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Purpose of Review: Tumor-informed circulating tumor DNA (ctDNA) is an emerging biomarker in urothelial carcinoma. Recent clinical trials have investigated the integration of ctDNA into clinical decision-making in patients with muscle-invasive bladder cancer, their findings suggest that ctDNA may potentially revolutionize the way we stratify patients to different treatment modalities., Recent Findings: ctDNA informed from TURBT specimens was found to be prognostic of disease outcomes among patients with localized nonmetastatic bladder cancer. Detectable precystectomy ctDNA status was associated with worse survival outcomes. Additionally, ctDNA status was predictive of adverse disease on radical cystectomy, including the likelihood of disease upstaging, lymph node involvement, and having a locally advanced disease (≥pT3a). In the postcystectomy minimal residual disease (MRD) period, ctDNA status may refine patient selection to adjuvant therapy, and if validated by ongoing clinical trials, patients with undetectable postcystectomy ctDNA status may forgo adjuvant treatment, regardless of pathological stage. On the contrary, patients with pre or postcystectomy detectable ctDNA status may benefit from treatment intensification., Summary: The integration of ctDNA in clinical decision-making has the potential to revolutionize the way we manage urothelial carcinoma by refining patient selection to different treatment modalities. This approach could ultimately lead to personalization of oncological care, with the potential to reduce both treatment-related and financial toxicity., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To assess recurrence-free survival (RFS) in patients with undetectable tumour-informed circulating tumour DNA (ctDNA) before radical cystectomy (RC) and evaluate if those who converted from detectable to undetectable ctDNA status after RC have similar RFS outcomes as those with persistently undetectable ctDNA status., Patients and Methods: Patients who underwent RC had prospectively and longitudinally collected tumour-informed ctDNA analyses during 2021-2023. ctDNA status was informed from the pre-RC specimen. The minimal residual disease (MRD) window was defined as the initial 90 days after RC. RFS was evaluated using the Kaplan-Meier method. Cox regression analysis was performed to find predictors of disease recurrence., Results: The cohort included 135 patients with 647 ctDNA analyses. The median (interquartile range [IQR]) age was 71 (63-77) years. Over a median (IQR) follow-up of 11 (7-18) months, 41 patients (30%) had a recurrence. Pre-RC undetectable ctDNA status was found in 54 patients (40%). The RFS rates at 6, 12, and 21 months were 98%, 93%, and 82%, respectively. Of 77 patients with undetectable ctDNA status at the MRD window available for conversion dynamics analysis, 43 had persistently undetectable ctDNA status (both at pre-RC and MRD window) and 31 converted from pre-RC detectable to MRD undetectable status (conversion group). The persistently undetectable group had significantly better RFS than the conversion group (log-rank, P < 0.001), with 12-month RFS rates of 97% vs 51%, and 18-month RFS rates of 88% vs 51%, respectively. On Cox multivariate analysis, only the conversion group status predicted disease recurrence., Conclusions: Patients with undetectable pre-RC ctDNA status have a favourable prognosis and may be candidates for treatment de-escalation. Those with persistently undetectable ctDNA had superior RFS compared to the conversion group. Pre-RC ctDNA status should be incorporated into trials examining ctDNA use in clinical decision-making., (© 2024 BJU International.)

Background and Objective: Decision-making on the use of neoadjuvant and adjuvant treatment for patients with bladder cancer undergoing radical cystectomy (RC) currently depends on assessment of clinical and pathological features, which lack sensitivity. Circulating tumor DNA (ctDNA) has emerged as a possible novel prognostic biomarker in the field. Our aim was to assess whether ctDNA status before RC is predictive of pathological and oncological outcomes. We also evaluated the dynamic changes in ctDNA status after RC in relation to recurrence-free survival (RFS)., Methods: We analyzed data for patients who underwent RC during 2021-2023 for whom prospective tumor-informed ctDNA analyses were conducted before and after RC. RFS was evaluated using the Kaplan-Meier method. Predictors for disease recurrence were assessed using Cox proportional-hazards models. Pathological outcomes associated with detectable ctDNA before RC were assessed in univariable and multivariable regression analyses., Key Findings and Limitations: We included 112 patients in the analysis. Median follow-up was 8 mo (interquartile range 4-13). ctDNA was detected before RC in 59 patients (53%) and was associated with poor RFS (log-rank p < 0.0001). Detectable ctDNA before RC was associated with poor outcomes regardless of clinical stage (

Background: Although previous literature shows tumor location as a prognostic factor in upper tract urothelial carcinoma (UTUC), there remains uninvestigated regarding the impact of tumor location on grade concordance and discrepancies between ureteroscopic (URS) biopsy and final radical nephroureterectomy (RNU) pathology. Methods: In this international study, we retrospectively reviewed the records of 1,498 patients with UTUC who underwent diagnostic URS with concomitant biopsy followed by RNU between 2005 and 2020. Tumor location was divided into four sections: the calyceal-pelvic system, proximal ureter, middle ureter, and distal ureter. Patients with multifocal tumors were excluded from the study. We performed multiple comparison tests and logistic regression analyses. Results: Overall, 1,154 patients were included; 54.4% of those with low-grade URS biopsies were upgraded on RNU. In the multiple comparison tests, middle ureter tumors exhibited the highest probability of upgrading, meanwhile pelvicalyceal tumors exhibited the lowest probability of upgrading (73.7% vs 48.5%, p = 0.007). Downgrading was comparable across all tumor locations. On multivariate analyses, middle ureteral location was significantly associated with a low probability of grade concordance (odds ratio [OR] 0.59; 95% confidence interval [CI], 0.35-1.00; p = 0.049) and an increased risk of upgrading (OR 2.80; 95% CI, 1.20-6.52; p = 0.017). The discordance did not vary regardless of caliceal location, including the lower calyx. Conclusions: Middle ureteral tumors diagnosed to be low grade had a high probability to be undergraded. Our data can inform providers and their patients regarding the likelihood of undergrading according to tumor location, facilitating patient counseling and shared decision making regarding the choice of kidney sparing vs RNU.

Background and Objective: Sequential intravesical gemcitabine/docetaxel (Gem/Doce) has emerged as a potential alternative to bacillus Calmette-Guérin (BCG) for the treatment of non-muscle-invasive bladder cancer (NMIBC). Our aim was to determine the comparative effectiveness of BCG and Gem/Doce for patients with intermediate-risk (IR) NMIBC, composed mainly of high-grade (HG) Ta disease., Methods: Patients with IR-NMIBC who received either BCG or Gem/Doce during 2013-2023 were included. Maintenance BCG (as per the Southwest Oncology Group protocol) and monthly Gem/Doce maintenance for 1 yr were offered to patients with no evidence of recurrence after induction. Routine surveillance with cystoscopy was performed according to the American Urological Association guidelines. The Kaplan-Meier method was used to assess high-grade and any-grade recurrence-free survival (RFS). Cox regression analysis was performed to find predictors of recurrence., Key Findings and Limitations: Of 483 patients, 127 had IR-NMIBC; 66 patients received BCG and 61 received Gem/Doce. Median age was 69 yr (interquartile range [IQR] 61-76) for the BCG group and 72 yr (IQR 62-76) for the Gem/Doce group. Median follow-up was 53.1 mo (IQR 25.3-71.2) for the BCG group and 20.2 mo (IQR 8.28-33.1) for the Gem/Doce group. The 2-yr high-grade RFS rates for primary high-grade tumors for BCG versus Gem/Doce groups were 81% versus 61%, with corresponding any-grade RFS rates of 60% versus 41%. Induction with Gem/Doce predicted any-grade recurrence (hazard ratio [HR] 1.87, 95% confidence interval [CI] 1.1-3.2) and high-grade recurrence for primary high-grade tumors (HR 3.4 95% CI 1.27-9.13), while receipt of maintenance therapy decreased the risk of any-grade recurrence (HR 0.4, 95% CI 0.22-0.72). This study is limited by its retrospective design., Conclusions and Clinical Implications: For patients with IR-NMIBC, BCG was associated with superior any-grade RFS and high-grade RFS for primary high-grade tumors. Maintenance therapy was associated with better RFS when receiving Gem/Doce. Standardization and longer maintenance therapy protocols should be considered for Gem/Doce treatment., Patient Summary: We compared outcomes for patients who received two different in-bladder treatments for intermediate-risk bladder cancer. Bacillus Calmette-Guérin (BCG) led to better outcomes than gemcitabine + docetaxel (Gem/Doce). Monthly maintenance therapy improved recurrence-free survival for patients who received Gem/Doce. We conclude that maintenance therapy is essential for patients receiving Gem/Doce to avoid bladder cancer recurrence after treatment., (Copyright © 2024 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

NK cells are innate lymphocytes critical for surveillance of viruses and tumors, however the mechanisms underlying NK cell dysfunction in cancer are incompletely understood. We assessed the effector function of NK cells from bladder cancer patients and found severe dysfunction in NK cells derived from tumors versus peripheral blood. While both peripheral and tumor-infiltrating NK cells exhibited conserved patterns of inhibitory receptor over-expression, this did not explain the observed defects in NK surveillance in bladder tumors. Rather, TME-specific TGF-β and metabolic perturbations such as hypoxia directly suppressed NK cell function. Specifically, an oxygen-dependent reduction in signaling through SLAMF6 was mechanistically responsible for poor NK cell function, as tumor-infiltrating NK cells cultured ex vivo under normoxic conditions exhibited complete restoration of function, while deletion of SLAMF6 abrogated NK cell cytolytic function even under normoxic conditions. Collectively, this work highlights the role of tissue-specific factors in dictating NK cell function, and implicates SLAMF6 signaling as a rational target for immuno-modulation to improve NK cell function in bladder cancer.

Background and Objective: Neoadjuvant therapy followed by radical cystectomy with lymphadenectomy remains the gold standard of treatment in patients with muscle-invasive bladder cancer. Pathologically positive lymph node (pN+) disease is known to convey a poor prognosis. Tumor-informed circulating tumor DNA (ctDNA) has emerged as a possible novel prognostic biomarker in the field. We seek to assess recurrence-free survival (RFS) for patients undergoing robotic-assisted radical cystectomy (RARC) with extended pelvic lymphadenectomy (ePLND) and to assess whether ctDNA status can be a prognostic marker for RFS outcomes in patients with pN+ disease., Methods: Patients who underwent RARC + ePLND during 2015 to 2023 were included. A sub-group analysis (n = 109) of patients who had prospectively collected serial-longitudinal tumor-informed ctDNA analyses during 2021-2023 was performed. Survival analysis and Cox-regression models were conducted., Results: Included were 458 patients with a median age of 69 (IQR 63-76), and a median follow-up time of 20 months (IQR 10-37). RFS for pN0 (n = 353) and pN+ (n = 105) at 12, 24 and 36 months were 87% vs. 54%, 80% vs. 39%, and 74% vs. 35%, respectively (log-rank, P < 0.0001). On Cox multivariate analysis ≥pT3 disease (Hazzard ratio [HR] = 3.36 [2.18-5.18], P < 0.001), pN+ disease (HR = 2.39 [1.55-3.7], P < 0.001), and recipients of neoadjuvant treatment (HR = 1.61 [1.11-2.34], P = 0.013) were predictive of disease relapse. Patients with pN+ disease and undetectable precystectomy or postcystectomy ctDNA status had similar RFS to patients with pN0 with undetectable ctDNA. On Cox-regression multivariate sub-group analysis, detectable precystectomy ctDNA status (HR = 3.89 [1.32-11.4], P = 0.014), detectable ctDNA status in the minimal residual disease window ([MRD], HR = 2.89 [1.12-7.47], P = 0.028), and having ≥pT3 with pN+ disease (HR = 4.2 [1.43-12.3], P = 0.009) were predictive of disease relapse., Conclusions: Patients with pN+ .after RARC had worse oncological outcomes than patients with pN0 disease. Undetectable ctDNA status was informative of RFS regardless of nodal status at both the precystectomy and the MRD window. Patients with undetectable ctDNA status and pN+ disease may benefit from treatment de-escalation., 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.)

New spatial molecular technologies are poised to transform our understanding and treatment of urological cancers. By mapping the spatial molecular architecture of tumours, these platforms uncover the complex heterogeneity within and around individual malignancies, offering novel insights into disease development, progression, diagnosis, and treatment. They enable tracking of clonal phylogenetics in situ and immune-cell interactions in the tumour microenvironment. A whole transcriptome/genome/proteome-level spatial analysis is hypothesis generating, particularly in the areas of risk stratification and precision medicine. Current challenges include reagent costs, harmonisation of protocols, and computational demands. Nonetheless, the evolving landscape of the technology and evolving machine learning applications have the potential to overcome these barriers, pushing towards a future of personalised cancer therapy, leveraging detailed spatial cellular and molecular data. PATIENT SUMMARY: Tumours are complex and contain many different components. Although we have been able to observe some of these differences visually under the microscope, until recently, we have not been able to observe the genetic changes that underpin cancer development. Scientists are now able to explore molecular/genetic differences using approaches such as "spatial transcriptomics" and "spatial proteomics", which allow them to see genetic and cellular variation across a region of normal and cancerous tissue without destroying the tissue architecture. Currently, these technologies are limited by high associated costs, and a need for powerful and complex computational analysis workflows. Future advancements and results through these new technologies may assist patients and their doctors as they make decisions about treating their cancer., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Purpose: Understanding the specific tumor characteristics associated with detectable circulating tumor DNA (ctDNA) in patients with renal cell carcinoma (RCC) is critical for informing future studies aiming to establish the clinical utility of such testing. We characterized the pathologic and clinical features associated with preoperatively detectable ctDNA in patients with renal masses suspicious for RCC., Methods: Consecutive patients who underwent partial or radical nephrectomy for nonmetastatic suspected RCC (cT1b-T3) during 2022-2023 had prospectively collected tumor-informed ctDNA analyses conducted preoperatively and postoperatively. Descriptive statistics and univariate analyses were used to describe the study findings., Results: Sixty-nine patients with a median age of 62 years (IQR, 51-70) and a median follow-up time of 7 months (IQR, 3-11) had 205 ctDNA samples collected for analysis. Thirty-nine (61%) had preoperative detectable ctDNA of 64 patients. Postoperative ctDNA status was available for 47 patients, and three (6%) had detectable ctDNA. Two had inferior vena cava (IVC) involvement, and one developed metastatic disease. Subgroup analysis of solely malignant RCC (n = 65) revealed that patients with preoperative detectable ctDNA had a higher pathologic stage ( P = .001), larger tumors (7 v 4.5 cm; P = .001), higher tumor complexity ( P = .022), and increased rates of tumor grades 3-4 ( P = .038). All patients with gross renal vein or IVC involvement (n = 9) and those with lymphovascular invasion (n = 6) on pathology had detectable preoperative ctDNA. On univariate analysis, high tumor complexity, larger tumors, and tumor grades 3-4 were found to be predictors of preoperatively detectable ctDNA status., Conclusion: Preoperative ctDNA was detectable in 61% of patients with nonmetastatic RCC, and it correlated with clinically relevant features. Clinical trials should consider incorporating both preoperative and postoperative ctDNA analyses to augment prediction of disease recurrence and to refine treatment decision making.

Due to bladder tumors' contact with urine, urine-derived cells (UDCs) may serve as a surrogate for monitoring the tumor microenvironment (TME) in bladder cancer (BC). However, the composition of UDCs and the extent to which they mirror the tumor remain poorly characterized. We generated the first single-cell RNA-sequencing of BC patient UDCs with matched tumor and peripheral blood mononuclear cells (PBMC). BC urine was more cellular than healthy donor (HD) urine, containing multiple immune populations including myeloid cells, CD4+ and CD8+ T cells, natural killer (NK) cells, B cells, and dendritic cells (DCs) in addition to tumor and stromal cells. Immune UDCs were transcriptionally more similar to tumor than blood. UDCs encompassed cytotoxic and activated CD4+ T cells, exhausted and tissue-resident memory CD8+ T cells, macrophages, germinal-center-like B cells, tissue-resident and adaptive NK cells, and regulatory DCs found in tumor but lacking or absent in blood. Our findings suggest BC UDCs may be surrogates for the TME and serve as therapeutic biomarkers., (© 2024 Tran et al.)

Objective: To compare limited (only inpatient) venous thromboembolism (VTE) prophylaxis after robot-assisted radical cystectomy (RARC) to limited plus extended prophylaxis. There is little consensus on postoperative VTE prophylaxis regimens after RARC with data mostly extrapolated from other cancers., Methods: Retrospective review of all RARC patients at our center between 2014-2022, identifying two groups: patients after a prospectively implemented protocol (January 2018 to present) utilizing a prolonged 21-day postoperative course of either enoxaparin 40 mg daily or apixaban 2.5 mg twice daily after discharge, or patients prior to January 2018 receiving only limited VTE prophylaxis during their immediate postoperative inpatient stay., Primary Outcome: incidence of symptomatic VTE confirmed with imaging within 90-days postoperatively., Secondary Outcomes: major hemorrhage, complications, readmission, and mortality within 30-days postoperatively. Descriptive statistics depicted baseline patient characteristics, operative information, and complications. Differences were compared between groups. Logistic regression was used to determine associations between variables and primary outcome., Results: Eighty-six patients received limited prophylaxis and 364 received extended prophylaxis. Twelve (2.7%) patients experienced VTE within 90-day postoperatively: (10 [2.7%] extended vs 2 [2.3%] limited, P = .9). Upon stratification into EAU "low-risk" or "high +intermediate-risk" groups, no statistically significant difference in VTE rates was seen between the extended or limited groups. When controlling for prophylaxis regimen, intracorporeal approach was found to be predictive of a lower with a lower risk of VTE (P = .019)., Conclusion: Limited and extended prophylaxis showed no significant differences in VTE rates among RARC patients. Further studies are necessary for RARC patients to improve guidelines., Competing Interests: Declaration of Competing Interest The authors have no conflict of interest to declare., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest.

Background and Objective: Despite curative-intent radical cystectomy (RC), patients with muscle-invasive bladder cancer (MIBC) are at high risk of recurrence. Biomarkers are urgently needed to refine prognostication and selection of appropriate perioperative systemic therapies. Our aim was to evaluate the prognostic and predictive value of tumor-informed circulating tumor DNA (ctDNA) results in a multicenter cohort of patients with bladder cancer who underwent RC., Methods: We performed a retrospective analysis of real-world data for a commercial ctDNA test (Signatera; Natera, Austin, TX, USA) performed in 167 patients (852 plasma samples) before RC and during molecular residual disease (MRD; adjuvant decision) and surveillance windows. We assessed the correlation between recurrence and ctDNA status before and after RC using Cox regression analysis., Results and Limitations: During study-defined postoperative MRD and surveillance windows, detectable ctDNA was associated with shorter disease-free survival (DFS) when compared to undetectable ctDNA (MRD: hazard ratio 6.93; p < 0.001; surveillance: hazard ratio 23.02; p < 0.001). Of note, patients with undetectable ctDNA did not appear to benefit from adjuvant therapy (p = 0.34). Detectable ctDNA in the pre-RC (p = 0.045), MRD (p = 0.002), and surveillance (p < 0.001) windows was the only risk factor independently associated with shorter DFS. Limitations include the retrospective and nonrandomized nature of the study., Conclusions: ctDNA testing in patients with bladder cancer undergoing RC was prognostic and potentially predictive. Identification of patients at high risk of recurrence may aid in patient counseling and decision-making., Patient Summary: We found that outcomes for patients with muscle-invasive bladder cancer are strongly linked to detection of tumor DNA in blood samples. The results show the value of tumor-informed testing for tumor DNA in blood for decisions on the best treatment for each individual patient., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

The pursuit of surgeons and oncologists in fulfilling the inherent desire of patients to retain their urinary bladder despite having muscle-invasive bladder cancer (MIBC) has sparked years of research and multiple debates, given its aggressive nature and the high risk of fatal metastatic recurrence. Historically, several approaches to bladder-sparing treatment have been explored, ranging from radical transurethral resection to concurrent chemoradiation. A less well-established approach involves a risk-adapted approach with local therapy deferred based on the clinical response to transurethral resection followed by systemic therapy. Each approach is associated with potential risks, benefits, and trade-offs. In this review, we aim to understand, navigate, and suggest future perspectives on bladder-sparing approaches in patients with MIBC., Competing Interests: Declaration of interests R.B-D. and J.P.S. have no disclosures. M.D.G. declares the following: (i) stock and other ownership interests: Rappta Therapeutics; (ii) consulting or advisory role: Janssen, Merck, Bristol-Myers Squibb, Pfizer, EMD Serono, AstraZeneca, Seattle Genetics, Gilead, AbbVie, Bicycle Therapeutics, Daiichi Sankyo Europe GmbH, and Curis; (iii) research funding: Janssen Oncology, Dendreon, Novartis, Bristol-Myers Squibb, Merck, AstraZeneca, and Genentech/Roche; and (iv) patents (20120322792)., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Introduction: The combination of sequential intravesical gemcitabine and docetaxel (Gem/Doce) chemotherapy has been considered a feasible option for BCG (Bacillus Calmette-Guérin) treatment in non-muscle invasive bladder cancer (NMIBC), gaining popularity during BCG shortage period. We seek to determine the efficacy of the treatment by comparing Gem/Doce induction alone vs induction with maintenance, and to evaluate the treatment outcomes of two different dosage protocols., Methods: A bi-center retrospective analysis of consecutive patients treated with Gem/Doce for NMIBC between 2018 and 2023 was performed. Baseline characteristics, risk group stratification (AUA 2020 guidelines), pathological, and surveillance reports were collected. Kaplan-Meier survival analysis was performed to detect Recurrence-free survival (RFS)., Results: Overall, 83 patients (68 males, 15 females) with a median age of 73 (IQR 66-79), and a median follow-up time of 18 months (IQR 9-25), were included. Forty-one had an intermediate-risk disease (49%) and 42 had a high-risk disease (51%). Thirty-seven patients (45%) had a recurrence; 19 (23%) had a high-grade recurrence. RFS of Gem/Doce induction-only vs induction + maintenance was at 6 months 88% vs 100%, at 12 months 71% vs 97%, at 18 months 57% vs 91%, and at 24 months 31% vs 87%, respectively (log-rank, p < 0.0001). Patients who received 2 g Gemcitabine with Docetaxel had better RFS for all-grade recurrences (log-rank, p = 0.017). However, no difference was found for high-grade recurrences., Conclusion: Gem/Doce induction with maintenance resulted in significantly better RFS than induction-only. Combining 2 g gemcitabine with docetaxel resulted in better RFS for all-grade but not for high-grade recurrences. Further prospective trials are necessary to validate our results., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Interactions within the tumor microenvironment (TME) significantly influence tumor progression and treatment responses. While single-cell RNA sequencing (scRNA-seq) and spatial genomics facilitate TME exploration, many clinical cohorts are assessed at the bulk tissue level. Integrating scRNA-seq and bulk tissue RNA-seq data through computational deconvolution is essential for obtaining clinically relevant insights. Our method, ProM, enables the examination of major and minor cell types. Through evaluation against existing methods using paired single-cell and bulk RNA sequencing of human urothelial cancer (UC) samples, ProM demonstrates superiority. Application to UC cohorts treated with immune checkpoint inhibitors reveals pre-treatment cellular features associated with poor outcomes, such as elevated SPP1 expression in macrophage/monocytes (MM). Our deconvolution method and paired single-cell and bulk tissue RNA-seq dataset contribute novel insights into TME heterogeneity and resistance to immune checkpoint blockade., Competing Interests: R.S. is a paid consultant and shareholder of GeneDx, Stamford, CT. A.H. receives research funds from Zumutor Biologics and is on the advisory boards of HTG Molecular Diagnostics, Immunorizon, UroGen, and Takeda. N.B. is an extramural member of the Parker Institute for Cancer Immunotherapy; receives research funds from Regeneron, Harbor Biomedical, DC Prime, and Dragonfly Therapeutics; and is on the advisory boards of Neon Therapeutics, Novartis, Avidea, Boehringer Ingelheim, Rome Therapeutics, Rubius Therapeutics, Roswell Park Comprehensive Cancer Center, BreakBio, Carisma Therapeutics, CureVac, Genotwin, BioNTech, Gilead Therapeutics, Tempest Therapeutics, and the Cancer Research Institute. M.D.G. has received grants or contracts from Bristol Myers Squibb, Novartis, Dendreon, AstraZeneca, and Merck; and has received consulting fees from Bristol Myers Squibb, Merck, Genentech, Inc., AstraZeneca, Pfizer, EMD Serono, Seagen, Janssen, Numab, Dragonfly, GlaxoSmithKline, Basilea, UroGen, RapptaTherapeutics, Alligator, Silverback, Fujifilm, and Curis., (© 2024 Published by Elsevier Inc.)

Bladder cancer is a heterogeneous disease. Treatment decisions are mostly decided based on disease stage (non-muscle invasive or muscle invasive). Patients with muscle-invasive disease will be offered a radical treatment combined with systemic therapy, while in those with non-muscle-invasive disease, an attempt to resect the tumor endoscopically will usually be followed by different intravesical instillations. The goal of intravesical therapy is to decrease the recurrence and/or progression of the tumor. In the current landscape of bladder cancer treatment, BCG is given intravesically to induce an inflammatory response and recruit immune cells to attack the malignant cells and induce immune memory. While the response to BCG treatment has changed the course of bladder cancer management and spared many "bladders", some patients may develop BCG-unresponsive disease, leaving radical surgery as the best choice of curative treatment. As a result, a lot of effort has been put into identifying novel therapies like systemic pembrolizumab and Nadofaragene-Firadenovac to continue sparing bladders if BCG is ineffective. Moreover, recent logistic issues with BCG production caused a worldwide BCG shortage, re-sparking interest in alternative BCG treatments including mitomycin C, sequential gemcitabine with docetaxel, and others. This review encompasses both the historic and current role of BCG in the treatment of non-muscle-invasive bladder cancer, revisiting BCG alternative therapies and reviewing the novel therapeutics that were approved for the BCG-unresponsive stage or are under active investigation.

Competing Interests: Yair Lotan: Editorial Board member of this journal, but not involved in the peer-review process nor had access to any information regarding its peer-review. Consultant for Nanorobotics, C2I genomics, Photocure, Astra-Zeneca, Merck, Fergene, Abbvie, Nucleix, Ambu, Seattle Genetics, Hitachi, Ferring Research, verity pharmaceutics, virtuoso surgical, Stimit, Urogen, Vessi medical, CAPs medical, Xcures, BMS, Nonagen, Aura Biosciences, Inc., Convergent Genomics, Pacific Edge, Pfizer, Phinomics Inc, CG oncology, Uroviu, On target lab. Daniel Barocas: Pacific Edge, Ambu, Lantheus, Pfizer, On target labs. Sam Chang: Editorial Board member of this journal, but was not involved in the peer-review process nor had access to any information regarding its peer-review. Consultant for Astellas, Merck, Janssen, Pfizer, Virtuoso Surgical, Photocure, Tu Therapeutics, Nonagen, Pacific Edge, Urogen, Prokarium, Valar Science. Siamak Daneshmand: Editorial Board member of this journal, but was not involved in the peer-review process nor had access to any information regarding its peer-review Consultant for: Janssen, Ferring, Photocure, Taris, Spectrum, Pacific Edge, BMS, Sesen, Protara, Pfizer, CG Oncology. Badrinath Konety: Editorial Board member of this journal, but was not involved in the peer-review process nor had access to any information regarding its peer-review. Consultant for Pacific Edge, Astrin Biosciences, Asieris Pharmaceuticals, Convergent Genomics, Illumina, Ferring Pharmaceuticals, Styx Biotechnology, Geneverify. Joshua Meeks: Consultant: Merck, AstraZeneca, Incyte, Janssen, BMS, UroGen, Prokarium, Imvax, Pfizer, Seagen/Astellas, Research Funding: VHA, NIH, DoD, Compensation for talks/educational courses: AUA, OncLive, Olympus, UroToday, Clinical Trials: SWOG, Genentech, Merck, AstraZeneca, Incyte. Sima Porten: Research with, KDx, Nonagen and Signatera, Consultant with Pacific Edge. Jay Raman: Education Chair for American Urological Association; Investment interest in United Medical Systems; Ongoing research with MDxHealth, Pacific Edge, Urogen Pharma, Steba Biotech. Charles Rosser: Executive team for Nonagen Bioscience Corp. Kristen Scarpato: Photocure, CxBladder. John P Sfakianos: Editorial Board member of this journal, but was not involved in the peer-review process nor had access to any information regarding its peer-review. Natera and pacific edge. Wade J. Sexton: Pacific Edge, Urogen Pharmaceuticals. Neal Shore: Arquer,Astra Zeneca, Aura biosciences, Diacarta, Ferring, Janssen, MDxHealth, Merck, Pacific Edge, Photocure, Protara, Roche. Robert Svatek: Editorial Board member of this journal, but was not involved in the peer-review process nor had access to any information regarding its peer-review. Consultant CG Oncology and Verity Pharma.

Introduction: Perioperative management of patients undergoing radical cystectomy and urinary diversion utilizing both open and minimally invasive techniques have routinely included the use of drains in the operative field. We herein demonstrate the safety of robotic-assisted radical cystectomy (RARC) without the routine use of postoperative drains., Methods: Patients who underwent drainless RARC with intracorporeal urinary diversion between 2017 and 2022 at our institution were reviewed. Baseline and clinical characteristics as well as perioperative and postoperative outcomes were analyzed. The primary study outcome was incidence of postoperative urinary leak or intra-abdominal infectious collections within 90 days of RARC. A univariate and multivariable logistic regression analysis was performed to determine associations between study variables and the primary outcome., Results: Of 381 patients, 298 (78.2%) were male and median age and BMI were 68 (63, 76) and 26.2 [23.0, 29.8], respectively. Overall 30 and 90-day complication rates were 39.6% and 50.4%, respectively. Twenty-one (5.5%) patients experienced a urine leak or intra-abdominal infectious collections. Sub-group analysis of patients who experienced the primary outcome demonstrated median postoperative day of presentation was day 19, and this group required 16 total additional procedures. On multivariable logistic regression analysis, only prior radiation therapy was associated with the development of the primary outcome of urinary leak or intra-abdominal infectious collection (odds ratio: 15.12, 95% confidence interval [1.52-156.8], p = 0.02)., Conclusion: Drainless RARC with totally intracorporeal urinary diversion achieved competitive perioperative and complications outcomes compared to prior open and robotic series. In the context of a larger enhanced recovery after surgery protocol in RARC patients, the routine use of drains may be safely omitted., (Copyright © 2023. Published by Elsevier Inc.)

Background: Enhanced recovery after surgery (ERAS) has significantly decreased the morbidity associated with radical cystectomy. However, infectious complications including sepsis, urinary tract (UTIs), wound (WIs), and intra-abdominal (AIs) infections remain common., Objective: To assess whether intracorporeal urinary diversion (ICUD) and antibiogram-directed antimicrobial prophylaxis would decrease infections after robotic-assisted radical cystectomy (RARC)., Design, Setting, and Participants: A retrospective analysis was performed of a prospectively maintained database of patients undergoing RARC between 2014 and 2022 at a tertiary care institution, identifying two groups based on adherence to a prospectively implemented modified ERAS protocol for RARC: modified-ERAS-ICUD and antibiogram-directed ampicillin-sulbactam, gentamicin, and fluconazole prophylaxis were utilized (from January 2019 to present time), and unmodified-ERAS-extracorporeal urinary diversion (UD) and guideline-recommended cephalosporin-based prophylaxis regimen were utilized (from November 2014 to June 2018). Patients receiving other prophylaxis regimens were excluded., Intervention: ICUD and antibiogram-directed infectious prophylaxis., Outcome Measurements and Statistical Analysis: The primary outcome was UTIs within 30 and 90 d postoperatively. The secondary outcomes were WIs, AIs, and sepsis within 30 and 90 d postoperatively, and Clostridioides difficile infection (CDI) within 90 d postoperatively., Results and Limitations: A total of 396 patients were studied (modified-ERAS: 258 [65.2%], unmodified-ERAS: 138 [34.8%]). UD via a neobladder was more common in the modified-ERAS cohort; all other intercohort demographic differences were not statistically different. Comparing cohorts, modified-ERAS had significantly reduced rates of 30-d (7.8% vs 15.9%, p = 0.027) and 90-d UTIs (11.2% vs 25.4%, p = 0.001), and 30-d WIs (1.2% vs. 8.7%, p < 0.001); neither group had a WI after 30 d. Rates of AIs, sepsis, and CDI did not differ between groups. On multivariate regression, the modified-ERAS protocol correlated with a reduced risk of UTIs and WIs (all p < 0.01). The primary limitation is the retrospective study design., Conclusions: Utilization of ICUD and antibiogram-based prophylaxis correlates with significantly decreased UTIs and WIs after RARC., Patient Summary: In this study of infections after robotic radical cystectomy for bladder cancer, we found that intracorporeal (performed entirely inside the body) urinary diversion and an institution-specific antibiogram-directed antibiotic prophylaxis regimen led to fewer urinary tract infections and wound infections at our institution., (Copyright © 2023 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Objective: We aimed to compare perioperative and oncologic outcomes for patients undergoing robotic-assisted radical cystectomy (RARC) with intracorporeal ileal conduit (IC) and neobladder (NB) urinary diversion., Methods: Patients undergoing RARC with intracorporeal urinary diversion between January 2017 and January 2022 at the Icahn School of Medicine at Mount Sinai, New York, NY, USA were indexed. Baseline demographics, clinical characteristics, perioperative, and oncologic outcomes were analyzed. Survival was estimated with Kaplan-Meier plots., Results: Of 261 patients (206 [78.9%] male), 190 (72.8%) received IC while 71 (27.2%) received NB diversion. Median age was greater in the IC group (71 [interquartile range, IQR 65-78] years vs. 64 [IQR 59-67] years, p <0.001) and BMI was 26.6 (IQR 23.2-30.4) kg/m 2 . IC group was more likely to have prior abdominal or pelvic radiation (15.8% vs. 2.8%, p =0.014). American Association of Anesthesiologists scores were comparable between groups. The IC group had a higher proportion of patients with pathological tumor stage 2 (pT2) tumors (34 [17.9%] vs. 10 [14.1%], p =0.008) and pathological node stages pN2-N3 (28 [14.7%] vs. 3 [4.2%], p <0.001). The IC group had less median operative time (272 [IQR 246-306] min vs . 341 [IQR 303-378] min, p <0.001) and estimated blood loss (250 [150-500] mL vs. 325 [200-575] mL, p =0.002). Thirty- and 90-day complication rates were 44.4% and 50.2%, respectively, and comparable between groups. Clavien-Dindo grades 3-5 complications occurred in 27 (10.3%) and 34 (13.0%) patients within 30 and 90 days, respectively, with comparable rates between groups. Median follow-up was 324 (IQR 167-552) days, and comparable between groups. Kaplan-Meier estimate for overall survival at 24 months was 89% for the IC cohort and 93% for the NB cohort (hazard ratio 1.23, 95% confidence interval 1.05-2.42, p =0.02). Kaplan-Meier estimate for recurrence-free survival at 24 months was 74% for IC and 87% for NB (hazard ratio 1.81, 95% confidence interval 0.82-4.04, p =0.10)., Conclusion: Patients undergoing intracorporeal IC urinary diversion had higher postoperative cancer stage, increased nodal involvement, similar complications outcomes, decreased overall survival, and similar recurrence-free survival compared to patients undergoing RARC with intracorporeal NB urinary diversion., Competing Interests: The authors declare no conflict of interest., (© 2023 Editorial Office of Asian Journal of Urology. Production and hosting by Elsevier B.V.)

Objectives: To compare the safety and efficacy of oral apixaban with that of injectable enoxaparin after robot-assisted radical cystectomy (RARC) for venous thromboembolism (VTE) thromboprophylaxis., Materials and Methods: We conducted a retrospective review of prospectively collected data for all RARC patients treated at our tertiary care centre between 2018 and 2022. The study included two groups: patients who were subject to a prospectively implemented protocol from October 2021 to the present, comprising a 21-day postoperative course of apixaban 2.5 mg twice daily after discharge, and patients treated prior to October 2021 who received enoxaparin 40 mg daily. Baseline demographics and clinical characteristics, such as VTE (defined as deep vein thrombosis and pulmonary embolism), were analysed. The primary outcome was incidence of symptomatic VTE confirmed with definitive imaging within 90 days of RARC. Secondary outcomes included major bleeding, complications, readmission, and mortality within 30 days postoperatively. Descriptive statistics included baseline patient characteristics, operative information and complications. Differences in baseline characteristics and postoperative data were compared between groups. Multivariate logistic regression was used to determine associations between variables and the primary outcome., Results: A total of 124 patients received apixaban and 250 patients received enoxaparin prophylaxis. Ten patients (2.7%) experienced a VTE within 90 days postoperatively (two [1.6%] apixaban group vs eight [3.2%] enoxaparin group; P = 0.5). After patient stratification into European Association of Urology risk groups, no statistically significant difference in VTE rates was seen between groups in the apixaban (2.7% high- + intermediate-risk group vs 1.1% low-risk group; P = 0.5) and enoxaparin cohorts (4.3% high- + intermediate-risk group vs 2.5% low-risk group; P = 0.5). On multivariate logistic regression, no variables were associated with the development of the primary outcome., Conclusion: Prophylaxis with apixaban and enoxaparin showed no statistically significant differences in VTE rates among RARC patients. Apixaban appears to be safe and effective for VTE prophylaxis after RARC., (© 2023 BJU International.)

CD40 is a central costimulatory receptor implicated in productive antitumor immune responses across multiple cancers, including bladder cancer. Despite strong preclinical rationale, systemic administration of therapeutic agonistic antibodies targeting the CD40 pathway has demonstrated dose-limiting toxicities with minimal clinical activity, emphasizing an important need for optimized CD40-targeted approaches, including rational combination therapy strategies. Here, we describe a role for the endogenous IL-15 pathway in contributing to the therapeutic activity of CD40 agonism in orthotopic bladder tumors, with upregulation of transpresented IL-15/IL-15Rα surface complexes, particularly by cross-presenting conventional type 1 DCs (Dendritic Cells), and associated enrichment of activated CD8 T cells. In bladder cancer patient samples, we identify DCs as the primary source of IL-15, although they lack high levels of IL-15Rα at baseline. Using humanized immunocompetent orthotopic bladder tumor models, we demonstrate the ability to therapeutically augment this interaction through combined treatment with anti-CD40 agonist antibodies and exogenous IL-15, including the fully-human Fc-optimized antibody 2141-V11 currently in clinical development for the treatment of bladder cancer. Collectively, these data reveal an important role for IL-15 in mediating antitumor CD40 agonist responses in bladder cancer and provide key proof-of-concept for combined use of Fc-optimized anti-CD40 agonist antibodies and agents targeting the IL-15 pathway. These data support expansion of ongoing clinical studies evaluating anti-CD40 agonist antibodies and IL-15-based approaches to develop combinations of these promising therapeutics for the treatment of patients with bladder cancer.

Context: Patients undergoing radical cystectomy frequently suffer from infectious complications, including urinary tract infections (UTIs) and surgical site infections (SSIs) leading to emergency department visits, hospital readmission, and added cost., Objective: To summarize the literature regarding perioperative antibiotic prophylaxis, ureteric stent usage, and prevalence of infectious complications after cystectomy., Evidence Acquisition: A systematic review of PubMed/Medline, EMBASE, Cochrane Library, and reference lists was conducted., Evidence Synthesis: We identified 20 reports including a total of 55 306 patients. The median rates of any infection, UTIs, SSIs, and bacteremia were 40%, 20%, 11%, and 6%, respectively. Perioperative antibiotic prophylaxis differed substantially between reports. Perioperative antibiotics were used only during surgery in one study but were continued over several days after surgery in all other studies. Empirical use of antibiotics for 1-3 d after surgery was described in 12 studies, 3-10 d in two studies, and >10 d in four studies. Time to stent removal ranged from 4 to 25 d after cystectomy. Prophylactic antibiotics were used before stent removal in nine of 20 studies; two of these studies used targeted antibiotics based on urine cultures from the ureteric stents, and the other seven studies used a single shot or 2 d of empirical antibiotics. Studies with any prophylactic antibiotic before stent removal found a lower median percentage of positive blood cultures after stent removal than studies without prophylactic antibiotics before stent removal (2% vs 9%)., Conclusions: We confirmed a high proportion of infectious complications after cystectomy, and a heterogeneous pattern of choice and duration of antibiotics during and after surgery or stent removal. These findings highlight a need for further studies and support quality prospective trials., Patient Summary: In this review, we observed wide variability in the use of antibiotics before or after surgical removal of the bladder., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objective: To profile the cell-free urine supernatant and plasma of a small cohort of clear-cell renal cell carcinoma (ccRCC) patients by measuring the relative concentrations of 92 proteins related to inflammation. Using The Cancer Genome Atlas (TCGA), we then performed a targeted mRNA analysis of genes encoding the above proteins and defined their effects on overall survival (OS)., Subjects/patients and Methods: Samples were collected prospectively from ccRCC patients. A multiplex proximity extension assay was used to measure the concentrations of 92 inflammation-related proteins in cell-free urine supernatants and plasma. Transcriptomic and clinical information from ccRCC patients was obtained from TCGA. Unsupervised clustering and differential protein expression analyses were performed on protein concentration data. Targeted mRNA analysis on genes encoding significant differentially expressed proteins was performed using TCGA. Backward stepwise regression analyses were used to build a nomogram. The performance of the nomogram and clinical benefit was assessed by discrimination and calibration, and a decision curve analysis, respectively., Results: Unsupervised clustering analysis revealed inflammatory signatures in the cell-free urine supernatant of ccRCC patients. Backward stepwise regressions using TCGA data identified transcriptomic risk factors and risk groups associated with OS. A nomogram to predict 2-year and 5-year OS was developed using these risk factors. The decision curve analysis showed that our model was associated with a net benefit improvement compared to the treat-all/none strategies., Conclusion: We defined four novel biomarkers using proteomic and transcriptomic data that distinguish severity of prognosis in ccRCC. We showed that these biomarkers can be used in a model to predict 2-year and 5-year OS in ccRCC across different tumour stages. This type of analysis, if validated in the future, provides non-invasive prognostic information that could inform either management or surveillance strategies for patients., (© 2023 BJU International.)

Background: For decades, immunotherapies have been integral for the treatment and management of bladder cancer, with immune checkpoint inhibitors (ICIs) transforming patient care in recent years. However, response rates are poor to T cell-targeted ICIs such as programmed cell death protein 1 (PD-1) and programmed cell death-ligand 1 (PD-L1) blocking antibodies, framing a critical need for complementary immunotherapies. Promising strategies involve harnessing the activation potential of natural killer (NK) cells. They quickly exert their antitumor activity via signaling through germline-encoded activating receptors and are rapidly sensitized to new tissue microenvironments via their regulation by polymorphic HLA class I, KIR and NKG2A receptors., Objective: In this review, we examined the roles of currently available NK-targeted antitumor treatment strategies such as engineered viral vectors, small-molecule IMiDs, NK agonist antibodies, interleukins, and chimeric antigen receptor (CAR) NK cells, and their potential for improving the efficacy of immunotherapy in the treatment of bladder cancer., Methods: Through review of current literature, we summarized our knowledge of NK cells in solid tumors and hematologic malignancies as their roles pertain to novel immunotherapies already being applied to the treatment of bladder cancer or that offer rationale for considering as potential novel immunotherapeutic strategies., Results: NK cells play a critical role in shaping the tumor microenvironment (TME) that can be exploited to improve T cell-targeted immunotherapies., Conclusions: Emerging evidence suggests that NK cells are a prime target for improving antitumor functions in immunotherapies for the treatment of bladder cancer. Further research into profiling NK cells in settings of immunotherapies for bladder cancer could help identify patients who might maximally benefit from NK cell-targeted immunotherapies and the various approaches for exploiting their antitumor properties., Competing Interests: A.H. is on the advisory boards of HTG Molecular Diagnostics and UroGen. J.P.S. is on the advisory boards of UroGen, Janssen, and Pacific Edge. M.G. is on the advisory board or consultant for Bristol Myers Squibb, Merck, Genentech, AstraZeneca, Pfizer, EMD Serono, SeaGen, Janssen, Numab, Dragonfly, GlaxoSmithKline, Basilea, UroGen, Rappta Therapeutics, Alligator, Silverback, Fujifilm, Curis. N.B. is an extramural member of the Parker Institute for Cancer Immunotherapy; and is on the advisory boards of Neon Therapeutics, Novartis, Avidea, Boehringer Ingelheim, Rome Therapeutics, Rubius Therapeutics, Roswell Park Comprehensive Cancer Center, BreakBio, Carisma Therapeutics, CureVac, Genotwin, BioNTech, Gilead Therapeutics, Tempest Therapeutics, and the Cancer Research Institute. M.G. and J.P.S. are Editorial Board members of this journal, but were not involved in the peer-review process nor had access to any information regarding its peer-review., (© 2023 – The authors. Published by IOS Press.)

Background: Data on Ta low-grade (LG) non-muscle invasive bladder cancer (NMIBC) have shown that follow-up cystoscopies are normal in 82% and 67% of patients with single and multiple tumors, respectively., Objective: To develop a predictive model associated with recurrence-free survival (RFS) at 6, 12, 18 and 24 months in TaLG cases that consider the patients' risk aversion., Materials and Methods: Data from a prospectively maintained database of 202 newly diagnosed TaLG NMIBC patients treated at Scandinavian institutions were used for the analysis. To identify risk groups associated with recurrence, we performed a classification tree analysis. Association between risk groups and RFS was evaluated by Kaplan Meier analysis. A Cox proportional hazard model selected significant risk factors associated with RFS using the variables defining the risk groups. The reported C index for the Cox model was 0.7. The model was internally validated and calibrated using 1000 bootstrapped samples. A nomogram to estimate RFS at 6, 12, 18, and 24 months was generated. The performance of our model was compared to EUA/AUA stratification using a decision curve analysis (DCA)., Results: The tree classification found that tumor number, tumor size and age were the most relevant variables associated with recurrence. The patients with the worst RFS were those with multifocal or single, ≥ 4cm tumors. All the relevant variables identified by the classification tree were significantly associated with RFS in the Cox proportional hazard model. DCA analysis showed that our model outperformed EUA/AUA stratification and the treat all/none approaches., Conclusion: We developed a predictive model to identify TaLG patients that benefit from less frequent follow-up cystoscopy schedule based on the estimated RFS and personal recurrence risk aversion., Competing Interests: Conflict of Interest None declared., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose: Examine patient, tumor, and treatment characteristics effect on the disparity between black and white patients with muscle-invasive bladder cancer (MIBC) who undergo radical cystectomy (RC)., Methods: 1,286 black patients in the 2004 to 2016 National Cancer Database fit inclusion criteria. A tapered match was performed from 17,374 white patients sequentially matched to the black cohort on demographics (age, gender, insurance, income, education, county, diagnosis year), presentation (demographic variables, stage, grade, tumor size, Charlson score), and treatment (demographic and presentation variables, lymph node count, hospital volume, neoadjuvant chemotherapy [NAC], treatment delay), creating 3 matched cohorts. Chi-square and Kruskal-Wallis tests were used to compare cohorts. Kaplan-Meier analysis was used to compare 5-year overall survival (OS)., Results: 5-year OS rate was 40.4% and 35.6% for unmatched white and black cohorts (P < 0.001), respectively. Following demographics and presentation match, 5-year OS rate for white patients decreased to 39.2% (P = 0.003) and 39.10% (P = 0.019), respectively. After treatment match, 5-year OS rate decreased to 36.7% for white patient (P = 0.32). Following presentation match, 7.2% of black patients vs. 5.8% of white patients had treatment delay, and 10.1% of black patients vs. 11.2% of white patients received NAC. The treatment match resulted in a 0.3% difference between groups for treatment delay and NAC., Conclusions: Our analysis demonstrates that disparity between black and white patients with muscle-invasive bladder cancer exists in demographic-, presentation-, and treatment-related variables. Treatment variables may be a large contributing factor to survival disparities. Further research is needed to identify social, biological, and organizational inputs that contribute to these disparities., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose: Treatment options for the management of upper tract urothelial cancer are based on accurate staging. However, the performance of conventional cross-sectional imaging for clinical lymph node staging (N-staging) remains poorly investigated. This study aims to evaluate the diagnostic accuracy of conventional cross-sectional imaging for upper tract urothelial cancer N-staging., Materials and Methods: This study was a multicenter, retrospective, observational study. We included 865 nonmetastatic (M0) upper tract urothelial cancer patients treated with curative intended surgery and lymph node dissection who had been staged with conventional cross-sectional imaging before surgery. We compared clinical (c) and pathological (p) N-staging results to evaluate the concordance of node-positive (N+) and node-negative (N0) disease and calculate cN-staging's diagnostic accuracy., Results: Conventional cross-sectional imaging categorized 750 patients cN0 and 115 cN+. Lymph node dissection categorized 641 patients pN0 and 224 pN+. The cN-stage was pathologically downstaged in 6.8% of patients, upstaged in 19%, and found concordant in 74%. The sensitivity and specificity of cN-staging were 25% (95% CI 20; 31) and 91% (95% CI 88; 93). Positive and negative likelihood ratios were 2.7 (95% CI 2.0; 3.8) and 0.83 (95% CI 0.76; 0.89). The area under the receiver operating characteristics curve (0.58, 95% CI 0.55; 0.61) revealed low diagnostic accuracy., Conclusions: Conventional cross-sectional imaging had low sensitivity in detecting upper tract urothelial cancer pN+ disease. However, cN+ increased the likelihood of pN+ by almost threefold. Thus, conventional cross-sectional imaging is a rule-in but not a rule-out test. Lymph node dissection should remain the standard during extirpative upper tract urothelial cancer surgery to obtain accurate N-staging. cN+ could be a strong argument for early systemic treatment.

Objectives: To identify correlates of survival and perioperative outcomes of upper tract urothelial carcinoma (UTUC) patients undergoing open (ORNU), laparoscopic (LRNU), and robotic (RRNU) radical nephroureterectomy (RNU)., Methods: We conducted a retrospective, multicenter study that included non-metastatic UTUC patients who underwent RNU between 1990-2020. Multiple imputation by chained equations was used to impute missing data. Patients were divided into three groups based on their surgical treatment and were adjusted by 1:1:1 propensity score matching (PSM). Survival outcomes per group were estimated for recurrence-free survival (RFS), bladder recurrence-free survival (BRFS), cancer-specific survival (CSS), and overall survival (OS). Perioperative outcomes: Intraoperative blood loss, hospital length of stay (LOS), and overall (OPC) and major postoperative complications (MPCs; defined as Clavien-Dindo > 3) were assessed between groups., Results: Of the 2434 patients included, 756 remained after PSM with 252 in each group. The three groups had similar baseline clinicopathological characteristics. The median follow-up was 32 months. Kaplan-Meier and log-rank tests demonstrated similar RFS, CSS, and OS between groups. BRFS was found to be superior with ORNU. Using multivariable regression analyses, LRNU and RRNU were independently associated with worse BRFS (HR 1.66, 95% CI 1.22-2.28, p = 0.001 and HR 1.73, 95%CI 1.22-2.47, p = 0.002, respectively). LRNU and RRNU were associated with a significantly shorter LOS (beta -1.1, 95% CI -2.2-0.02, p = 0.047 and beta -6.1, 95% CI -7.2-5.0, p < 0.001, respectively) and fewer MPCs (OR 0.5, 95% CI 0.31-0.79, p = 0.003 and OR 0.27, 95% CI 0.16-0.46, p < 0.001, respectively)., Conclusions: In this large international cohort, we demonstrated similar RFS, CSS, and OS among ORNU, LRNU, and RRNU. However, LRNU and RRNU were associated with significantly worse BRFS, but a shorter LOS and fewer MPCs.

Objectives: Technical limitations of ureteroscopic (URS) biopsy has been considered responsible for substantial upgrading rate in upper tract urothelial carcinoma (UTUC). However, the impact of tumor specific factors for upgrading remain uninvestigated., Methods: Patients who underwent URS biopsy were included between 2005 and 2020 at 13 institutions. We assessed the prognostic impact of upgrading (low-grade on URS biopsy) versus same grade (high-grade on URS biopsy) for high-grade UTUC tumors on radical nephroureterectomy (RNU) specimens., Results: This study included 371 patients, of whom 112 (30%) and 259 (70%) were biopsy-based low- and high-grade tumors, respectively. Median follow-up was 27.3 months. Patients with high-grade biopsy were more likely to harbor unfavorable pathologic features, such as lymphovascular invasion (p < 0.001) and positive lymph nodes (LNs; p < 0.001). On multivariable analyses adjusting for the established risk factors, high-grade biopsy was significantly associated with worse overall (hazard ratio [HR] 1.74; 95% confidence interval [CI], 1.10-2.75; p = 0.018), cancer-specific (HR 1.94; 95% CI, 1.07-3.52; p = 0.03), and recurrence-free survival (HR 1.80; 95% CI, 1.13-2.87; p = 0.013). In subgroup analyses of patients with pT2-T4 and/or positive LN, its significant association retained. Furthermore, high-grade biopsy in clinically non-muscle invasive disease significantly predicted upstaging to final pathologically advanced disease (≥pT2) compared to low-grade biopsy., Conclusions: High tumor grade on URS biopsy is associated with features of biologically and clinically aggressive UTUC tumors. URS low-grade UTUC that becomes upgraded to high-grade might carry a better prognosis than high-grade UTUC on URS. Tumor specific factors are likely to be responsible for upgrading to high-grade on RNU., (© 2022 The Authors. International Journal of Urology published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Urological Association.)

Objectives: To prospectively analyse robotically administered transperitoneal transversus abdominis plane (robot-assisted transversus abdominis plane [RTAP]) compared with both ultrasonography-guided transversus abdominis plane (UTAP) and local anaesthesia (LA) with regard to pain control and narcotic use in patients undergoing robot-assisted prostatectomy (RARP) or robot-assisted partial nephrectomy (RAPN)., Subjects/patients and Methods: Patients undergoing RARP or RAPN were randomized in a single-blind 2:2:1 fashion to RTAP:UTAP:LA, with the study powered to evaluate superiority of UTAP to LA and non-inferiority of RTAP to UTAP. We compared time to deliver the block, operating room time, postoperative pain scores using the visual analogue scale, and intra-operative and postoperative analgesia consumption., Results: A total of 143 patients were randomized and received treatment. There was no significant difference in patient baseline characteristics. UTAP did not demonstrate superiority to LA in terms of pain control. RTAP and LA were faster to administer than UTAP (time to perform block 2.5 vs 2.5 vs 6.25 min; P &lt; 0.001). There was no difference in postoperative narcotic, acetaminophen, ketorolac or ondansetron requirements among the three groups (P &gt; 0.05). The study was terminated early due to the unexpected efficacy of LA., Conclusion: This study showed that UTAP and RTAP do not provide superior pain control to LA. The efficiency, effectiveness, and ease of administration of LA make it an excellent option for first-line therapy for postoperative analgesia., (© 2022 BJU International.)

Significance: Most patients with bladder cancer do not respond to ICB targeting of the PD-L1 signaling axis. Our modeling applied a de novo resistance signature to show that tumor-infiltrating myeloid cells promote poor treatment response in a TGFβ-dependent mechanism., (©2022 American Association for Cancer Research.)

Kidney stones are one of the most common renal pathologies. While emerging evidence has implicated a potential association between kidney stones and upper urinary tract cancers (including renal cancer), there is limited understanding as to the common underlying biological pathways functionally linking the etiology of kidney stone formation and the incidence, development, and progression of urinary tract cancers. From a clinical perspective, kidney stone disease can be a barrier to oncologic care due to renal obstruction. From the epidemiological perspective, risk factors associated with both conditions include smoking, alcohol consumption, diet, and gender. Herein, we review the association between renal calculi and malignancy of the upper urinary tract and discuss the current understanding of (a) potential shared mechanisms, and (b) the impact this has on shared therapeutic management of both conditions., Competing Interests: None., (AJCEU Copyright © 2022.)

Programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1)-blockade immunotherapies have limited efficacy in the treatment of bladder cancer. Here, we show that NKG2A associates with improved survival and responsiveness to PD-L1 blockade immunotherapy in bladder tumors that have high abundance of CD8 + T cells. In bladder tumors, NKG2A is acquired on CD8 + T cells later than PD-1 as well as other well-established immune checkpoints. NKG2A + PD-1 + CD8 + T cells diverge from classically defined exhausted T cells through their ability to react to human leukocyte antigen (HLA) class I-deficient tumors using T cell receptor (TCR)-independent innate-like mechanisms. HLA-ABC expression by bladder tumors is progressively diminished as disease progresses, framing the importance of targeting TCR-independent anti-tumor functions. Notably, NKG2A + CD8 + T cells are inhibited when HLA-E is expressed by tumors and partly restored upon NKG2A blockade in an HLA-E-dependent manner. Overall, our study provides a framework for subsequent clinical trials combining NKG2A blockade with other T cell-targeted immunotherapies, where tumors express higher levels of HLA-E., Competing Interests: Declaration of interests L.W., R.P.S., and J.Z. are employees of Sema4. A.H. receives research funds from Zumutor Biologics and is on the advisory boards of HTG Molecular Diagnostics, Immunorizon, UroGen, and Takeda. N.B. is an extramural member of the Parker Institute for Cancer Immunotherapy; receives research funds from Regeneron, Harbor Biomedical, DC Prime, and Dragonfly Therapeutics; and is on the advisory boards of Neon Therapeutics, Novartis, Avidea, Boehringer Ingelheim, Rome Therapeutics, Rubius Therapeutics, Roswell Park Comprehensive Cancer Center, BreakBio, Carisma Therapeutics, CureVac, Genotwin, BioNTech, Gilead Therapeutics, Tempest Therapeutics, and the Cancer Research Institute. A patent related to this work was filed to the United States Patent and Trademark Office (63/313,823)., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The resurgence of immunotherapy as an effective anticancer strategy has been coupled with more mature understandings of the underlying immune pathways and the development of novel immune checkpoint targets. The clinical development of antibodies first directed against cytotoxic T-lymphocyte-associated antigen 4, and later against program death 1, achieved durable disease control in a subset of patients across a large number of tumor types. Previous work demonstrates that targeting the programmed death 1 pathway alone does not result in complete restoration of T cell function and in some cancers, targeting this axis does not restore T cell function at all, suggesting a need to identify other molecules and inhibitory pathways that are involved in T cell exhaustion. In a comprehensive immune profiling study of patients with bladder cancer, we demonstrate T-cell immunoglobulin domain and mucin domain-containing molecule and T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain as possible targets as perhaps monotherapy or in combination with other immune checkpoint inhibitors., (Copyright © 2020. Published by Elsevier Inc.)

Objective: To test whether body mass index (BMI) amongst patients with metastatic castration-resistant prostate cancer (mCRPC) is associated with overall survival (OS) and cancer-specific survival., Methods: Individual patient data from 1577 men with mCRPC treated with docetaxel and prednisone from the control arms of ASCENT2, VENICE, and MAINSAIL were considered. The role of BMI on survival outcomes was investigated both as a continuous and categorical variable (≤24.9 vs. 25-29.9 vs. ≥30 km/m 2 ). BMI ≥ 30 kg/m 2 was considered obese. Analyses were adjusted for age, PSA, ECOG performance status, number of metastases and prior treatment. The Cox semi-proportional hazard model was used to predict OS, whereas competing risks regression was used for predicting cancer-specific mortality (CSM). To exclude any possible effect attributable to higher doses of chemotherapy (titrated according to body-surface area), we checked for eventual interactions between BMI and chemotherapy dose (both as continuous-continuous and categorical-continuous interactions)., Results: The median (IQR) age for the patient population was 69 (63,74) years with a median (IQR) BMI of 28 (25-31) kg/m 2 . Median follow-up for survivors was 12 months. Of the 1577 patients included, 655 were deceased by the end of the studies. Regarding OS, BMI emerged as a protective factor both as a continuous variable (HR: 0.96; 95% CI: 0.94, 0.99; p = 0.015) and as a categorical variable (obesity: HR: 0.71, 95% CI: 0.53, 0.96; p = 0.027, relatively to normal weight). The protective effect of high BMI on CSM was confirmed both as a continuous (SHR: 0.94; 95% CI: 0.91, 0.98; p = 0.002) and as a categorical variable (obesity SHR: 0.65; 95% CI: 0.45, 0.93; p = 0.018). No interaction was detected between the BMI categories and the docetaxel dose at any level in our analyses (all p » 0.05)., Conclusions: Obese patients with mCRPC had better cancer-specific and overall survival as compared to overweight and normal weight patients. The protective effect of BMI was not related to receiving higher chemotherapy doses. Further studies aimed at elucidating the biological mechanism behind this effect are warranted., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Non-muscle invasive bladder cancer, a disease with the oldest immunotherapeutic standard of care, has seen recent improvements in treatment via the application of checkpoint blocking antibodies. Unfortunately, response rates to programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) blocking antibodies remain low despite stratification by biomarkers. Sharing common biology with T cells but lacking true antigen-specificity and responding earlier to tumorigenic threats, natural killer (NK) cells present an ideal target for combination immunotherapies. NK-targeted immunotherapies under clinical investigation, including anti-NKG2A antibodies, interleukin agonists, and engineered viral vectors, hold promise in altering the immunotherapeutic landscape in bladder cancer and will be the focus of this review., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Treatment-emergent small cell neuroendocrine prostate cancer (t-SCNC) is associated with an epithelial lineage switch from an androgen receptor (AR)-positive to neuroendocrine (NE)-marker-positive status. Understanding the potential for reversibility of this aggressive disease state has been hampered by the paucity of models suitable for studying rate-limiting, transitional, or intermediate tumor cell subpopulations. We define a dual reporter model that measures acute transcriptional changes in response to castration or AR targeting agents. We identify steady-state transcriptional heterogeneity in AR and NE biomarkers, including intermediate subpopulations that are coordinately high for prostate-specific antigen (PSA) and neuron-specific enoclase (NSE) promoter activity. In the presence of castration or AR inhibitors, intermediate cells were necessary and sufficient for therapy-induced conversion of human PC cells to an NSE-high transcriptional status. Using hormone add-back studies, treatment-induced PSA-NSE transcriptional plasticity was reversible in PTEN-deficient PC cells but not in the presence of secondary genetic driver genes, including MYCN., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: To review non-opioid based protocols in urologic oncologic surgery and describe our institutional methods of eliminating peri-operative opioids., Methods: A thorough literature review was performed using PUBMED to identify articles pertaining to reducing or eliminating narcotic use in genitourinary cancer surgery. Studies were analyzed pertaining to protocols utilized in genitourinary cancer surgery, major abdominal and/or pelvic non-urologic surgery., Results: Reducing or eliminating peri-operative narcotics should begin with an institutionalized protocol made in conjunction with the anesthesia department. Pre-operative regimens should consist of appropriate counseling, gabapentin, and acetaminophen with or without a non-steroidal anti-inflammatory medications. Prior to incision, a regional block or local anesthetic should be delivered. Anesthesiologists may develop opioid-free protocols for achieving and maintaining general anesthesia. Post-operatively, patients should be on a scheduled regimen of ketorolac, gabapentin, and acetaminophen., Conclusion: Eliminating peri-operative narcotic use is feasible for major genitourinary oncologic surgery. Patients not only have improved peri-operative outcomes but also are at significantly reduced risk of developing long-term opioid use. Through the implementation of a non-opioid protocol, urologists are able to best serve their patients while positively contributing to reducing the opioid epidemic., (© 2020. Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: In patients with muscle invasive bladder cancer or high risk noninvasive bladder cancer, renal function decline is a concern after radical cystectomy with urinary diversion. The pathophysiology of this decline is multifactorial, with subclinical acidosis and metabolic derangements from the diversion thought to contribute. It is unknown whether patients with baseline chronic kidney disease (CKD) are at increased risk of further decline in renal function., Methods: We performed a retrospective review of two high volume robotic assisted radical cystectomy (RARC) centers between 2016 and 2020. Preoperative demographics and comorbidities were collected. Postoperative estimated glomerular filtration rate (eGFR) was calculated at 12 and 24 months to determine short-term rate in decline of eGFR. Absolute and percent changes in eGFR were calculated., Results: There were a total of 555 patients who underwent RARC. Men comprised 76.2% of the cohort. Neoadjuvant chemotherapy was given in 31% of patients and adjuvant chemotherapy was given in 4.81% of patients. Higher preoperative eGFR (B -0.549, 95% CI -0.708 to -0.391, P < 0.001) and presence of diabetes mellitus (B -15.414, 95% CI -24.820 to -6.008, P = 0.001) were significant predictors of eGFR decline at 12 months. At 24 months, presence of diabetes mellitus (B -11.799, 95% CI -21.816 to -1.782, P = 0.021) and higher preoperative eGFR (B -0.621, 95% CI -0.796 to -0.446, P < 0.001) were correlated with a steeper decline in eGFR. Higher preoperative eGFR was also predictive of upstaging to CKD3 or higher post operatively (OR 1.019, 95% CI 1.004-1.034, P = 0.015). Intracorporeal diversion was protective, whereas presence of hypertension, diabetes mellitus, and higher preoperative eGFR predicted greater decline in eGFR., Conclusion: Patients with higher preoperative eGFR and diabetes are at increased risk of renal function decline post RARC at 12 and 24 months. This suggests that patients with risk factors for renal function decline, but otherwise normal renal function at baseline, are a particularly vulnerable population for progression to CKD after RARC and should be counseled and closely followed postoperatively for renal function deterioration., Competing Interests: Conflict of interest All authors declare no conflict of interest., (Copyright © 2022. Published by Elsevier Inc.)

Background: It is hypothesised that simulation enhances progression along the initial phase of the surgical learning curve., Objective: To evaluate whether residents undergoing additional simulation, compared to conventional training, are able to achieve proficiency sooner with better patient outcomes., Design, Setting, and Participants: This international, multicentre, randomised controlled trial recruited 94 urology residents with experience of zero to ten procedures and no prior exposure to simulation in ureterorenoscopy, selected as an index procedure., Intervention: Participants were randomised to simulation or conventional operating room training, as is the current standard globally, and followed for 25 procedures or over 18 mo., Outcome Measurements and Statistical Analysis: The number of procedures required to achieve proficiency, defined as achieving a score of ≥28 on the Objective Structured Assessment of Technical Skill (OSATS) scale over three consecutive operations, was measured. Surgical complications were evaluated as a key secondary outcome. This trial is registered at www.isrctn.com as ISCRTN 12260261., Results and Limitations: A total of 1140 cases were performed by 65 participants, with proficiency achieved by 21 simulation and 18 conventional participants over a median of eight and nine procedures, respectively (hazard ratio [HR] 1.41, 95% confidence interval [CI] 0.72-2.75). More participants reached proficiency in the simulation arm in flexible ureterorenoscopy, requiring a lower number of procedures (HR 0.89, 95% CI 0.39-2.02). Significant differences were observed in overall comparison of OSATS scores between the groups (mean difference 1.42, 95% CI 0.91-1.92; p < 0.001), with fewer total complications (15 vs 37; p = 0.003) and ureteric injuries (3 vs 9; p < 0.001) in the simulation group., Conclusions: Although the number of procedures required to reach proficiency was similar, simulation-based training led to higher overall proficiency scores than for conventional training. Fewer procedures were required to achieve proficiency in the complex form of the index procedure, with fewer serious complications overall., Patient Summary: This study investigated the effect of simulation training in junior surgeons and found that it may improve performance in real operating settings and reduce surgical complications for complex procedures., (Copyright © 2021 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Introduction: Renal function impairment is often cited as a contraindication to continent diversion strategies. There is little evidence exploring renal function changes between continent and incontinent surgery in patients with preoperative chronic kidney disease (CKD), in particular CKD3B., Methods: This was a retrospective review of two high-volume centers performing robotic assisted radical cystectomy (RARC) with orthotopic neobladder (ONB) or ileal conduit (IC) between 2014 to 2020. Patients were stratified based on CKD estimated glomerular filtration (eGFR) stage, which was estimated via the CKD-EPI equation. Postoperative renal function was compared for up to 60 months postoperative. Surgical, post-surgical, complications, and readmission data were gathered and compared between all patients RESULTS: 522 cystectomy patients, 430 with IC and 125 with ONB, were included. eGFR decline was statistically significant in a matched cohort of IC and ONB patients only at 3 months. There were no statistically significant differences between readmission rates, time to readmission, or complications. 34.6% of stage 3B patients had hydronephrosis on imaging prior to surgery, compared to 11.4%, 22.1% and 21.8% of CKD stage 1, 2, and 3A patients. CKD stage 3B had statistically and clinically improved eGFR through 24 months., Conclusion: ONB surgery may be a viable diversion strategy in patients previously thought to be contraindicated due to low renal function., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Measuring quality of care indicators is important for clinicians and decision making in health care to improve patient outcomes. Objective: The primary objective was to identify quality of care indicators for patients with upper tract urothelial carcinoma (UTUC) and to validate these in an international cohort treated with radical nephroureterectomy (RNU). The secondary objective was to assess the factors associated with failure to validate the pentafecta. Design: We performed a retrospective multicenter study of patients treated with RNU for EAU high-risk (HR) UTUC. Outcome measurements and statistical analysis: Five quality indicators were consensually approved, including a negative surgical margin, a complete bladder-cuff resection, the absence of hematological complications, the absence of major complications, and the absence of a 12-month postoperative recurrence. After multiple imputations and propensity-score matching, log-rank tests and a Cox regression were used to assess the survival outcomes. Logistic regression analyses assessed predictors for pentafecta failure. Results: Among the 1718 included patients, 844 (49%) achieved the pentafecta. The median follow-up was 31 months. Patients who achieved the pentafecta had superior 5-year overall- (OS) and cancer-specific survival (CSS) compared to those who did not (68.7 vs. 50.1% and 79.8 vs. 62.7%, respectively, all p < 0.001). On multivariable analyses, achieving the pentafecta was associated with improved recurrence-free survival (RFS), CSS, and OS. No preoperative clinical factors predicted a failure to validate the pentafecta. Conclusions: Establishing quality indicators for UTUC may help define prognosis and improve patient care. We propose a pentafecta quality criteria in RNU patients. Approximately half of the patients evaluated herein reached this endpoint, which in turn was independently associated with survival outcomes. Extended validation is needed.

Introduction: Non muscle invasive bladder cancer (NMIBC) has recurrence and progression rates of approximately 55-75% and 5-45% respectively. After diagnosis, risk stratification guides management decisions regarding surveillance, intravesical therapy or surgery. This prospective cohort of patients from Stockholm County is ideal for external validation of the current risk stratification models used in clinical practice., Patients & Methods: The cohort consisted of 395 patients diagnosed with bladder cancer across all the hospitals in Stockholm County between the years 1995-96, with up to 25 years follow up. All patients with pathologic Ta or T1 disease were included. Patients with muscle invasive disease (MIBC) referred for radical treatment at diagnosis were excluded. External validation of EORTC, CUETO and updated EAU Sylvester et al. (2021) models was done and multivariate Cox regression analysis was performed to generate hazard ratios for covariables of interest using both WHO '73 and WHO '04/16 pathological grade classifications., Results: Overall Harrel's C-indices (CIs) for EORTC and CUETO models for recurrence were 0.66 and 0.63 respectively. The CIs for the EORTC, CUETO and EAU Sylvester et al. (2021) WHO '73 and '04/16 models for progression were higher at 0.82, 0.84, 0.83 and 0.83 respectively. All models tended to underestimate both recurrence and progression rates at 1 and 5 yrs. A simplified model devised to include only multifocality, tumor stage, size and grade performed with similar accuracy to all models for both recurrence and progression., Conclusion: Current risk stratification models are clinically useful but only moderately accurate across different patient populations, and the results of this study suggest a model using fewer variables is of similar accuracy to all models tested. In the future, research into the use of genomic classifiers will hopefully contribute to more accurate, modern risk stratification models., Competing Interests: Conflict of interest There are no conflicts of interest for any of the five authors Zachary Dovey, John Pfail, Alberto Martini, John P. Sfakianos or Peter Wiklund, (Copyright © 2021. Published by Elsevier Inc.)

Background: The aim of this study was to evaluate the association between tumor complexity based on RENAL nephrometry score and complications., Methods: We retrospectively identified 2555 patients who underwent RPN for renal cell carcinoma. Major complication was defined as Clavien Grade ≥3. The relationship between baseline demographic, clinical characteristics, perioperative and postoperative outcomes, and tumor complexity were assessed using χ2 test of independence, Fisher's Exact Test and Kruskal Wallis Test. An unadjusted and adjusted logistic regression model was used to assess the relationship between major complication and demographic, clinical characteristics, and perioperative outcomes., Results: There was a significant relationship between tumor complexity and WIT (P<0.001), operative time (P<0.001), estimated blood loss (P<0.001), and major complication (P=0.019). However, there was no relationship with overall complications (P=0.237) and length of stay (LOS) (P=0.085). In the unadjusted model, higher tumor complexity was associated with major complication (P=0.009). Controlling for other variables, there was no significant difference between major complication and tumor complexity (low vs. moderate, P=0.142 and high, P=0.204). LOS (P<0.001) and operative time (P=0.025) remained a significant predictor of major complication in the adjusted model., Conclusions: Tumor complexity is not associated with an increase in overall or major complication rate after RPN. Experience in high-volume centers is demonstrating a standardization of low complications rates after RPN independent of tumor complexity.