Total Margin Control Is Superior to Traditional Margin Assessment for Treatment of Low-Stage Penile Squamous Cell Carcinoma.

PURPOSE: Penile cancer is rare, with significant morbidity and limited literature assessing utility of peripheral and deep en face margin assessment (PDEMA) vs traditional margin assessment (vertical sections) on treatment outcomes. MATERIALS AND METHODS: This was a 32-year retrospective multicenter cohort study at 3 academic tertiary care centers. The cohort consisted of 189 patients with histologic diagnosis of in situ or T1a cutaneous squamous cell carcinoma of the penis at Brigham and Women's, Massachusetts General Hospital (1988-2020), and Memorial Sloan Kettering Cancer Center (1995-2020) treated with PDEMA surgical excision, excision/circumcision, or penectomy/glansectomy. Local recurrence, metastasis, and disease-specific death were assessed via multivariable Cox proportional hazard models. RESULTS: The cohort consisted of 189 patients. Median age at diagnosis was 62 years. Median tumor diameter was 1.3 cm. The following outcomes of interest occurred: 30 local recurrences, 13 metastases, and 5 disease-specific deaths. Primary tumors were excised with PDEMA (N = 30), excision/circumcision (N = 110), or penectomy/glansectomy (N = 49). Of patients treated with traditional margin assessment (non-PDEMA), 12% had narrow or positive margins. Five-year proportions were as follows with respect to local recurrence-free survival, metastasis-free survival, and disease-specific survival/progression-free survival, respectively: 100%, 100%, and 100% following PDEMA; 82%, 96%, and 99% following excision/circumcision; 83%, 91%, and 95% following penectomy/glansectomy. A limitation is that this multi-institutional cohort study was not externally validated. CONCLUSIONS: Initial results are encouraging that PDEMA surgical management effectively controls early-stage penile squamous cell carcinoma.

Factors predictive of recurrence, metastasis and death in node-negative penile squamous cell carcinoma: A retrospective multicentre cohort study.

BACKGROUND: Penile squamous cell carcinoma (PSCC) carries significant morbidity and mortality. Literature is limited regarding prognostic factors, especially prognostic factors for development of metastasis. OBJECTIVES: To identify independent prognostic factors associated with poor outcomes, defined as local recurrence (LR), metastasis and disease-specific death (DSD) in clinically node-negative PSCC undergoing local therapy. METHODS: Thirty-two-year Retrospective Multicenter Cohort Study of 265 patients with histologically diagnosed PSCC at three tertiary care centres. Predictive models based on patient or tumour characteristics were developed. RESULTS: Local recurrence occurred in 56 patients, metastasis in 52 patients and DSD in 40 patients. In multivariable models, the following five factors were independent prognostic factors based on subhazard ratio (SHR): history of balanitis (LR SHR: 2.3; 95% CI 1.2-4.2), poor differentiation (metastasis SHR 1.9; 95% CI 1.0-3.6), invasion into the corpora (metastasis SHR: 3.0; 95% CI 1.5-5.8 and DSD SHR: 4.5; 95% CI 1.7-12.1), perineural invasion (PNI) (metastasis SHR: 2.8; 95% CI 1.4-5.5 and DSD SHR: 3.5; 95% CI, 1.6-7.8) and a history of phimosis (DSD SHR: 2.5; 95% CI 1.2-5.3). The 5-year cumulative incidence of metastasis was higher for tumours with PNI [cumulative incidence function (CIF) = 55%, 95% CI 38-75 vs. CIF 15%, 95% CI 11-22], corporal invasion (CIF: 35%, 95% CI 26-47 vs. 12%, 95% CI 7-19) and poorly differentiated tumours (CIF = 46%, 95% CI 31-64 vs. CIF 15%, 95% CI 11-22). CONCLUSIONS: History of balanitis, history of phimosis, PNI, corporal invasion and poor differentiation are independent risk factors associated with poor outcomes. Since poor differentiation and PNI currently constitute only T1b disease, prognostic staging can likely be improved.

Smoking characteristics and years since quitting smoking of US adults diagnosed with lung and bladder cancer: A national health and nutrition examination survey analysis.

PURPOSE: Smoking is a recognized risk factor for bladder BC and lung cancer LC. We investigated the enduring risk of BC after smoking cessation using U.S. national survey data. Our analysis focused on comparing characteristics of LC and BC patients, emphasizing smoking status and the latency period from smoking cessation to cancer diagnosis in former smokers. MATERIALS AND METHODS: We analyzed data from the National Health and Examination Survey (2003-2016), identifying adults with LC or BC history. Smoking status (never, active, former) and the interval between quitting smoking and cancer diagnosis for former smokers were assessed. We reported descriptive statistics using frequencies and percentages for categorical variables and median with interquartile ranges (IQR) for continuous variables. RESULTS: Among LC patients, 8.9% never smoked, 18.9% active smokers, and 72.2% former smokers. Former smokers had a median interval of 8 years (IQR 2-12) between quitting and LC diagnosis, with 88.3% quitting within 0-19 years before diagnosis. For BC patients, 26.8% never smoked, 22.4% were active smokers, and 50.8% former smokers. Former smokers had a median interval of 21 years (IQR 14-33) between quitting and BC diagnosis, with 49.3% quitting within 0-19 years before diagnosis. CONCLUSIONS: BC patients exhibit a prolonged latency period between smoking cessation and cancer diagnosis compared to LC patients. Despite smoking status evaluation in microhematuria, current risk stratification models for urothelial cancer do not incorporate it. Our findings emphasize the significance of long-term post-smoking cessation surveillance and advocate for integrating smoking history into future risk stratification guidelines.

Promoting the use of the PI-QUAL score for prostate MRI quality: results from the ESOR Nicholas Gourtsoyiannis teaching fellowship.

OBJECTIVES: The Prostate Imaging Quality (PI-QUAL) score is a new metric to evaluate the diagnostic quality of multiparametric magnetic resonance imaging (MRI) of the prostate. This study assesses the impact of an intervention, namely a prostate MRI quality training lecture, on the participant's ability to apply PI-QUAL. METHODS: Sixteen participants (radiologists, urologists, physicists, and computer scientists) of varying experience in reviewing diagnostic prostate MRI all assessed the image quality of ten examinations from different vendors and machines. Then, they attended a dedicated lecture followed by a hands-on workshop on MRI quality assessment using the PI-QUAL score. Five scans assessed by the participants were evaluated in the workshop using the PI-QUAL score for teaching purposes. After the course, the same participants evaluated the image quality of a new set of ten scans applying the PI-QUAL score. Results were assessed using receiver operating characteristic analysis. The reference standard was the PI-QUAL score assessed by one of the developers of PI-QUAL. RESULTS: There was a significant improvement in average area under the curve for the evaluation of image quality from baseline (0.59 [95 % confidence intervals: 0.50-0.66]) to post-teaching (0.96 [0.92-0.98]), an improvement of 0.37 [0.21-0.41] (p < 0.001). CONCLUSIONS: A teaching course (dedicated lecture + hands-on workshop) on PI-QUAL significantly improved the application of this scoring system to assess the quality of prostate MRI examinations. KEY POINTS: • A significant improvement in the application of PI-QUAL for the assessment of prostate MR image quality was observed after an educational intervention. • Appropriate training on image quality can be delivered to those involved in the acquisition and interpretation of prostate MRI. • Further investigation will be needed to understand the impact on improving the acquisition of high-quality diagnostic prostate MR examinations.

Impact of COVID-19 pandemic on ambulatory urologic oncology surgeries.

INTRODUCTION: Robot-assisted laparoscopic prostatectomy (RALP) and transurethral resection of bladder tumor (TURBT) are two common surgeries for prostate and bladder cancer. We aim to assess the trends in the site of care for RALP and TURBT before and after the COVID outbreak. MATERIALS AND METHODS: We identified adults who underwent RALP and TURBT within the California Healthcare Cost and Utilization Project State Inpatient Database and the State Ambulatory Surgery Database between 2018 and 2020. Multivariable analysis and spline analysis with a knot at COVID outbreak were performed to investigate the time trend and factors associated with ambulatory RALP and TURBT. RESULTS: Among 17,386 RALPs, 6,774 (39.0%) were ambulatory. Among 25,070 TURBTs, 21,573 (86.0%) were ambulatory. Pre-COVID, 33.5% of RALP and 85.3% and TURBT were ambulatory, which increased to 53.8% and 88.0% post-COVID (both p < 0.001). In multivariable model, RALP and TURBT performed after outbreak in March 2020 were more likely ambulatory (OR 2.31, p < 0.0001; OR 1.25, p < 0.0001). There was an overall increasing trend in use of ambulatory RALP both pre- and post-COVID, with no significant change of trend at the time of outbreak (p = 0.642). TURBT exhibited an increased shift towards ambulatory sites post-COVID (p < 0.0001). CONCLUSIONS: We found a shift towards ambulatory RALP and TURBT following COVID outbreak. There was a large increase in ambulatory RALP post-COVID, but the trend of change was not significantly different pre- and post-COVID - possibly due to a pre-existing trend towards ambulatory RALP which predated the pandemic.

Validating the predictors of outcomes after radical cystectomy for bladder cancer.

BACKGROUND: An assessment of surgical risk is essential for patient counseling and decision making, and it can provide rationale adjustment for patient populations as health care moves from a fee-for-service to a value-based reimbursement model. The modified Frailty Index (mFI) has been proposed as a risk-stratification tool for radical cystectomy (RC), and the objective of the current study was to validate this potential use of the mFI using an institutional cohort. METHODS: A retrospective review of all patients who underwent RC for bladder cancer was conducted at the authors' institution from 2012 to 2016. In addition to detailed clinicopathologic and treatment parameters, patients were categorized according to the mFI, the Charlson Comorbidity Index (CCI), and the American Society of Anesthesiologists (ASA) classification. Covariates were analyzed to determine associations with 1-month complication rates (according to the Clavien-Dindo system), 3-month readmission rates, hospitalization length, and hospitalization costs. RESULTS: In total, 346 patients were included in the analysis. The overall complication rate was 56.6%, the major (Clavien grade ≥3) complication rate was 19.4%, and the readmission rate was 27.9%. Receiver operating curve analysis demonstrated a weak association of all indices with major complications after RC: the area under the curve was 0.535 (95% confidence interval [CI], 0.460-0.611) for the ASA classification; 0.565 (95% CI, 0.485-0.645) for the CCI score; and 0.551 (95% CI, 0.471-0.631) for the mFI. There were no significant differences in the rate of major complications when stratifying the results according to the mFI, CCI, or ASA class. Length of hospitalization and associated costs were correlated with mFI. CONCLUSIONS: Frailty was not associated with postoperative complications and provided little additional predictive ability over the ASA classification and the CCI score. Further research is required to identify patients who are likely to suffer significant complications after RC.

Discordance between Ureteroscopic Biopsy and Final Pathology for Upper Tract Urothelial Carcinoma.

PURPOSE: We evaluated the discordance between ureteroscopic biopsy and surgical pathology findings for grading and staging upper tract urothelial carcinoma. We also sought to establish preoperative predictors of aggressive tumors. MATERIALS AND METHODS: We retrospectively reviewed the records of 314 patients who underwent ureteroscopic biopsy followed by surgical management of upper tract urothelial carcinoma from 2000 to 2016 at a total of 3 institutions. Our primary outcomes were muscle invasive (pT2 or greater) disease at surgical pathology and upgrading of clinical low grade tumors to pathological high grade. RESULTS: At biopsy 61% of the patients had clinical high grade tumors and 21% had subepithelial connective tissue invasion (cT1+). On final pathology 79% of the patients had pathological high grade tumors and 45% had stage pT2 or greater. On multivariate analysis advanced patient age, clinical high grade and cT1+ were independently associated with pT2 or greater. The combined presence of clinical high grade and cT1+ had 86% positive predictive value for muscle invasion while the combined absence of clinical high grade and cT1+ had 80% negative predictive value. The likelihood of missing invasion on biopsy in patients with muscle invasive disease was increased when biopsy fragments were limited to 1 mm or less. Of clinical low grade cases on biopsy 51% were upgraded at surgery. The presence of positive urine cytology was associated with an increased risk of upgrading but this was not statistically significant. CONCLUSIONS: Clinical high grade, cT1+ on biopsy and advanced patient age are independent risk factors for muscle invasive upper tract urothelial carcinoma. There is a significant risk of upgrading in patients with clinical low grade tumors on biopsy, especially when urine cytology is positive. The predictive value of biopsy can likely be improved by more extensive ureteroscopic sampling.

The use of blue light flexible cystoscopy with hexaminolevulinate & the diagnosis of bladder cancer.

Blue light cystoscopy improves the detection of bladder cancer at time of transurethral resection of bladder tumor for nonmuscle-invasive bladder cancer. This has translated to decreased tumor recurrence. Given this improvement in rigid cystoscopy, the question remains whether the use of blue light flexible cystoscopy (BLFC) in the surveillance setting provides the same benefits. This review aims to evaluate the recently reported Phase III prospective multicenter study of BLFC which evaluated the detection of bladder cancer during surveillance, which in its earliest reporting demonstrated improved detection of bladder cancer. This study evaluated 304 patients with findings of 63 confirmed malignancies, with 13 (20.6%) only identified by BLFC (p < 0.0001). The question still remains whether the improved detection rate will translate to improved clinical outcomes. Further, studies will be necessary to determine which patients will benefit from BLFC, optimal ways to incorporate into surveillance strategies and cost-effectiveness.

'7-flap' perineal urethrostomy: an effective option for obese men with devastated urethras.

INTRODUCTION: To present an updated experience using our previously reported lateral perineal '7-flap' technique for perineal urethrostomy (PU), highlighting its role in a variety of patients with advanced urethral stricture disease. MATERIALS AND METHODS: All patients who underwent 7-flap PU from 2009-2013 were reviewed. PU was constructed by advancing a "7"-shaped laterally based perineal skin flap into a spatulated, amputated bulbomembranous urethra. The contralateral side of the amputated proximal urethra was then matured to the advanced perineal skin. Patients were stratified by body mass index (BMI) and outcomes were compared. RESULTS: Among 748 patients undergoing urethroplasty during the study period, 22 men (2.9%; mean age 61, range 31-80) received a 7-flap PU for advanced stricture disease (mean follow up 32 months). A majority of patients (14/22, 64%) were obese (BMI = 30). Disease etiologies consisted primarily of lichen sclerosus (9/22, 41%) while 6/22 (27%) had failed prior urethral reconstructions elsewhere. Mean operative time was 108 min (range 54-214), mean estimated blood loss (EBL) was 76 cc (30-200), and all patients were discharged immediately after surgery. Urethrostomy creation was possible in all patients regardless of BMI (mean 33, range 22-43), and there were no differences with regards to EBL (p = 0.71), operative time (p = 0.38), or success rate (p = 0.76) in obese versus non-obese patients undergoing 7-flap PU. Nearly all patients (21/22, 95%) are voiding spontaneously on follow up without the need for any additional procedure. CONCLUSION: In our updated experience, performance of 7-flap urethrostomy has resulted in durable long term success with acceptable performance in technically challenging cases.

Impact of Angiotensin Converting Enzyme Inhibitors on Pathologic Complete Response With Neoadjuvant Chemotherapy for Muscle Invasive Bladder Cancer.

INTRODUCTION: The renin-angiotensin system (RAS) has been demonstrated to modulate cell proliferation, desmoplasia, angiogenesis and immunosuppression. We examined the association of RAS inhibitors (RASi)-namely angiotensin converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB)-with neoadjuvant chemotherapy (NAC) for muscle-invasive bladder cancer (MIBC) preceding radical cystectomy (RC). PATIENTS AND METHODS: We retrospectively investigated concurrent RASi use with NAC prior to RC in 302 patients with MIBC from 3 academic institutions. Outcomes included pathologic complete response (pCR) and overall survival (OS). Pathologic features, performance status (PS), clinical stage, type/number of cycles of NAC, and toxicities were collected. RESULTS: Overall pCR rate was 26.2% and 5-year OS was 62%. Concurrent ACEi intake with NAC approached significance for association with pCR (odds ratio [OR] = 1.71; 95% CI, 0.94-3.11; P = .077). Patients with cT3/4N0-N1 disease receiving ACEi had higher pCR rates (30.8% vs. 17.7%, P = .056) than those not on ACEi. Female sex had a statistically significant favorable interaction for pCR with ACEi intake (P = .044). ACEi intake was not associated with OS, while pCR, PS and lower clinical stage were significantly associated with improved OS. CONCLUSION: ACEi intake is potentially associated with increased pCR in patients with MIBC receiving NAC prior to RC, and this association is more pronounced in patients with higher clinical stage of disease at the initiation of therapy and female sex. Our data suggest the potential relevance of the RAS as a therapeutic target in aggressive MIBC.

Changes in the Perioperative Management and Outcomes of Patients With Upper Tract Urothelial Carcinoma Undergoing Radical Nephroureterectomy at Memorial Sloan Kettering Cancer Center: Over 20 Years of Experience.

INTRODUCTION: We evaluated surgical trends, perioperative management evolution, and oncologic outcomes in patients who underwent radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC) at a tertiary cancer center over a 24-year period. METHODS: Between 1995 and 2018, we evaluated 743 consecutive patients with UTUC who underwent RNU. Generalized additive models were used to estimate the associations between date of surgery and continuous outcomes using a linear model, dichotomous outcomes using a logit link, categorical outcomes using multinomial models, and 2- and 5-year survival outcomes using Cox proportional hazards models. RESULTS: Over the study period, preoperative diagnostic endoscopic biopsies increased from 10% to 66%, along with the proportion of patients who underwent RNU for high-grade disease from 55% to 91%. The rate of open RNU declined from 100% to 56% with a rise in minimally invasive approaches. Median lymph node yield increased with more retroperitoneal lymph node dissections performed. Neoadjuvant chemotherapy utilization increased with a contemporary utilization rate of 32%, coinciding with an increase in pT0 rate from 2% to 8%. Cancer-specific survival probabilities improved over the study period, while metastasis-free and overall survival remained stable. CONCLUSIONS: We found several changes in treatment patterns and outcomes for patients with UTUC over the past 2 decades. How individual alterations in management factors, such as patient selection, perioperative chemotherapy, lymphadenectomy, and salvage therapies, impact patient outcomes is challenging in the setting of multiple overlapping practice changes for this rare disease and warrants further investigation.

Natural History and Genomic Landscape of Chemotherapy-Resistant Muscle-Invasive Bladder Cancer.

PURPOSE: Patients with residual invasive bladder cancer after neoadjuvant chemotherapy (NAC) and radical cystectomy have a poor prognosis. Data on adjuvant therapy for these patients are conflicting. We sought to evaluate the natural history and genomic landscape of chemotherapy-resistant bladder cancer to inform patient management and clinical trials. METHODS: Data were collected on patients with clinically localized muscle-invasive urothelial bladder cancer treated with NAC and cystectomy at our institution between May 15, 2001, and August 15, 2019, and completed four cycles of gemcitabine and cisplatin NAC, excluding those treated with adjuvant therapies. Survival was estimated using the Kaplan-Meier method, and multivariable Cox proportional hazards models were used to identify predictors of recurrence-free survival (RFS). Genomic alterations were identified in targeted exome sequencing (Memorial Sloan Kettering Integrated Mutation Profiling of Actionable Cancer Targets) data from post-NAC specimens from a subset of patients. RESULTS: Lymphovascular invasion (LVI) was the strongest predictor of RFS (hazard ratio, 2.15 [95% CI, 1.37 to 3.39]) on multivariable analysis. Patients with ypT2N0 disease without LVI had a significantly prolonged RFS compared with those with LVI (70% RFS at 5 years). Lymph node yield did not affect RFS. Among patients with sequencing data (n = 101), chemotherapy-resistant tumors had fewer alterations in DNA damage response genes compared with tumors from a publicly available chemotherapy-naïve cohort (15% v 29%; P = .021). Alterations in CDKN2A/B were associated with shorter RFS. PIK3CA alterations were associated with LVI. Potentially actionable alterations were identified in more than 75% of tumors. CONCLUSION: Although chemotherapy-resistant bladder cancer generally portends a poor prognosis, patients with organ-confined disease without LVI may be candidates for close observation without adjuvant therapy. The genomic landscape of chemotherapy-resistant tumors is similar to chemotherapy-naïve tumors. Therapeutic opportunities exist for targeted therapies as adjuvant treatment in chemotherapy-resistant disease.

Impact of exercise on physical health status in bladder cancer patients.

INTRODUCTION: There is a scarcity of data on the impact of behavioral habits, such as exercise, on physical health in patients with bladder cancer. We investigated the association of exercise on self-reported physical health status and examined the prevalence of bladder cancer patients with sedentary lifestyle. METHODS: We examined cross-sectional data of participants diagnosed with bladder cancer within the Behavioral Risk Factor Surveillance System (BRFSS) from 2016-2020. Patient health status was surveyed using self-reported measures, such as the total days per month when their "physical health is not good." The primary outcome was patient-reported poor physical health for more than 14 days within a one-month period. RESULTS: Out of 2 193 981 survey participants, we identified 936 with a history of bladder cancer. Nearly one in three bladder cancer patients reported being sedentary within the last month, as a total of 307 (32.8%) patients reported no exercise within the last 30 days. The remaining 628 (67.2%) reported exercising for at least one day within the last month. In multivariable logistic regression model analysis, we found that exercise is protective for self-reported poor physical health status (odds ratio 0.37, 95% confidence interval 0.25-0.56, p<0.001). Patients that exercised were less likely to report bad physical health. CONCLUSIONS: Approximately one in three bladder cancer patients report no exercise within 30 days, suggesting a sedentary lifestyle. Patients that are active are less likely to self-report poor physical health status. Implementation of exercise programs for bladder cancer patients could be promising in improving health status.

Evidence-Based Analysis of the Critical Steps of Radical Cystectomy for Bladder Cancer.

Radical cystectomy (RC) is an integral part of the management of patients with advanced-stage bladder cancer. This major oncologic operation is prone to complications resulting in morbidity and mortality. We analyzed the critical steps of open RC, performed an evidence-based review of these steps, and discussed our experience and approach. We conducted a literature review of the open RC technique, identified the critical steps that consistently appeared across different sources, and organized these steps into a framework. PubMed was queried with the critical steps as keywords for relevant articles published from 1 January 2013 to 1 August 2023. We utilized this query to conduct a systematic review of the literature using the outcomes of overall survival and 90-day complication rate. We developed the "Summary for the 10 Critical Operative Steps of Radical Cystectomy", a concise guide to the approach to open RC. When available, an evidence-based analysis of each critical step was performed. We also included additional components of cystectomy optimization such as pre-habilitation in the preoperative phase, standard versus extended lymphadenectomy, the vaginal-sparing approach to female radical cystectomy, patient-reported outcomes following urinary diversion, the use of a mesh for stoma formation, and the use of the ERAS protocol for postoperative care. An evidence-based assessment of RC may help provide valuable information to optimize surgical techniques and patient outcomes.

Anticoagulation prophylaxis patterns following retroperitoneal lymph node dissection for testis cancer.

INTRODUCTION: Retroperitoneal lymph node dissection (RPLND) is the standard of care for testicular cancer in various disease settings. Deep vein thrombosis (DVT) complications have been reported to occur in <1% of primary RPLND cases and up to 3% of postchemotherapy (PC-RPLND) cases. While prophylactic anticoagulation (AC) has been well-documented to reduce DVT rates in patients undergoing surgery in general, the benefit of prophylactic AC in RPLND has not been assessed. In this retrospective cohort study, we seek to address this unmet need by evaluating the rates and associated risk factors of DVT and pulmonary embolism (PE) with a national and institutional database, assess the changing patterns in DVT prophylaxis with postoperative AC following RPLND, and quantify the potential benefit of prophylactic AC in patients who have undergone RPLND using a risk-stratified approach. METHODS: The National Surgical Quality Improvement Program (NSQIP) database was queried for patients who underwent RPLND during the 10-year period from 2011 to 2021. An institutional database was queried for all patients undergoing RPLND from 2013 to 2022. Patient characteristics and operative outcomes were compared between the NSQIP and the institutional database. The institutional database was stratified by prior oncologic treatment (i.e., primary RPLND vs. PC-RPLND) and outcomes were compared. Postoperative AC rate was determined and trended by year. The use of postoperative AC and PE events were stratified by clinical stage. The absolute risk reduction (ARR) of AC prophylaxis on PE events and the number needed to treat (NNT) with AC prophylaxis to prevent a single PE event was determined. RESULTS: In total, the NSQIP database query resulted in 779 patients and our institutional database query resulted in 188 patients. The rate of DVT and PE was 1.2% and 0.5% vs. 2.1% and 1.6% in the NSQIP and institutional cohort, respectively. The rate of postoperative AC following RPLND in patients from the institutional database increased from 5% in 2013 to 43% in 2022 (P = 0.01). There were no statistically significant differences in complication rates, including bleeding events, chyle leaks, or hospital readmissions amongst patients who were prescribed AC at discharge and those who were not. No stage I patients developed PEs and no stage I patients were prescribed AC. The ARR for AC prophylaxis for development of PE was found to be 0.023 for the clinical stage II and stage III cohorts. The NNT to prevent a single PE with AC was 44 and 43 for the stage II and stage III cohorts, respectively. CONCLUSIONS: AC appears beneficial with minimal risk of harm after RPLND, especially in patients with higher risk of developing DVT/PE, highlighting the safety and efficacy of this regimen. There was a significant increase in the rate of AC prophylaxis at discharge amongst patients undergoing RPLND in the institutional database from 2013 to 2022. A risk-stratified protocol of postoperative AC following RPLND appears reasonable, and further prospective trials are warranted to formally confirm this recommendation.

Sequential intravesical gemcitabine/docetaxel provides a durable remission in recurrent high-risk NMIBC following BCG therapy.

PURPOSE: Bacillus Calmette-Guerin (BCG) is the standard of care for high-risk nonmuscle invasive bladder cancer (NMIBC), but half of patients develop disease recurrence. Intravesical regimens for BCG unresponsive NMIBC are limited. We report the safety, efficacy, and differential response of sequential gemcitabine/docetaxel (gem/doce) depending on BCG failure classification. METHODS: Multi-institutional retrospective analysis of patients treated with induction intravesical gem/doce (≥5/6 instillations) for recurrent high-risk NMIBC after BCG therapy from May 2018 to December 2021. Maintenance therapy was provided to those without high-grade (HG) recurrence on surveillance cystoscopy. Kaplan-Meier curves and Cox regression analyses were utilized to assess survival and risk factors for disease recurrence. RESULTS: Our cohort included 102 patients with BCG-unresponsive NMIBC. Median age was 72 years and median follow-up was 18 months. Six-, 12-, and 24-month high-grade recurrence-free survival was 78%, 65%, and 49%, respectively. Twenty patients underwent radical cystectomy (median 15.5 months from induction). Six patients progressed to muscle invasive disease. Fifty-seven percent of patients experienced mild/moderate adverse effects (AE), but only 6.9% experienced a delay in treatment schedule. Most common AE were urinary frequency/urgency (41%) and dysuria (21%). Patients with BCG refractory disease were more likely to develop HG recurrence when compared to patients with BCG relapsing disease (HR 2.14; 95% CI 1.02-4.49). CONCLUSIONS: In patients with recurrence after BCG therapy, sequential intravesical gem/doce is an effective and well-tolerated alternative to early cystectomy. Patients with BCG relapsing disease are more likely to respond to additional intravesical gem/doce. Further investigation with a prospective trial is imperative.

Inherited Germline Cancer Susceptibility Gene Variants in Individuals with Non-Muscle-Invasive Bladder Cancer.

PURPOSE: Identification of inherited germline variants can guide personalized cancer screening, prevention, and treatment. Pathogenic and likely pathogenic (P/LP) germline variants in cancer predisposition genes are frequent among patients with locally advanced or metastatic urothelial carcinoma, but their prevalence and significance in patients with non-muscle-invasive bladder cancer (NMIBC), the most common form of urothelial carcinoma, is understudied. EXPERIMENTAL DESIGN: Germline analysis was conducted on paired tumor/normal sequencing results from two distinct cohorts of patients initially diagnosed with NMIBC. Associations between clinicopathologic features and clinical outcomes with the presence of P/LP germline variants in ≥76 hereditary cancer predisposition genes were analyzed. RESULTS: A similar frequency of P/LP germline variants were seen in our two NMIBC cohorts [12% (12/99) vs. 8.7% (10/115), P = 0.4]. In the combined analysis, P/LP germline variants were found only in patients with high-grade NMIBC (22/163), but none of the 46 patients with low-grade NMIBC (13.5% vs. 0%, P = 0.005). Fifteen (9.2%) patients with high-grade NMIBC had P/LP variants in DNA damage response genes, most within the nucleotide excision repair (ERCC2/3) and homologous recombination repair (BRCA1, NBN, RAD50) pathways. Contrary to prior reports in patients with NMIBC not receiving Bacillus Calmette-Guerin (BCG), P/LP germline variants were not associated with worse recurrence-free or progression-free survival in patients treated with BCG or with risk of developing upper tract urothelial carcinoma. CONCLUSIONS: Our results support offering germline counseling and testing for all patients with high-grade bladder cancer, regardless of initial tumor stage. Therapeutic strategies that target impaired DNA repair may benefit patients with high-grade NMIBC.

Genomic heterogeneity as a barrier to precision oncology in urothelial cancer.

Precision oncology relies on the accurate molecular characterization of individual patients with cancer at the time of treatment initiation. However, tumor molecular profiles are not static, and cancers continually evolve because of ongoing mutagenesis and clonal selection. Here, we performed genomic analyses of primary tumors, metastases, and plasma collected from individual patients to define the concordance of actionable genomic alterations and to identify drivers of metastatic disease progression. We observed a high degree of discordance of actionable genomic alterations, with 23% discordant between primary and metastatic disease sites. Among chromatin-modifying genes, ARID1A mutations, when discordant, were exclusive to the metastatic tumor samples. Our findings indicate that the high degree of lesion-to-lesion genomic heterogeneity may be a barrier to precision oncology approaches for bladder cancer and that circulating tumor DNA profiling may be preferred to tumor sequencing for a subset of patients.

FOXA1 repression drives lineage plasticity and immune heterogeneity in bladder cancers with squamous differentiation.

Cancers arising from the bladder urothelium often exhibit lineage plasticity with regions of urothelial carcinoma adjacent to or admixed with regions of divergent histomorphology, most commonly squamous differentiation. To define the biologic basis for and clinical significance of this morphologic heterogeneity, here we perform integrated genomic analyses of mixed histology bladder cancers with separable regions of urothelial and squamous differentiation. We find that squamous differentiation is a marker of intratumoral genomic and immunologic heterogeneity in patients with bladder cancer and a biomarker of intrinsic immunotherapy resistance. Phylogenetic analysis confirms that in all cases the urothelial and squamous regions are derived from a common shared precursor. Despite the presence of marked genomic heterogeneity between co-existent urothelial and squamous differentiated regions, no recurrent genomic alteration exclusive to the urothelial or squamous morphologies is identified. Rather, lineage plasticity in bladder cancers with squamous differentiation is associated with loss of expression of FOXA1, GATA3, and PPARG, transcription factors critical for maintenance of urothelial cell identity. Of clinical significance, lineage plasticity and PD-L1 expression is coordinately dysregulated via FOXA1, with patients exhibiting morphologic heterogeneity pre-treatment significantly less likely to respond to immune checkpoint inhibitors.

Novel Classification for Upper Tract Urothelial Carcinoma to Better Risk-stratify Patients Eligible for Kidney-sparing Strategies: An International Collaborative Study.

BACKGROUND: The European Association of Urology risk stratification dichotomizes patients with upper tract urothelial carcinoma (UTUC) into two risk categories. OBJECTIVE: To evaluate the predictive value of a new classification to better risk stratify patients eligible for kidney-sparing surgery (KSS). DESIGN, SETTING, AND PARTICIPANTS: This was a retrospective study including 1214 patients from 21 centers who underwent ureterorenoscopy (URS) with biopsy followed by radical nephroureterectomy (RNU) for nonmetastatic UTUC between 2000 and 2017. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: A multivariate logistic regression analysis identified predictors of muscle invasion (≥pT2) at RNU. The Youden index was used to identify cutoff points. RESULTS AND LIMITATIONS: A total of 811 patients (67%) were male and the median age was 71 yr (interquartile range 63-77). The presence of non-organ-confined disease on preoperative imaging (p < 0.0001), sessile tumor (p < 0.0001), hydronephrosis (p = 0.0003), high-grade cytology (p = 0.0043), or biopsy (p = 0.0174) and higher age at diagnosis (p = 0.029) were independently associated with ≥pT2 at RNU. Tumor size was significantly associated with ≥pT2 disease only in univariate analysis with a cutoff of 2 cm. Tumor size and all significant categorical variables defined the high-risk category. Tumor multifocality and a history of radical cystectomy help to dichotomize between low-risk and intermediate-risk categories. The odds ratio for muscle invasion were 5.5 (95% confidence interval [CI] 1.3-24.0; p = 0.023) for intermediate risk versus low risk, and 12.7 (95% CI 3.0-54.5; p = 0.0006) for high risk versus low risk. Limitations include the retrospective design and selection bias (all patients underwent RNU). CONCLUSIONS: Patients with low-risk UTUC represent ideal candidates for KSS, while some patients with intermediate-risk UTUC may also be considered. This classification needs further prospective validation and may help stratification in clinical trial design. PATIENT SUMMARY: We investigated factors predicting stage 2 or greater cancer of the upper urinary tract at the time of surgery for ureter and kidney removal and designed a new risk stratification. Patients with low or intermediate risk may be eligible for kidney-sparing surgery with close follow-up. Our classification scheme needs further validation based on cancer outcomes.