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.

Cutaneous Ureterostomy Following Radical Cystectomy for Bladder Cancer: A Contemporary Series.

OBJECTIVE: To report peri-operative outcomes of a contemporary series of bladder cancer patients undergoing radical cystectomy (RC) with cutaneous ureterostomy (CU) urinary diversion at a tertiary referral center. METHODS: We retrospectively identified patients who underwent RC with CU at Mayo Clinic between 2016 and 2021. Clinicopathologic and perioperative characteristics were analyzed using standard descriptive statistics. RESULTS: A total of 31 patients underwent RC with CU at our institution. Median age was 72years and 21 were male. This was highly comorbid cohort (83% had an American Society of Anesthesiologists [ASA] Physical Status Classification System ≥3; median Charlson Comorbidity index= 8). Median time to flatus, tolerating regular diet, and length of stay were 3 (interquartile range [IQR] 3-3), 3 (IQR 3-4), and 4days (IQR 4-7), respectively. A total of 14 patients experienced a high-grade complication (Clavien-Dindo ≥3) within 30days of surgery, and 8 were readmitted. The most common 30-day complication was sepsis, which affected 13% (4/31) of patients. At 90days postsurgery, the readmission rate was 32% (10/31), most commonly for sepsis. Three patients required reoperation within 90days, including one patient who required CU revision due to stomal ischemia. One patient died within this time frame from causes unrelated to bladder cancer. CONCLUSION: In a comorbid, relatively elderly bladder cancer cohort undergoing RC, the use of CU was associated with expeditious surgery and postoperative recovery. CU represents an option for urinary diversion in high-risk patients undergoing RC. Higher rate of postoperative ureteral obstruction can be pre-emptively addressed with chronic stent placement.

Perioperative and Oncologic Outcomes Associated with Simultaneous Radical Cystectomy and Nephroureterectomy.

OBJECTIVE: To compare the perioperative and oncologic outcomes associated with RCNU to a matched cohort undergoing RC alone. Simultaneous radical cystectomy and nephroureterectomy (RCNU) for synchronous upper tract and bladder urothelial carcinoma is an uncommon procedure. Sparse literature exists comparing outcomes in patients treated with radical cystectomy (RC) alone versus RCNU. METHODS: Adults treated with RCNU for urothelial carcinoma of the bladder (UCB) and upper tract urothelial carcinoma (UTUC) between 1980 and 2020 were identified. Patients were matched 2:1 to patients undergoing RC alone for UCB based on age (+/- 5 years), gender, BMI (+/- 5), Charlson Comorbidity Index, pathologic staging (stage ≤pT2 vs >pT2), and receipt of neoadjuvant chemotherapy. Outcomes included overall survival (OS), recurrence free survival (RFS), cancer specific survival (CSS), 30-day complications, length of stay (LOS), operative time, and estimated blood loss (EBL). RESULTS: A total of 39 patients undergoing RCNU were identified and matched to 74 patients undergoing RC. There were no significant differences in LOS, EBL, or 30-day complication rates. Operative time was significantly longer in the RC cohort. OS (HR 0.58, CI 0.35-0.97, P = .036) was significantly better for patients undergoing RC alone, while no significant difference was noted in RFS (HR 0.65, 0.34-1.24) and CSS (HR 0.58, CI 0.31-1.08, P = .08). CONCLUSIONS: Patients undergoing RCNU had significantly lower OS compared to a matched group of patients undergoing RC alone. Perioperative outcomes between the groups did not differ significantly. This data can inform patient counseling for treatment of this rare disease state.

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 salvage intravesical therapy following BCG with pathologic outcomes and survival after radical cystectomy for patients with high-grade non-muscle invasive bladder cancer: A multi-institution analysis.

INTRODUCTION: While numerous current clinical trials are testing novel salvage therapies (ST) for patients with recurrent nonmuscle invasive bladder cancer (NMIBC) after bacillus Calmette-Guérin (BCG), the natural history of this disease state has been poorly defined to date. Herein, we evaluated oncologic outcomes in patients previously treated with BCG and ST who subsequently underwent radical cystectomy (RC). METHODS: We identified 378 patients with high-grade NMIBC who received at least one complete induction course of BCG (n = 378) with (n = 62) or without (n = 316) additional ST and who then underwent RC between 2000 and 2018. Oncologic outcomes were compared using the Kaplan-Meier method and Cox proportional hazards models. Sensitivity analyses were conducted stratifying by presenting tumor stage, matched 1:3 for receipt vs. no receipt of ST. RESULTS: Patients receiving ST were more likely to initially present with CIS (26% vs. 17%) and less likely with T1 disease (34% vs. 50%, P = 0.06) compared to patients not treated with ST. Receipt of ST was not associated with increased risk of adverse pathology (≥pT2 or pN+) at RC (31% vs. 41%, P = 0.14). Likewise, 5-year cancer-specific survival did not significantly differ between groups on univariable Kaplan-Meier analysis (73% for ST and 74% for no ST, P = 0.7). Moreover, on multivariable analysis, receipt of ST was not significantly associated the risk of death from bladder cancer (HR 1.12; 95% CI 0.60-2.09, P = 0.7). Results were unchanged on sensitivity analysis. CONCLUSIONS: These data suggest that, in carefully selected patients, ST following BCG for high grade NMIBC does not compromise oncologic outcomes for patients who ultimately undergo RC.

Association of intraoperative hypothermia with oncologic outcomes following radical cystectomy.

INTRODUCTION: Intraoperative hypothermia (IOH) has been suggested to adversely impact outcomes following surgery. The objective of this study was to evaluate the association between IOH and survival following radical cystectomy (RC). METHODS: Patients who underwent RC for bladder cancer from 2003 to 2018 were identified in our cystectomy registry. Intraoperative temperatures were extracted from the anesthesia record. IOH was defined as a median intraoperative temperature <36°C, and severe IOH as ≤ 35°C. Time under 36°C was assessed as a continuous variable. Recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS) were estimated using the Kaplan-Meier method. Associations between IOH and outcomes were assessed with multivariable Cox proportional hazards models. RESULTS: A total of 852 patients were identified, among whom 274 (32%) had IOH. Median follow up among survivors was 4.9 years (IQR 2.4-8.7), during which time 483 patients died, including 343 from bladder cancer. Two-year survival was not significantly different between patients with and without IOH (CSS: 74% vs. 71%, P= 0.31; OS: 68% vs. 67%, P= 0.13). Following multivariable adjustment, neither IOH nor time under 36°C was significantly associated with survival. A total of 37 patients (4.3%) had severe IOH. These patients were observed to have significantly lower 2-year OS (56% vs. 68%, P= 0.005); however, this association did not remain statistically significant after multivariable adjustment (P= 0.92). CONCLUSION: IOH was not independently associated with survival following RC. These data do not support IOH as a prognostic factor for cancer outcomes among patients undergoing RC.

Long-term outcomes of incidental prostate cancer at radical cystectomy.

OBJECTIVE: We evaluated the natural history and long-term outcomes of incidentally detected prostate cancer (PCa) at radical cystectomy (RC) for bladder cancer (BCa). PATIENTS AND METHODS: We identified 1,640 male patients who underwent RC between 1992 and 2012. Patients were stratified as clinically insignificant and clinically significant PCa, based on Grade Group (GG) 1 and ≥2, respectively. Survival was assessed using the Kaplan-Meier method. RESULTS: There were 329 (20%) patients with incidentally detected PCa at RC: 245 (15%) GG1, 52 (3.2%) GG2, 20 (1.2%) GG3, 6 (0.4%) GG4, and 6 (0.4%) GG5. Median follow-up among survivors was 9.6 years (interquartile range 7.5-13.3), during which time 253 patients died, of whom 127 died of BCa and 1 died of PCa. Nine patients experienced biochemical recurrence (BCR), 4 underwent salvage PCa therapies, and 2 developed PCa metastases. Patients with clinically significant PCa were significantly more likely to experience BCR (6% vs. 1.6%; P = 0.04) and had shorter median time to BCR (1.8 vs. 10.4 years; P = 0.01) than those with clinically insignificant PCa. No patients with BCR had greater than pT2N0 BCa or positive BCa margins. Ten-year PCa-specific survival, BCa-specific survival, other cause-specific survival, and overall survival were 99%, 57%, 63%, and 35%, respectively. CONCLUSIONS: In a large RC series, we note a 20% rate of incidental PCa, the majority of which are clinically insignificant. On long-term follow-up, we determined that BCR and PCa mortality are extremely rare events among these patients. Pending validation, future guidelines may consider omission of PCa surveillance for some patients with incidental PCa at RC.

Persistent, long-term risk for ureteroenteric anastomotic stricture formation: the case for long term follow-up.

BACKGROUND: Up to one in ten patients undergoing cystectomy with urinary diversion develop a ureteroenteric stricture (UES). Despite unrecognized ureteral obstruction contributing to infection, nephrolithiasis, and/or progression of kidney disease, the long-term natural history and risk factors associated with UES remains understudied. Herein, we report our single institutional experience with the long-term incidence, clinical presentation, and risk factors associated with UES formation following urinary diversion. METHODS: We reviewed 2,285 patients who underwent RC with urinary diversion between 1980-2008. UES was defined as radiographic evidence of ureteral obstruction at the level of the ureteroenteric anastomosis. The diagnosis of benign UES was confirmed by pathology. UES-free survival was estimated using the Kaplan-Meier method. The association between clinicopathologic features and the development of a UES were assessed using multivariable models. RESULTS: A total of 192 (8%) patients developed a benign UES, at a median of 7 months (IQR 4-24) following RC, with 5% occurring after 10 years. Seventy seven percent of patients exhibited signs and/or symptoms of ureteral obstruction. Patients who developed a UES had a greater body mass index (BMI) (28 vs. 27), operative time (330 vs. 301 minutes) and were more likely to experience a <30-day Clavien ≥3 complication (all P<0.05). Receipt of abdominal radiation and smoking history were not significantly associated with UES stricture risk. On multivariable analysis, only greater BMI (per 1-unit increase) (OR 1.06, 95% CI: 1.02-1.09; P=0.0009) and <30-day Clavien ≥3 complication (OR 2.85, 95% CI: 1.90-4.28; P<0.0001) were associated with the development of a UES. Development of UES was associated with renal function deterioration. CONCLUSIONS: UES was identified in 8% of patients following RC with urinary diversion, with the majority presenting with symptoms. While the majority of these occur in the first 2 years after surgery, a patients' risk for the development of this complication persists beyond 10 years. Due to the adverse sequelae of UES, long-term functional and imaging surveillance following urinary diversion is warranted, and early reconstruction should be considered.

Sarcopenia and Response to Neoadjuvant Chemotherapy for Muscle-Invasive Bladder Cancer.

INTRODUCTION: The objective of the study was to determine whether sarcopenia is associated with pathologic and survival outcomes for patients with muscle-invasive bladder cancer (MIBC) treated with neoadjuvant chemotherapy (NAC) followed by radical cystectomy (RC). PATIENTS AND METHODS: We identified MIBC patients treated with cisplatin-based NAC in our cystectomy registry from 2000 to 2016. Pre- and post-NAC computed tomography images were analyzed with BodyCompSlicer, a validated body composition assessment tool. Sarcopenia was defined as a skeletal muscle index (SMI) below sex-specific international consensus values. Associations of clinical features with pathologic downstaging ( .05). Meanwhile, only post-NAC sarcopenia (hazard ratio, 1.90; 95% confidence interval, 1.02-3.56; P = .04) was independently associated with an increased risk of CSM. CONCLUSION: Sarcopenia after NAC and before RC appeared to be prognostic. Although skeletal muscle mass declined significantly during NAC, neither the degree of muscle loss nor pretreatment SMI were significantly associated with downstaging after NAC and RC. These data do not support the use of sarcopenia as a risk stratification tool for selection of patients for or monitoring response to NAC.

Comprehensive characterization of perioperative reoperation following radical cystectomy.

INTRODUCTION: To examine the nature, timing, and risk factors underlying return to the operating room (ROR) following radical cystectomy (RC). ROR has been proposed as a surgical quality metric based on data from the general surgery literature, but ROR has not been comprehensively characterized following RC. PATIENTS AND METHODS: We queried our institutional Cystectomy Registry from 2000 to 2016 to identify patients with ROR within 90 days of RC. Multivariable logistic regression was used to examine associations between patient features and ROR. Survival outcomes were studied based on whether ROR was necessary. RESULTS: Of 1968 patients treated with RC, 112 (5.7%) underwent 125 reoperations within 90 days of RC, of which 93% were unanticipated and due to postsurgical complications. The most common reasons for ROR were facial dehiscence (29%), bowel obstruction (21%), and enteric anastomotic leak (8%). On multivariable analysis, increasing body mass index (odds ratio 1.04, 95% confidence interval (CI) 1.01-1.08, P = 0.045) and albumin <3.5 g/dl (odds ratio 2.15, 95% CI 1.28-3.59, P = 0.004) were associated with greater odds of ROR. Patients with a ROR had significantly decreased 5-year overall survival compared to patients who did not undergo ROR (43% vs. 55%; P = 0.003), and ROR was associated with increased all-cause mortality after multivariable adjustment (hazard ratio 1.33, 95% CI 1.01-1.74, P = 0.04). CONCLUSION: ROR principally occurred due to unanticipated complications and was associated with increased mortality after RC. These data suggest ROR may be a useful metric by which urological programs can track the efficacy of interventions aimed at improving perioperative care for RC patients.

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.

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.

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.

Oncologic Outcomes for Patients with Residual Cancer at Cystectomy Following Neoadjuvant Chemotherapy: A Pathologic Stage-matched Analysis.

While it has been demonstrated that receipt of neoadjuvant chemotherapy (NAC) before radical cystectomy (RC) improves survival compared to RC alone, the driving factor for this benefit may be from patients with ypT0 status at surgery. Meanwhile, the implications of having residual urothelial carcinoma of the bladder (rUCB) at RC after NAC are less clear. We therefore evaluated whether survival differed between patients with rUCB at RC after NAC and stage-matched controls who underwent RC alone. Patients who underwent NAC + RC (n = 180) were matched to controls who underwent RC alone (n=324) on the basis of pT and pN stage, margin status, and year of RC. The 5-yr recurrence-free survival (RFS; 90% vs 94%; p=1), cancer-specific survival (CSS; 82% vs 93%; p=0.4), and overall survival (OS; 82% vs 82%; p=0.5) were not significantly different between the NAC and control groups for patients with ypT0N0/pT0N0 disease (n=103). Conversely, among patients with rUCB at RC (n=401), patients who received NAC had significantly worse 5-yr RFS (50% vs 63%; p=0.01), CSS (40% vs 59%; p=0.003), and OS (33% vs 48%; p=0.02). On multivariable analysis for patients with rUCB, NAC receipt remained independently associated with worse RFS (hazard ratio [HR] 1.84, 95% confidence interval [CI] 1.28-2.66; p=0.001), CSS (HR 1.81, 95% CI 1.30-2.52; p<0.001), and OS (HR 1.57, 95% CI 1.18-2.08; p=0.002). Limitations include potential for selection bias owing to the retrospective observational design. Thus, while patients who achieve a complete response to NAC have excellent survival outcomes, those with rUCB after NAC have a worse prognosis compared to stage-matched controls undergoing RC alone. It may be worthwhile considering these patients for clinical trials evaluating the role of additional treatments after RC using newer agents while we await further research on predicting which patients achieve ypT0 status from NAC before RC. PATIENT SUMMARY: On surgical removal of the bladder, patients without residual bladder cancer after neoadjuvant chemotherapy have excellent survival outcomes. However, patients with residual cancer after neoadjuvant chemotherapy and surgery have worse outcomes compared to patients undergoing surgery alone. These patients should therefore be considered for additional treatments after surgery using newer agents while we await further research on predicting which patients will benefit from neoadjuvant chemotherapy before bladder removal for cancer.

Prognostic significance of lymphatic, vascular and perineural invasion for bladder cancer patients treated by radical cystectomy.

In radical cystectomy specimens with bladder cancer, lymphatic and vascular invasion are often reported as 'angiolymphatic' or 'lymphovascular' invasion, terms that combine the findings of tumour within simple endothelial-lined lymphatic spaces and tumour within muscle-lined blood vessels. It is unclear if these patterns of invasion have different prognostic significance. In addition, there are conflicting data regarding the significance of lymphatic, vascular and perineural invasion in patients with bladder cancer. Herein, we studied 1504 patients treated by radical cystectomy for bladder cancer at our institution and followed for a mean of 10.6 years. Cases were re-reviewed by a urological pathologist for lymphatic invasion defined as tumour within a non-muscle-lined endothelial-lined lymphatic space, vascular invasion defined as tumour in a muscle-lined blood vessel, and perineural invasion defined as tumour within the perineural sheath. Associations of clinical and pathological features with bladder cancer death were evaluated using Cox proportional hazards regression models and summarised with hazard ratios and 95% confidence intervals. Survival was estimated by the Kaplan-Meier method. Multivariate analysis showed that lymphatic and vascular invasion but not perineural invasion were significantly associated with cancer specific survival (p<0.0001 and p=0.02, respectively). There was a significant association of lymphatic and vascular invasion but not perineural invasion with involved regional lymph nodes (p<0.0001 and p=0.004, respectively). In patients with metastasis to regional lymph nodes, lymphatic invasion remained significantly associated with outcome (p=0.02). The frequency of lymphatic and vascular invasion varied amongst histological subtypes of bladder cancer. Vascular and lymphatic invasion should be clearly defined and reported for radical cystectomy specimens containing bladder cancer.

Outcomes Following Radical Cystectomy for Plasmacytoid Urothelial Carcinoma: Defining the Need for Improved Local Cancer Control.

OBJECTIVE: To evaluate oncological outcomes after radical cystectomy (RC) in patients with plasmacytoid urothelial carcinoma (UC) and to compare survival to that in patients with pure UC of the bladder. MATERIALS AND METHODS: We identified 46 patients with plasmacytoid UC and 972 with pure UC who were treated with RC between 1980 and 2009. All pathologic specimens were re-reviewed by a single GU pathologist. Patients were matched 1:2 by age, gender, Eastern Cooperative Oncology Group performance status, pathologic tumor stage, and nodal status to patients with pure UC. Survival was estimated using the Kaplan-Meier method and compared with the log rank test. RESULTS: Patients with plasmacytoid UC were more likely to have extravesical disease (≥pT3) (83% vs 43%, P < .0001) and positive margins (31% vs 2.1%, P < .0001) than patients with pure UC. Plasmacytoid UC was associated with decreased overall survival (27% vs 45% at 5 years, relative risk [RR] 1.4, P = .04), cancer-specific survival (36% vs 57% at 5 years, RR 1.7, P = .01), and local recurrence-free survival (63% vs 81% at 5 years, RR 2, P = .01). When patients with plasmacytoid UC were matched to those with pure UC, there were no significant differences in 5-year overall, cancer-specific, and local or distant recurrence-free survival. CONCLUSION: Plasmacytoid UC is associated with a high rate of locally advanced disease and positive margins at RC, as well as increased local recurrence rates. Further research is necessary to delineate adjuvant or neoadjuvant treatment strategies to improve local cancer control of this rare subtype of UC.

Malignant ureteroenteric anastomotic stricture following radical cystectomy with urinary diversion: Patterns, risk factors, and outcomes.

OBJECTIVE: The development of a ureteroenteric anastomotic (UEA) stricture has been reported in up to 15% of patients undergoing radical cystectomy (RC) with urinary diversion. Although benign strictures are thought to be the result of ischemia, the incidence, risk factors, and outcomes of patients with malignant UEA strictures have not been well described. MATERIAL AND METHODS: We reviewed 2,523 patients treated with RC for bladder cancer from 1980 to 2012 at Mayo Clinic. Patients diagnosed with a UEA stricture following the surgery were identified, and a subset with malignant UEA was then analyzed. Cox proportional hazard regression models were performed to evaluate factors associated with the diagnosis of malignant UEA. Survival was assessed using the Kaplan-Meier method. RESULTS: At a median of 10.5 years of follow-up, 232 (9.2%) patients were diagnosed with UEA stricture, of which 38 (16.4%) had malignant strictures (MS). Median time from RC to the diagnosis of a malignant vs. benign UEA stricture was 32.4 months and 7.2 months, respectively (P = 0.004). Pathologic non-muscle-invasive disease stage at RC was more common among patients diagnosed with a MS compared with patients who did not develop a MS (71.1% vs. 45.9%; P = 0.002). The presence of carcinoma in situ on initial ureteral margin at RC was associated with a significantly increased risk of subsequent diagnosis (hazard ratio = 4.1; P<0.001). Following malignant stricture diagnosis, 2- and 5-year cancer-specific survival was 50% and 30%, respectively, whereas overall survival was 44% and 23%, respectively. CONCLUSIONS: MS are uncommon after RC, and present later than benign strictures. Ureteral margin involvement with carcinoma in situ was associated with a significantly increased risk of MS diagnosis.

The association of ABO blood type with disease recurrence and mortality among patients with urothelial carcinoma of the bladder undergoing radical cystectomy.

OBJECTIVES: To evaluate the association of ABO blood type with clinicopathologic outcomes and mortality among patients with urothelial carcinoma of the bladder treated with radical cystectomy (RC). PATIENTS AND METHODS: We identified 2,086 consecutive patients who underwent RC between 1980 and 2008. Postoperative recurrence-free survival (RFS) and cancer-specific survival (CSS) were estimated using the Kaplan Meier method and compared with the log-rank test. Cox proportional hazards regression models were used to evaluate the association of ABO blood type with outcomes. RESULTS: A total of 913 (44%), 881 (42%), 216 (10%), and 76 (4%) patients had blood type O, A, B, and AB, respectively. Median postoperative follow-up among survivors was 11.0 years (interquartile range: 7.7-15.9y). Overall, 1,561 patients died, with 770 deaths attributable to bladder cancer. Non-O blood type was associated with significantly worse 5-year RFS (65% vs. 69%; P = 0.04) and/or CSS (64% vs. 70%; P = 0.02). In particular, among patients with≤pT2N0 disease, the 5-year RFS for those with non-O vs. O blood type was 75% vs. 82%, respectively (P = 0.002), whereas the 5-year CSS was 77% vs. 85%, respectively (P = 0.001). Moreover, on multivariable analysis, blood type A remained independently associated with an increased risk of cancer-specific mortality (hazard ratio = 1.22; P = 0.01). CONCLUSIONS: Non-O blood type, particularly blood type A, is associated with a significantly increased risk of death from bladder cancer among patients undergoing RC. If validated, the utility of a multimodal therapy approach, including perioperative chemotherapy, or more frequent postoperative surveillance in this cohort warrants further study.