The impact of bladder cuff excision on outcomes after nephroureterectomy for upper tract urothelial carcinoma: An analysis of the ROBUUST 2.0 registry.

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.

Optimal Management for Primary High Grade Ta Bladder Cancer: Role of re-staging TURBT and Intravesical Adjuvant Therapy.

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.

N-803 Plus BCG Treatment for BCG-Naïve or -Unresponsive Non-Muscle Invasive Bladder Cancer: A Plain Language Review.

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).

Addition of the IL-15 superagonist N-803 to BCG therapy produces a high rate of success in eliminating non-muscle invasive bladder cancer in both BCG-naive and BCG-unresponsive patients, with long-lasting effects that allow patients to avoid surgical removal of the bladder.

Robotic distal ureterectomy for high-risk distal ureteral urothelial carcinoma: a retrospective multicenter comparative analysis (ROBUUST 2.0 collaborative group).

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.

Decisional and prognostic impact of diagnostic ureteroscopy in high-risk upper tract urothelial carcinoma: A multi-institutional collaborative analysis (ROBUUST collaborative group).

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.

Combined holmium laser enucleation of the prostate with high-intensity focused ultrasound in treating patients with localized prostate cancer in a prostate with volume > 60 g: Oncological and functional outcomes from single-institution study.

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.

GPR1 and CMKLR1 Control Lipid Metabolism to Support the Development of Clear Cell Renal Cell Carcinoma.

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.

Clinical variables associated with major adverse cardiac events following radical cystectomy.

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.

Radical prostatectomy cancer grade and percentage of Gleason pattern 4 estimated by global vs individual tumor grading correlate differently with the risk of biochemical recurrence in Grade Group 2 and 3 cancers.

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.

Quality of Life in the Phase 2/3 Trial of N-803 Plus Bacillus Calmette-Guérin in Bacillus Calmette-Guérin‒Unresponsive Nonmuscle-Invasive Bladder Cancer.

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.

The Influence of the Microbiome on Urological Malignancies: A Systematic Review.

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.

Racial disparity in the utilization of immunotherapy for advanced prostate cancer.

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."

Incidence and predictors of deep incisional and organ/space surgical site infection following radical cystectomy.

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.

Predictors of discharge to home following major surgery for urologic malignancies: Results from the national surgical quality improvement program.

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.

Impact of Variant Histology on Oncological Outcomes in Upper Tract Urothelial Carcinoma: Results From the ROBUUST Collaborative Group.

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.

Fibromyxoid Nephrogenic Adenoma: A Series of 43 Cases Reassessing Predisposing Conditions, Clinical Presentation, and Morphology.

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.

Fatty acid metabolism reprogramming in ccRCC: mechanisms and potential targets.

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.

IL-15 Superagonist NAI in BCG-Unresponsive Non-Muscle-Invasive Bladder Cancer.

BACKGROUND: Patients with Bacillus Calmette­Guérin (BCG)­unresponsive non­muscle-invasive bladder cancer (NMIBC) have limited treatment options. The immune cell­activating 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 Kaplan­Meier estimated probability of avoiding cystectomy and of DSS was 89.2% and 100%, respectively. In cohort B (n=72), the Kaplan­Meier 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 cancer­specific survival at 24 months. The study is ongoing, with an estimated target enrollment of 200 participants (Funded by ImmunityBio.)

Practice trends for perioperative intravesical chemotherapy in upper tract urothelial carcinoma: Low but increasing utilization during minimally invasive nephroureterectomy.

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.