Induction and maintenance of sequential intravesical gemcitabine/docetaxel for intermediate and high-risk non-muscle invasive bladder cancer with different dosage protocols.

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.

Surveillance for Nonmuscle Invasive Bladder Cancer: Identifying the Point of Diminishing Returns.

OBJECTIVE: To characterize first and second recurrence patterns using 26years of cohort-level follow-up and microsimulation modeling. METHODS: Patients diagnosed with nonmuscle-invasive bladder cancer in Stockholm County between 1995 and 1996 were included. Clinical, pathological, and longitudinal follow-up data were gathered. Logistic regressions, Kaplan Meier curves, and Cox proportional hazards models were run to generate assumptions for a microsimulation model, simulating first and second recurrence and progression for 10,000 patients. RESULTS: Three hundred eighty-six patients were included: 67.4% were male; >50% were TaLG; and 37.5% were American Urological Association high-risk. Median time to recurrence was 300days. Three patients had missing data. Cohort follow-up has been carried out for 26years. For simulated first-recurrences, low-risk patients recurred at 56.6% over 15years of follow-up, with 2.2% muscle-invasive (MI) progression; intermediate-risk patients recurred at 62.8%, with 4.3% MI progression; high-risk patients recurred at 48.7% over 15years, with MI progression at 14.3%. For second recurrences, 70.7%, 75.7%, and 84.7% of low, medium, and high-risk patients recurred. No patients were seen to have first recurrences after 9years, with low, but notable, rates beyond 5years. CONCLUSION: These data suggest that low-, intermediate-, and high-risk patients without recurrence at 5years may be potentially transitioned to less invasive monitoring.

Factors that influence preference for male or female urologist among underserved patients in New York City.

Objective: To examine the prevalence of patient preference for male or female urologic provider and explore which patient characteristics influence this preference. Materials and Methods: After obtaining hospital Institutional Review Board approval, a 14-question survey in English and Spanish was administered across four general urology clinic sites in a single hospital system in New York City. The survey asked demographic questions and preference for a male or a female urologist. The survey included questions pertaining to the nature of the clinic visit and subsequent provider preference as well. Statistics were performed using Stata 16 (StataCorp, College Station, TX). Results: A total of 540 patients completed the 14-question survey. The vast majority of survey respondents identified as male (90%). The largest proportion demographic groups were those aged 41-60 (47%), Hispanic or Latino (43%), Catholic (47%), unemployed (40%) and those with a high school level of education (34%). Most patients (60%) did not have a preference for a specific gender provider, whereas 37% preferred a male provider, and 3% preferred a female provider. On univariate analysis, patient age 25-40, less than high school education level and lack of employment were significant predictors of provider gender preference (p < 0.05), with most patients indicating a male provider preference. On multivariate analysis of gender, age, education level and employment status, gender and education level were not significant predictors of preference, whereas age 25-40 and being unemployed were significant predictors (p < 0.05). Conclusion: Patient gender, race and religion do not appear to influence their preference to be seen by a male or a female urologist in the clinic setting. However, patient age, unemployment and potentially educational attainment were significantly associated with a provider gender preference.

Midline submuscular penile prosthesis reservoir placement for patients with bilateral inaccessible inguinal rings: technique and outcomes.

Introduction: One of the most challenging aspects of inflatable penile prosthesis (IPP) surgery is reservoir placement. The traditional space of Retzius (SOR) is not suitable for all patients. For example, radical cystectomy or prostatectomy may alter the anatomical SOR. Hence, traditional placement of the reservoir in this space increases the risk of bowel or vascular injury. Also, patients with bilateral inguinal hernias repaired with mesh, or those with previous reservoirs that have been retained, are not eligible for a Retzius reservoir. Our study reports on the use of midline sub-rectus muscle placement of a penile prosthesis reservoir in these patients as an alternative to high submuscular placement commonly used. Methods: A retrospective chart review of male patients who underwent IPP surgery between June 2017 and 2021 was conducted. Patients were divided into two groups based on the location of the reservoir: SOR versus Midline Submuscular Reservoir (MSMR). Complication rates were compared, including herniated reservoirs, infections, bowel injuries, and vascular injuries. Results: Our cohort included 461 patients who underwent IPP surgery between June 2017 and 2021 in one tertiary center. SOR was used in 89% of patients and MSMR in 11% of patients (n = 413 and 48, respectively). Median follow-up for all patients was 28 months. The mean age was 67 ± 8 years. There was no statistically significant difference between the two groups regarding age or comorbidities (BMI, diabetes mellitus, hypertension, hyperlipidemia, and coronary artery disease). The complication rate was low in both the SOR and MSMR groups, with device malfunction being the most common (2% versus 4%, respectively; p = 0.32). The infection rate was 0.5% in the SOR group with no infections in the MSMR group (NS). There was only one case of herniation requiring surgical revision in the SOR group and no cases of bowel or vascular injury. Conclusion: Placement of a penile prosthesis reservoir within a midline rectus submuscular space is a safe and effective technique when the SOR is compromised by previous surgery or bilateral inguinal canals are not accessible.

Isolated corpora cavernosa germ cell tumor metastasis requiring complex excision and reconstruction.

Germ cell tumors (GCT) are rare, frequently diagnosed in men aged 20-34 years old, and have a 95% 5-year relative survival rate. Metastasis from GCT has predictable spread to retroperitoneal lymph nodes. However, in cases of scrotal violation or tumor spillage, lymphatic drainage can be altered. Beyond the retroperitoneum, the most reported extra-nodal sites of metastases include the liver, lung, brain, and bone. Here we report a case of an unusual site of metastasis to the corpora cavernosa, as well as the complex reconstruction required to preserve sexual function.

Elevated T-cell Exhaustion and Urinary Tumor DNA Levels Are Associated with Bacillus Calmette-Guérin Failure in Patients with Non-muscle-invasive Bladder Cancer.

BACKGROUND: The functional status of immune cells in the tumor microenvironment and tumor characteristics may explain bacillus Calmette-Guérin (BCG) failure in high-risk non-muscle-invasive bladder cancer (NMIBC). OBJECTIVE: To characterize molecular correlates of post-BCG high-grade (HG) recurrence using multiomics analysis. DESIGN, SETTING, AND PARTICIPANTS: Patients with BCG-treated NMIBC (n = 156) were included in the study. Metachronous tumors were analyzed using RNA sequencing (n = 170) and whole-exome sequencing (n = 195). Urine samples were analyzed for immuno-oncology-related proteins (n = 190) and tumor-derived DNA (tdDNA; n = 187). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was post-BCG HG recurrence. Cox regression and Wilcoxon rank-sum, t, and Fisher's exact tests were used for analyses. RESULTS AND LIMITATIONS: BCG induced activation of the immune system regardless of clinical response; however, immunoinhibitory proteins were observed in the urine of patients with post-BCG HG recurrence (CD70, PD1, CD5). Post-BCG HG recurrence was associated with post-BCG T-cell exhaustion (p = 0.002). Pre-BCG tumors from patients with post-BCG T-cell exhaustion had high expression of genes related to cell division and immune function. A high predicted post-BCG exhaustion score for pre-BCG tumors was associated with worse post-BCG HG recurrence-free survival (HGRFS; p = 0.002). This was validated in independent cohorts. Pre-BCG class 2a and 2b tumors (UROMOL2021 scheme) were associated with worse post-BCG HGRFS (p = 0.015). Post-BCG exhaustion was observed in patients with high pre-BCG neoantigen load (p = 0.017) and MUC4 mutations (p = 0.002). Finally, the absence of post-BCG tdDNA clearance identified patients at high risk of recurrence (p = 0.018). The retrospective design and partial overlap for analyses are study limitations. CONCLUSIONS: Post-BCG HG recurrence may be caused by T-cell exhaustion. Tumor subtype and pre-BCG tumor characteristics may identify patients at high risk of post-BCG HG recurrence. Urinary measurements have potential for real-time assessment of treatment response. PATIENT SUMMARY: A dysfunctional immune response to bacillus Calmette-Guérin (BCG) therapy may explain high-grade recurrences of bladder cancer.

NKG2A and HLA-E define an alternative immune checkpoint axis in bladder cancer.

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.

Natural killer cells: unlocking new treatments for bladder cancer.

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.

Neobladder creation in patients with chronic kidney disease: A viable diversion strategy.

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.