Long-Term Oncological Outcomes in Patients Diagnosed With Nonmetastatic Plasmacytoid Variant of Bladder Cancer: A 20-Year University of Texas MD Anderson Cancer Center Experience.

PURPOSE: The treated natural history of nonmetastatic plasmacytoid variant of bladder cancer (PV-BCa) is poorly understood owing to its rarity. We sought to examine the disease recurrence and metastasis patterns in this select group of patients in order to identify opportunities for intervention. MATERIALS AND METHODS: We conducted a natural language processing algorithm-augmented retrospective chart review of 56 consecutive patients who were treated with curative intent for nonmetastatic PV-BCa at our institution between 1998 and 2018. Kaplan-Meier and multivariable Cox regression methods were used for survival analyses. RESULTS: The stage at presentation was: ≤ cT2N0 in 22 (39.3%), cT3N0 in 15 (26.8%), cT4N0 in 13 (23.2%), and ≥ cN1 in 6 patients (10.7%). Forty-nine patients (87.5%) received chemotherapy, and 42 (75%) were able to undergo the planned surgery. Notably, only 4 patients (7.2%) had pT0 stage, while 22 (52.4%) had pN+ disease at the time of surgery. At 36-month follow-up, 28.4% of patients (95% CI: 22.1%-34.5%) were alive and 22.2% (95% CI: 16.1%-28.5%) were free of metastatic disease. The benefit of surgical extirpation was stage specific: successful completion of surgery was associated with improved metastasis-free survival (at 36 months 32.4% vs 0%, log-rank P < .001) in patients with localized or locally advanced disease (≤cT2N0/cT3N0); however, in patients with regionally advanced disease (cT4N0/≥cN1), consolidative surgery following chemotherapy was not associated with improved metastasis-free survival (12.5% vs 10% at 36 months, log-rank P = .49). The median time to metastasis from primary treatment end was 6.5 months (IQR: 2.9-14.7). The predominant site of recurrence/metastasis was the peritoneum (76.1%), either in isolation or along with extraperitoneal lesions. Salvage immunotherapy in these patients significantly reduced the risk of death (HR = 0.11, P = .001). CONCLUSIONS: PV-BCa is a disease with high lethality. Despite multimodal treatment, a vast majority of patients develop atypical intraperitoneal metastasis soon after therapy and rapidly succumb to it. Clinical trials evaluating utility of hyperthermic intraperitoneal chemotherapy and/or immunotherapy may be warranted in this high-risk population.

Impact of age >70 years on oncological outcomes in patients with non-muscle-invasive bladder cancer treated with Bacillus Calmette-Guérin.

OBJECTIVE: To evaluate the impact of age on oncological outcomes in a large contemporary cohort of patients with non-muscle-invasive bladder cancer (NMIBC) treated with adequate Bacillus Calmette-Guérin (BCG). PATIENTS AND METHODS: We performed an Institutional Review Board-approved retrospective study analysing patients with NMIBC treated with adequate BCG at our institution from 2000 to 2020. Adequate BCG was defined as per United States Food and Drug Administration (FDA) guidelines as being receipt of at least five of six induction BCG instillations with a minimum of two additional doses (of planned maintenance or of re-induction) of BCG instillations within a span of 6 months. The study's primary outcome was to determine if age >70 years was associated with progression to MIBC cancer or distant metastasis. The cumulative incidence method and the competing-risk regression analyses were used to investigate the association of advanced age (>70 years) with progression, high-grade (HG) recurrence and cancer-specific mortality (CSM). RESULTS: Overall, data from 632 patients were analysed: 355 patients (56.2%) were aged ≤70 years and 277 (43.8%) were >70 years. Age >70 years did not adversely affect either cumulative incidence of progression or HG recurrence (P = 0.067 and P = 0.644, respectively). On competing-risk regression analyses, age >70 years did not emerge as an independent predictor of progression or HG recurrence (sub-standardised hazard ratio [SHR] 1.57, 95% confidence interval [CI] 0.87-2.81, P = 0.134; and SHR 1.05, 95% CI 0.77-1.44, P = 0.749). Not unexpectedly, patients in the older group did have higher overall mortality (P < 0.001) but not CSM (P = 0.057). CONCLUSION: Age >70 years was not associated with adverse oncological outcomes in a large contemporary cohort of patients receiving adequate intravesical BCG for NMIBC. BCG should not be withheld from older patients seeking for bladder sparing options.

Influence of lamina propria invasion extension on T1 high-grade non-muscle-invasive bladder cancer in patients undergoing BCG or radical cystectomy.

OBJECTIVE: To evaluate the prognostic value of T1 substaging in patients treated with bacillus Calmette-Guérin (BCG) or immediate radical cystectomy (iRC). MATERIALS AND METHODS: We performed an institutional review board-approved retrospective study analysing non-muscle-invasive bladder cancer (NMIBC) patients with pT1 disease treated with either BCG or iRC between 2000 and 2020. Lamina propria (LP) invasion characteristics were extracted from the pathology report. The Kaplan-Meier method was used to calculate overall survival (OS), cancer-specific survival (CSS) and metastasis-free survival (MFS). Multivariable Cox models were used to determine the association between progression-free survival (PFS) and characteristics in the BCG cohort. A logistic regression model explored the relationship between T1 substaging and upstaging to >pT2 at iRC. RESULTS: A total of 411 T1 high-grade patients were identified. LP invasion characteristics were as follows: not specified: 115 (28%); focal/superficial (F/S): 147 (35.8%); and extensive/multifocal (E/M): 149 (36.2%). Overall, 303 patients (73.7%) received BCG, and 108 patients (26.3%) underwent iRC. The median (interquartile range) follow-up was 53 (32-96) months. Patients with E/M LP invasion were significantly more likely to undergo iRC (34% vs. 19%; P = 0.003). Patients with E/M LP invasion showed poorer MFS and CSS compared to those with F/S LP invasion when treated with BCG but not when treated with iRC. Among BCG-treated patients, progression occurred in 41 patients and E/M LP invasion was independently associated with progression after BCG (hazard ratio 5.3, 95% confidence interval [CI] 2.2-13.1; P < 0.001). T1 substaging was not associated with upstaging at RC (odds ratio 3.15, 95% CI 0.82-12.12; P = 0.095). CONCLUSIONS: Extensive/multifocal LP invasion was associated with poor PFS, MFS and CSS in patients treated with BCG. T1 substaging provides valuable prognostic information and should be reported in pathology reports.

Repeat Transurethral Resection of Muscle-invasive Bladder Cancer Prior to Radical Cystectomy is Prognostic but Not Therapeutic.

PURPOSE: We sought to evaluate the impact of repeat transurethral resection of bladder tumor prior to radical cystectomy on oncologic outcomes in a contemporary cohort at a tertiary care center. MATERIALS AND METHODS: An Institutional Review Board approved review of 657 patients diagnosed with muscle-invasive bladder cancer who underwent radical cystectomy at our institution for clinical stage T2 urothelial carcinoma between 2005 and 2017 was performed. Patients with and without repeat transurethral resection of bladder tumor were matched 1-to-1 by propensity score. Matching was done by age, gender, receipt of neoadjuvant chemotherapy, preoperative hydronephrosis, variant histology, lymphovascular invasion, or carcinoma in situ on index transurethral resection of bladder tumor. RESULTS: A total of 548 patients with muscle-invasive bladder cancer were included after matching (2 groups of 274 patients). Kaplan-Meier estimates of recurrence-free and overall survival demonstrated no significant difference based upon performance of repeat transurethral resection of bladder tumor (P = 1.0 and P = .3, respectively). When outcomes were stratified by pathology of repeat transurethral resection of bladder tumor specimens, those with pT0 had superior recurrence-free and overall survival compared to those with residual muscle invasive disease (P < .001 and P = .001, respectively). Notably, more than 60% of patients who were pT0 on repeat transurethral resection of bladder tumor had residual disease at the time of radical cystectomy. CONCLUSIONS: Repeat transurethral resection of bladder tumor prior to radical cystectomy, irrespective of receipt of neoadjuvant chemotherapy, was not associated with improved survival outcomes in this propensity score matched muscle-invasive bladder cancer cohort. The absence of residual tumor on pathological evaluation of repeat transurethral resection of bladder tumor specimen was prognostic and was associated with improved survival outcomes. However, a large percentage of patients with pT0 disease on repeat transurethral resection of bladder tumor had residual disease on radical cystectomy pathology.

All High-Grade Ta Tumors Should Be Classified as High Risk: Bacillus Calmette-Guérin Response in High-Grade Ta Tumors.

PURPOSE: There is variation amongst guidelines with respect to risk stratification of Ta tumors, specifically high-grade (HG) Ta tumors. We sought to investigate the response of all Ta tumors to bacillus Calmette-Guérin (BCG) and compare response rates based on European Association of Urology (EAU) classification as intermediate- (IR) or high-risk (HR). MATERIALS AND METHODS: An institutional review of all patients who received adequate BCG from 2000-2018 was conducted. EAU 2021 prognostic risk groups were used to stratify patients including by the newly proposed adverse risk factors. RESULTS: When patient with Ta tumors were stratified into IR and HR, 37 (16%) had IR low-grade (LG) Ta, 92 (40%) had IR HG Ta and 101 (44%) had HR HG Ta tumors. BCG unresponsiveness developed in 13% of HR HG Ta tumors and 14% of IR HG Ta tumors compared to 0.0% of IR LG Ta tumors (p=0.003). While no patients with IR LG Ta tumors progressed, progression rates were similar in HR HG Ta and IR HG Ta tumors (≥T2: 5.9% and 6.5%; [Formula: see text]T1: 13% and 13%, respectively). Rates of recurrence, BCG unresponsiveness and progression were similar, irrespective of number of EAU risk factors present (p=0.9, p=0.8 and p=0.9, respectively). CONCLUSIONS: All HG Ta tumors, regardless of EAU risk stratification, have inferior response to BCG and increased rates of progression compared to IR LG Ta tumors. EAU clinical risk factors did not improve prediction of oncologic outcomes among HG Ta patients who received adequate BCG. These data support consideration of all HG tumors as high risk.

Role of Lymphadenectomy during Radical Cystectomy for Nonmuscle-Invasive Bladder Cancer: Results from a Multi-Institutional Experience.

PURPOSE: While lymph node dissection (LND) at radical cystectomy (RC) for muscle-invasive bladder cancer has been studied extensively, the role of LND for nonmuscle-invasive bladder cancer (NMIBC) remains incompletely defined. Herein, we aim to assess the association between extent of LND during RC for NMIBC and local pelvic recurrence-free survival (LPRS), cancer-specific survival (CSS) and overall survival (OS). MATERIALS AND METHODS: A multi-institutional retrospective review was performed of patients with NMIBC undergoing RC at 3 large tertiary referral centers. To identify a threshold for lymph node yield (LNY) to optimize LPRS, CSS and OS, separate Cox regression models were developed for each possible LNY threshold. Model performance including Q-statistics and hazard ratios (HRs) were used to identify optimal LNY thresholds. RESULTS: A total of 1,647 patients underwent RC for NMIBC, with a median LNY of 15 (quartiles 9,23). Model performance curves suggested LNY of 10 and 20 to optimize LPRS and CSS/OS, respectively. On multivariable regression, LNY >10 was associated with lower risk of LPR compared to LNY ≤10 (HR 0.63, 95% CI 0.42-0.93, p=0.02). Similarly, LNY >20 was associated with improved CSS (HR 0.67, 95% CI 0.52-0.87, p=0.002) and OS (HR 0.75, 95% CI 0.64-0.88, p <0.001) compared to LNY ≤20. Similar results were observed in the cT1 and cTis subgroups. CONCLUSIONS: Greater extent of LND during RC for NMIBC is associated with improved LPRS, CSS and OS, supporting the inclusion of LND during RC for NMIBC, particularly among patients with cTis or cT1 disease. Future prospective studies are warranted to assess the ideal anatomical template of LND in NMIBC.

Reduced-dose bacillus Calmette-Guérin (BCG) in an era of BCG shortage: real-world experience from a tertiary cancer centre.

OBJECTIVE: To evaluate the impact of one-third-dose (1/3D) bacillus Calmette-Guérin (BCG) on oncological outcomes in a large cohort of patients with non-muscle-invasive bladder cancer (NMIBC) treated with adequate BCG (as defined by the US Food & Drug Administration (FDA)) in a real-world setting. PATIENTS AND METHODS: We performed an institutional review board-approved review of patients with NMIBC treated with adequate BCG at our institution between 2000 and 2020. Patients were stratified according to whether they had received 1/3D BCG or full-dose (FD) BCG. Time to recurrence, time to progression and cancer-specific survival were estimated using Kaplan-Meier methods. RESULTS: Of 563 patients with NMIBC treated with adequate BCG, 150 (26.6%) received 1/3D and 413 (73.4%) received FD. The use of 1/3D BCG did not adversely affect time to recurrence (P = 0.449) or time to progression (P = 0.716), and this remained consistent when patients were stratified by individual 2021 European Association of Urology (EAU) prognostic factor risk groups. Cancer-specific survival was similar in patients receiving 1/3D and those receiving FD BCG (P = 0.320). CONCLUSION: The use of 1/3D BCG was not associated with adverse oncological outcomes in a large cohort of patients receiving adequate BCG for intermediate- and high-risk NMIBC. Based on this real-world experience, risk-stratified split-vial dosing may represent a valuable approach for other institutions facing BCG shortages whilst also providing reassurance to patients who may be concerned about suboptimal outcomes.

Should patients with non-muscle-invasive bladder cancer discontinue fibrin clot inhibitors during bacille Calmette-Guérin?

OBJECTIVE: To determine the impact of fibrin clot inhibitor (FCI) use on oncological outcomes in a large contemporary cohort of patients with non-muscle-invasive bladder cancer (NMIBC) treated with adequate bacille Calmette-Guérin (BCG). PATIENTS AND METHODS: We performed an Institutional Review Board-approved review of patients with NMIBC treated with adequate intravesical BCG, at our institution between 2000 and 2018. FCI use at the time of BCG therapy was recorded for each patient. Patients were stratified according to use of FCI medication. Recurrence- and progression-free survival were analysed using Kaplan-Meier methods and Cox proportional hazard models. RESULTS: Overall, 226 of 526 patients (43.0%) used a FCI: aspirin (205), clopidogrel (38), warfarin (18) and novel oral anticoagulant (NOAC; seven). The use of FCIs did not adversely affect either recurrence- or progression-free survival (P = 0.385 and P = 0.131, respectively). These results did not change when the impact of aspirin, clopidogrel or warfarin/NOAC use on recurrence and progression was evaluated separately. On multivariate analysis, FCI use was neither associated with tumour recurrence nor progression. CONCLUSION: The use of FCIs was not associated with adverse oncological outcomes in a large contemporary cohort of patients receiving adequate intravesical BCG for NMIBC. Based on these results, FCIs may be safely continued during BCG immunotherapy.

Contemporary Outcomes of Patients with Nonmuscle-Invasive Bladder Cancer Treated with bacillus Calmette-Guérin: Implications for Clinical Trial Design.

PURPOSE: Recurrent disease after bacillus Calmette-Guérin treatment presents a therapeutic challenge. To aid trial development, the U.S. Food and Drug Administration defined "adequate bacillus Calmette-Guérin" therapy and adopted the "bacillus Calmette-Guérin unresponsive" disease state. Available data for efficacy benchmark comparison are outdated, leading to concerns about appropriate control arms and sample size calculations. We describe a contemporary cohort of patients with nonmuscle-invasive bladder cancer treated with intravesical bacillus Calmette-Guérin, and provide benchmark outcomes data. MATERIALS AND METHODS: We retrospectively reviewed patients receiving adequate bacillus Calmette-Guérin therapy at a tertiary cancer center between January 2004 and August 2018. Unadjusted univariable analysis was conducted using the Pearson chi-square test. Kaplan-Meier estimates for recurrence-free survival-high grade, progression-free survival-muscle-invasive bladder cancer and overall survival were used to create survival curves and compared using the log-rank test. RESULTS: Of the 542 patients who received adequate bacillus Calmette-Guérin, 518 (90%) had European Association Urology high risk disease, with carcinoma in situ present in 175 (32%). With a median followup of 47.8 months, freedom from high grade recurrence at 1, 3 and 5 years was 81%, 76% and 74%, respectively, and progression-free survival was 97%, 93% and 92%. Progression to muscle invasion at 5 years was exclusively seen in patients with high risk disease (progression-free survival 91%; log-rank test, p=0.024). CONCLUSIONS: A contemporary cohort of patients with nonmuscle-invasive bladder cancer treated with adequate bacillus Calmette-Guérin demonstrated markedly better outcomes than seen in prior studies. These data could be used in the design of clinical trials, to guide power calculations, as well as serve as benchmarks for comparison to evaluate nonrandomized studies.

Contemporary Rates of Gynecologic Organ Involvement in Females with Muscle Invasive Bladder Cancer: A Retrospective Review of Women Undergoing Radical Cystectomy following Neoadjuvant Chemotherapy.

PURPOSE: According to the American Urological Association/American Society of Clinical Oncology/American Society for Radiation Oncology/Society of Urologic Oncology Guideline on treatment of nonmetastatic muscle invasive bladder cancer (MIBC), females requiring radical cystectomy (RC) should undergo concomitant anterior pelvic exenteration despite low rates of malignant involvement of gynecologic organs. We present the clinicopathological characteristics of patients with MIBC treated with neoadjuvant chemotherapy (NAC) and evaluate the impact of NAC on gynecologic organ involvement. MATERIALS AND METHODS: An institutional review board approved review of patients with cT2-T3 MIBC treated with RC at our institution between 2005 and 2018 was performed. Patients were stratified by receipt of NAC. RESULTS: A total of 186 females with cT2-T3 MIBC underwent RC during the study period, of whom 67.7% received NAC prior to RC. Patients who received NAC were more likely to have cT3 disease, preoperative hydronephrosis, and variant histology on transurethral resection (p <0.001, p=0.004, p=0.029, respectively). Rates of recurrence or metastasis were similar between groups (27.0% vs 26.7%, p=0.964). No patients had isolated genitourinary organ recurrence (median followup 32.1 months). Nine patients (5.7%) had gynecologic organ involvement (6 NAC vs 3 no NAC, p=0.978). Among those who underwent hysterectomy, 2 patients (3.1%) who received NAC had uterine involvement compared to none in the no NAC cohort (p=0.551). Rates of vaginal involvement were similar between the groups (4 NAC vs 3 no NAC, p=0.402). Additionally, 1 patient who received NAC had incidentally diagnosed localized endometrial cancer. No women had fallopian tube or ovarian involvement. CONCLUSIONS: Even among high risk patients with MIBC, gynecologic organ involvement of MIBC is rare, and organ preservation, especially of the ovaries, is likely safe.

Progression of Disease after Bacillus Calmette-Guérin Therapy: Refining Patient Selection for Neoadjuvant Chemotherapy before Radical Cystectomy.

PURPOSE: Data from the pre-neoadjuvant chemotherapy (NAC) era suggests patients who progress on bacillus Calmette-Guérin (BCG) to muscle-invasive bladder cancer (P-MIBC) exhibit worse outcomes compared to de novo MIBC (D-MIBC). Herein, we investigate whether P-MIBC is an independent poor risk factor in the setting of contemporary NAC use. MATERIALS AND METHODS: A review of patients who underwent radical cystectomy (RC) for cT2-3 MIBC from 2005 to 2018 was performed. Patients were stratified into high risk (lymphovascular invasion, variant histology, hydronephrosis, cT3b) vs low risk (no risk factors) and P-MIBC (≤pT1 treated with at least induction BCG who progressed to ≥cT2) vs D-MIBC. RESULTS: Among 801 patients who underwent RC 20.3% had P-MIBC and 79.7% had D-MIBC. In low-risk patients treated without NAC, P-MIBC was associated with pathological upstaging (64.9% vs 42.7%, p=0.004) and worse overall (OS, p=0.006) and cancer-specific survival (CSS, p=0.001) compared to D-MIBC. P-MIBC status conferred uniformly poor survival outcomes to patients who did not receive NAC compared to D-MIBC without NAC (median OS 51.5 months [95% CI 40.0-81.0] vs 85.1 months [95% CI 62.8-96.0], p=0.040; median CSS not reached, p=0.014). However, P-MIBC status did not remain a negative prognostic factor in the setting of NAC (median OS 90.5 months [95% CI 34.0-not estimable] vs 87.8 months [95% CI 68.7-not estimable], p=0.606; median CSS not reached, p=0.448). CONCLUSIONS: P-MIBC confers a poor prognosis when managed with RC alone. Treatment with NAC results in equivalent pathological response and survival outcomes compared to D-MIBC. P-MIBC should be included in risk-stratified approaches to NAC selection.

Impact of upper tract urothelial carcinoma on response to BCG in patients with non-muscle-invasive bladder cancer.

OBJECTIVE: To evaluate the impact of upper tract urothelial carcinoma (UTUC) on bacillus Calmette-Guerin (BCG) response and progression in patients with non-muscle-invasive bladder cancer (NMIBC). PATIENTS AND METHODS: We performed an institutional review board-approved review of patients with NMIBC treated with adequate intravesical BCG, as defined by the US Food and Drug Administration, at our institution between 2000 and 2018. Patients were stratified by presence of any UTUC and time of UTUC diagnosis (preceding vs synchronous to NMIBC diagnosis or metachronous disease after NMIBC diagnosis). Descriptive statistics were used to summarize the data overall and by groups, and t-tests or Wilcoxon's rank sum tests and Pearson's chi-squared or Fisher's exact tests were used to analyse continuous and categorical data, respectively. RESULTS: Of 541 patients with NMIBC treated with adequate BCG, 59 (10.9 %) were diagnosed with UTUC. Of these, 34 had a history of UTUC prior to NMIBC (UTUC-P; median [interquartile range {IQR}] 13.1 [7.4-27.6] months prior), while 25 developed UTUC after diagnosis of NMIBC (six synchronous and 19 metachronous; median [IQR] 12.1 [1.7-28.1] months after). Compared to the non-UTUC group, patients with UTUC-P were more likely to exhibit Tis without papillary tumour in the bladder (20.6% vs 5.0%; P < 0.001), but were less likely to have T1 disease on index transurethral resection (8.8% vs 49.4%; P < 0.001). Patients with UTUC-P developed more recurrences (55.9% vs 34.0%; P = 0.010), any stage/grade progression (23.5% vs 9.8%; P = 0.012) and progression to muscle-invasive or metastatic disease (17.6% vs 6.4%; P = 0.014). The presence of high-grade UTUC-P compared to low-grade UTUC-P was associated with increased NMIBC recurrence (68.2% vs 25.0%; P = 0.049). There was no significant difference in rates of recurrence or progression based on timing of UTUC with respect to the index bladder tumour, although this analysis was limited by small numbers. CONCLUSIONS: Presence of UTUC prior to a diagnosis of NMIBC was associated with an almost twofold increased recurrence and progression rates after adequate BCG therapy. This should be considered when counselling patients and designing cohorts for clinical trials.

Time interval from transurethral resection of bladder tumour to bacille Calmette-Guérin induction does not impact therapeutic response.

OBJECTIVES: To investigate bacille Calmette-Guérin (BCG) tolerability and response with respect to the timing of BCG administration after transurethral resection of bladder tumour (TURBT) in patients with non-muscle-invasive bladder cancer (NMIBC). PATIENTS AND METHODS: A review of patients with NMIBC at our institution managed with at least 'adequate BCG' (defined by the United States Food and Drug Administration as at least five of six induction instillations, with two additional instillations comprising either maintenance or repeat induction) at our institution from 2000 to 2018 was performed. Time from TURBT to first instillation of induction BCG was stratified by quartile and analysed as a continuous variable. Kaplan-Meier and log-rank tests analysed differences in recurrence-free (RFS) and progression-free survival (PFS). Cox proportional hazards regression models identified associations between risk factors and survival outcomes. RESULTS: A total of 518 patients received adequate BCG at a median (range) of 26 (6-188) days from TURBT. Overall, 45 patients (9%) developed BCG intolerance at a median (range) 12 (7-33) instillations. When time from TURBT to BCG was stratified into quartiles, there was no difference with respect BCG intolerance (P = 0.966), RFS (P = 0.632) or PFS (P = 0.789). On both uni- and multivariate regression analysis for RFS and PFS, time from TURBT to BCG was not a significant predictor when analysed by quartile or as a continuous variable (the hazard ratio for RFS was 1.00, 95% confidence interval [CI] 0.99-1.00, P = 0.449; and for PFS was 0.99, 95% CI 0.98-1.00, P = 0.074). CONCLUSION: The rates of tolerability and response to adequate BCG are not predicated by the timing of induction BCG instillation after TURBT. Early administration in properly selected patients is safe and delays do not affect therapeutic response.

The obesity paradox: defining the impact of body mass index and diabetes mellitus for patients with non-muscle-invasive bladder cancer treated with bacillus Calmette-Guérin.

OBJECTIVES: To evaluate if the obesity paradox, wherein obesity portends worse overall prognosis for a disease but improved outcomes for patients receiving immunotherapy, exists for patients receiving bacillus Calmette-Guérin (BCG) in a contemporary cohort. PATIENTS AND METHODS: We performed an Institutional Review Board-approved database review to identify patients with non-muscle-invasive bladder cancer (NMIBC) completing at least an induction course of BCG. Clinicopathological variables collected included: body mass index (BMI), medications, and diabetes mellitus (DM). Outcomes of interest included: recurrence-free (RFS), progression-free (PFS), cancer-specific (CSS), and overall survival (OS). Univariate and multivariate modelling were used to evaluate the association between outcomes and clinical factors. RESULTS: A total of 579 patients (median follow-up 4.6 years) received BCG induction for NMIBC; 90% had high-grade disease (47.2% clinical stage T1). In all, 75.7% of patients were overweight or obese and 18% had DM. Aspirin, statins, metformin and ß-blockers were used in 34%, 42%, 11%, and 29% of patients, respectively. Overweight and obese patients had improved PFS, CSS and OS. DM was associated with worse RFS. Medications of interest had no association with outcomes. CONCLUSION: Elevated BMI is associated with improved outcomes in patients with NMIBC treated with BCG immunotherapy. Patients with DM are at increased risk of recurrence. These findings support a potential obesity paradox in bladder cancer. Evaluation of the underlying mechanism and the role of global patient assessment, counselling, and risk factor modification are warranted.

Impact of sex on response to BCG in non-muscle invasive bladder cancer patients: a contemporary review from a tertiary care center.

PURPOSE: Female sex has been implicated with higher stage at diagnosis and as a negative prognostic factor amongst patients with non-muscle invasive bladder cancer (NMIBC). Whether this holds true with contemporary management paradigms is unknown. We analyzed a cohort of patients treated with adequate bacillus Calmette-Guerin (BCG) for NMIBC in an effort to identify sex-specific influence on BCG response. METHODS: An IRB-approved review of patients with NMIBC treated at our institution with at least 'adequate BCG', as defined by the US FDA and EAU, from 2000 to 2018 was performed. Patients were then stratified by sex and response to BCG. Non-parametric tests were used to summarize the data overall and by groups. The Kaplan-Meier product limit method was used to calculate median survival endpoints. RESULTS: Of the 541 patients treated with adequate BCG, 111 (20.5%) were female and 430 (79.5%) were male. Female patients were younger (median 66 vs. 69, p = 0.071), had a lower BMI (median 27.3 vs. 28.8, p = 0.010) and were more likely to have no smoking history (49.5% vs. 27.0%, p < 0.001). Tumor characteristics with respect to stage, size, multifocality, presence of carcinoma in situ, and presence of variant histology were similar between sexes. While rates of recurrence were higher in females than in males this, was not statistically significant (44.1% vs. 34.7%, p = 0.064) and Kaplan-Meier estimates of recurrence-free, progression-free and overall survival demonstrated no significant difference between sexes (p = 0.409, p = 0.253, p = 0.171, respectively). CONCLUSION: In a contemporary cohort of patients with NMIBC treated with adequate BCG, female sex was not associated with adverse oncologic outcomes.

Prolyl Hydroxylase 3 Knockdown Accelerates VHL-Mutant Kidney Cancer Growth In Vivo.

Von Hippel Lindau (VHL) inactivation, which is common in clear cell renal cell carcinoma (ccRCC), leads directly to the disruption of oxygen homoeostasis. VHL works through hypoxia-inducible factors (HIFs). Within this VHL-HIF system, prolyl hydroxylases (PHDs) are the intermediary proteins that initiate the degradation of HIFs. PHD isoform 3's (PHD3) role in ccRCC growth in vivo is poorly understood. Using viral transduction, we knocked down the expression of PHD3 in the human ccRCC cell line UMRC3. Compared with control cells transduced with scrambled vector (UMRC3-SC cells), PHD3-knockdown cells (UMRC3-PHD3KD cells) showed increased cell invasion, tumor growth, and response to sunitinib. PHD3 knockdown reduced HIF2α expression and increased phosphorylated epidermal growth factor (EGFR) expression in untreated tumor models. However, following sunitinib treatment, expression of HIF2α and phosphorylated EGFR were equivalent in both PHD3 knockdown and control tumors. PHD3 knockdown changed the overall redox state of the cell as seen by the increased concentration of glutathione in PHD3 knockdown tumors relative to control tumors. UMRC3-PHD3KD cells had increased proliferation in cell culture when grown in the presence of hydrogen peroxide compared to UMRC3-SC control cells. Our findings illustrate (1) the variable effect of PHD3 on HIF2α expression, (2) an inverse relationship between PHD3 expression and tumor growth in ccRCC animal models, and (3) the role of PHD3 in maintaining the redox state of UMRC3 cells and their proliferative rate under oxidative stress.

Contemporary prostate cancer treatment choices in multidisciplinary clinics referenced to national trends.

BACKGROUND: The purpose of this study was to assess treatment choices among men with prostate cancer who presented at The University of Texas MD Anderson Cancer Center multidisciplinary (MultiD) clinic compared with nationwide trends. METHODS: In total, 4451 men with prostate cancer who presented at the MultiD clinic from 2004 to 2016 were analyzed. To assess nationwide trends, the authors analyzed 392,710 men with prostate cancer who were diagnosed between 2004 and 2015 from the Surveillance, Epidemiology, and End Results (SEER) database. The primary endpoint was treatment choice as a function of pretreatment demographics. RESULTS: Univariate analyses revealed similar treatment trends in the MultiD and SEER cohorts. The use of procedural forms of definitive therapy decreased with age, including brachytherapy and prostatectomy (all P < .05). Later year of diagnosis/clinic visit was associated with decreased use of definitive treatments, whereas higher risk grouping was associated with increased use (all P < .001). Patients with low-risk disease treated at the MultiD clinic were more likely to receive nondefinitive therapy than patients in SEER, whereas the opposite trend was observed for patients with high-risk disease, with a substantial portion of high-risk patients in SEER not receiving definitive therapy. In the MultiD clinic, African American men with intermediate-risk and high-risk disease were more likely to receive definitive therapy than white men, but for SEER the opposite was true. CONCLUSIONS: Presentation at a MultiD clinic facilitates the appropriate disposition of patients with low-risk disease to nondefinitive strategies of patients with high-risk disease to definitive treatment, and it may obviate the influence of race.

Radical Cystectomy and Perioperative Sexual Function: A Cross-Sectional Analysis.

BACKGROUND: Cancer-related changes in sexual function (SF) negatively impact quality of life and intimate partner relationships. There is a lack of data regarding SF among patients who underwent radical cystectomy (RC). AIM: To comparatively evaluate perioperative SF among patients who underwent RC. METHODS: A prospective cohort of 150 patients undergoing RC for bladder cancer and participating in an internal validation study at a single institution from 2016 to 2019 were eligible for analysis. The European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire-Bladder Cancer Muscle Invasive (EORTC QLQ-BLM 30) and Functional Assessment of Cancer Therapy-Bladder were administered; those completing the SF subscale of the EORTC QLQ-BLM 30 were included in final analysis. Analysis was performed using descriptive statistics and generalized linear modeling. OUTCOMES: The primary outcome was interest or engagement in sexual activity within 4 weeks of survey completion, whereas the secondary outcome was a mean score on the EORTC QLQ-BLM 30 SF subscale. RESULTS: Overall, 132 of 150 (88%) of patients were eligible, of whom 82% were male, and the median age was 68.5 years. 53% reported at least a little interest in sexual activity, and 40% endorsed sexual activity within the last 4 weeks. The mean SF subscale score was 61.5 ± 25.2. Women had significantly worse mean scores of 72.9 ± 27.1 versus 59.1 ± 24.2 for men (P = .02). On multivariate analysis, both age and female gender were independently associated with higher SF domain scores. CLINICAL IMPLICATIONS: A substantial portion of patients who underwent RC endorse being sexually active or express interest in sexually activity in the perioperative period. Given the recent increase in attention given to SF outcomes and quality of life, this work supports further efforts to explore this area and develop novel interventions to improve outcomes. STRENGTHS AND LIMITATIONS: Strengths include rigorously collected, cross-sectional data using standardized methodology. Limitations include a relatively small sample size of female patients and unknown meaningful clinical difference. CONCLUSIONS: A substantial portion of patients report sexual interest and activity in the perioperative period; however, female gender is associated with worse SF domain scores. These findings support further inquiry into this topic. Westerman ME, Kokorovic A, Wang XS, et al. Radical Cystectomy and Perioperative Sexual Function: A Cross-Sectional Analysis. J Sex Med 2020;17:1995-2004.

Effect of reversal of deep neuromuscular block with sugammadex or moderate block by neostigmine on shoulder pain in elderly patients undergoing robotic prostatectomy.

BACKGROUND: For some laparoscopic procedures, deep neuromuscular block has been shown to facilitate lower insufflation pressures and lower patient pain scores, and enhance postoperative recovery. We investigated the impact of deep neuromuscular block and its reversal on postoperative shoulder pain and outcomes after robotic prostate surgery. METHODS: Elderly men undergoing robotic prostatectomy were randomised to deep neuromuscular block (target post-tetanic twitch of 1-2 at the facial nerve) with sugammadex reversal or moderate neuromuscular block (target 1-2 train-of-four ratio) with neostigmine reversal. The primary endpoint was postoperative shoulder pain. The secondary endpoints included intraoperative insufflation pressure, surgical rating score, incidence of residual neuromuscular block, and postoperative recovery. RESULTS: A total of 50 subjects for each treatment arm were included in the analysis. The degree of neuromuscular block had no effect on the incidence of shoulder pain (deep block group 12% vs moderate block group 10%; P=1.0) or average insufflation pressure (median [inter-quartile range]) (13.3 [12.5-13.6] mm Hg vs 13.3 [11.7-14] mm Hg, P=0.86). After surgery, the deep block group had a higher normalised train-of-four ratio (0.98 [0.79-1.11] vs 0.85 [0.74-1.00]; P=0.008). The presence of postoperative shoulder pain was associated with higher BMI (31.8 [28-33.9] kg m-2vs 28 [24.8-31.1] kg m-2; P=0.036) and longer insufflation time (186 [156-257] min vs 154 [126-198] min; P=0.028). CONCLUSIONS: The use of deep neuromuscular block during surgery does not decrease postoperative shoulder pain or enhance recovery after robotic prostatectomy. CLINICAL TRIAL REGISTRATION: NCT03210376.

Determining the Safety and Efficacy of Enhanced Recovery Protocols in Major Oncologic Surgery: An Institutional NSQIP Analysis.

BACKGROUND: Enhanced-recovery (ER) protocols are increasingly being utilized in surgical practice. Outside of colorectal surgery, however, their feasibility, safety, and efficacy in major oncologic surgery have not been proven. This study compared patient outcomes before and after multispecialty implementation of ER protocols at a large, comprehensive cancer center. METHODS: Surgical cases performed from 2011 to 2016 and captured by an institutional NSQIP database were reviewed. Following exclusion of outpatient and emergent surgeries, 2747 cases were included in the analyses. Cases were stratified by presence or absence of ER compliance, defined by preoperative patient education and electronic medical record order set-driven opioid-sparing analgesia, goal-directed fluid therapy, and early postoperative diet advancement and ambulation. RESULTS: Approximately half of patients were treated on ER protocols (46%) and the remaining on traditional postoperative (TP) protocols (54%). Treatment on an ER protocol was associated with decreased overall complication rates (20% vs. 33%, p < 0.0001), severe complication rates (7.4% vs. 10%, p = 0.010), and median hospital length of stay (4 vs. 5 days, p < 0.0001). There was no change in readmission rates (ER vs. TP, 8.6% vs. 9.0%, p = 0.701). Subanalyses of high magnitude cases and specialty-specific outcomes consistently demonstrated improved outcomes with ER protocol adherence, including decreased opioid use. CONCLUSIONS: This assessment of a large-scale ER implementation in multispecialty major oncologic surgery indicates its feasibility, safety, and efficacy. Future efforts should be directed toward defining the long-term oncologic benefits of these protocols.