients (10%) reported at least moderate problems with feeling depressed; 1563 (16%) had at least moderate problems with lack of energy and 586 (6.0%) with both. Younger men reported feeling depressed more frequently than older men. Lack of energy was more common for treatments that included androgen deprivation therapy than not (moderate/big problems: 31% vs. 13%), irrespective of disease risk category. Both outcomes were associated with poorer urinary, bowel, and sexual functional domain scores. CONCLUSIONS: Self-reported depressive feelings and lack of energy were frequent in this population-based registry. Problems with feeling depressed were more common in younger men and lack of energy more common in men having hormonal treatment. Clinicians should be aware of the incidence of these symptoms in these at-risk groups and be able to screen for them.

Genetics of neuroendocrine prostate cancer: recent progress in genetic understanding is translating into therapeutic opportunities.

PURPOSE OF REVIEW: Neuroendocrine prostate cancer (NEPC) is a rare histologic subtype of prostate cancer with extremely aggressive clinical behaviour and very limited data regarding treatment options. This review is intended to relay new research advances in the understanding of the genetic and epigenetic aberrations underlying NEPC development and to review new targeted therapeutic options developed based on NEPC genetics. RECENT FINDINGS: Multiple genomic alterations and epigenetic regulators have been identified in NEPC development. Among these are amplifications of oncogenic transcriptional factors, changes in expression of cell surface markers and epigenetic alterations. This in turn has facilitated a number of new targeted therapies for NEPC that act via different mechanisms including catalytic inhibitors, immune-modulators and epigenetic modifiers. These targeted therapies are now being studied in different phases of clinical trials with some preliminary results showing efficacy. SUMMARY: NEPC is a highly aggressive malignancy with currently lack of effective treatments. Considerable challenges still remains to improve clinical outcomes in NEPC; however, ongoing trials exploiting novel genetic and epigenetic alterations hold promise for patients suffering from this aggressive disease.

New approaches to targeting epigenetic regulation in prostate cancer.

PURPOSE OF REVIEW: Many clinical trials are currently underway to target the epigenome of castration-resistant prostate cancer. In this review, we summarize the major epigenetic alterations that occur during prostate cancer progression, describe their biological consequences, and highlight potential of therapies that target epigenetic regulators for use in patients. RECENT FINDINGS: Epigenetic alterations frequently occur in tumour suppressor genes, DNA repair genes, and genes that regulate cell proliferation and differentiation. Unlike genetic alterations, epigenetic changes are reversible, making them promising targets for cancer therapy. Epigenetic regulators can be divided into three broad groups: writers, readers, and erasers , each with specific drug targets that are being assessed in phase I and II clinical trials for prostate cancer. CBP/p300, and BRD4 are coregulators of the androgen receptor and inhibit androgen signalling, making bromodomain extra-terminal inhibitors and CBP/p300 inhibitors attractive targets in prostate cancer. Enhancer of zeste homolog 2, a histone methyltransferase, is also a potential target in castrate-resistant prostate cancer. An emerging direction is to combine epigenetic inhibitors with other compounds to enhance their efficacy. SUMMARY: Preclinical studies indicate that the epigenome is a potential target in prostate cancer, and clinical trials are testing multiple agents that target the epigenome in different ways. However, the process of translating these therapies into the clinic is ongoing and none have yet been approved for castrate-resistant prostate cancer.

Modern paradigms for prostate cancer detection and management.

Early detection and management of prostate cancer has evolved over the past decade, with a focus now on harm minimisation and reducing overdiagnosis and overtreatment, given the proven improvements in survival from randomised controlled trials. Multiparametric magnetic resonance imaging (mpMRI) is now an important aspect of the diagnostic pathway in prostate cancer, improving the detection of clinically significant prostate cancer, enabling accurate localisation of appropriate sites to biopsy, and reducing unnecessary biopsies in most patients with normal magnetic resonance imaging scans. Biopsies are now performed transperineally, substantially reducing the risk of post-procedure sepsis. Australian-led research has shown that prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) has superior accuracy in the staging of prostate cancer than conventional imaging (CT and whole-body bone scan). Localised prostate cancer that is low risk (International Society for Urological Pathology [ISUP] grade 1, Gleason score 3 + 3 = 6; and ISUP grade group 2, Gleason score 3 + 4 = 7 with less than 10% pattern 4) can be offered active surveillance, reducing harms from overtreatment. Prostatectomy and definitive radiation remain the gold standard for localised intermediate and high risk disease. However, focal therapy is an emerging experimental treatment modality in Australia in carefully selected patients. The management of advanced prostate cancer treatment has evolved to now include several novel agents both in the metastatic hormone-sensitive and castration-resistant disease settings. Multimodal therapy with androgen deprivation therapy, additional systemic therapy and radiotherapy are often recommended. PSMA-based radioligand therapy has emerged as a treatment option for metastatic castration-resistant prostate cancer and is currently being evaluated in earlier disease states.