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Purpose: Immune checkpoint inhibitor (ICI)-based combination therapy is a standard systemic treatment for metastatic renal cell carcinoma (mRCC). Although differential pharmacologic action between ICI+ICI and ICI+tyrosine kinase inhibitor (TKI) combinations may affect outcomes, comparative studies using real-world data are few., Methods: We retrospectively analyzed the records of 447 mRCC patients treated with 1st-line ICI-based combinations at multiple institutions between January 2018 and August 2023, and selected 320 patients diagnosed with clear cell RCC (ccRCC) for further study. Cohorts were matched using one-to-one propensity scores based on IMDC risk classification. Overall survival (OS), progression-free survival (PFS), objective response rates (ORRs), and treatment-related adverse events (TrAE) were compared., Results: The matching process yielded 228 metastatic ccRCC patients treated with ICI+ICI (n = 114) or ICI+TKI (n = 114). Median OS was 53 months (95%CI: 33-NA) in patients treated with ICI+ICI and was not reached (95%CI: 43-NA) with ICI+TKI (P = 0.24). Median PFS was significantly shorter for ICI+ICI (13 months, 95%CI: 7-25) than for ICI+TKI (25 months, 95%CI: 13-NA) (P = 0.047). There were no differences in second-line PFS for sequential therapy after 1st-line combinations of ICI+ICI or ICI+TKI (6 vs. 8 months, P = 0.6). There were no differences in ORR between the 2 groups (ICI+ICI: 51% vs. ICI+TKI: 55%, P = 0.8); the progressive disease (PD) rate was significantly higher in patients treated with the ICI+ICI combination (24% vs. 11%, P = 0.029). The rate of any grade TrAE was significantly higher in patients treated with ICI+TKI (71% vs. 85%, P = 0.016), but we found no differences in severe TrAE between the 2 groups (39% vs. 36%, P = 0.8)., Conclusions: In a matched cohort of real-world data, we confirmed comparable OS benefits between ICI+ICI and ICI+TKI combinations. However, differential clinical behaviors in terms of PFS, PD rates, and TrAE between ICI-based combinations may enrich clinical decision-making., Competing Interests: Declaration of competing interest Takahiro Kimura is a paid consultant/advisor of Astellas, Bayer, Janssen, Sanofi and Takeda. The other authors declare no conflicts of interest associated with this manuscript., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background and Objective: While active surveillance (AS) is an alternative to surgical interventions in patients with small renal masses (SRMs), evidence regarding its oncological efficacy is still debated. We aimed to evaluate oncological outcomes for patients with SRMs who underwent AS in comparison to surgical interventions., Methods: In April 2024, PubMed, Scopus, and Web of Science were queried for comparative studies evaluating AS in patients with SRMs (PROSPERO: CRD42024530299). The primary outcomes were overall (OS) and cancer-specific survival (CSS). A random-effects model was used for quantitative analysis., Key Findings and Limitations: We identified eight eligible studies (three prospective, four retrospective, and one study based on Surveillance, Epidemiology and End Results [SEER] data) involving 4947 patients. Pooling of data with the SEER data set revealed significantly higher OS rates for patients receiving surgical interventions (hazard ratio [HR] 0.73; p = 0.007), especially partial nephrectomy (PN; HR 0.62; p < 0.001). However, in a sensitivity analysis excluding the SEER data set there was no significant difference in OS between AS and surgical interventions overall (HR 0.84; p = 0.3), but the PN subgroup had longer OS than the AS group (HR 0.6; p = 0.002). Only the study based on the SEER data set showed a significant difference in CSS. The main limitations include selection bias in retrospective studies, and classification of interventions in the SEER database study., Conclusions and Clinical Implications: Patients treated with AS had similar OS to those who underwent surgery or ablation, although caution is needed in interpreting the data owing to the potential for selection bias and variability in AS protocols. Our review reinforces the need for personalized shared decision-making to identify patients with SRMs who are most likely to benefit from AS., Patient Summary: For well-selected patients with a small kidney mass suspicious for cancer, active surveillance seems to be a safe alternative to surgery, with similar overall survival. However, the evidence is still limited and more studies are needed to help in identifying the best candidates for active surveillance., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy with a high recurrence rate after surgical therapy with curative intent. Adjuvant radiotherapy (RT) and mitotane therapy have been proposed as options following the adrenalectomy. However, the efficacy of adjuvant RT or mitotane therapy remains controversial. We aimed to evaluate the efficacy of adjuvant therapy in patients who underwent adrenalectomy for localised ACC. The PubMed, Scopus, and Web of Science databases were queried on March 2024 for studies evaluating adjuvant therapies in patients treated with surgery for localized ACC (PROSPERO: CRD42024512849). The endpoints of interest were overall survival (OS) and recurrence-free survival (RFS). Hazard ratios (HR) with 95% confidence intervals (95%CI) were pooled in a random-effects model meta-analysis. One randomized controlled trial (n = 91) and eleven retrospective studies (n = 4,515) were included. Adjuvant mitotane therapy was associated with improved RFS (HR: 0.63, 95%CI: 0.44-0.92, p = 0.016), while adjuvant RT did not reach conventional levels of statistical significance (HR:0.79, 95%CI:0.58-1.06, p = 0.11). Conversely, Adjuvant RT was associated with improved OS (HR:0.69, 95%CI:0.58-0.83, p<0.001), whereas adjuvant mitotane did not (HR: 0.76, 95%CI: 0.57-1.02, p = 0.07). In the subgroup analyses, adjuvant mitotane was associated with better OS (HR:0.46, 95%CI: 0.30-0.69, p < 0.001) and RFS (HR:0.56, 95%CI: 0.32-0.98, p = 0.04) in patients with negative surgical margin. Both adjuvant RT and mitotane were found to be associated with improved oncologic outcomes in patients treated with adrenalectomy for localised ACC. While adjuvant RT significantly improved OS in general population, mitotane appears as an especially promising treatment option in patients with negative surgical margin. These data can support the shared decision-making process, better understanding of the risks, benefits, and effectiveness of these therapies is still needed to guide tailored management of each individual patient., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objectives: This study aimed to compare the clinical outcomes of robot-assisted partial nephrectomy (RAPN) and image-guided percutaneous cryoablation (IG-PCA) for clinical T1 renal cell carcinoma., Materials and Methods: We conducted a retrospective analysis of 679 patients with clinical T1 renal cell carcinoma treated with RAPN or IG-PCA between 2012 and 2021. Propensity scores were calculated via logistic analysis to adjust for imbalances in baseline characteristics. We compared oncological and functional outcomes between the 2 treatment groups., Results: Following the matching process, 108 patients were included in each group. No patient in the RAPN group developed local recurrence. In the IG-PCA group, three patients experienced local tumor progression. The patients underwent salvage thermal ablations by the secondary technique; 2 underwent IG-PCA and 1 underwent microwave ablation, resulting in a local control rate of 100%. The Kaplan-Meier analysis showed no statistically significant differences between the groups in terms of 5-year recurrence-free survival, metastasis-free survival, and overall survival (log-rank test; P = 0.11, P = 0.64, and P = 0.17, respectively). No significant differences were observed in the 2 treatments in major and overall complication rates (P = 0.75 and P = 0.82, respectively). Both groups showed similar rates of less than 10% estimated glomerular filtration rate decline at 12 months post-treatment and 5-year renal function preservation rates (P = 0.88 and P = 0.38, respectively)., Conclusions: IG-PCA demonstrated oncological outcomes comparable to those of RAPN. RAPN addressed the disadvantages of conventional procedures and allowed for safety outcomes comparable to IG-PCA., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: To evaluate the impact of adjuvant therapy on oncological outcomes in patients with intermediate-risk non-muscle-invasive bladder cancer (NMIBC), as due to the poorly-defined and overlapping diagnostic criteria optimal decision-making remains challenging in these patients., Patients and Methods: In this multicentre study, patients treated with transurethral resection of bladder tumour for Ta disease were retrospectively analysed. All patients with low- or high-risk NMIBC were excluded from the analysis. Associations between adjuvant therapy administration with recurrence-free survival (RFS) and progression-free survival (PFS) rates were assessed in Cox regression models., Results: A total of 2206 patients with intermediate-risk NMIBC were included in the analysis. Among them, 1427 patients underwent adjuvant therapy, such as bacille Calmette-Guérin (n = 168), or chemotherapeutic agents, such as mitomycin C or epirubicin (n = 1259), in different regimens up to 1 year. The median (interquartile range) follow-up was 73.3 (38.4-106.9) months. The RFS at 1 and 5 years in patients treated with adjuvant therapy and those without were 72.6% vs 69.5% and 50.8% vs 41.3%, respectively. Adjuvant therapy was associated with better RFS (hazard ratio [HR] 0.79, 95% confidence interval [CI] 0.70-0.89, P < 0.001), but not with PFS (P = 0.09). In the subgroup of patients aged ≤70 years with primary, single Ta Grade 2 <3 cm tumours (n = 328), adjuvant therapy was not associated with RFS (HR 0.71, 95% CI 0.50-1.02, P = 0.06). While in the subgroup of patients with at least one risk factor including patient age >70 years, tumour multiplicity, recurrent tumour and tumour size ≥3 cm (n = 1878), adjuvant intravesical therapy was associated with improved RFS (HR 0.78, 95% CI 0.68-0.88, P < 0.001)., Conclusion: In our study, patients with intermediate-risk NMIBC benefit from adjuvant intravesical therapy in terms of RFS. However, in patients without risk factors, adjuvant intravesical therapy did not result in a clear reduction in the recurrence rate., (© 2024 The Authors. BJU International published by John Wiley & Sons Ltd on behalf of BJU International.)

Objective: To compare the differential efficacy of first-line immune checkpoint inhibitor (ICI)-based combined therapies among patients with intermediate- and poor-risk metastatic renal cell carcinoma (mRCC), as recently, the efficacy of triplet therapy comprising nivolumab plus ipilimumab plus cabozantinib has been published., Patients and Methods: Three databases were searched in December 2022 for randomised controlled trials (RCTs) analysing oncological outcomes in patients with mRCC treated with first-line ICI-based combined therapies. We performed network meta-analysis (NMA) to compare the outcomes, including progression-free survival (PFS) and objective response rates (ORRs), in patients with intermediate- and poor-risk mRCC; we also assessed treatment-related adverse events., Results: Overall, seven RCTs were included in the meta-analyses and NMAs. Treatment ranking analysis revealed that pembrolizumab + lenvatinib (99%) had the highest likelihood of improved PFS, followed by nivolumab + cabozantinib (79%), and nivolumab + ipilimumab + cabozantinib (77%). Notably, compared to nivolumab + cabozantinib, adding ipilimumab to nivolumab + cabozantinib did not improve PFS (hazard ratio 1.02, 95% confidence interval 0.72-1.43). Regarding ORRs, treatment ranking analysis also revealed that pembrolizumab + lenvatinib had the highest likelihood of providing better ORRs (99.7%). The likelihoods of improved PFS and ORRs of pembrolizumab + lenvatinib were true in both International Metastatic RCC Database Consortium (IMDC) risk groups., Conclusions: Our analyses confirmed the robust efficacy of pembrolizumab + lenvatinib as first-line treatment for patients with intermediate or poor IMDC risk mRCC. Triplet therapy did not result in superior efficacy. Considering both toxicity and the lack of mature overall survival data, triplet therapy should only be considered in selected patients., (© 2024 The Authors. BJU International published by John Wiley & Sons Ltd on behalf of BJU International.)

Context: Radical nephroureterectomy (RNU) with bladder cuff resection is the standard treatment in patients with high-risk upper tract urothelial cancer (UTUC). However, it is unclear which specific surgical technique may lead to improve oncological outcomes in term of intravesical recurrence (IVR) in patients with UTUC., Objective: To evaluate the efficacy of surgical techniques and approaches of RNU in reducing IVR in UTUC patients., Evidence Acquisition: Three databases were queried in January 2024 for studies analyzing UTUC patients who underwent RNU. The primary outcome of interest was the rate of IVR among various types of surgical techniques and approaches of RNU., Evidence Synthesis: Thirty-one studies, comprising 1 randomized controlled trial and 1 prospective study, were included for a systematic review and meta-analysis. The rate of IVR was significantly lower in RNU patients who had an early ligation (EL) of the ureter compared to those who did not (HR: 0.64, 95% CI: 0.44-0.94, p = 0.02). Laparoscopic RNU significantly increased the IVR compared to open RNU (HR: 1.28, 95% CI: 1.06-1.54, p < 0.001). Intravesical bladder cuff removal significantly reduced the IVR compared to both extravesical and transurethral bladder cuff removal (HR: 0.65, 95% CI: 0.51-0.83, p = 0.02 and HR: 1.64, 95% CI: 1.15-2.34, p = 0.006, respectively)., Conclusions: EL of the affected upper tract system, ureteral management, open RNU, and intravesical bladder cuff removal seem to yield the lowest IVR rate in patients with UTUC. Well-designed prospective studies are needed to conclusively elucidate the optimal surgical technique in the setting of single post-operative intravesical chemotherapy., (© 2024. The Author(s).)

Background and Objective: Although digital rectal examination (DRE) is recommended in combination with prostate-specific antigen (PSA) for detection of prostate cancer (PCa), there are limited data to support its use as a screening/early detection test. Our objective was to assess the diagnostic value of DRE in screening for early detection of PCa., Methods: In August 2023, we queried the PubMed, Scopus, and Web of Science databases to identify prospective studies simultaneously investigating the diagnostic performance of DRE and PSA for PCa screening. The primary endpoints were the positive predictive value (PPV) and cancer detection rate (CDR) of DRE. Secondary endpoints included the PPV and CDR of both PSA alone and in combination with DRE. We conducted meta-regression analysis to compare the CDR and PPV of different screening strategies. This meta-analysis is registered on PROSPERO (CRD42023446940)., Key Findings and Limitations: We identified eight studies involving 85,798 participants, of which three were randomized controlled trials and five were prospective diagnostic studies, that reported the PPV and CDR of both DRE and PSA for the same cohort. Our analysis revealed a pooled PPV of 0.21 (95% confidence interval [CI] 0.13-0.33) for DRE, which is similar to the PPV of PSA (0.22, 95% CI 0.15-0.30; p = 0.9), with no benefit from combining DRE and PSA (PPV 0.19, 95% CI 0.13-0.26; p = 0.5). However, the CDR of DRE (0.01, 95% CI: 0.01-0.02) was significantly lower than that of PSA (0.03, 95% CI 0.02-0.03; p < 0.05) and the combination of DRE and PSA (0.03, 95% CI 0.02-0.04; p < 0.05). The screening strategy combining DRE and PSA was not different to that of PSA alone in terms of CDR (p = 0.5) and PPV (p = 0.5)., Conclusions and Clinical Implications: Our comprehensive review and meta-analysis indicates that both as an independent test and as a supplementary measure to PSA for PCa detection, DRE exhibits a notably low diagnostic value. The collective findings from the included studies suggest that, in the absence of clinical symptoms and signs, DRE could be potentially omitted from PCa screening and early detection strategies., Patient Summary: Our review shows that the screening performance of digital rectal examination for detection of prostate cancer is not particularly impressive, suggesting that it might not be necessary to conduct this examination routinely., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Context: The optimal therapeutic agent with respect to metastatic sites is unclear in advanced urothelial carcinoma (UC)., Objective: To investigate the metastatic organotropism differential treatment response in patients with advanced or metastatic UC., Evidence Acquisition: A systematic search and network meta-analysis (NMA) was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement. The primary endpoints of interest were the objective response rate, overall survival (OS), and progression-free survival with respect to different metastatic sites., Evidence Synthesis: Twenty-six trials comprising 9082 patients met our eligibility criteria, and a formal NMA was conducted. Durvalumab plus tremelimumab as first-line systemic therapy was significantly associated with better OS than chemotherapy in visceral metastasis (hazard ratio [HR] 0.81, 95% confidence interval [CI] 0.67-0.98). Pembrolizumab as second-line systemic therapy was significantly associated with better OS than chemotherapy in patients with visceral metastasis (HR 0.75, 95% CI 0.60-0.95). Atezolizumab as second-line systemic therapy was significantly associated with better OS than chemotherapy in patients with liver metastasis (in the population of >5% of tumor-infiltrating immune cells) and lymph node metastasis (HR 0.51, 95% CI 0.28-0.96, and HR 0.59, 95% CI 0.37-0.96, respectively)., Conclusions: Administration of immune-oncology treatments with respect to metastatic sites in patients with advanced or metastatic UC might have a positive impact on survival outcomes in both the first- and the second-line setting. Nevertheless, further investigations focusing on metastatic organotropism differential response with reliable oncological outcomes are needed to identify the optimal management strategy for these patients., Patient Summary: Although the supporting evidence for oncological benefits of therapeutic systemic agents with respect to metastatic sites is not yet strong enough to provide a recommendation in advanced or metastatic urothelial carcinoma, clinicians may take into account tumor organotropism only in discussion with the patient fully informed on the optimal treatment decision to be taken., (Copyright © 2023. Published by Elsevier B.V.)

Introduction: Concomitant medications can affect the efficacy of immune checkpoint inhibitors. The association between histamine-2 receptor antagonists (H2RAs), major antacids similar to proton pump inhibitors (PPIs), and the efficacy of pembrolizumab for metastatic urothelial carcinoma (mUC) treatment has been poorly evaluated. We evaluated the impact of PPIs and H2RAs on oncological outcomes in mUC patients treated with pembrolizumab., Patients and Methods: This retrospective multicenter study included patients with mUC treated with pembrolizumab. Patients prescribed PPIs or H2RAs within 30 days before and after the initial administration were extracted. The overall survival (OS), cancer-specific survival (CSS), progression-free survival (PFS), and objective response rates (ORR) were assessed. Kaplan-Meier survival curve analysis and multivariable Cox proportional hazard models were employed to assess the association between PPIs or H2RAs and survival outcomes., Results: Overall, 404 patients were eligible for this study; 121 patients (29.9%) used PPIs, and 34 (8.4%) used H2RAs. Kaplan-Meier analysis showed significantly worse OS, CSS, and PFS in patients using PPIs compared to no PPIs (P = .010, .018, and .012, respectively). In multivariable analyses, the use of PPIs was a significant prognostic factor for worse OS (HR = 1.42, 95% CI 1.08-1.87, P = .011), CSS (HR = 1.45, 95% CI 1.09-1.93, P = .011), and PFS (HR = 1.35, 95% CI 1.05-1.73, P = .020). PPIs were not associated with ORRs. The use of H2RAs was not associated with survival or ORRs., Conclusion: PPIs were significantly associated with worse survival of patients with mUC treated with pembrolizumab, and H2RAs could be an alternative during administration. Both the oncological and gastrointestinal implications should be carefully considered when switching these antacids., Competing Interests: Disclosure The authors declare that they have no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

(1) Background: Intravesical chemotherapy is the standard of care in intermediate-risk non-muscleinvasive bladder cancer (NMIBC). Different agents are used across the world based on availability, cost, and practice patterns. Epirubicin (EPI), one of these agents, has been used by many centers over many decades. However, its true differential efficacy compared to other agents and its tolerability are still poorly reported. We aimed to assess the differential efficacy and safety of intravesical EPI in NMIBC patients. (2) Methods : This study aimed to systematically review the efficacy and safety profile of Epirubicin (EPI) in the management of non-muscle invasive bladder cancer (NMIBC) compared to other adjuvant therapies. A systematic search of the PUBMED, Web of Science, clinicaltrials.gov, and Google Scholar databases was conducted on 31 December 2023, using relevant terms related to EPI, bladder cancer, and NMIBC. The inclusion criteria targeted studies that evaluated patients treated with EPI following the transurethral resection of bladder tumors (TURBT) for NMIBC and compared oncological outcomes such as recurrence and progression with other adjuvant therapies, including Mitomycin C (MMC), Gemcitabine (GEM), and Bacillus Calmette-Guérin (BCG). Additionally, studies investigating the safety profile of EPI administered intravesically at room temperature and under hyperthermia, as well as oncological outcomes associated with hyperthermic intravesical EPI administration, were included. (3) Results: Eleven studies reported adverse events after adjuvant intravesical instillations with EPI; the most frequently reported adverse events included cystitis (34%), dysuria, pollakiuria, hematuria, bladder irritation/spasms, fever, nausea and vomiting, and generalized skin rash (2.3%). Nine studies compared EPI to BCG in terms of recurrence and progression rates; BCG instillations showed a lower recurrence rate compared to EPI, with limited or non-significant differences in progression rates. Two studies found no significant differences between EPI and MMC regarding progression and recurrence rates. One study showed statistically significant lower recurrence and progression rates with GEM in high-risk NMIBC patients. Another study found no significant differences between EPI and GEM regarding recurrence and progression. (4) Conclusions : EPI exhibits similar oncological performances to Gemcitabine and Mitomycin C currently used for adjuvant therapy in NMIBC. Novel delivery mechanisms such as hyperthermia are interesting newcomers.

Background: No head-to-head clinical trials have compared the differences in adverse events (AEs) between nivolumab plus ipilimumab (NIVO-IPI) and nivolumab plus cabozantinib (NIVO-CABO) in the treatment of metastatic renal cell carcinoma (mRCC)., Aim: We analysed the two largest real-world databases, the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) and the World Health Organization's VigiBase, to elucidate the differences in AEs between NIVO-IPI and NIVO-CABO., Method: In total, 40,376 and 38,022 records were extracted from FAERS and VigiBase, and 193 AEs were analysed. The reporting odds ratios (ROR) with 95% confidence interval were calculated using a disproportionality analysis (NIVO-CABO/NIVO-IPI)., Results: The reported numbers of immune-related AEs, including myocarditis, colitis, and hepatitis, were significantly higher with NIVO-IPI (ROR = 0.18 for FAERS and 0.13 for VigiBase). Contrarily, the reported numbers of other AEs, including gastrointestinal disorders (ROR = 2.68 and 2.92) and skin and subcutaneous tissue disorders (ROR = 2.94 and 3.55), considered to be potentiated by the combination of NIVO and CABO, were higher with NIVO-CABO., Conclusion: Our findings contribute to the selection and clinical management of NIVO-IPI and NIVO-CABO, which minimizes the risk of AEs for individual patients with mRCC by considering distinctive differences in the AE profiles., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: Triplet therapy, androgen receptor signaling inhibitors (ARSIs) plus docetaxel plus androgen-deprivation therapy (ADT), is a novel guideline-recommended treatment for metastatic hormone-sensitive prostate cancer (mHSPC). However, the optimal selection of the patient most likely to benefit from triplet therapy remains unclear., Methods: We performed a systematic review, meta-analysis, and network meta-analysis to assess the oncologic benefit of triplet therapy in mHSPC patients stratified by disease volume and compare them with doublet treatment regimens. Three databases and meeting abstracts were queried in March 2023 for randomized controlled trials (RCTs) evaluating patients treated with systemic therapy for mHSPC stratified by disease volume. Primary interests of measure were overall survival (OS). We followed the PRISMA guideline and AMSTAR2 checklist., Results: Overall, eight RCTs were included for meta-analyses and network meta-analyses (NMAs). Triplet therapy outperformed docetaxel plus ADT in terms of OS in both patients with high-(pooled HR: 0.73, 95%CI 0.64-0.84) and low-volume mHSPC (pooled HR: 0.71, 95%CI 0.52-0.97). There was no statistically significant difference between patients with low- vs. high-volume in terms of OS benefit from adding ARSI to docetaxel plus ADT (p = 0.9). Analysis of treatment rankings showed that darolutamide plus docetaxel plus ADT (90%) had the highest likelihood of improved OS in patients with high-volume disease, while enzalutamide plus ADT (84%) had the highest in with low-volume disease., Conclusions: Triplet therapy improves OS in mHSPC patients compared to docetaxel-based doublet therapy, irrespective of disease volume. However, based on treatment ranking, triplet therapy should preferably be considered for patients with high-volume mHSPC while those with low-volume are likely to be adequately treated with ARSI + ADT., (© 2024. The Author(s).)

Context: Active surveillance (AS) is a standard of care for patients with low-risk and selected intermediate-risk prostate cancer (PCa). Nevertheless, there is a lack of summary evidence on how to impact disease trajectory during AS., Objective: To assess which interventions prevent PCa progression effectively during AS., Evidence Acquisition: We queried PubMed, Scopus, and Web of Science databases to identify studies examining the impact of interventions aimed at slowing disease progression during AS. The primary endpoint was PCa progression, the definition of which must have included pathological upgrading. The secondary endpoint included treatment toxicities., Evidence Synthesis: We identified 22 studies, six randomized controlled trials and 16 observational studies, which analyzed the association between different interventions and PCa progression during AS. The interventions considered in the studies included 5-alpha reductase inhibitors (5-ARIs), statins, diet, exercise, chlormadinone, fexapotide triflutate (FT), enzalutamide, coffee, vitamin D3, and PROSTVAC. We found that administration of 5-ARIs was associated with improved progression-free survival (PFS; hazard ratio: 0.59; 95% confidence interval 0.48-0.72), with no increased toxicity signals. Therapies such as vitamin D3, chlormadinone, FT, and enzalutamide have shown some efficacy. However, these anticancer drugs have been associated with treatment-related adverse events in up to 88% of patients., Conclusions: The use of 5-ARIs in PCa patients on AS is associated with longer PFS. However, for the other interventions, it is difficult to draw clear conclusions based on the weak available evidence., Patient Summary: Patients with prostate cancer managed with active surveillance (AS) who are treated with 5-alpha reductase inhibitors have a lower risk of disease progression, with minimal adverse events. Other interventions require more studies to determine their efficacy and safety profile in men on AS., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

This review presents the latest insights on robot-assisted kidney autotransplantation (RAKAT). RAKAT is a minimally invasive surgical procedure and represents a promising alternative to conventional laparoscopic nephrectomy followed by open kidney transplantation for the treatment of various complex urological and vascular conditions. RAKAT can be performed either extracorporeally or intracorporeally. Additionally, a single-port approach can be performed through one small incision without the need to reposition the patient. Of 86 patients undergoing RAKAT, 8 (9.3%) developed postoperative > Grade 2 Clavien-Dindo (CD) complications. Although the feasibility of RAKAT was established in 2014, the long-term efficacy and safety along with outcomes of this surgical approach are still being evaluated, and additional studies are needed. With improvements in the technology of RAKAT and as surgeons gain more experience, RAKAT should become increasingly used and further refined, thereby leading to improved surgical outcomes and improved patients' quality of life., (© 2024 The Japanese Urological Association.)

Background: To prevent infectious complications after transrectal ultrasound-guided prostate biopsy (TRUS-PB), some studies have investigated the efficacy of rectal disinfection using povidone-iodine (PI) and antibiotic prophylaxis (AP)., Objective: To summarize available data and compare the efficacy of rectal disinfection using PI with non-PI methods prior to TRUS-PB., Evidence Acquisition: Three databases were queried through November 2023 for randomized controlled trials (RCTs) analyzing patients who underwent TRUS-PB. We compared the effectiveness of rectal disinfection between PI groups and non-PI groups with or without AP. The primary outcomes of interest were the rates of overall infectious complications, fever, and sepsis. Subgroups analyses were conducted to assess the differential outcomes in patients using fluoroquinolone groups compared to those using other antibiotics groups., Evidence Synthesis: We included ten RCTs in the meta-analyses. The overall rates of infectious complications were significantly lower when rectal disinfection with PI was performed (RR 0.56, 95% CI 0.42-0.74, p < 0.001). Compared to AP monotherapy, the combination of AP and PI was associated with significantly lower risk of infectious complications (RR 0.54, 95% CI 0.40-0.73, p < 0.001) and fever (RR 0.47, 95% CI 0.30-0.75, p = 0.001), but not with sepsis (RR 0.49, 95% CI 0.23-1.04, p = 0.06). The use of fluoroquinolone antibiotics was associated with a lower risk of infectious complications and fever compared to non-FQ antibiotics., Conclusion: Rectal disinfection with PI significantly reduces the rates of infectious complications and fever in patients undergoing TRUS-PB. However, this approach does not show a significant impact on reducing the rate of sepsis following the procedure., (© 2024. The Author(s).)

Context: It remains unclear to what extent the therapy of the primary local tumor, such as radical prostatectomy (RP) and radiation therapy (RT), improves overall survival in patients with low-volume metastatic hormone-sensitive prostate cancer (mHSPC). However, data suggest a benefit of these therapies in preventing local events secondary to local tumor progression., Objective: To evaluate the efficacy of adding local therapy (RP or RT) to systemic therapies, including androgen deprivation therapy, docetaxel, and/or androgen receptor axis-targeted agents, in preventing local events in mHSPC patients compared with systemic therapy alone (ie, without RT of the prostate or RP)., Evidence Acquisition: Three databases and meeting abstracts were queried in November 2023 for studies analyzing mHSPC patients treated with local therapy. The primary outcome of interest was the prevention of overall local events (urinary tract infection, urinary tract obstruction, and gross hematuria) due to local disease progression. Subgroup analyses were conducted to assess the differential outcomes according to the type of local therapy (RP or RT)., Evidence Synthesis: Overall, six studies, comprising two randomized controlled trials, were included for a systematic review and meta-analysis. The overall incidence of local events was significantly lower in the local treatment plus systemic therapy group than in the systemic therapy only groups (relative risk [RR]: 0.50, 95% confidence interval [CI]: 0.28-0.88, p = 0.016). RP significantly reduced the incidence of overall local events (RR: 0.24, 95% CI: 0.11-0.52) and that of local events requiring surgical intervention (RR: 0.08, 95% CI: 0.03-0.25). Although there was no statistically significant difference between the RT plus systemic therapy and systemic therapy only groups in terms of overall local events, the incidence of local events requiring surgical intervention was significantly lower in the RT plus systemic therapy group (RR: 0.70, 95% CI: 0.49-0.99); local events requiring surgical intervention of the upper urinary tract was significantly lower in local treatment groups (RR: 0.60, 95% CI: 0.37-0.98, p = 0.04). However, a subgroup analysis revealed that neither RP nor RT significantly impacted the prevention of local events requiring surgical intervention of the upper urinary tract., Conclusions: In some patients with mHSPC, RP or RT of primary tumor seems to reduce the incidence of local progression and events requiring surgical intervention. Identifying which patients are most likely to benefit from local therapy, and at what time point (eg, after response of metastases), will be necessary to set up a study assessing the risk, benefits, and alternatives to therapy of the primary tumor in the mHSPC setting., Patient Summary: Our study suggests that local therapy of the prostate, such as radical prostatectomy or radiotherapy, in patients with metastatic hormone-sensitive prostate cancer can prevent local events, such as urinary obstruction and gross hematuria., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Transgender individuals undergo the gender-affirming hormone therapy (GAHT) to achieve physical changes consistent with their gender identity. Few studies are available on the long-term safety and efficacy of GAHT., Objectives: To investigate the long-term physical effects and the safety of the testosterone therapy for trans men and to assess the impact of differential hormone dose., Materials and Methods: Trans men who initiated GAHT between May 2000 and December 2021 were included in this retrospective analysis. Physical findings (body mass index, body fat percentage (BFP), lean body mass (LBM), and grip strength), blood testing results (hemoglobin, hematocrit, uric acid, creatinine, total cholesterol, triglycerides, and total testosterone), and menstrual cessation were recorded. We assessed the effects of testosterone on body composition changes and laboratory parameters, comparing a low-dose group (≤ 62.5 mg/wk) to a high-dose group (> 62.5 mg/wk)., Results: Of 291 participants, 188 patients (64.6%) were in the low-dose group and 103 (35.4%) in the high-dose group. Cumulative menstrual cessation rates up to 12 months were not significantly different between groups. Both groups showed a decrease in BFP and an increase in LBM during the first year of therapy, followed by a slight increase in both over the long term. The high-dose group exhibited greater LBM gains during the first year. Higher hormone doses and lower initial LBM values were associated with LBM increases at 3 and 6 months (3 mo, P = 0.006, P < 0.001; 6 mo, P = 0.015, P < 0.001). There were no long-term, dose-dependent side effects such as polycythemia or dyslipidemia., Conclusion: Long-term GAHT for trans men is safe and effective. Low-dose testosterone administration is sufficient to increase LBM in trans men. Higher testosterone doses can lead to an earlier increase in muscle mass., (© 2024 American Society of Andrology and European Academy of Andrology.)

To evaluate the oncological outcomes and safety of primary retroperitoneal lymph node dissection (RPLND) in patients with clinical stage (CS) II seminomatous testicular germ cell tumor (TGCT). A literature search using PubMed, Scopus, and Cochrane Library was conducted on July 2023 to identify relevant studies according to the Preferred Reporting Items for Systematic Review and Meta Analysis (PRISMA) guidelines. The pooled recurrence rate and treatment-related complications were calculated using a random effects model. Overall 8 studies published between 1997 and 2023 including a total of 355 patients were selected for systematic review and meta-analysis with the overall median follow-up of 38 months. The overall and infield recurrence rate were 0.14 (95% CI: 0.08-0.22) and 0.04 (95% CI: 0.00-0.11), respectively. The overall pooled rate of ≥ Clavien Dindo grade III complications was 0.04 (95% CI: 0.01-0.10); there was no significant heterogeneity (I^2 = 35.10%, P = 0.19). Antegrade ejaculation was preserved with the overall pooled rate of 0.98 (95% CI: 0.95-1.00); there was no significant heterogeneity on Chi-square and I2 tests (I^2 = 0.00%, P = 0.58). Primary RPLND is a safe and effective treatment option for patients with CS II seminomatous TGCT resulting highly promising cure rates combined with low treatment-associated adverse events, at medium-term follow-up. However, owing to the lack of comparative studies to the current standard of care and the limited follow-up, individual decision must be made with the informed patient in a shared decision process together with a multidisciplinary team., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Boron neutron capture therapy (BNCT) is a treatment method that focuses on improving the cure rate of patients with cancer who are difficult to treat using traditional clinical methods. By utilizing the high neutron absorption cross-section of boron, material rich in boron inside tumor cells can absorb neutrons and release high-energy ions, thereby destroying tumor cells. Owing to the short range of alpha particles, this method can precisely target tumor cells while minimizing the inflicted damage to the surrounding normal tissues, making it a potentially advantageous method for treating tumors. Globally, institutions have progressed in registered clinical trials of BNCT for multiple body parts. This review summarized the current achievements in registered clinical trials, Investigator-initiated clinical trials, aimed to integrate the latest clinical research literature on BNCT and to shed light on future study directions., Competing Interests: None., (AJCR Copyright © 2024.)

Immune checkpoint inhibitor (ICI)-based combination therapies are the recommended first-line treatment for metastatic renal cell carcinoma (mRCC). However, no head-to-head phase-3 randomized controlled trials (RCTs) have compared the efficacy of different ICI-based combination therapies. Here, we compared the efficacy of various first-line ICI-based combination therapies in patients with mRCC using updated survival data from phase-3 RCTs. Three databases were searched in June 2023 for RCTs that analyzed oncologic outcomes in mRCC patients treated with ICI-based combination therapies as first-line treatment. A network meta-analysis compared outcomes including overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and complete response (CR) rate. Subgroup analyses were based on the International mRCC Database Consortium risk classification. The treatment ranking analysis of the entire cohort showed that nivolumab + cabozantinib (81%) had the highest likelihood of improving OS, followed by nivolumab + ipilimumab (75%); pembrolizumab + lenvatinib had the highest likelihood of improving PFS (99%), ORR (97%), and CR (86%). These results remained valid even when the analysis was limited to patients with intermediate/poor risk, except that nivolumab + ipilimumab had the highest likelihood of achieving CR (100%). Further, OS benefits of ICI doublets were not inferior to those of ICI + tyrosine kinase inhibitor combinations. Recommendation of combination therapies with ICIs and/or tyrosine kinase inhibitors based on survival benefits and patient pretreatment risk classification will help advance personalized medicine for mRCC., (© 2024. The Author(s).)

Background/aim: Patients with advanced renal cell carcinoma (aRCC) treated with immune-oncology (IO) drugs may need to discontinue the treatment when severe immune-related adverse events (irAE) occur; however, the impact of discontinuation on survival remains unknown., Patients and Methods: This is a retrospective multicenter analysis using a database of 183 aRCC patients treated with first-line IO drugs combination. The patients were divided into two groups according to the necessity of discontinuation due to irAEs. The primary endpoint was overall survival (OS). Cox proportional hazard models determined the predictive factors on OS., Results: Among a total of 135 patients who experienced irAE, 38 patients had to discontinue and 52 continued the treatment while treating irAE. When compared to patients who were able to continue treatment, discontinuation was associated with significantly higher rates of IO-IO doublet use, severe irAE (grade ≥3), steroid use, and the occurrence of immune-related pneumonitis (p=0.03, p<0.001, p<0.001, and p=0.02, respectively). The objective response rates were comparable between the two groups (discontinuation 55.6% vs. no discontinuation 56.0%, p=0.7). On univariate analysis, patients who discontinued had a significantly worse OS when compared to those who continued treatment (p=0.02). On the contrary, on multivariate analysis treatment discontinuation was not associated with poor OS (HR=1.1, p=0.9)., Conclusion: Treatment discontinuation due to irAE was not associated with poor prognosis in aRCC patients treated with ICI-based combination therapy. Treatment discontinuation may be a reasonable treatment option for well-selected patients, specifically for those who experienced good treatment responses., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Context: Repeat transurethral resection (reTUR) is a guideline-recommended treatment strategy in high-risk non-muscle-invasive bladder cancer (NMIBC) patients treated with transurethral resection of bladder tumor (TURBT); however, the impact of recent procedural/technological developments on reTUR outcomes has not been assessed yet., Objective: To assess the outcomes of reTUR for NMIBC in the contemporary era, focusing on whether temporal differences and technical advancement, specifically, photodynamic diagnosis and en bloc resection of bladder tumor (ERBT), affect the outcomes., Evidence Acquisition: Multiple databases were queried in February 2023 for studies investigating reTUR outcomes, such as residual tumor and/or upstaging rates, its predictive factors, and oncologic outcomes, including recurrence-free (RFS), progression-free (PFS), cancer-specific (CSS), and overall (OS) survival. We synthesized comparative outcomes adjusting for the effect of possible confounders., Evidence Synthesis: Overall, 81 studies were eligible for the meta-analysis. In T1 patients initially treated with conventional TURBT (cTURBT) in the 2010s, the pooled rates of any residual tumors and upstaging on reTUR were 31.4% (95% confidence interval [CI]: 26.0-37.2%) and 2.8% (95% CI: 2.0-3.8%), respectively. Despite a potential publication bias, these rates were significantly lower than those in patients treated in the 1990-2000s (both p < 0.001). ERBT and visual enhancement-guided cTURBT significantly improved any residual tumor rates on reTUR compared with cTURBT based on both matched-cohort and multivariable analyses. Among studies adjusting for the effect of possible confounders, patients who underwent reTUR had better RFS (hazard ratio [HR]: 0.78, 95% CI: 0.62-0.97) and OS (HR: 0.86, 95% CI: 0.81-0.93) than those who did not, while it did not lead to superior PFS (HR: 0.74, 95% CI: 0.47-1.15) and CSS (HR: 0.94, 95% CI: 0.86-1.03)., Conclusions: reTUR is currently recommended for high-risk NMIBC based on the persistent high rates of residual tumors after primary resection. Improvement of resection quality based on checklist applications and recent technical/procedural advancements hold the promise to omit reTUR., Patient Summary: Recent endoscopic/procedural developments improve the outcomes of repeat resection for high-risk non-muscle-invasive bladder cancer. Further investigations are urgently needed to clarify the potential impact of the use of these techniques on the need for repeat transurethral resection in the contemporary era., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Non-metastatic upper urinary tract carcinoma (UTUC) is a comparatively rare condition, typically managed with either kidney-sparing surgery (KSS) or radical nephroureterectomy (RNU). Irrespective of the chosen therapeutic modality, patients with UTUC remain at risk of recurrence in the bladder; in patients treated with KSS, the risk of recurrence is high in the remnant ipsilateral upper tract system but there is a low but existent risk in the contralateral system as well as in the chest and in the abdomen/pelvis. For patients treated with RNU for high-risk UTUC, the risk of recurrence in the chest, abdomen, and pelvis, as well as the contralateral UT, depends on the tumor stage, grade, and nodal status. Hence, implementing a risk-stratified, location-specific follow-up is indicated to ensure timely detection of cancer recurrence. However, there are no data on the type and frequency/schedule of follow-up or on the impact of the recurrence type and site on outcomes; indeed, it is not well known whether imaging-detected asymptomatic recurrences confer a better outcome than recurrences detected due to symptoms/signs. Novel imaging techniques and more precise risk stratification methods based on time-dependent probabilistic events hold significant promise for making a cost-efficient individualized, patient-centered, outcomes-oriented follow-up strategy possible. We show and discuss the follow-up protocols of the major urologic societies.

One-third of renal cell carcinomas (RCCs) without metastases develop metastatic disease after extirpative surgery for the primary tumors. The majority of metastatic RCC cases, along with treated primary lesions, involve limited lesions termed "oligo-recurrent" disease. The role of metastasis-directed therapy (MDT), including stereotactic body radiation therapy (SBRT) and metastasectomy, in the treatment of oligo-recurrent RCC has evolved. Although the surgical resection of all lesions alone can have a curative intent, SBRT is a valuable treatment option, especially for patients concurrently receiving systemic therapy. Contemporary immune checkpoint inhibitor (ICI) combination therapies remain central to the management of metastatic RCC. However, one objective of MDT is to delay the initiation of systemic therapies, thereby sparing patients from potentially unnecessary burdens. Undertaking MDT for cases showing progression under systemic therapies, known as "oligo-progression", can be complex in considering the treatment approach. Its efficacy may be diminished compared to patients with stable disease. SBRT combined with ICI can be a promising treatment for these cases because radiation therapy has been shown to affect the tumor microenvironment and areas beyond the irradiated sites. This may enhance the efficacy of ICIs, although their efficacy has only been demonstrated in clinical trials.

Purpose: This study aimed to investigate the effectiveness of the Geriatric Nutritional Risk Index (GNRI) in predicting the efficacy of first-line immune checkpoint inhibitor (ICI) combination therapy for metastatic or unresectable renal cell carcinoma (RCC) and associated patient prognosis., Methods: A retrospective study was conducted using data from 19 institutions. The GNRI was calculated using body mass index and serum albumin level, and patients were classified into two groups using the GNRI values, with 98 set as the cutoff point., Results: In all, 119 patients with clear cell RCC who received first-line drug therapy with ICIs were analyzed. Patients with GNRI ≥ 98 had significantly better overall survival (OS) (p = 0.008) and cancer-specific survival (CSS) (p = 0.001) rates than those with GNRI < 98; however, progression-free survival (PFS) did not differ significantly. Inverse probability of treatment weighting analysis showed that low GNRI scores were significantly associated with poor OS (p = 0.004) and CSS (p = 0.015). Multivariate analysis showed that the Karnofsky performance status (KPS) score was a better predictor of prognosis (OS; HR 5.17, p < 0.001, CSS; HR 4.82, p = 0.003) than GNRI (OS; HR 0.36, p = 0.066, CSS; HR 0.35, p = 0.072). In a subgroup analysis of patients with a good KPS and GNRI ≥ 98 vs < 98, the 2-year OS rates were 91.4% vs 66.9% (p = 0.068), 2-year CSS rates were 91.4% vs 70.1% (p = 0.073), and PFS rates were 39.7% vs 21.4 (p = 0.27), respectively., Conclusion: The prognostic efficiency of GNRI was inferior to that of the KPS score at the initiation of the first-line ICI combination therapy for clear cell RCC., (© 2023. The Author(s).)

Aim: To compare the efficacy of first-line immune checkpoint inhibitor (ICI)-based combinations in metastatic renal cell carcinoma (mRCC) patients stratified by chronological age. Methods: According to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, hazard ratios for overall survival (OS) from randomized controlled trials were synthesized. Results: Five RCTs were eligible for meta-analyses. ICI-based combinations significantly improved OS compared with sunitinib alone, both in younger (<65 years) and older (≥65 years) patients, whereas the OS benefit was significantly better in younger patients (p = 0.007). ICI-based combinations did not improve OS in patients aged ≥75 years. Treatment rankings showed age-related differential recommendations regarding improved OS. Conclusion: OS benefit from first-line ICI-based combinations was significantly greater in younger patients. Age-related differences could help enrich shared decision-making.

Aim: We aimed to review the evidence of reducing the dose or number of BCG instillations in non-muscle invasive bladder cancer (NMIBC) patients. Material & methods: A literature search was done according to Preferred Reporting Items for Meta-Analyses statement. Results: Overall, 15 and 13 studies were eligible for qualitative and quantitative synthesis, respectively. In patients with NMIBC, lowering either the dose or number of BCG instillations increases the risk of recurrence, but not the risk of progression. Lowering the dose of BCG decreases the risk of adverse events compared with standard-dose BCG. Conclusion: Standard-dose and -number of BCG is preferred for NMIBC patients based on oncologic efficacy; however, low-dose BCG could be considered in selected patients who suffer from significant adverse events.

Purpose of Review: Lymph node dissection (LND) during radical nephrectomy (RN) for renal cell carcinoma (RCC) is not considered as a standard. The emergence of robot-assisted surgery and effective immune checkpoint inhibitors (ICI) in recent years may change this and lymph node (LN) staging has become easier and has a clinical impact. In this review, we aimed to reconsider the role of LND today., Recent Findings: Although the extent of LND has still not been well established, removal of more LN seems to provide better oncologic outcomes for a select group of patients with high-risk factors such as clinical T3-4. Adjuvant therapy using pembrolizumab has been shown to improve disease free survival if complete resection of metastatic lesions as well as the primary site is obtained in combination. Robot assisted RN for localized RCC has been widespread and the studies regarding LND for RCC has been recently appeared., Summary: The staging and surgical benefits and its extent of LND during RN for RCC remains unclear, but it is becoming increasingly important. Technologies that allow an easier LND and adjuvant ICI that improve survival in LN-positive patients are engaging the role of LND, a procedure that was needed, but almost never done, is now indicated sometimes. Now, the goal is to identify the clinical and molecular imaging tools that can help identify with sufficient accuracy who needs a LND and which LNs to remove in a targeted personalized approach., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)