Intraoperative Blood Transfusion Is Associated With Increased Risk of Venous Thromboembolism After Radical Cystectomy.

PURPOSE: Our objective was to examine whether perioperative blood transfusion is associated with venous thromboembolism following radical cystectomy adjusting for both patient- and disease-related factors. MATERIALS AND METHODS: Patients who underwent radical cystectomy for bladder cancer from 1980-2020 were identified in the Mayo Clinic cystectomy registry. Blood transfusion during the initial postoperative hospitalization was analyzed as a 3-tiered variable: no transfusion, postoperative transfusion alone, or intraoperative with or without postoperative transfusion. The primary outcome was venous thromboembolism within 90 days of radical cystectomy. Associations between clinicopathological variables and 90-day venous thromboembolism were assessed using multivariable logistic regression, with transfusion analyzed as both a categorical and a continuous variable. RESULTS: A total of 3,755 radical cystectomy patients were identified, of whom 162 (4.3%) experienced a venous thromboembolism within 90 days of radical cystectomy. Overall, 2,112 patients (56%) received a median of 1 (IQR: 0-3) unit of blood transfusion, including 811 (38%) with intraoperative transfusion only, 572 (27%) with postoperative transfusion only, and 729 (35%) with intraoperative and postoperative transfusion. On multivariable analysis, intraoperative with or without postoperative blood transfusion was associated with a significantly increased risk of venous thromboembolism (adjusted OR 1.73, 95% CI 1.17-2.56, P = .002). Moreover, when analyzed as a continuous variable, each unit of blood transfused intraoperatively was associated with 7% higher odds of venous thromboembolism (adjusted OR 1.07, 95% CI 1.01-1.13, P = .03). CONCLUSIONS: Intraoperative blood transfusion was significantly associated with venous thromboembolism within 90 days of radical cystectomy. To ensure optimal perioperative outcomes, continued effort to limit blood transfusion in radical cystectomy patients is warranted.

A Contemporary Analysis of Urethral Recurrence following Radical Cystectomy.

PURPOSE: Oncologic outcomes following urethral recurrence (UR) remain incompletely described, with reports limited by small cohort sizes. We evaluated risk factors for UR as well as cancer-specific survival (CSS) and overall survival (OS) among patients with UR. MATERIALS AND METHODS: We reviewed our institutional radical cystectomy (RC) registry to identify patients with UR. Cox proportional hazards regression was used to assess risk factors for UR. Kaplan-Meier and Cox models were used to assess the relationship between UR and CSS/OS as well as to compare outcomes following symptomatic vs asymptomatic presentation of UR. RESULTS: Overall, 2,930 patients underwent RC from 1980 to 2018, with a median postoperative followup of 7.1 years (IQR 2.8-13.1), of whom 144 (4.9%) were subsequently diagnosed with UR. Carcinoma in situ (HR 1.98, 95% CI 1.30-3.04), multifocal disease (HR 1.59, 95% CI 1.07-2.36) and prostatic urethral involvement at RC (HR 3.01, 95% CI 1.98-4.57) were associated with increased risk of UR. UR was associated with decreased CSS (HR 7.30, 95% CI 5.46-9.76) and OS (HR 1.86, 95% CI 1.54-2.24). A total of 63/144 patients were diagnosed with UR based on symptoms, while 104/144 patients with UR underwent urethrectomy. Patients with symptomatic UR had higher tumor stage at urethrectomy (≥pT2 in 13.1% vs 3.1%, p=0.007), while patients with asymptomatic UR experienced longer median CSS (12.1 vs 6.1 years) and OS (8.30 vs 4.82 years; p=0.05 for both). CONCLUSIONS: We identified pathological risk factors for UR after RC and report adverse subsequent survival outcomes for these patients. Presentation with symptomatic UR was associated with higher tumor stage and poorer prognosis, supporting a value to continued urethral surveillance after RC.

The Association of Aspirin Use with Survival Following Radical Cystectomy.

PURPOSE: Aspirin may have antineoplastic properties through the inhibition of inflammatory cytokines that regulate cell proliferation, angiogenesis and apoptosis. In patients with nonmuscle invasive bladder cancer aspirin use has been linked to a reduced risk of recurrence. We evaluated the association of aspirin with survival following radical cystectomy. MATERIALS AND METHODS: A total of 1,061 patients underwent radical cystectomy at our institution between 2007 and 2016, of whom 461 (43%) were aspirin users at the time of surgery. Survival estimates were assessed by the Kaplan-Meier method. The Cox proportional hazards model was applied to evaluate associations between patient features and survival. RESULTS: Median followup after radical cystectomy among survivors was 4.2 years (IQR 2-6.2). During this time 442 patients died, including 331 of bladder cancer. Aspirin users were significantly older, more likely to have a history of cardiovascular disease and diabetes, and more likely to use metformin or statin (each p <0.05). Nevertheless, we found that patients who ingested a daily aspirin had significantly higher 5-year cancer specific survival (68% vs 60%, p = 0.02) and overall survival (59% vs 52%, p = 0.03) compared to nonusers. Moreover, after multivariable adjustment aspirin use remained independently associated with lower cancer specific mortality (HR 0.64, 95% CI 0.45-0.89, p = 0.01) as well as all cause mortality (HR 0.70, 95% CI 0.53-0.93, p = 0.02) but not with distant metastasis (p >0.05). CONCLUSIONS: Daily aspirin use was associated with significantly improved survival outcomes following radical cystectomy. Further research is warranted to evaluate the potential underlying biological mechanisms and investigate causality.

Prevalence and Outcome of High-Risk QT Prolongation Recorded in the Emergency Department from an Institution-Wide QT Alert System.

BACKGROUND: QT prolongation is an independent risk factor for sudden death, stroke, and all-cause mortality. However, additional studies have shown that in certain settings, QT prolongation may be transient and a result of external factors. OBJECTIVE: In this study, we evaluated the clinical characteristics and outcomes of patients seen in the emergency department (ED) with QT prolongation. METHODS: Between November 2010 and June 2011, 7522 patients had an electrocardiogram (ECG) obtained during their evaluation in the ED. Clinical, laboratory, and therapeutic information was collected for all patients with QT prolongation (i.e., ≥ 500 ms and QRS < 120 ms). Potential QT-inciting factors (drugs, electrolyte disturbances, and comorbidities) were synthesized into a pro-QT score. RESULTS: Among the 7522 patients with an ECG obtained in the ED, a QT alert was activated in 93 (1.2%; mean QTc 521 ± 34 ms). The majority of ED patients (64%) had more than one underlying condition associated with QT prolongation, with electrolyte disturbances in 51%, a QT prolonging condition in 56%, and QT-prolonging drugs in 77%. Thirty-day mortality was 13% for patients with QT prolongation noted in the ED. CONCLUSIONS: One percent of patients evaluated with an ECG in the ED activated our prolonged QTc warning system, with most demonstrating > 1 QT-prolonging condition. Thirty-day mortality was significant, but it requires further investigation to determine whether the QTc simply provided a non-invasive indicator of increased risk or heralded the presence of a vulnerable host at risk of a QT-mediated sudden dysrhythmic death.

Radical cystectomy for recurrent urothelial carcinoma after prior partial cystectomy: perioperative and oncologic outcomes.

PURPOSE: To evaluate perioperative and oncologic outcomes of patients undergoing radical cystectomy (RC) for recurrence of urothelial carcinoma (UC) after prior partial cystectomy (PC), and to compare these outcomes to patients undergoing primary RC. METHODS: Patients who underwent RC for recurrence of UC after prior PC were matched 1:3 to patients undergoing primary RC based on age, pathologic stage, and decade of surgery. Perioperative and oncologic outcomes were compared using Wilcoxon sign-rank test, McNemars test, the Kaplan-Meier method, and Cox proportional hazards regression analyses. RESULTS: Overall, the cohorts were well matched on clinical and pathological characteristics. No difference was noted in operative time (median 322 versus 303 min; p = 0.41), estimated blood loss (median 800 versus 700 cc, p = 0.10) or length of stay (median 9 versus 10 days; p = 0.09). Similarly, there were no differences in minor (51.7 versus 44.3%; p = 0.32) or major (10.3 versus 12.6%; p = 0.66) perioperative complications. Median follow-up after RC was 5.0 years (IQR 1.5, 13.1 years). Notably, CSS was significantly worse for patients who underwent RC after PC (10 year-46.8 versus 65.9%; p = 0.03). On multivariable analysis, prior PC remained independently associated with an increased risk of bladder cancer death (HR 2.28; 95% CI 1.17, 4.42). CONCLUSIONS: RC after PC is feasible, without significantly adverse perioperative outcomes compared to patients undergoing primary RC. However, the risk of death from bladder cancer may be higher, suggesting the need for careful patient counseling prior to PC and the consideration of such patients for adjuvant therapy after RC.

Providers' Response to Clinical Decision Support for QT Prolonging Drugs.

Commonly used drugs in hospital setting can cause QT prolongation and trigger life-threatening arrhythmias. We evaluate changes in prescribing behavior after the implementation of a clinical decision support system to prevent the use of QT prolonging medications in the hospital setting. We conducted a quasi-experimental study, before and after the implementation of a clinical decision support system integrated in the electronic medical record (QT-alert system). This system detects patients at risk of significant QT prolongation (QTc>500ms) and alerts providers ordering QT prolonging drugs. We reviewed the electronic health record to assess the provider's responses which were classified as "action taken" (QT drug avoided, QT drug changed, other QT drug(s) avoided, ECG monitoring, electrolytes monitoring, QT issue acknowledged, other actions) or "no action taken". Approximately, 15.5% (95/612) of the alerts were followed by a provider's action in the pre-intervention phase compared with 21% (228/1085) in the post-intervention phase (p=0.006). The most common type of actions taken during pre-intervention phase compared to post-intervention phase were ECG monitoring (8% vs. 13%, p=0.002) and QT issue acknowledgment (2.1% vs. 4.1%, p=0.03). Notably, there was no significant difference for other actions including QT drug avoided (p=0.8), QT drug changed (p=0.06) and other QT drug(s) avoided (p=0.3). Our study demonstrated that the QT alert system prompted a higher proportion of providers to take action on patients at risk of complications. However, the overall impact was modest underscoring the need for educating providers and optimizing clinical decision support to further reduce drug-induced QT prolongation.

Intravesical gemcitabine in combination with mitomycin C as salvage treatment in recurrent non-muscle-invasive bladder cancer.

OBJECTIVES: To evaluate oncological outcomes after combination intravesical therapy with gemcitabine (GC) and mitomycin C (MMC) in the setting of recurrent non-muscle-invasive bladder cancer (NMIBC) after failure of previous intravesical therapy. PATIENTS AND METHODS: We retrospectively identified patients with recurrent NMIBC after previous intravesical therapy, who refused or were not candidates for cystectomy, between 2005 and 2011. GC and MMC were sequentially instilled weekly for 6-8 weeks. Data were collected regarding patient demographics, bladder cancer history, and number and type of intravesical therapies before GC/MMC. Outcomes evaluated included time to recurrence and/or progression after GC/MMC. Recurrence-free outcomes were estimated using the Kaplan-Meier method, and Cox proportional hazards regression models were used to test the association of clinicopathological features with outcomes. RESULTS: In all, 27 patients were identified, 23 with high-risk disease (high-grade or carcinoma in situ) and four with intermediate-risk disease (multifocal or recurrent low-grade). All patients received prior intravesical therapy, and 17 patients (63%) received multiple courses. Twenty-four patients were treated with BCG. The median (range) disease-free survival of all patients was 15.2 (1.7-39.3) months. Seventeen patients (63%) developed recurrent bladder cancer, a median of 15.2 months after therapy. One patient progressed to muscle-invasive disease 5 months after treatment, and one developed metastatic disease 22 months after treatment. Three patients went on to cystectomy. Ten patients (37%) had no evidence of disease at last follow-up, with a median follow-up of 22.1 months. CONCLUSION: The combination of intravesical GC and MMC could offer durable recurrence-free survival to some patients with recurrent NMIBC who are not candidates for, or refuse, cystectomy.

Mortality after radical cystectomy: impact of obesity versus adiposity after adjusting for skeletal muscle wasting.

PURPOSE: We assess the impact of obesity, as measured conventionally by body mass index vs excess adiposity as measured by fat mass index, on mortality after radical cystectomy for bladder cancer, adjusting for the presence of skeletal muscle wasting. MATERIALS AND METHODS: This retrospective cohort study included 262 patients treated with radical cystectomy for bladder cancer between 2000 and 2008 at the Mayo Clinic. Lumbar skeletal muscle and adipose compartment areas were measured on preoperative imaging. Overall survival was compared according to gender specific consensus fat mass index and skeletal muscle index thresholds as well as conventional body mass index based criteria. Predictors of all cause mortality were assessed by multivariable modeling. RESULTS: Increasing body mass index correlated with improved overall survival (p=0.03) while fat mass index based obesity did not (p=0.08). After stratification by sarcopenia, no obesity related 5-year overall survival benefit was observed (68% vs 51.4%, p=0.2 obese vs normal and 40% vs 37.4%, p=0.7 sarcopenia vs sarcopenic/obese). On multivariable analysis class I obesity according to body mass index (HR 0.79, p=0.33) or fat mass index criteria (HR 0.85, p=0.45) was not independently associated with all cause mortality after adjusting for sarcopenia (HR 1.7, p=0.01) as well as age, performance status, pTN stage and smoking status. However, in patients with normal lean muscle mass each 1 kg/m(2) increase in weight or adipose mass was associated with a 7% to 14% decrease in all cause mortality. CONCLUSIONS: After adjusting for lean muscle wasting, neither measurements of obesity nor adiposity were significantly associated with all cause mortality in patients treated with radical cystectomy, although subanalyses suggest a potential benefit among those with normal lean muscle mass.

Phenotype of Children with QT Prolongation Identified Using an Institution-Wide QT Alert System.

QT prolongation is an independent risk factor for cardiovascular mortality in adults. However, there is little information available on pediatric patients with QT prolongation and their outcomes. Herein, we evaluated the prevalence of QT prolongation in pediatric patients identified by an institution-wide QT alert system, and the spectrum of their phenotype. Patients with documented QT prolongation on an ECG obtained between November 2010 and June 2011 were included. There were 1303 pediatric ECGs, and 68 children had electrographically isolated QT prolongation. Comprehensive review of medical records was performed with particular attention to QT-prolonging clinical, laboratory, and medication data, which were summarized into a pro-QTc score. Overall, 68 (5 %) pediatric patients had isolated QT prolongation. The mean age of this pediatric cohort was 9 ± 6 years, and the average QTc was 494 ± 42 ms. All children had 1 or more QT-prolonging risk factor(s), most commonly QT-prolonging medications. One patient was identified with congenital long QT syndrome (LQTS), which was not previously diagnosed. In one-year follow-up, only one pediatric death (non-cardiac) occurred (1.5 %). Potentially QT-offending/pro-arrhythmic medications were changed in 80 % of pediatric patients after the physician received the QT alert. Children with QT prolongation had very low mortality and minimal polypharmacy. Still, medications and other modifiable conditions were the most common causes of QT prolongation. Children with a prolonged QTc should be evaluated for modifiable QT-prolonging factors. However, if no risk factors are present or the QTc does not attenuate after risk factor modification/removal, the child should be evaluated for congenital LQTS.

Comparative impact of continent and incontinent urinary diversion on long-term renal function after radical cystectomy in patients with preoperative chronic kidney disease 2 and chronic kidney disease 3a.

OBJECTIVES: To evaluate the differences in estimated glomerular filtration rate decline by urinary diversion type (incontinent diversion vs continent diversion) and preoperative estimated glomerular filtration rate among patients undergoing radical cystectomy and urinary diversion. METHODS: We evaluated 1383 patients treated with radical cystectomy between 1980-2006 who had a preoperative estimated glomerular filtration rate of 45-89 mL/min/1.73 m(2). Estimated glomerular filtration rate was estimated using Chronic Kidney Disease Epidemiology Collaboration equations, and patients were stratified by preoperative estimated glomerular filtration rate into chronic kidney disease 2 (estimated glomerular filtration rate 60-89 mL/min/1.73 m(2)) and chronic kidney disease 3a (estimated glomerular filtration rate 45-59 mL/min/1.73 m(2)). Multiple definitions of estimated glomerular filtration rate decline were evaluated: (i) 10-point decline in estimated glomerular filtration rate; (ii) 20% decline in estimated glomerular filtration rate; and (iii) 10% decline in estimated glomerular filtration rate. Time to estimated glomerular filtration rate decline was compared using the Kaplan-Meier method stratified by diversion type. Cox regression models were used to evaluate the association of diversion type with estimated glomerular filtration rate decline risk. RESULTS: In total, 74% (1021/1383) of patients underwent incontinent diversion and 26% (362/1383) underwent continent diversion. Preoperative chronic kidney disease 2 and chronic kidney disease 3a were noted among 59% and 41% of patients who underwent incontinent diversion, versus 74% and 26% with continent diversion. Median follow up after RC was 11.2 years. The rate of estimated glomerular filtration rate decline in patients with incontinent diversion versus continent diversion was similar when stratified by preoperative chronic kidney disease 2 and preoperative chronic kidney disease 3a, regardless of estimated glomerular filtration rate decline definition. On multivariable analysis, continent diversion was not associated with estimated glomerular filtration rate decline for patients with preoperative chronic kidney disease 3a. CONCLUSIONS: The risk of estimated glomerular filtration rate decline over 10 years was not significantly different after incontinent diversion versus continent diversion among patients with preoperative chronic kidney disease 2 or chronic kidney disease 3a. Continent diversion does not appear to confer an independently increased risk of estimated glomerular filtration rate decline in patients with preoperative chronic kidney disease 3a.

Long-term results of radical cystectomy and role of adjuvant chemotherapy for small cell carcinoma of the bladder.

OBJECTIVE: To review our experience with radical cystectomy for small cell carcinoma of the bladder, to compare outcomes with a cohort of patients with urothelial carcinoma, and to determine the effect of adjuvant chemotherapy and pathology re-review in this setting. METHODS: Among 2427 patients who underwent radical cystectomy, 68 patients had small cell carcinoma of the bladder. Patients with small cell carcinoma of the bladder were compared with an unmatched cohort of 1146 patients with urothelial carcinoma, and were then matched (1:2) based on TNM stage. Survival was estimated using the Kaplan-Meier method, and Cox models were used to evaluate association of clinicopathological features with outcome. RESULTS: Among the 68 small cell carcinoma of the bladder patients, 37 (54%) were found to have small cell carcinoma of the bladder only after pathology re-review. Patients with small cell carcinoma of the bladder had a higher rate of advanced (pT3/4) tumor stage (84% vs 46%; P < 0.0001) and pN+ disease (37% vs 20%; P = 0.001) compared with patients with urothelial carcinoma. When matched for stage and lymph node status, no significant difference in 5-year cancer-specific survival was observed between the two groups (27% vs 29%; P = 0.64). Among small cell carcinoma of the bladder patients, those receiving adjuvant chemotherapy had improved 5-year overall survival compared with patients who did not receive adjuvant chemotherapy (43% vs 20%; P = 0.03), and a trend toward superior cancer-specific survival (40% vs 23%; P = 0.07). CONCLUSIONS: Small cell carcinoma of the bladder is often an unrecognized pathological entity, which is associated with a higher rate of locally advanced and N+ disease. However, although when matched for pathological features, survival outcomes appear similar to urothelial carcinoma. Small cell carcinoma of the bladder patients receiving adjuvant chemotherapy had improved overall survival and cancer-specific survival, and these results require further investigation.

Sarcopenia in patients with bladder cancer undergoing radical cystectomy: impact on cancer-specific and all-cause mortality.

BACKGROUND: The authors evaluated sarcopenia as a predictor of cancer-specific survival (CSS) and overall survival (OS) among patients with urothelial cancer of the bladder undergoing radical cystectomy (RC). METHODS: The lumbar skeletal muscle index (SMI) of 205 patients treated with RC for urothelial cancer between 2000 and 2007 was measured. Sarcopenia was classified according to international consensus definitions (SMI of < 55 cm(2)/m(2) for men and < 39 cm(2)/m(2) for women). The CSS and OS were estimated using the Kaplan-Meier method and compared with the log-rank test. Variables associated with CSS and all-cause mortality were summarized with hazard ratios (HRs). RESULTS: Of 205 patients, 141 (68.8%) were sarcopenic. Patients with sarcopenia were older, but were otherwise similar to patients without sarcopenia with respect to sex, Charlson comorbidity index, American Society of Anesthesiologists score, Eastern Cooperative Oncology Group performance status, receipt of neoadjuvant chemotherapy, TNM stage of disease, and tumor grade (P > .05 for all). The median follow-up was 6.7 years, during which time 135 patients died, including 91 who died of bladder cancer. Sarcopenic patients had significantly worse 5-year CSS (49% vs 72%; P = .003) and OS (39% vs 70%; P = .003) compared with patients without sarcopenia. Moreover, sarcopenia was found to be independently associated with both increased CSS (HR, 2.14; P = .007) and all-cause mortality (HR, 1.93; P = .004) on multivariable analysis. CONCLUSIONS: The presence of sarcopenia was found to significantly increase a patient's risk of CSS and all-cause mortality after undergoing RC for bladder cancer.

Outcome of patients with micropapillary urothelial carcinoma following radical cystectomy: ERBB2 (HER2) amplification identifies patients with poor outcome.

Micropapillary urothelial carcinoma exhibits amplification of the human epidermal growth factor receptor, ERBB2(HER2), and overexpression of the ERBB2 protein product. The clinical significance of this has yet to be established. The objective of this study was to examine ERBB2 amplification and protein expression in micropapillary urothelial carcinoma and stage-matched typical urothelial carcinoma treated by radical cystectomy to assess the frequency of amplification and protein expression, and to determine the association with cancer-specific survival. Pathologic material and data from patients undergoing cystectomy at Mayo Clinic between 1980 and 2008 were reviewed. ERBB2 amplification by fluorescence in situ hybridization (FISH) and protein expression by immunohistochemistry were assessed. Univariate and multivariate Cox proportional hazards regression models were used to evaluate for associations of ERBB2 amplification and protein expression with survival. ERBB2 amplification was identified in 9 (15%) of 61 micropapillary carcinomas compared with 9 (9%) of 100 urothelial carcinomas. In patients with micropapillary carcinoma, ERBB2 amplification was associated with a nearly threefold increased risk of cancer death. ERBB2 amplification (hazard ratio 4.3; P=0.0008) remained associated with an increased risk of death from bladder cancer among patients with micropapillary urothelial carcinoma on multivariate analysis. The association of cancer-specific survival and ERBB2 amplification was not seen in patients with urothelial carcinoma. ERBB2 immunohistochemistry correlated with ERBB2 amplification but there was no association of ERBB2 protein expression and survival. ERBB2 amplification is more frequent in micropapillary urothelial carcinoma than typical urothelial carcinoma, and patients with micropapillary carcinoma who have ERBB2 amplification have worse cancer-specific survival than those who do not. Identification of ERBB2 amplification in micropapillary carcinoma could provide important prognostic information and possibly provide a role for ERBB2 targeted therapy.

Cystectomy for refractory hemorrhagic cystitis: contemporary etiology, presentation and outcomes.

PURPOSE: We evaluate the clinical presentation, management and outcomes of patients undergoing cystectomy for refractory hemorrhagic cystitis. MATERIALS AND METHODS: We identified 21 patients with refractory hematuria treated with cystectomy at our institution between 2000 and 2012. Clot evacuation, bladder fulguration and bladder irrigation had failed in all patients before cystectomy. In addition, 45% of patients had received prior intravesical therapy (aminocaproic acid, alum or formalin), hyperbaric oxygen therapy (25%), nephrostomy tube placement for attempted urinary diversion (15%) and/or selective bladder angioembolization (5%). RESULTS: Median patient age at surgery was 77 years (IQR 72, 80) and 81% (17 of 21) of patients were male. The most common etiology for hemorrhagic cystitis was prior radiation therapy for prostate cancer (17, 81%). Median time from receipt of radiation to cystectomy in these patients was 91 months (IQR 73, 125). Median ASA® (American Society of Anesthesiologists) score at cystectomy was 3 and median preoperative hemoglobin was 10.2 gm/dl. Median length of stay after cystectomy was 10 days (IQR 7, 19). Severe (Clavien grade III to V) complications were noted in 42% of patients (8 of 19) and the 90-day mortality rate in this cohort was 16% (3 of 19). With a median postoperative followup of 13 months (IQR 4, 21), the 1 and 3-year overall survival was 84% and 52%, respectively. CONCLUSIONS: Cystectomy for hemorrhagic cystitis is associated with a high risk of perioperative complications and mortality, consistent with the baseline clinical status of this patient cohort and, as such, should remain a last resort to control bleeding after failure of conservative measures.

Late recurrence after radical cystectomy: patterns, risk factors and outcomes.

PURPOSE: We evaluated the outcome in patients with late recurrence of urothelial carcinoma after radical cystectomy. MATERIALS AND METHODS: We identified 2,091 patients who underwent radical cystectomy at our institution between 1980 and 2006. Survival was estimated using the Kaplan-Meier method and compared based on recurrence timing (less than 5 years vs 5 or greater) and location (urothelial vs nonurothelial) using the log rank test. Cox proportional hazard regression models were used to evaluate variables associated with late recurrence and death from bladder cancer. RESULTS: Median postoperative followup was 16.6 years. Late recurrence was identified in 82 patients (3.9%). On multivariate analysis younger age (p = 0.0008), nonmuscle invasive disease (p = 0.01) and prostatic urethral involvement (p <0.0001) were significantly associated with an increased risk of late recurrence. Five-year post-recurrence cancer specific survival was significantly worse after recurrence within 5 years from radical cystectomy vs after late recurrence (17% vs 37%, p = 0.001). Patients with nonurothelial late recurrence had adverse 5-year cancer specific survival compared to those with urothelial late recurrence (19% vs 67%, p <0.0001). On multivariate analysis younger patient age (HR 1.01, p = 0.003), muscle invasive disease (HR 1.31, p <0.0001) and nonurothelial recurrence site (HR 2.76, p <0.0001) but not time to recurrence (p = 0.38) were associated with a significantly increased risk of death from bladder cancer following recurrence after radical cystectomy. CONCLUSIONS: Late recurrence is uncommon after radical cystectomy. Younger patient age, nonmuscle invasive disease and prostatic urethral involvement were associated with a significantly increased risk of late recurrence. Interestingly, time to recurrence was not associated with a subsequent risk of patient death.

Long-term renal function outcomes after radical cystectomy.

PURPOSE: We evaluated the long-term natural history of renal function after radical cystectomy with urinary diversion and determined factors associated with decreased renal function. MATERIALS AND METHODS: We reviewed the records of 1,631 patients who underwent radical cystectomy between 1980 and 2006. The estimated glomerular filtration rate was calculated preoperatively and at various intervals after surgery. A renal function decrease was defined as a greater than 10 ml per minute/1.73 m(2) reduction in the estimated glomerular filtration rate. Multivariate analysis was done to evaluate the association of clinicopathological features, incontinent vs continent diversion type and postoperative complications with decreased renal function. RESULTS: A total of 1,241 patients (76%) underwent incontinent diversion and 390 (24%) underwent continent diversion. Median followup after radical cystectomy in patients alive at last followup was 10.5 years (IQR 7.1, 15.3). The median preoperative estimated glomerular filtration rate was higher in the continent diversion cohort (67 vs 59 ml per minute/1.73 m(2), p <0.0001). This difference was maintained until 7 years postoperatively, after which no difference was noted in renal function by diversion type. By 10 years after radical cystectomy the risk of a renal function decrease was similar for incontinent and continent diversion (71% and 74%, respectively, p = 0.13). On multivariate analysis risk factors associated with decreased renal function included age (HR 1.03, p <0.0001), preoperative estimated glomerular filtration rate (HR 1.05, p <0.0001), chronic hypertension (HR 1.2, p = 0.01), postoperative hydronephrosis (HR 1.2, p = 0.03), pyelonephritis (HR 1.3, p = 0.01) and ureteroenteric stricture (HR 1.6, p <0.0001). CONCLUSIONS: Decreased renal function is noted in most patients during long-term followup after radical cystectomy. Postoperative hydronephrosis, pyelonephritis and ureteroenteric stricture represent potentially modifiable factors associated with a decrease. Choice of urinary diversion was not independently associated with decreased renal function.

Urothelial carcinoma involving the prostate: the association of revised tumour stage and coexistent bladder cancer with survival after radical cystectomy.

OBJECTIVE: To evaluate survival among patients with urothelial carcinoma (UC) within the prostate in order to assess the impact of depth of tumour invasion as well as the importance of a concurrent bladder tumour. PATIENTS AND METHODS: We identified 201 patients who underwent radical cystectomy (RC) between 1980 and 2006 and were found to have UC involving the prostate. All specimens were re-reviewed by a genitourinary pathologist. Survival was estimated using the Kaplan-Meier method and compared with the log-rank test. Cox hazard regression models tested the association of clinicopathological variables with outcome. RESULTS: In all, 93 patients had pTis disease in the prostate, 43 had pT2 tumours, and 66 patients were pT4a. The median follow-up was 10.5 years. The 5-year cancer-specific survival for patients with pTis, pT2, and pT4a prostate UC was 73%, 57%, and 21% respectively (P < 0.001). On multivariable analysis, higher prostate tumour stage (hazard ratio [HR] 2.09; P = 0.01), positive lymph node status (HR 2.09; P = 0.002), and concurrent ≥pT3 bladder cancer (HR 4.16; P < 0.001) were significantly associated with an increased risk of death from UC. CONCLUSIONS: Among patients with prostatic UC involvement, depth of tumour invasion was significantly associated with cancer-specific mortality, validating the staging reclassification. Concurrent locally advanced bladder cancer also negatively impacted survival, suggesting the potential prognostic value of reporting a secondary tumour stage in such cases.

Gender-specific survival following radical cystectomy for pT4 bladder cancer.

PURPOSE: To evaluate the association of gender with survival following radical cystectomy (RC) for patients with pT4 bladder cancer. MATERIALS AND METHODS: We reviewed our institutional registry of 2,088 patients treated with RC between 1980 and 2005 to identify 128 with pT4 tumors, including 91 males and 37 females. Survival was estimated using the Kaplan-Meier method and compared with log-rank test. Cox hazard regression models were used to analyze the association of clinicopathologic demographics, including gender, with outcome. RESULTS: A total of 7 women and 30 men with pT4 tumor received perioperative chemotherapy. Median postoperative follow-up was 10.5 years, during which time 27 patients experienced local recurrence (LR) and 120 died, including 90 who died from bladder cancer. Women with pT4 tumor trended to have higher 5-year LR-free survival (72 vs. 59 %; p = 0.83), cancer-specific survival (31 vs. 17 %; p = 0.50), and overall survival (19 vs. 11 %; p = 0.33), although these differences did not reach statistical significance. On multivariate analysis, moreover, gender was not significantly associated with LR (HR 0.96; p = 0.93), cancer-specific mortality (HR 1.05; p = 0.87), or all-cause mortality (ACM) (HR 1.14; p = 0.58). Instead, poor ECOG performance status and pN+ disease were associated with an increased risk of ACM, while removal of a greater number of lymph nodes was associated with decreased ACM. CONCLUSION: We did not find gender-specific disparities in survival following RC for pT4 bladder cancer. Prognosis was instead driven by patient performance status and lymph node status.

Impact of Neoadjuvant Chemotherapy on Pathologic Downstaging in Patients With Variant Histology Undergoing Radical Cystectomy.

INTRODUCTION: Variant histology (VH) bladder cancer is often associated with poor outcomes and the role of neoadjuvant chemotherapy (NAC) remains incompletely defined. Our objective was to determine comparative pathologic downstaging at radical cystectomy (RC) following NAC for patients with and without VH. PATIENTS AND METHODS: Patients who underwent RC at 2 tertiary referral centers (1996-2018) were included. Patients with VH (sarcomatoid, nested, micropapillary, plasmacytoid) were matched 1:2 to patients with pure urothelial carcinoma by age, sex, clinical T (cT)stage, clinical N (cN)stage, cystectomy year and receipt of NAC. The primary outcome was pathologic downstaging (pT-stage < cT-stage). The differential impact of NAC on pathologic downstaging between VH and non-VH was assessed using multivariable logistic regression with interaction analysis. RESULTS: 225 VH and 437 non-VH patients were included. One hundred twenty-eight of six hundred sixty-two (19.3%) patients experienced downstaging, including 54/121 (44.6%) patients who received NAC and 74/542 (13.2%) patients who did not (P < .01). Rates of downstaging after NAC for subgroups were: 45/78 (57.7%) urothelial, 3/8 (37.5%) sarcomatoid, 2/12 (16.7%) nested, 3/14 (21.4%) micropapillary, and 1/8 (12.5%) plasmacytoid. Collectively, 9/42 (21.4%) of VH patients who received NAC were downstaged. On multivariable analyses, NAC was associated with increased likelihood of downstaging in the overall cohort (OR 5.25, 95% CI, 3.29-8.36, P < .0001) and this effect was not modified by VH versus non-VH histology (P = .13 for interaction). VH patients had worse survival outcomes compared to non-VH (P < 0.01 for all). CONCLUSION: When comparing patients with VH to matched pure urothelial carcinoma controls, VH did not have an adverse effect on downstaging following NAC. VH patients should not be excluded from NAC if otherwise eligible.

Outcomes following radical cystectomy for nested variant of urothelial carcinoma: a matched cohort analysis.

PURPOSE: We evaluated oncological outcomes after radical cystectomy in patients with the nested variant of urothelial carcinoma and compared survival to that in patients with pure urothelial carcinoma of the bladder. MATERIALS AND METHODS: We identified 52 patients with the nested variant who were treated with radical cystectomy between 1980 and 2004. Pathological specimens were re-reviewed by a single genitourinary pathologist. Patients were matched 1:2 by age, gender, ECOG (Eastern Cooperative Oncology Group) performance status, pathological tumor stage and nodal status to patients with pure urothelial carcinoma. Survival was estimated using the Kaplan-Meier method and compared with the log rank test. RESULTS: Patients with the nested variant had a median age of 69.5 years (IQR 62, 74) and a median postoperative followup of 10.8 years (IQR 9.3, 11.2). Nested variant cancer was associated with a high rate of adverse pathological features since 36 patients (69%) had pT3-T4 disease and 10 (19%) had nodal invasion. Eight patients (15%) with nested variant cancer received perioperative chemotherapy. When patients with the nested variant were matched to a cohort with pure urothelial carcinoma, no significant differences were noted in 10-year local recurrence-free survival (83% vs 80%, p = 0.46) or 10-year cancer specific survival (41% vs 46%, p = 0.75). CONCLUSIONS: The nested variant of urothelial carcinoma is associated with a high rate of locally advanced disease at radical cystectomy. However, when stage matched to patients with pure urothelial carcinoma, patients with the nested variant did not have an increased rate of recurrence or adverse survival. Further studies are required to validate these findings and guide the optimal multimodal treatment approach to these patients.