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The majority of men undergoing radical prostatectomy today are candidates for bilateral NVB preservation. Performed appropriately, bilateral NVB preservation optimizes patient recovery of potency without compromising cancer control Some men, however, require more extensive dissection of the periprostatic tissue to optimize their likelihood of cure. The decision to modify surgical technique should be individualized and based on preoperative and intraoperative findings. [ABSTRACT FROM AUTHOR]

Background: In the Western Hemisphere, 90% of bladder cancers are transitional cell carcinomas, while only 7% are classified as squamous cell carcinomas. In contrast, in Egypt and regions of the Middle East and Africa, where infection by the trematode Schistosoma haematobium is endemic, squamous cell carcinoma is the most common bladder cancer as well as the most common cancer in men.Purpose: We planned experiments to understand the genetic defects underlying the development of squamous cell carcinoma and to determine if the morphologically and clinically distinct squamous cell carcinoma and transitional cell carcinoma of the bladder evolve following different genetic alterations.Methods: Squamous cell carcinoma specimens from high-risk (Egypt, n = 19) and low-risk (Sweden, n = 12) populations were examined for genetic defects known to be involved in transitional cell carcinoma tumorigenesis. Homozygous deletions of the CDKN2 tumor suppressor gene were detected by comparative multiplex polymerase chain reaction. Mutations in the CDKN2 and p53 (also known as TP53) genes were analyzed by single-strand conformation polymorphism and DNA sequencing. Immunohistochemical staining of p53 protein was also performed. Allelic losses in chromosome arms 9p, 9q, and 17p were determined by microsatellite analysis.Results: Homozygous deletions and sequence mutations in the CDKN2 gene were found in 67% (eight of 12) of squamous cell carcinoma specimens, a frequency three times higher than that reported for uncultured transitional cell carcinomas (P = .009). Hemizygous and homozygous deletions in 9p, where CDKN2 resides, were found in 92% (11 of 12) of uncultured squamous cell carcinomas, while only about 39% (35 of 90) of transitional cell carcinomas showed these losses (P = .001). Deletions in 9p with no change in 9q were found in 92% (10 of 11) of squamous cell carcinomas compared with only 10% (11 of 110) of transitional cell carcinomas (P < .001) reported in the literature. The frequency of p53 mutations in squamous cell carcinomas was similar to that reported for invasive transitional cell carcinomas (60%), but the type and position of mutations differed between the two tumor types. Allelic losses in chromosome arm 17p, where the p53 gene resides, were found to be less frequent in squamous cell carcinomas (38%) than in invasive transitional cell carcinomas (60%).Conclusions: Our results suggest that a putative tumor suppressor gene on 9p, possibly CDKN2, may contribute to squamous cell carcinoma tumorigenesis. Our data on squamous cell carcinoma and previously reported data on transitional cell carcinoma indicate that these two bladder carcinomas differ in their genetic alterations, suggesting that distinct underlying genetic defects may explain, at least in part, the pathological differences between the two tumors of the bladder epithelium.Implications: Development of diagnostic and therapeutic strategies for squamous cell carcinoma of the bladder based on its distinct genetic alterations is warranted. [ABSTRACT FROM AUTHOR]

Our increasing knowledge about the biologic and molecular properties of bladder cancer is leading towards the establishment of more effective yet less invasive surveillance schemes. [ABSTRACT FROM AUTHOR]

Objectives: We sought to determine whether bladder cuff excision and its technique influence outcomes after radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC)., Methods and Materials: A multicenter, international, retrospective analysis using the ROBotic surgery for Upper tract Urothelial cancer Study (ROBUUST) 2.0 registry identified 1,718 patients undergoing RNU for UTUC between 2015 and 2023 at 17 centers across the United States, Europe, and Asia. Data was gathered on (1) whether bladder cuff excision was performed and (2) what technique was used, including formal excision or other techniques (pluck technique, stripping/intussusception technique) and outcomes. Multivariate and survival analyses were performed to compare the groups., Results: Most patients (90%, 1,540/1,718) underwent formal bladder cuff excision in accordance with EAU and AUA guidelines. Only 4% (68/1,718) underwent resection using other techniques, and 6% (110/1,718) did not have a bladder cuff excised. Median follow up for the cohort was 24 months (IQR 9-44). When comparing formal bladder cuff excision to other excision techniques, there were no differences in oncologic or survival outcomes including bladder recurrence-free survival (BRFS), recurrence-free survival (RFS), metastasis-free survival (MFS), overall survival (OS), or cancer-specific survival (CSS). However, excision of any kind conferred a decreased risk of bladder-specific recurrence compared to no excision. There was no difference in RFS, MFS, OS, or CSS when comparing bladder cuff excision, other techniques, and no excision., Conclusions: Bladder cuff excision improves recurrence-free survival, particularly when considering bladder recurrence. This benefit is conferred regardless of technique, as long as the intramural ureter and ureteral orifice are excised. However, the benefit of bladder cuff excision on metastasis-free, overall, and cancer-specific survival is unclear., 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.)

Purpose: To assess the impact of neoadjuvant and adjuvant chemotherapy on survival outcomes, within a large multicenter cohort of Upper tract urothelial carcinoma patients treated with Nephroureterectomy., Methods: A multicenter retrospective analysis utilizing the Robotic surgery for Upper Tract Urothelial Cancer Study registry was performed. Baseline, preoperative, perioperative, and pathologic variables of three groups of patients receiving surgery only, neoadjuvant or adjuvant chemotherapy were compared. Categorical and continuous variables among the three subgroups were compared with Chi square and ANOVA tests. The impact of perioperative chemotherapy on survival outcomes was assessed with the Kaplan Meier method. Univariable and multivariable Cox regression analyses were performed to identify predictors of survival., Results: Overall, 1,994 patients were included. Overall and Clavien grade ≥3 complications rates were comparable among the three subgroups (p = 0.65 and p = 0.92). At Kaplan Meier analysis, neoadjuvant chemotherapy significantly improved cancer-specific survival (p = 0.03) and overall survival (p = 0.03) probabilities of patients with cT ≥ 3 tumors and of those with positive cN (p = 0.03 and p = 0.02). On multivariable analysis, neoadjuvant chemotherapy was independently associated with an improvement of cancer-specific survival in cT ≥ 3 patients (HR 0.44; p = 0.04), and of both cancer-specific survival (HR 0.50; p = 0.03) and overall survival (HR 0.53; p = 0.02) probabilities in positive cN patients., Conclusions: This large multicenter retrospective analysis suggests significant survival benefit in Upper tract urothelial carcinoma patients with either locally advanced or clinically positive nodes disease receiving neoadjuvant chemotherapy. These findings can be regarded as "hypothesis generating", stimulating future trials focusing on such advanced stages., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: Recent advancements in screening, prostate MRI, robotic surgery, and active surveillance have influenced the profile of patients undergoing radical prostatectomy (RP). We sought to examine their impact on trends in clinicodemographic, risk classification, and adverse pathology in men undergoing surgery., Methods: We queried the National Cancer Database for clinicodemographic, risk group, and pathology data in men undergoing upfront RP between 2006 and 2020. Patients were categorized by NCCN risk groups, and trends were assessed among 2006-2010, 2011-2015, and 2016-2020 periods. Endpoints included rates of pT3, positive surgical margins (PSM), pathologic upstaging, and Gleason grade group (GG) upgrading., Results: 610,762 patients were included. There were significant increases in African Americans (9.8-14.1%), comorbidities (2.1-5.2% with Charlson scores > 1), and robot-assisted RP (78-84%). Over the three time periods, high-risk cases increased from 15 to 20 to 27%, and intermediate-risk from 54 to 51 to 60%. Overall rates of pT3 rose from 20 to 38%, and PSM from 20 to 27% (p < 0.001). Pathologic upstaging increased in low (6-15%), intermediate (20-33%), and high-risk groups (42-58%) -p < 0.001. Gleason upgrading rose in low-risk (45-59%, p < 0.001), with slight reductions in the intermediate and high-risk groups., Conclusions: Recent trends in RP indicate a shift towards more advanced disease, evidenced by increasing rates of pT3, PSM, and pathologic upstaging across all NCCN risk groups. These findings emphasize the need for a careful balance in applying fascia and nerve-sparing techniques to avoid compromising oncological safety., (© 2024. The Author(s).)

Background: 4Kscore is used to aid the decision for prostate biopsy, however its role in active surveillance (AS) has not been investigated in a magnetic resonance imaging (MRI)-based protocol. Our objective was to assess the association between 4Kscore and progression in men undergoing AS on a prospective MRI-based protocol., Methods: This was a single-institution, single-arm, non-therapeutic, interventional trial of 166 men with biopsy-confirmed prostate cancer enrolled between 2014-2020. Patients were placed on a trial-mandated AS protocol including yearly multiparametric (mp)MRI, prostate biopsy, and 4Kscore followed for 48 months after diagnosis. We analyzed protocol-defined and grade progression at confirmatory and subsequent surveillance biopsies., Results: Out of 166 patients, 83 (50%) men progressed per protocol and of them 41 (24.7% of whole cohort) progressed by grade. At confirmatory biopsy, men with a baseline 4Kscore ≥ 20% had a higher risk of grade progression compared to those with 4Kscore < 20% (OR = 4.04, 95% CI: 1.05-15.59, p = 0.043) after adjusting for National Comprehensive Cancer Network (NCCN) risk and baseline PIRADS score. At surveillance biopsies, most recent 4Kscore ≥ 20% significantly predicted per protocol (OR = 2.61, 95% CI: 1.03-6.63, p = 0.044) and grade progression (OR = 5.13, 95% CI: 1.63-16.11, p = 0.005)., Conclusions: For patients on AS, baseline 4Kscore predicted grade progression at confirmatory biopsy, and most recent 4Kscore predicted per-protocol and grade progression at surveillance biopsy., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Objective: Discrepancies in survival outcomes of various genitourinary tract malignancies have been documented across different racial and ethnic groups. Here we sought to examine long-term survival outcomes of patients with upper tract urothelial carcinoma (UTUC) following radical nephroureterectomy (RNU) when stratified by race., Methods: A multicenter retrospective analysis using the ROBUUST (ROBotic surgery for Upper tract Urothelial cancer Study) registry identified patients undergoing RNU for UTUC between 2015 and 2022 at 12 centers across the United States, Europe, and Asia. Patients were stratified by race (white, black, Hispanic, and Asian) and primary outcomes of interest-including recurrence-free survival (RFS), metastasis free survival (MFS) and overall survival (OS) - were assessed using univariate analysis, multivariate Cox regression modeling, and Kaplan-Meier analysis., Results: 1446 patients (white n = 652, black n = 70, Hispanic n = 87, and Asian n = 637) who underwent RNU for treatment of the UTUC were included in our analysis. Cox regression modeling demonstrated pathologic nodal staging to be a significant predictor of RFS (HR 2.25; P = .0010), MFS (HR 2.50; P = .0028), and OS (HR 5.11; P < .0001). When using whites as the reference group, there were no significant differences in RFS, MFS, or OS across racial groups., Conclusions: Unlike other genitourinary tract malignancies, our study failed to demonstrate a survival disadvantage among minority racial groups with UTUC who underwent RNU. Furthermore, a significant difference in RFS, MFS, and OS was not identified across whites, blacks, Asians, or Hispanics with UTUC who underwent RNU., Competing Interests: Disclosure The authors have stated that they have no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: To assess the efficacy and safety of combined High-Intensity Focused Ultrasound (HIFU) and Holmium Laser Enucleation of the Prostate (HoLEP) in treating patients with both localized prostate cancer (PCa) and prostate > 60 g., Methods: All patients who underwent HIFU for treatment of localized PCa were prospectively enrolled in our study. We reviewed records of patients undergoing procedures from January 2016 to January 2023. For patients with prostate sizes > 60 g, HoLEP was offered before HIFU to prevent worsened urinary symptoms post-treatment. Oncological outcomes-prostatic-specific (PSA) kinetics, recurrence rates, treatment failure - and functional results-Sexual Health Inventory for Men (SHIM), International Prostate Symptoms Score (IPSS), and urinary complications were compared between patients undergoing combined HoLEP and HIFU with those underwent HIFU-monotherapy., Results: Among 100 patients, 74 underwent HIFU-monotherapy and 26 underwent the combined HoLEP and HIFU. The majority had intermediate-risk PCa (67%). Pathologic assessment of HoLEP specimens showed no tumor evidence in 57% of cases. In comparison to the HIFU-only group, the combined group exhibited significantly lower PSA metrics across various intervals, however, no differences were found regarding overall and infield recurrences and treatment failure rates. While the combined treatment initially resulted in higher incontinence rates and shorter catheterization durations (P < 0.001), no significant difference in IPSS was observed during subsequent follow-ups., Conclusion: HoLEP and HIFU can be safely combined for the treatment of PCa in patients with >60 g prostate volume without compromising early oncological outcomes thereby expanding the therapeutic scope of HIFU in treating patients with localized PCa and large adenomas., 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.)

Background: Diagnostic ureteroscopy (URS) with or without biopsy remains a subject of contention in the management of upper tract urothelial carcinoma (UTUC), with varying recommendations across different guidelines. The study aims to analyse the decision-making and prognostic role of diagnostic ureteroscopy (URS) in high-risk UTUC patients undergoing curative surgery., Materials and Methods: In this retrospective multi-institutional analysis of high-risk UTUC patients from the ROBUUST dataset, a comparison between patients who received or not preoperative URS and biopsy before curative surgery was carried out. Logistic regression analysis evaluated differences between patients receiving URS and its impact on treatment strategy. Survival analysis included 5-year recurrence-free survival (RFS), metastasis-free survival (MFS), cancer-specific survival (CSS) and overall survival (OS). After adjusting for high-risk prognostic group features, Cox proportional hazard model estimated significant predictors of time-to-event outcomes., Results: Overall, 1,912 patients were included, 1,035 with preoperative URS and biopsy and 877 without. Median follow-up: 24 months. Robot-assisted radical nephroureterectomy was the most common procedure (55.1%), in both subgroups. The 5-year OS (P = 0.04) and CSS (P < 0.001) were significantly higher for patients undergoing URS. The 5-year RFS (P = 0.6), and MFS (P = 0.3) were comparable between the 2 groups. Preoperative URS and biopsy were neither a significant predictor of worse oncological outcomes nor of a specific treatment modality., Conclusions: The advantage in terms of OS and CSS in patients undergoing preoperative URS could derive from a better selection of candidates for curative treatment. The treatment strategy is likely more influenced by tumor features than by URS findings., 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.)

Objective: To analyse surgical, functional, and mid-term oncological outcomes of robot-assisted nephroureterectomy (RANU) in a contemporary large multi-institutional setting., Patients and Methods: Data were retrieved from the ROBotic surgery for Upper tract Urothelial cancer STtudy (ROBUUST) 2.0 database, an international, multicentre registry encompassing data of patients with upper urinary tract urothelial carcinoma undergoing curative surgery between 2015 and 2022. The analysis included all consecutive patients undergoing RANU except those with missing data in predictors. Detailed surgical, pathological, and postoperative functional data were recorded and analysed. Oncological time-to-event outcomes were: recurrence-free survival (RFS), metastasis-free survival (MFS), cancer-specific survival (CSS), and overall survival (OS). Survival analysis was performed using the Kaplan-Meier method, with a 3-year cut-off. A multivariable Cox proportional hazard model was built to evaluate predictors of each oncological outcome., Results: A total of 1118 patients underwent RANU during the study period. The postoperative complications rate was 14.1%; the positive surgical margin rate was 4.7%. A postoperative median (interquartile range) estimated glomerular filtration rate decrease of -13.1 (-27.5 to 0) mL/min/1.73 m 2 from baseline was observed. The 3-year RFS was 59% and the 3-year MFS was 76%, with a 3-year OS and CSS of 76% and 88%, respectively. Significant predictors of worse oncological outcomes were bladder-cuff excision, high-grade tumour, pathological T stage ≥3, and nodal involvement., Conclusions: The present study contributes to the growing body of evidence supporting the increasing adoption of RANU. The procedure consistently offers low surgical morbidity and can provide favourable mid-term oncological outcomes, mirroring those of open NU, even in non-organ-confined disease., (© 2024 The Author(s). BJU International published by John Wiley & Sons Ltd on behalf of BJU International.)

Objectives: There are 2 grading approaches to radical prostatectomy (RP) in multifocal cancer: Grade Group (GG) and percentage of Gleason pattern 4 (GP4%). We investigated whether RP GG and GP4% generated by global vs individual tumor grading correlate differently with biochemical recurrence., Methods: We reviewed 531 RP specimens with GG2 or GG3 cancer. Each tumor was scored separately with assessment of tumor volume and GP4%. Global grade and GP4% were assigned by combining Gleason pattern 3 and 4 volumes for all tumors. Correlation of GG and GP4% generated by 2 methods with biochemical recurrence was assessed by Cox proportional hazard regression and receiver operating characteristic curves, with optimism adjustment using a bootstrap analysis., Results: Median age was 63 (range, 42-79) years. Median prostate-specific antigen was 6.3 (range, 0.3-62.9) ng/mL. In total, the highest-grade tumor in 371 (36.9%) men was GG2 and in 160 (30.1%) men was GG3. Global grading was downgraded from GG3 to GG2 in 37 of 121 (30.6%) specimens with multifocal disease, and 145 of 404 (35.9%) specimens had GP4% decreased by at least 10%. Ninety-eight men experienced biochemical recurrence within a median of 13 (range, 3-119) months. Men without biochemical recurrence were followed up for a median of 47 (range, 12-205) months. Grade Group, GP4%, and margin status correlated with the risk of biochemical recurrence using highest-grade tumor and global grading, but the degrees of these correlations varied and were statistically significantly different between the 2 grading approaches., Conclusions: Grade Group, GP4%, and margin status derived by global vs individual tumor grading predict postoperative biochemical recurrence statistically significantly differently. This difference has important implications if results derived from cohorts graded using different methods are compared., (© The Author(s) 2024. Published by Oxford University Press on behalf of American Society for Clinical Pathology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Clear cell renal cell carcinoma (ccRCC), the most common type of kidney cancer, is largely incurable in the metastatic setting. ccRCC is characterized by excessive lipid accumulation that protects cells from stress and promotes tumor growth, suggesting that the underlying regulators of lipid storage could represent potential therapeutic targets. Here, we evaluated the regulatory roles of GPR1 and CMKLR1, two G protein-coupled receptors of the protumorigenic adipokine chemerin that is involved in ccRCC lipid metabolism. Both genetic and pharmacologic suppression of either receptor suppressed lipid formation and induced multiple forms of cell death, including apoptosis, ferroptosis, and autophagy, thereby significantly impeding ccRCC growth in cell lines and patient-derived xenograft models. Comprehensive lipidomic and transcriptomic profiling of receptor competent and depleted cells revealed overlapping and unique signaling of the receptors granting control over triglyceride synthesis, ceramide production, and fatty acid saturation and class production. Mechanistically, both receptors enforced suppression of adipose triglyceride lipase, but each receptor also demonstrated distinct functions, such as the unique ability of CMKLR1 to control lipid uptake through regulation of sterol regulatory element-binding protein 1c and the CD36 scavenger receptor. Treating patient-derived xenograft models with the CMKLR1-targeting small molecule 2-(α-naphthoyl) ethyltrimethylammonium iodide (α-NETA) led to a dramatic reduction in tumor growth, lipid storage, and clear-cell morphology. Together, these findings provide mechanistic insights into lipid regulation in ccRCC and identify a targetable axis at the core of the histologic definition of this tumor that could be exploited therapeutically. Significance: Extracellular control of lipid accumulation via G protein receptor-mediated cell signaling is a metabolic vulnerability in clear cell renal cell carcinoma, which depends on lipid storage to avoid oxidative toxicity., (©2024 American Association for Cancer Research.)

Background: The role of kidney-sparing surgery in patients with high-risk upper urinary tract urothelial carcinoma is controversial. The present study aimed to assess oncological and functional outcomes of robot-assisted distal ureterectomy in patients with high-risk distal ureteral tumors., Methods: The ROBUUST 2.0 multicenter international (2015-2022) dataset was used for this retrospective cohort analysis. High-risk patients with distal ureteral tumors were divided based on type of surgery: robot-assisted distal ureterectomy or robot-assisted nephroureterectomy. A survival analysis was performed for local recurrence-free survival, distant metastasis-free survival, and overall survival. After adjusting for clinical features of the high-risk prognostic group, Cox proportional hazard model was plotted to evaluate significant predictors of time-to-event outcomes., Results: Overall, 477 patients were retrieved, of which 58 received robot-assisted distal ureterectomy and 419 robot-assisted nephroureterectomy, respectively, with a mean (±SD) follow-up of 29.6 months (±2.6). The two groups were comparable in terms of baseline features. At survival analysis, no significant difference was observed in terms of recurrence-free survival (P=0.6), metastasis-free survival (P=0.5) and overall survival (P=0.7) between robot-assisted distal ureterectomy and robot-assisted nephroureterectomy. At Cox regression analysis, type of surgery was never a significant predictor of worse oncological outcomes. At last follow-up patients undergoing robot-assisted distal ureterectomy had significantly better postoperative renal function., Conclusions: Comparable outcomes in terms of recurrence-free survival, metastasis-free survival, and overall survival between robot-assisted distal ureterectomy and robot-assisted nephroureterectomy patients, and better postoperative renal function preservation in the former group were observed. Kidney-sparing surgery should be considered as a potential option for selected patients with high-risk distal ureteral UTUC.

Objective: This study aims to investigate the impact of risk group classification, restaging transurethral resection (re-TURBT), and adjuvant treatment intensity on recurrence and progression risks in high-grade Ta tumours in patients with non-muscle invasive bladder cancer (NMIBC)., Materials and Methods: Data from a comprehensive bladder cancer database were utilized for this study. Patients with primary high-grade Ta tumours were included. Risk groups were classified according to AUA/SUO criteria. Tumour characteristics and patient demographics were analysed using descriptive statistics. Cox proportional hazard regression models were used to assess the effect of re-TURBT and other clinical/treatment-related predictors on recurrence- and progression-free survivals. The survivals by selected predictors were estimated using Kaplan-Meier method, and groups were compared by the log-rank test., Results: Among 218 patients with high-grade Ta bladder cancer, those who underwent re-TURBT had significantly better 5-year recurrence-free survival (71.1% vs. 26.8%, p  = 0.0009) and progression-free survival (98.6% vs. 73%, p  = 0.0018) compared with those with initial TURBT alone. Full BCG treatment (induction and maintenance) showed lower recurrence risk, especially in high-risk patients. However, residual disease at re-TURBT did not significantly affect recurrence risk., Conclusions: This study highlights the significance of risk group classification, the role of re-TURBT, and the intensity of adjuvant treatment in the management of high-grade Ta tumours. A risk-adapted model is crucial to reduce the burden of unnecessary intravesical treatment and endoscopic procedures., Competing Interests: The authors declare no conflicts of interest., (© 2024 The Authors. BJUI Compass published by John Wiley & Sons Ltd on behalf of BJU International Company.)

Introduction: In the phase 2/3 study QUILT-3.032 (NCT03022825), the ability of the IL-15RαFc superagonist N-803 (nogapendekin alfa inbakicept) plus bacillus Calmette-Guérin (BCG) to elicit durable complete responses in patients with BCG-unresponsive nonmuscle-invasive bladder cancer (NMIBC) was demonstrated. As a secondary end point, patient-reported outcomes (PROs) were assessed., Methods: Both cohort A patients with carcinoma in situ with or without Ta/T1 disease and cohort B patients with high-grade Ta/T1 papillary disease who received N-803 plus BCG therapy completed the EORTC (European Organization for Research and Treatment of Cancer) Core 30 and Quality of Life NMIBC-Specific 24 questionnaires at baseline and months 6, 12, 18, and 24 on study. Scores were analyzed using descriptive statistics, and multivariable analyses were performed to identify baseline variables associated with PROs., Results: On study, mean physical function (PF) and global health (GH) scores remained relatively stable from baseline for cohorts A (n = 86) and B (n = 78). At month 6, cohort A patients with a complete response reported higher PF scores than those without ( P = .0659); at month 12, > 3 as compared with ≤ 3 prior transurethral resections of bladder tumor was associated ( P = .0729) with lower GH scores. In cohort B, baseline disease type was associated ( P = .0738) with PF and race was significantly associated ( P = .0478) with GH at month 6. NMIBC-Specific 24 summary scores also remained stable on study for both cohorts., Conclusions: The overall stability of PROs scores, taken together with the efficacy findings, indicates a favorable risk-benefit ratio and quality of life following N-803 plus BCG.

What Is This Summary About?: This is a summary of two studies that looked at the safety and effectiveness of a potential new treatment, N-803 (Anktiva), in combination with a standard treatment bacillus Calmette-Guerin (BCG) for people with non-muscle invasive bladder cancer (NMIBC) .One study was a Phase 1b study that tested increasing doses of N-803 in combination with the same dose of BCG in people with NMIBC who had never received BCG previously (BCG-naive). The other study is a Phase 2/3 study of N-803 and BCG in people with NMIBC whose cancer wasn't eliminated by BCG alone (BCGunresponsive)., What Happened in the Studies?: In the Phase 1b study, the nine participants were split into three groups of 3 participants who received a dose of 100, 200, or 400 μg N-803 along with a standard 50 mg dose of BCG. In the Phase 2/3 study, one group (cohort A) of participants with carcinoma in situ (CIS) disease and another group (cohort B) with papillary disease were treated with 400 μg N-803 plus 50 mg BCG. There was also a cohort C that received only 400 μg N-803. Treatments were delivered directly into the bladder once a week for 6 weeks in a row., What Were the Key Takeaways?: N-803 plus BCG eliminated NMIBC in all nine BCG-naive participants and the effects were long-lasting, with participants remaining NMIBC-free for a range of 8.3 to 9.2 years.As reported in 2022, cancer was eliminated in 58 of 82 (71%) participants with BCG-unresponsive CIS disease and the effect was also long-lasting. Importantly, approximately 90% of the successfully treated participants avoided surgical removal of the bladder. In cohort B participants with papillary disease, 40 of 72 (55.4%) were cancer-free 12 months after treatment. N-803 used alone was only effective in 2 of 10 participants. In both studies, the combination of N-803 and BCG was found to be associated with very few adverse events.Based on results from the Phase 2/3 study, the U.S. Food and Drug Association (FDA) approved the use of N-803 plus BCG for the treatment of BCG-unresponsive bladder CIS with or without Ta/T1 papillary disease. Clinical Trial Registration: NCT02138734 (Phase 1b study), NCT03022825 (Phase 2/3 study).

Objectives: The objective of this study is to investigate the association between major adverse cardiac events (MACE) and clinical factors of patients undergoing radical cystectomy (RC) for bladder cancer., Materials and Methods: A retrospective analysis using the 2015-2020 National Surgical Quality Improvement Program database was performed on patients who underwent RC for bladder cancer. MACE was defined as any report of cerebrovascular accident, myocardial infarction, or thromboembolic events (pulmonary embolism or deep vein thrombosis). A multivariable-adjusted logistic regression was conducted to identify clinical predictors of postoperative MACE., Results: A total of 10 308 (84.2%) patients underwent RC with incontinent urinary diversion (iUD), and 1938 (15.8%) underwent RC with continent urinary diversion (cUD). A total of 629 (5.1%) patients recorded a MACE, and on the multivariable-adjusted logistic regression, it was shown that MACE was significantly associated with increased age (OR = 1.035, 95% CI: 1.024-1.046, p  < 0.001), obesity (OR = 1.583, 95% CI: 1.266-1.978, p  < 0.001), current smokers (OR = 1.386, 95% CI: 1.130-1.700, p  = 0.002), congestive heart failure before surgery (OR = 1.991, 95% CI: 1.016-3.900; p  = 0.045), hypertension (OR = 1.209, 95% CI: 1.016-1.453, p  = 0.043), and increase the surgical time (per 10 min increase, OR = 1.010, 95% CI: 1.003-1.017, p  = 0.009). We also report that increased age, obesity, and patients undergoing cUD (OR = 1.368, 95% CI: 1.040-1.798; p  = 0.025) are associated with thromboembolic events., Conclusion: By considering the preoperative characteristics of patients, including age, obesity, smoking, congestive heart failure, and hypertension status, urologists may be able to decrease the incidence of MACE in patients undergoing RC. Urologists should aim for lower operative times as this was associated with a decreased risk of thromboembolic events., Competing Interests: The authors have no conflict of interest to disclose., (© 2023 The Authors. BJUI Compass published by John Wiley & Sons Ltd on behalf of BJU International Company.)

Purpose: To identify whether there was a disparity in the utilization of immunotherapy in the treatment of black patients with metastatic castration resistant prostate cancer (mCRPC)., Methods: Using the National Cancer Database, we identified patients between 2010- 2015 with likely minimally/asymptomatic mCRPC. We analyzed annual trends for chemotherapy and immunotherapy use and compared utilization by demographic and clinical features. Multivariable analysis was performed to determine predictors of receiving immunotherapy vs chemotherapy., Results: We identified 1301 patients with likely mCRPC. The majority were non Hispanic White (NHW - 63 %) and 23 % were non-Hispanic Black (NHB). Overall, there was increased utilization of immunotherapy in mCRPC from 2010 onwards, with the peak occurring in 2014 (4.6 %). Chemotherapy use increased significantly, peaking in 2014 to 26.1 %. However, the increased utilization of immunotherapy in the mCRPC was mainly seen in White patients: from 50 % to 74.2 % of the cohort. Conversely, there was a decrease in utilization of immunotherapy among Black mCPRC patients: from 50 % to 25.8 %. On multivariable analysis, there was no statistically significant difference between treatment types by race., Conclusion: FDA approval of Sipuleucel-T for mCRPC led to increased utilization of immunotherapy shortly thereafter, but this was mainly noted in white patients. Black patients comparatively did not exhibit increased utilization of this novel agent after 2010. Further studies are necessary to help understand barriers to access to new treatment in mCRPC and eliminate the burden of disease in minority populations.", Competing Interests: Declaration of Competing Interest The authors have no competing interests to declare that are relevant to the content of this article., (Copyright © 2023 National Medical Association. Published by Elsevier Inc. All rights reserved.)

Objective: To investigate clinical risk factors associated with postoperative deep incisional or organ/space surgical site infections (SSI) following radical cystectomy (RC) in a well characterized and large contemporary cohort., Methods: We used the American College of Surgeons National Surgical Quality Improvement Program database to identify adult patients who underwent RC for bladder cancer between 2015 and 2020 (n = 13,081). We conducted multivariable-adjusted logistic regression and Cox adjusted proportional hazards regression analysis to identify clinical predictors of deep incisional or organ/space SSI in the 30-day postoperative-period following RC., Results: Deep incisional or organ/space SSI risk increased with continent urinary diversion (HR = 1.61, 95% CI: 1.38-1.88; P < 0.001), obesity (HR = 1.60, 95% CI: 1.35-1.90; P < 0.001), diabetes mellitus (HR = 1.30, 95% CI: 1.13-1.51; P < 0.001), and being functionally dependent before surgery (HR = 2.09, 95% CI: 1.44-3.03; P < 0.001)., Conclusions: Postoperative deep incisional or organ/space SSIs following RC occur more frequently in patients who were obese, diabetic, functionally dependent before surgery, and those who underwent continent urinary diversion. These findings may assist urologists in preoperative counseling, medical optimization, and choice of urinary diversion approach, as well as improved patient monitoring and identification of candidates for intervention postoperatively., 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 © 2023 Elsevier Inc. All rights reserved.)

The microbiome, once considered peripheral, is emerging as a relevant player in the intricate web of factors contributing to cancer development and progression. These often overlooked microorganisms, in the context of urological malignancies, have been investigated primarily focusing on the gut microbiome, while exploration of urogenital microorganisms remains limited. Considering this, our systematic review delves into the complex role of these understudied actors in various neoplastic conditions, including prostate, bladder, kidney, penile, and testicular cancers. Our analysis found a total of 37 studies (prostate cancer 12, bladder cancer 20, kidney cancer 4, penile/testicular cancer 1), revealing distinct associations specific to each condition and hinting at potential therapeutic avenues and future biomarker discoveries. It becomes evident that further research is imperative to unravel the complexities of this domain and provide a more comprehensive understanding.

Introduction: Oncologic implications of variant histology (VH) have been extensively studied in bladder cancer; however, further investigation is needed in upper tract urothelial carcinoma (UTUC). Our study aims to evaluate the impact of VH on oncological outcomes in UTUC patients treated with radical nephroureterectomy (RNU)., Methods: A retrospective analysis was performed on patients who underwent a robotic or laparoscopic RNU for UTUC using the ROBUUST database, a multi-institutional collaborative including 17 centers worldwide. Logistic regression was used to assess the effect of VH on urothelial recurrence (bladder, contralateral upper tract), metastasis, and survival following RNU., Results: A total of 687 patients were included in this study. Median (IQR) age was 71 (64-78) years and 470 (68%) had organ confined disease. VH was present in 70 (10.2%) patients. In a median follow-up of 16 months, the incidence of urothelial recurrence, metastasis, and mortality was 26.8%, 15.3%, and 11.8%, respectively. VH was associated with increased risk of metastasis (HR 4.3, P <.0001) and death (HR 2.0, P =.046). In multivariable analysis, VH was noted to be an independent risk factor for metastasis (HR 1.8, P =.03) but not for urothelial recurrence (HR 0.99, P =.97) or death (HR 1.4, P =.2)., Conclusion: Variant histology can be found in 10% of patients with UTUC and is an independent risk factor for metastasis following RNU. Overall survival rates and the risk of urothelial recurrence in the bladder or contralateral kidney are not affected by the presence of VH., Competing Interests: Disclosure The authors have stated that they have no conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objectives: To identify patient risk factors that predict nonhome discharge after surgery for urologic malignancies as well as determine whether discharge status had an impact on readmission rates in patients undergoing surgery for urologic malignancies., Methods: We identified patients who had undergone surgery for urologic malignancies including prostate, bladder, kidney, or upper tract urothelial cancer from 2011 to 2019 in the American College of Surgeon National Surgical Quality Improvement Program (ACS-NSQIP) database. Multivariable logistic regression analyses were performed to identify patient characteristics that were associated with nonhome discharges and 30-day postoperative readmission., Results: Nonhome discharge occurred in 2.8% of our study population. Women were less likely to be discharged to home (OR 0.60 p < 0.0001). Nonhome discharge was more common in patients who underwent cystectomy when compared to nephrectomy (OR 1.41 p < 0.0001) or prostatectomy (OR 4.16 p < 0.0001). Those with elevated BMI were less likely to experience non-home discharge (OR 0.86 p=0.0095) while patients who were identified as underweight and those with unexpected weight loss prior to surgery were more likely to have nonhome discharges (OR 1.76 p = 0.0002, OR 1.67, p < 0.0001). Comorbidities and presence of postoperative complications were also found to be significant independent predictors of nonhome discharges. Thirty-day postoperative readmission occurred in 6.9% of our study population. Of the patients who were readmitted 93.1% were initially discharged home, and 6.9% had nonhome discharges. Higher risk of readmission was seen in elderly patients and those with significant comorbidities. When controlling for predictors of readmission, on multivariate analysis, non-home discharge was associated with a decreased likelihood of readmission (OR 0.79, p = 0.0004)., Conclusions: Patient factors including age, gender, weight, comorbidities, postoperative complications, and site of procedure were found to be independent predictors of non-home discharge following surgery for urologic malignancies. Patients with these risk factors should be counseled preoperatively on the likelihood of requiring a non-home discharge to help manage expectations and create a standardized transition of care pathway following surgery., Competing Interests: Declaration of Competing Interest I, nor any of the authors of this paper have any competing interest or anything to disclose., (Copyright © 2023 Elsevier Inc. All rights reserved.)

BACKGROUND: Patients with Bacillus Calmette–Guérin (BCG)–unresponsive non–muscle-invasive bladder cancer (NMIBC) have limited treatment options. The immune cell–activating interleukin-15 (IL-15) superagonist Nogapendekin alfa inbakicept (NAI), also known as N-803, may act synergistically with BCG to elicit durable complete responses (CRs) in this patient population. METHODS: In this open-label, multicenter study, patients with BCG-unresponsive bladder carcinoma in situ (CIS) with or without Ta/T1 papillary disease were treated with intravesical NAI plus BCG (cohort A) or NAI alone (cohort C). Patients with BCG-unresponsive high-grade Ta/T1 papillary NMIBC also received NAI plus BCG (cohort B). The primary end point was the incidence of CR at the 3- or 6-month assessment visit for cohorts A and C, and the disease-free survival (DFS) rate at 12 months for cohort B. Durability, cystectomy avoidance, progression-free survival, disease-specific survival (DSS), and overall survival were secondary end points for cohort A. RESULTS: In cohort A, CR was achieved in 58 (71%) of 82 patients (95% confidence interval [CI]=59.6 to 80.3; median follow-up, 23.9 months), with a median duration of 26.6 months (95% CI=9.9 months to [upper bound not reached]). At 24 months in patients with CR, the Kaplan–Meier estimated probability of avoiding cystectomy and of DSS was 89.2% and 100%, respectively. In cohort B (n=72), the Kaplan–Meier estimated DFS rate was 55.4% (95% CI=42.0% to 66.8%) at 12 months, with median DFS of 19.3 months (95% CI=7.4 months to [upper bound not reached]). Most treatment-emergent adverse events for patients receiving BCG plus NAI were grade 1 to 2 (86%); three grade 3 immune-related treatment-emergent adverse events occurred. CONCLUSIONS: In patients with BCG-unresponsive bladder carcinoma in situ and papillary NMIBC treated with BCG and the novel agent NAI, CRs were achieved with a persistence of effect, cystectomy avoidance, and 100% bladder cancer–specific survival at 24 months. The study is ongoing, with an estimated target enrollment of 200 participants (Funded by ImmunityBio.)

Lipid droplet formation is a defining histological feature in clear-cell renal cell carcinoma (ccRCC) but the underlying mechanisms and importance of this biological behaviour have remained enigmatic. De novo fatty acid (FA) synthesis, uptake and suppression of FA oxidation have all been shown to contribute to lipid storage, which is a necessary tumour adaptation rather than a bystander effect. Clinical studies and mechanistic investigations into the roles of different enzymes in FA metabolism pathways have revealed new metabolic vulnerabilities that hold promise for clinical effect. Several metabolic alterations are associated with worse clinical outcomes in patients with ccRCC, as lipogenic genes drive tumorigenesis. Enzymes involved in the intrinsic FA metabolism pathway include FA synthase, acetyl-CoA carboxylase, ATP citrate lyase, stearoyl-CoA desaturase 1, cluster of differentiation 36, carnitine palmitoyltransferase 1A and the perilipin family, and each might be potential therapeutic targets in ccRCC owing to the link between lipid deposition and ccRCC risk. Adipokines and lipid species are potential biomarkers for diagnosis and treatment monitoring in patients with ccRCC. FA metabolism could potentially be targeted for therapeutic intervention in ccRCC as small-molecule inhibitors targeting the pathway have shown promising results in preclinical models., (© 2022. Springer Nature Limited.)

Nephrogenic adenoma is a benign epithelial lesion of the genitourinary tract that arises from the reimplantation and proliferation of shed renal tubular cells in areas of urothelial injury and denudation. Fibromyxoid nephrogenic adenoma is a rare variant that consists of compressed spindle-shaped renal epithelial cells in a fibromyxoid background. Only 14 observations of this variant are reported in the literature. We performed a retrospective analysis of fibromyxoid nephrogenic adenomas from 3 large reference centers. We identified 43 lesions in 6 women and 36 men (2 in 1 man) with a median age of 72 years (range, 31 to 94 y). Median lesion size was 0.7 cm (range, 0.2 to 5 cm). Nephrogenic adenomas were in the bladder (n=15), prostate/prostatic urethra (n=14), kidney (n=7), ureter (n=3), penile urethra (n=3), and urethral diverticulum (n=1). One of the kidney lesions developed in an end-stage kidney and radiologically mimicked cancer. Of 37 patients with information, 36 had predisposing conditions including prior biopsy, transurethral resection of bladder tumor, resection, Foley catheter, BCG treatment, urinary stones, (chemo)radiation, or diverticulum. Only 4/37 (10.8%) had a history of prior irradiation. Fifteen lesions had pure fibromyxoid morphology and 28 were admixed classic and fibromyxoid patterns. Three nephrogenic adenomas involved prostatic stroma, 3 renal sinus fat, 2 muscularis propria (1 bladder, 1 renal pelvis), 1 perinephric fat, and 1 corpus spongiosum. Ten fibromyxoid nephrogenic adenomas were intermixed with urothelial carcinoma, 1 with prostate adenocarcinoma, and 1 with malignant melanoma. By immunohistochemistry, PAX8 was positive in all the examined lesions (n=31). Napsin A was negative in all examined fibromyxoid nephrogenic adenomas (n=30). Twenty of them had classic nephrogenic adenoma component which was positive for napsin A. Similar to classic nephrogenic adenoma, fibromyxoid nephrogenic adenoma can occur anywhere along the urinary tract and is associated with a prior history that causes urothelial injury. In nearly a quarter of the cases, fibromyxoid nephrogenic adenoma extended beyond the lamina propria. Unlike previously suggested, fibromyxoid nephrogenic adenoma is not specifically related to prior radiation therapy. Awareness of this variant is important to avoid misdiagnosis and overtreatment., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Perioperative intravesical chemotherapy (IVC) at or around the time of radical nephroureterectomy (RNU) reduces the risk of intravesical recurrence. Guidelines since 2013 have recommended its use. The objective of this study is to examine IVC utilization and determine predictors of its administration within a large international consortium., Methods and Materials: Data was collected from 17 academic centers on patients who underwent robotic/laparoscopic RNU between 2006 and 2020. Patients who underwent concomitant radical cystectomy and cases in which IVC administration details were unknown were excluded. Univariate and multivariate analyses were utilized to determine predictors of IVC administration. A Joinpoint regression was performed to evaluate utilization by year., Results: Six hundred and fifty-nine patients were included. A total of 512 (78%) did not receive IVC while 147 (22%) did. Non-IVC patients were older (P < 0.001), had higher ECOG scores (P = 0.003), and had more multifocal disease (23% vs. 12%, P = 0.005). Those in the IVC group were more likely to have higher clinical T stage disease (P = 0.008), undergone laparoscopic RNU (83% vs. 68%, P < 0.001), undergone endoscopic management of the bladder cuff (20% vs. 4%, P = 0.008). Multivariable regression showed that decreased age (OR 0.940, P < 0.001), laparoscopic approach (OR 2.403, P = 0.008), and endoscopic management of the bladder cuff (OR 7.619, P < 0.001) were significant predictors favoring IVC administration. Treatment at a European center was associated with lower IVC use (OR 0.278, P = 0.018). Overall utilization of IVC after the 2013 European Association of Urology (EAU) guideline was 24% vs. 0% prior to 2013 (P < 0.001). Limitations include limited data regarding IVC timing/agent and inclusion of minimally invasive RNU patients only., Conclusions: While IVC use has increased since being added to the EAU UTUC guidelines, its use remains low at academic centers, particularly within Europe., Competing Interests: Conflict of interest The authors have no conflict of interest., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Context.—: Multifocal prostate cancer at radical prostatectomy (RP) may be graded with assessment of each individual tumor nodule (TN) or global grading of all TNs in aggregate., Objective.—: To assess case-level grade variability between these 2 grading approaches., Design.—: We reviewed 776 RPs with multifocal prostate cancer with 2 or more separate TNs of different Grade Groups (GGs). Two separate grades were assigned to each RP: one based on the TN with the highest grade and a global grade based on the Gleason pattern volumes for all TNs. We then compared the results of these 2 methods., Results.—: The case-level grade changed by 1 or more GGs between the 2 grading methods in 35% (132 of 374) of GG3 through GG5 cases. Twelve percent (37 of 309) of GG2 cases with Gleason pattern 4 of more than 5% based on individual TN grading decreased their Gleason pattern 4 to less than 5% based on the global approach. Minor tertiary pattern 5 (Gleason pattern 5 <5%) was observed in 6.8% (11 of 161) of GG4 (Gleason score 3 + 5 = 8 and 5 + 3 = 8) and GG5 cases with global grading. The risk of grade discrepancy between the 2 methods was associated with the highest-grade TN volume (inverse relationship), patient age, and number of TNs (P < .001, P = .003, and P < .001, respectively)., Conclusions.—: The global grading approach resulted in a lower grade in 35% of GG3 through GG5 cases compared with grading based on the highest-grade TN. Two significant risk factors for this discrepancy with a global grading approach occur when the highest-grade TN has a relatively small tumor volume and with a higher number of TNs per RP. The observed grade variability between the 2 grading schemes most likely limits the interchangeability of post-RP multi-institutional databases if those institutions use different grading approaches.

Purpose: We sought to evaluate outcomes of lymph node dissection (LND) in patients with upper tract urothelial carcinoma., Materials and Methods: We performed a multicenter retrospective analysis utilizing the ROBUUST (for RObotic surgery for Upper Tract Urothelial Cancer Study) registry for patients who did not undergo LND (pNx), LND with negative lymph nodes (pN0) and LND with positive nodes (pN+). Primary and secondary outcomes were overall survival (OS) and recurrence-free survival (RFS). Multivariable analyses evaluated predictors of outcomes and pathological node positivity. Kaplan-Meier analyses (KMAs) compared survival outcomes., Results: A total of 877 patients were analyzed (LND performed in 358 [40.8%]/pN+ in 73 [8.3%]). Median nodes obtained were 10.2 for pN+ and 9.8 for pN0. Multivariable analyses noted increasing age (OR 1.1, p <0.001), pN+ (OR 3.1, p <0.001) and pathological stage pTis/3/4 (OR 3.4, p <0.001) as predictors for all-cause mortality. Clinical high-grade tumors (OR 11.74, p=0.015) and increasing tumor size (OR 1.14, p=0.001) were predictive for lymph node positivity. KMAs for pNx, pN0 and pN+ demonstrated 2-year OS of 80%, 86% and 42% (p <0.001) and 2-year RFS of 53%, 61% and 35% (p <0.001), respectively. KMAs comparing pNx, pN0 ≥10 nodes and pN0 <10 nodes showed no significant difference in 2-year OS (82% vs 85% vs 84%, p=0.6) but elicited significantly higher 2-year RFS in the pN0 ≥10 group (60% vs 74% vs 54%, p=0.043)., Conclusions: LND during nephroureterectomy in patients with positive lymph nodes provides prognostic data, but is not associated with improved OS. LND yields ≥10 in patients with clinical node negative disease were associated with improved RFS. In high-grade and large tumors, lymphadenectomy should be considered.

Context.—: Prostatic ductal adenocarcinoma (PDA) has historically been considered to be an aggressive subtype of prostate cancer., Objective.—: To investigate if PDA is independently associated with worse biochemical recurrence (BCR)-free survival after radical prostatectomy., Design.—: A review of 1584 radical prostatectomies was performed to grade, stage, and assess margin status in each tumor nodule. Radical prostatectomies with localized PDA (ie, those lacking metastasis) in the tumor nodule with the highest grade and stage and worst margin status were matched with prostatic acinar adenocarcinoma according to grade, stage, and margin status. The effect of PDA on BCR was assessed by multivariable Cox regression and Kaplan-Meier analyses., Results.—: Prostatic ductal adenocarcinoma was present in 171 cases. We excluded 24 cases because of lymph node metastasis (n = 13), PDA not in the highest-grade tumor nodule (n = 9), and positive surgical margin in a lower-grade tumor nodule (n = 2). The remaining 147 cases included 26 Grade Group (GG) 2, 44 GG3, 6 GG4, and 71 GG5 cancers. Seventy-six cases had extraprostatic extension, 33 had seminal vesicle invasion, and 65 had positive margins. Follow-up was available for 113 PDA and 109 prostatic acinar adenocarcinoma cases. Prostate-specific antigen density (odds ratio, 3.7; P = .001), cancer grade (odds ratio, 3.3-4.3; P = .02), positive surgical margin (odds ratio, 1.7; P = .02), and tumor volume (odds ratio, 1.3; P = .02) were associated with BCR in multivariable analysis. Prostatic ductal adenocarcinoma, its percentage, intraductal carcinoma, and cribriform Gleason pattern 4 were not significant independent predictors of BCR., Conclusions.—: Advanced locoregional stage, higher tumor grade, and positive surgical margin status rather than the mere presence of PDA are more predictive of worse BCR-free survival outcomes following radical prostatectomy in men with a component of PDA.

Purpose: Radical prostatectomy (RP) outcomes in Hispanic men with prostate cancer are not well-described. Prior studies showed varying results regarding the rate of upgrading and upstaging, and these studies included limited pathologic data and lack of central pathology review. We characterized the rate of upgrading, adverse pathology, and oncologic outcomes in Hispanics after prostatectomy using a large institutional database., Methods: We included Hispanic white (HW), non-Hispanic white (NHW), and black men who underwent (RP) between 2010 and 2021 at a single institution. We recorded differences in grade group between biopsy and prostatectomy and performed multivariable analyses for odds of upgrading and adverse pathologic findings. The primary outcome was rate of upgrading in HWs. Using a sub-cohort with follow-up data, we assessed race/ethnicity and upgrading as a predictor of biochemical recurrence (BCR)-free survival., Results: Our cohort included 1877 men: 36.7% were NHW, 40.6% were HW, and 22.7% were black. Rates of upgrading were not different between NHW, NHW, and black men at 34.0, 33.8, and 37.3%, respectively (p = 0.4). In the multivariable analysis for upgrading, significant predictors for upgrading were older age (p = 0.002), higher PSA (p < 0.001), and lower prostate weight (p = 0.02), but race/ethnicity did not predict upgrading. In patients with available follow-up (1083, 58%), upgrading predicted worse BCR-free survival (HR 2.17, CI 1.46-3.22, p < 0.0001) but race/ethnicity did not., Conclusions: HW men undergoing RP had similar rates of upgrading and adverse pathologic outcomes as NHW men. Race/ethnicity does not independently predict upgrading or worse oncologic outcomes after RP., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Context.—: Effect of tumor nodule (TN) location in the prostate on adverse radical prostatectomy (RP) outcomes is not well studied in contemporary cohorts., Objective.—: To investigate the significance of TN location with respect to extraprostatic extension (EPE), seminal vesicle invasion (SVI), and positive surgical margin (SM+) in 1388 RPs., Design.—: Each TN at RP was independently graded, staged, and volumetrically assessed. TNs with at least 80% of their volume occupying either the anterior or posterior part of the prostate were categorized accordingly and included in our study, while all other TNs were excluded., Results.—: A total of 3570 separate TNs (median = 3 per RP; range = 1-7 per RP) were scored. There were 1320 of 3570 (37%) anterior TNs and 2250 of 3570 (63%) posterior TNs. Posterior TNs were more likely to be higher grade, and exhibit EPE (18% versus 9.4%) and SVI (4% versus 0.15%), all P < .001. Anterior TNs with EPE were more likely to exhibit SM+ than posterior TNs with EPE (62% versus 30.8%, P < .001). TN location, grade, and volume were significant factors associated with adverse RP outcomes in our univariable analysis. When we controlled for grade and tumor volume in a multivariable analysis using anterior TN location as a reference, posterior TN location was an independent predictor of EPE and SVI and was less likely to be associated with SM+ (odds ratio = 3.1, 81.5, and 0.7, respectively)., Conclusions.—: These associations may be useful in preoperative surgical planning, particularly with respect to improving radiographic analysis of prostate cancer.

Objective: To investigate if localized amyloidosis of the seminal tract (LAST) is associated with subsequent development of systemic amyloidosis. Prior reports recorded no systemic amyloidosis at the time of LAST diagnosis. However, no follow-up studies exist to confirm that LAST is not a risk factor for subsequent development of systemic amyloidosis., Methods: Our study cohort included patients whose prostate biopsy (PB) or radical prostatectomy (RP) specimen demonstrated LAST between 2014-2021. Clinical variables including age, race/ethnicity, prostate specific antigen (PSA), and prostate weight were analyzed. Patients were assessed for clinical and laboratory evidence of systemic amyloidosis and lymphoproliferative conditions during the follow-up period., Results: Thirty-six men (26 RPs, 9 PBs, and 1 cystoprostatectomy) had LAST. Our study cohort included 18 white Hispanic, 9 white non-Hispanic, 7 black, and 1 Asian men. Median age was 67 years, mean PSA was 9.8 ng/mL. Over a median follow-up period of 20 months (mean, 30) in 27 men, none developed systemic amyloidosis. Frequency of LAST in RP specimens was 1.2% (26/2,135) and corelated with age (67 vs 63 years, P-value = .004). Race/ethnicity, PSA, and prostate weight were not associated with the incidence of LAST., Conclusions: LAST is not a harbinger of systemic disease. The incidence of LAST in a contemporary RP cohort is significantly lower than in previously published studies. While patient age positively corelates with LAST, PSA and prostate weight are not associated with the condition. There is no difference in the frequency of LAST between white Hispanic, white non-Hispanic, and black men., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose: To compare the outcomes of robotic radical nephroureterectomy (RRNU) and laparoscopic radical nephroureterectomy (LRNU) within a large multi-institutional worldwide dataset. Materials and Methods: The ROBotic surgery for Upper tract Urothelial cancer STudy (ROBUUST) includes data from 17 centers worldwide regarding 877 RRNU and LRNU performed between 2015 and 2019. Baseline features, perioperative and oncologic outcomes, were included. A 2:1 nearest-neighbor propensity-score matching with a 0.001 caliper was performed. A univariable and a multivariable logistic regression model were built to evaluate the predictors of a composite "tetrafecta" outcome defined as occurrence of bladder cuff excision+LND+no complications+negative surgical margins. Results: After matching, 185 RRNU and 91 LRNU were assessed. Patients in the RRNU group were more likely to undergo bladder cuff excision (81.9% vs 63.7%; p  < 0.001) compared to the LRNU group. A statistically significant difference was found in terms of overall postoperative complications ( p  = 0.003) and length of stay ( p  < 0.001) in favor of RRNU. Multivariable analysis demonstrated that LRNU was an independent predictor negatively associated with achievement of "tetrafecta" (odds ratio: 0.09; p  = 0.003). Conclusions: In general, RRNU and LRNU offer comparable outcomes. While the rate of overall complications is higher for LRNU in this study population, this is mostly related to low-grade complications, and therefore with more limited clinical relevance. RRNU seems to offer shorter hospital stay, but this might also be related to the different geographical location of participating centers. Overall, the implementation of robotics might facilitate achievement of a "tetrafecta" outcome as defined in the present study.

Importance: No data exist on time to recovery of patient-reported and performance-related measures of functional independence after radical cystectomy (open or robotic)., Objective: To determine recovery of functional independence after radical cystectomy and whether robot-assisted radical cystectomy (RARC) is associated with any advantage over open procedures., Design, Setting, and Participants: Data for this secondary analysis from the RAZOR (Randomized Open vs Robotic Cystectomy) trial were used. RAZOR was a phase 3 multicenter noninferiority trial across 15 academic medical centers in the US from July 1, 2011, to November 18, 2014, with a median follow-up of 2 years. Participants included the per-protocol population (n = 302). Data were analyzed from February 1, 2017, to May 1, 2021., Interventions: Robot-assisted radical cystectomy or open radical cystectomy (ORC)., Main Outcomes and Measures: Patient-reported (activities of daily living [ADL] and independent ADL [iADL]) and performance-related (hand grip strength [HGS] and Timed Up & Go walking test [TUGWT]) measures of independence were assessed. Patterns of postoperative recovery for the entire cohort and comparisons between RARC and ORC were performed. Exploratory analyses to assess measures of independence across diversion type and to determine whether baseline impairments were associated with 90-day complications or 1-year mortality were performed., Findings: Of the 302 patients included in the analysis (254 men [84.1%]; mean [SD] age at consent, 68.0 [9.7] years), 150 underwent RARC and 152 underwent ORC. Baseline characteristics were similar in both groups. For the entire cohort, ADL, iADL, and TUGWT recovered to baseline by 3 postoperative months, whereas HGS recovered by 6 months. There was no difference between RARC and ORC for ADL, iADL, TUGWT, or HGS scores at any time. Activities of daily living recovered 1 month after RARC (mean estimated score, 7.7 [95% CI, 7.3-8.0]) vs 3 months after ORC (mean estimated score, 7.5 [95% CI, 7.2-7.8]). Hand grip strength recovered by 3 months after RARC (mean estimated HGS, 29.0 [95% CI, 26.3-31.7] kg) vs 6 months after ORC (mean estimated HGS, 31.2 [95% CI, 28.8-34.2] kg). In the RARC group, 32 of 90 patients (35.6%) showed a recovery in HGS at 3 months vs 32 of 88 (36.4%) in the ORC group (P = .91), indicating a rejection of the primary study hypothesis for HGS. Independent ADL and TUGWT recovered in 3 months for both approaches. Hand grip strength showed earlier recovery in patients undergoing continent urinary diversion (mean HGS at 3 months, 31.3 [95% CI, 27.7-34.8] vs 33.9 [95% CI, 30.5-37.3] at baseline; P = .09) than noncontinent urinary diversion (mean HGS at 6 months, 27.4 [95% CI, 24.9-30.0] vs 29.5 [95% CI, 27.2-31.9] kg at baseline; P = .02), with no differences in other parameters. Baseline impairments in any parameter were not associated with 90-day complications or 1-year mortality., Conclusions and Relevance: The results of this secondary analysis suggest that patients require 3 to 6 months to recover baseline levels after radical cystectomy irrespective of surgical approach. These data will be invaluable in patient counseling and preparation. Hand grip strength and ADL tended to recover to baseline earlier after RARC; however, there was no difference in the percentage of patients recovering when compared with ORC. Further study is needed to assess the clinical significance of these findings., Trial Registration: ClinicalTrials.gov Identifier: NCT01157676.

Background: Postoperative renal function impairment represents a main limitation for delivering adjuvant chemotherapy after radical nephroureterectomy (RNU)., Objective: To create a model predicting renal function decline after minimally invasive RNU., Design, Setting, and Participants: A total of 490 patients with nonmetastatic UTUC who underwent minimally invasive RNU were identified from a collaborative database including 17 institutions worldwide (February 2006 to March 2020). Renal function insufficiency for cisplatin-based regimen was defined as estimated glomerular filtration rate (eGFR) <50 ml/min/1.73 m 2 at 3 mo after RNU. Patients with baseline eGFR >50 ml/min/1.73 m 2 (n = 361) were geographically divided into a training set (n = 226) and an independent external validation set (n = 135) for further analysis., Outcome Measurements and Statistical Analysis: Using transparent reporting of a multivariable prediction model for individual prognosis or diagnosis (TRIPOD) guidelines, a nomogram to predict postoperative eGFR <50 ml/min/1.73 m 2 was built based on the coefficients of the least absolute shrinkage and selection operation (LASSO) logistic regression. The discrimination, calibration, and clinical use of the nomogram were investigated., Results and Limitations: The model that incorporated age, body mass index, preoperative eGFR, and hydroureteronephrosis was developed with an area under the curve of 0.771, which was confirmed to be 0.773 in the external validation set. The calibration curve demonstrated good agreement. Besides, the model was converted into a risk score with a cutoff value of 0.583, and the difference between the low- and high-risk groups both in overall death risk (hazard ratio [HR]: 4.59, p < 0.001) and cancer-specific death risk (HR: 5.19, p < 0.001) was statistically significant. The limitation mainly lies in its retrospective design., Conclusions: A nomogram incorporating immediately available clinical variables can accurately predict renal insufficiency for cisplatin-based adjuvant chemotherapy after minimally invasive RNU and may serve as a tool facilitating patient selection., Patient Summary: We have developed a model for the prediction of renal function loss after radical nephroureterectomy to facilitate patient selection for perioperative chemotherapy., (Copyright © 2021 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Objective: To determine the potential association between plant-based dietary content and PSA levels among men enrolled in the National Health and Nutrition Examination Survey (NHANES)., Methods: Data on demographics, diet, and PSA levels was acquired from the NHANES database. Plant-based diet index (PDI) and healthful plant-based diet index (hPDI) were calculated using food frequency questionnaires. A higher score on PDI and hPDI indicates higher consumption of plant foods or healthy plant foods, respectively. Multivariable-adjusted logistic regression analysis was performed to determine the association between elevated PSA, clinical variables, demographics, and plant-based diet indices., Results: A total of 1399 men were included in the final cohort. Median age of participants was 54 [46-63] years. Median PSA level was 0.9 [0.6-1.5] ng/dL, and 69 (4.9%) men had a PSA level ≥4 ng/dL. Although there was no association between elevated PSA and PDI, on multivariable analysis patients with higher consumption of healthy plant-based diet (high hPDI scores) had a decreased probability of having an elevated PSA (OR = 0.47, 95% CI: 0.24-0.95; P = .034)., Conclusion: There is a significant association between increased consumption of a healthy plant-based diet and lower PSA levels. This finding may be incorporated into the shared-decision making process with patients to promote healthier lifestyle choices to reduce the likelihood of prostate biopsy and potential treatment-related morbidity., (Copyright © 2021. Published by Elsevier Inc.)

Background: We compared survival outcomes among patients who received either NAC or AC and RC., Methods: We identified patients in the National Cancer Data Base (NCDB) diagnosed with clinical T2-T4, N0, M0 urothelial carcinoma who underwent RC. Patients who received NAC were propensity matched by age, race, ethnicity, sex, insurance type, academic/research program, comorbidity, and clinical stage to patients receiving AC within 90 days of RC. Median survival was calculated using Kaplan-Meier analysis. Adjusted hazard ratios (aHR) and 95% confidence intervals (95% CI) were calculated from multivariable Cox regression models to compare overall survival (OS), downstaging to non-MIBC (NMIBC), and N upstaging., Results: A total of 417 patients treated with NAC and 272 patients treated with AC were identified from 2004-2013. Patients who received NAC had better 5-year OS (46.2%, 95% CI: 39.2-53.0%) compared to patients who received AC (37.6%, 95% CI: 31.5-43.7%). NAC was a significant predictor of decreased mortality, decreased progression to node positivity, and downstaging to NMIBC (0.76, 0.60-0.96, P=0.023; 0.19, 0.13-0.28, P<0.001; 23.96, 8.91-64.42, P<0.001)., Conclusions: The use of NAC+RC was associated with improved OS compared to RC+AC for patients diagnosed with T2-T4, N0, M0 bladder cancer. The increased survival benefit associated with NAC compared to AC among patients undergoing RC may be due to decreased progression to node positivity and pathological downstaging.

Purpose: Intravesical recurrence (IVR) after radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC) has an incidence of approximately 20%-50%. Studies to date have been composed of mixed treatment cohorts-open, laparoscopic and robotic. The objective of this study is to assess clinicopathological risk factors for intravesical recurrence after RNU for UTUC in a completely minimally invasive cohort., Materials and Methods: We performed a multicenter, retrospective analysis of 485 patients with UTUC without prior or concurrent bladder cancer who underwent robotic or laparoscopic RNU. Patients were selected from an international cohort of 17 institutions across the United States, Europe and Asia. Univariate and multiple Cox regression models were used to identify risk factors for bladder recurrence., Results: A total of 485 (396 robotic, 89 laparoscopic) patients were included in analysis. Overall, 110 (22.7%) of patients developed IVR. The average time to recurrence was 15.2 months (SD 15.5 months). Hypertension was a significant risk factor on multiple regression (HR 1.99, CI 1.06; 3.71, p=0.030). Diagnostic ureteroscopic biopsy incurred a 50% higher chance of developing IVR (HR 1.49, CI 1.00; 2.20, p=0.048). Treatment specific risk factors included positive surgical margins (HR 3.36, CI 1.36; 8.33, p=0.009) and transurethral resection for bladder cuff management (HR 2.73, CI 1.10; 6.76, p=0.031)., Conclusions: IVR after minimally invasive RNU for UTUC is a relatively common event. Risk factors include a ureteroscopic biopsy, transurethral resection of the bladder cuff, and positive surgical margins. When possible, avoidance of transurethral resection of the bladder cuff and alternative strategies for obtaining biopsy tissue sample should be considered.

Background: Increasing percentages of Gleason pattern 4 (GP4%) in radical prostatectomy (RP) correlate with an increased likelihood of nonorgan-confined disease and earlier biochemical recurrence (BCR). However, there are no detailed RP studies assessing the impact of GP4% and corresponding tumor volume (TV) on extraprostatic extension (EPE), seminal vesicle (SV) invasion (SV+), and positive surgical margin (SM) status (SM+)., Methods: In 1301 consecutive RPs, we analyzed each tumor nodule (TN) for TV, Grade Group (GG), presence of focal versus nonfocal EPE, SV+ , and SM+. Using GG1 (GP4% = 0) TNs as a reference, we recorded GP4% for all GG2 or GG3 TNs. We performed a multivariable analysis (MVA) using a mixed effects logistic regression that tested significant variables for risk of EPE, SV+, and SM+, as well as a multinomial logistic regression model that tested significant variables for risks of nonorgan-confined disease (pT2+, pT3a, and pT3b) versus organ-confined disease (pT2)., Results: We identified 3231 discrete TNs ranging from 1 to 7 (median: 2.5) per RP. These included GG1 (n = 2115), GG2 (n = 818), GG3 (n = 274), and GG4 (n = 24) TNs. Increasing GP4% weakly paralleled increasing TV (tau = 0.07, p < .001). In MVA, increasing GP4% and TV predicted a greater likelihood of EPE (odds ratio [OR]: 1.03 and 4.41), SV+ (OR: 1.03 and 3.83), and SM+ (1.01, p = .01 and 2.83), all p < .001. Our multinomial logistic regression model demonstrated an association between GP4% and the risk of EPE (i.e., pT3a and pT3b disease), as well as an association between TV and risk of upstaging (all p < .001)., Conclusions: Both GP4% and TV are independent predictors of adverse pathological stage and margin status at RP. However, the risks for adverse outcomes associated with GP4% are marginal, while those for TV are strong. The prognostic significance of GP4% on BCR-free survival has not been studied controlling for TV and other adverse RP findings. Whether adverse pathological stage and margin status associated with larger TV could decrease BCR-free survival to a greater extent than increasing RP GP4% remains to be studied., (© 2021 Wiley Periodicals LLC.)

Robotic radical cystectomy with urinary diversion has become increasingly utilized for the surgical management of bladder cancer. Orthotopic neobladder reconstruction is still performed worldwide primarily via an extracorporeal approach because of the difficulty associated with robotic intracorporeal reconstruction. The objective of this article is to demonstrate a stepwise approach for robotic intracorporeal neobladder in a standardized manner that adheres to the principles of open surgery.

Clear cell renal cell carcinoma (ccRCC) is characterized by accumulation of neutral lipids and adipogenic transdifferentiation. We assessed adipokine expression in ccRCC and found that tumor tissues and patient plasma exhibit obesity-dependent elevations of the adipokine chemerin. Attenuation of chemerin by several approaches led to significant reduction in lipid deposition and impairment of tumor cell growth in vitro and in vivo . A multi-omics approach revealed that chemerin suppresses fatty acid oxidation, preventing ferroptosis, and maintains fatty acid levels that activate hypoxia-inducible factor 2α expression. The lipid coenzyme Q and mitochondrial complex IV, whose biogeneses are lipid-dependent, were found to be decreased after chemerin inhibition, contributing to lipid reactive oxygen species production. Monoclonal antibody targeting chemerin led to reduced lipid storage and diminished tumor growth, demonstrating translational potential of chemerin inhibition. Collectively, the results suggest that obesity and tumor cells contribute to ccRCC through the expression of chemerin, which is indispensable in ccRCC biology. SIGNIFICANCE: Identification of a hypoxia-inducible factor-dependent adipokine that prevents fatty acid oxidation and causes escape from ferroptosis highlights a critical metabolic dependency unique in the clear cell subtype of kidney cancer. Targeting lipid metabolism via inhibition of a soluble factor is a promising pharmacologic approach to expand therapeutic strategies for patients with ccRCC. See related commentary by Reznik et al., p. 1879 . This article is highlighted in the In This Issue feature, p. 1861 ., (©2021 American Association for Cancer Research.)

Purpose: We sought to determine the optimal cystoscopic interval for intermediate risk, nonmuscle invasive bladder cancer., Materials and Methods: A retrospective analysis of patients with intermediate risk, nonmuscle invasive bladder cancer (2010-2017) was performed and 3 hypothetical models of surveillance intensity were applied: model 1: high (3 months), model 2: moderate (6 months) and model 3: low intensity (12 months) over a 2-year period. We compared timing of actual detection of recurrence and progression to proposed cystoscopy timing between each model. We calculated number of avoidable cystoscopies and associated costs., Results: Of 107 patients with median followup of 37 months, 66/107 (77.6%) developed recurrence and 12/107(14.1%) had progression. Relative to model 1, there were 33 (50%) delayed detection of recurrences in model 2 and 41 (62%) in model 3. There was a 1.7-month mean delay in detection of recurrence for model 1 vs 3.2, and a 7.6-month delay for models 2 and 3 (p <0.001 model 1 vs 2; p <0.001 model 2 vs 3). Relative to model 1, there were 8 (67%) and 9 (75%) delayed detection of progression events in model 2 and 3. There were no progression-related bladder cancer deaths or radical cystectomies due to delayed detection. Mean number of avoidable cystoscopies was higher in model 1 (2) vs model 2 (1) and 3 (0). Model 1 had the highest aggregate cost of surveillance ($46,262.52)., Conclusions: High intensity (3-month) surveillance intervals provide faster detection of recurrences but with increased cost and more avoidable cystoscopies without clear oncologic benefit. Moderate intensity (6-month) intervals in intermediate risk, nonmuscle invasive bladder cancer allows timely detection without oncologic compromise and is less costly with fewer cystoscopies.

Purpose: Genomic prognostic signatures are used on prostate biopsy tissue for cancer risk assessment, but tumor heterogeneity and multifocality may be an issue. We evaluated the variability in genomic risk assessment from different biopsy cores within the prostate using 3 prognostic signatures (Decipher, CCP, GPS)., Materials and Methods: Men in this study came from 2 prospective prostate cancer trials of patients undergoing multiparametric magnetic resonance imaging and magnetic resonance imaging targeted biopsy with genomic profiling of positive biopsy cores. We explored the relationship among tumor grade, magnetic resonance imaging risk and genomic risk for each signature. We evaluated the variability in genomic risk assessment between different biopsy cores and assessed how often magnetic resonance imaging targeted biopsy or the current standard of care (profiling the core with the highest grade) resulted in the highest genomic risk level., Results: In all, 224 positive biopsy cores from 78 men with prostate cancer were profiled. For each signature, higher biopsy grade (p <0.001) and magnetic resonance imaging risk level (p <0.001) were associated with higher genomic scores. Genomic scores from different biopsy cores varied with risk categories changing by 21% to 62% depending on which core or signature was used. Magnetic resonance imaging targeted biopsy and profiling the core with the highest grade resulted in the highest genomic risk level in 72% to 84% and 75% to 87% of cases, respectively, depending on the signature used., Conclusions: There is variation in genomic risk assessment from different biopsy cores regardless of the signature used. Magnetic resonance imaging directed biopsy or profiling the highest grade core resulted in the highest genomic risk level in most cases.