Timothy F. Donahue

Risk Factors for the Development of Parastomal Hernia after Radical Cystectomy

PURPOSE Parastomal hernia is a frequent complication of stoma formation after radical cystectomy. We determined the prevalence and risk factors for the development of parastomal hernia after radical cystectomy. MATERIALS AND METHODS We conducted a retrospective study of 433 consecutive patients who underwent open radical cystectomy and ileal conduit between 2006 and 2010. Postoperative cross-sectional imaging studies performed for routine oncologic followup (1,736) were evaluated for parastomal hernia, defined as radiographic evidence of protrusion of abdominal contents through the abdominal wall defect created by forming the stoma. Univariable and multivariable Cox regression analyses were used to determine clinical and surgical factors associated with parastomal hernia. RESULTS Complete data were available for 386 patients with radiographic parastomal hernia occurring in 136. The risk of a parastomal hernia developing was 27% (95% CI 22, 33) and 48% (95% CI 42, 55) at 1 and 2 years, respectively. Clinical diagnosis of parastomal hernia was documented in 93 patients and 37 were symptomatic. Of 16 patients with clinical parastomal hernia referred for repair 8 had surgery. On multivariable analysis female gender (HR 2.25; 95% CI 1.58, 3.21; p<0.0001), higher body mass index (HR 1.08 per unit increase; 95% CI 1.05, 1.12; p<0.0001) and lower preoperative albumin (HR 0.43 per gm/dl; 95% CI 0.25, 0.75; p=0.003) were significantly associated with parastomal hernia. CONCLUSIONS The overall risk of radiographic evidence of parastomal hernia approached 50% at 2 years. Female gender, higher body mass index and lower preoperative albumin were most associated with the development of parastomal hernia. Identifying those at greatest risk may allow for prospective surgical maneuvers at the time of initial surgery, such as placement of prophylactic mesh in selected patients, to prevent the occurrence of parastomal hernia.

Alkaline phosphatase velocity predicts overall survival and bone metastasis in patients with castration-resistant prostate cancer

INTRODUCTION AND OBJECTIVES Identifying patients with prostate cancer (CaP) who will ultimately develop bone metastasis (BM) or die of disease is essential. Alkaline phosphatase velocity (APV) has been shown to predict overall survival (OS) and bone metastasis-free survival (BMFS) in an earlier study of an equal access military patient cohort of patients with castrate-resistant prostate cancer (CRPC). To confirm these findings, we examined a cohort of patients from a high-volume cancer center to validate a previous observation that faster alkaline phosphatase (AP) kinetics are predictive of OS and BMFS in this second cohort of patients. MATERIALS AND METHODS A retrospective cohort study was conducted of patients with CRPC treated at Memorial Sloan Kettering Cancer Center between 1989 and 2010. All patients who received androgen deprivation therapy (ADT) as primary treatment in response to a rising PSA after definitive surgery for CaP were eligible. For those who received primary ADT or surgery followed by ADT, CRPC was defined as one rising PSA value after a PSA nadir ≤4ng/ml, and confirmed by a second rising PSA value, with concurrently documented testosterone levels <50ng/dl. APV was computed as the slope of the linear regression line of all AP values (>2 values per patient) plotted against time. Study outcome included BMFS and OS. Univariable Kaplan-Meier analysis was used to examine time-to-event outcomes. Multivariable Cox proportional hazards regression analysis was used to model time to BMFS and OS. RESULTS Of 89 patients with CRPC with evaluable data and CRPC, 17 (19%) experienced BM and 26 (29%) died. APV was dichotomized at the uppermost quartile split of all observed APV values:≥5.42U/l/y vs. the lower 3 quartiles combined,<5.42U/l/y. Patients with faster APV had significantly worse outcomes, including faster progression to BM and poorer OS when compared with those with slower APV (P = 0.0451 and P = 0.0109, respectively). There was strong correlation between PSA doubling time (PSADT) (<10,≥10mo) and APV (≥5.42U/l/y vs.<5.42U/l/y) (P = 0.0289), preventing simultaneous evaluation of both factors in multivariable analysis. Kaplan-Meier analysis showed that PSADT was also predictive of BM and OS (log-rank P<0.0001). Separate multivariable Cox proportional hazards regression models were used to examine PSADT and APV, as predictors of each study outcome (BMFS and OS). Both PSADT and APV were strongly predictive of BMFS and OS (respectively). CONCLUSIONS APV and PSADT were predictors of BM and OS in patients with CRPC, respectively. These data are additional evidence of the potential value of AP kinetics in patients with advanced CaP. Prospective studies will be required to clarify these associations. However, given the restrictions on the current patient population in excluding metastatic disease within 12 months of ADT and a PSA nadir >4ng/ml, the findings are not inappropriately generalized to other men.

Prognostic Value of TERT Alterations, Mutational and Copy Number Alterations Burden in Urothelial Carcinoma

Point mutations in the TERT gene promoter occur at high frequency in multiple cancers, including urothelial carcinoma (UC). However, the relationship between TERT promoter mutations and UC patient outcomes is unclear due to conflicting reports in the literature. In this study, we examined the association of TERT alterations, tumor mutational burden per megabase (Mb), and copy number alteration (CNA) burden with clinical parameters and their prognostic value in a cohort of 398 urothelial tumors. The majority of TERT mutations were located at two promoter region hotspots (chromosome 5, 1 295 228 C>T and 1 295 250 C>T). TERT alterations were more frequently present in bladder tumors than in upper tract tumors (73% vs 53%; p=0.001). ARID1A, PIK3CA, RB1, ERCC2, ERBB2, TSC1, CDKN1A, CDKN2A, CDKN2B, and PTPRD alterations showed significant co-occurrence with TERT alterations (all p<0.0025). TERT alterations and the mutational burden/Mb were independently associated with overall survival (hazard ratio[HR] 2.31, 95% confidence interval [CI] 1.46-3.65; p<0.001; and HR 0.96, 95% CI 0.93-0.99; p=0.002), disease-specific survival (HR 2.23, 95% CI 1.41-3.53; p<0.001; and HR 0.96, 95% CI 0.93-0.99; p=0.002), and metastasis-free survival (HR 1.63, 95% CI 1.05-2.53; p=0.029; and HR 0.98, 95% CI 0.96-1.00; p=0.063) in multivariate models. PATIENT SUMMARY: The majority of TERT gene mutations that we detected in urothelial carcinoma are located at two promoter hotspots. Urothelial tumors with TERT alterations had worse prognosis compared to tumors without TERT alterations, whereas tumors with a higher mutational burden had more favorable outcome compared to tumors with low mutational burden.

Incidence and Effect of Thromboembolic Events in Radical Cystectomy Patients Undergoing Preoperative Chemotherapy for Muscle-invasive Bladder Cancer.

Background We evaluated the incidence and effect of thromboembolic events (TEEs) in patients with muscle‐invasive bladder cancer treated with preoperative chemotherapy (POC) and radical cystectomy (RC) with pelvic lymph node dissection (PLND). Patients and Methods We performed a retrospective review of all patients who had undergone POC followed by RC plus PLND for muscle‐invasive bladder cancer from June 2000 to January 2013 (n = 357). The chemotherapy type (neoadjuvant vs. induction), incidence and timing of TEE diagnosis (preoperatively vs. ≤ 90 days postoperatively), and effect of TEEs on clinical outcomes were recorded. Results Overall, 79 patients (22%; 95% confidence interval [CI], 18%‐27%) experienced a TEE: 57 (16%) occurred during POC and 22 (6.2%) were diagnosed postoperatively. Forty patients (11%; 95% CI, 8.1%‐15%) required an inferior vena cava filter. We found no significant differences in neoadjuvant versus induction chemotherapy and the risk of TEEs (difference, 3.3%; 95% CI, −5% to 12%; P = .5). No significant difference were found in the rates of POC completion according to the presence of a TEE (difference, 1.0%; 95% CI, −11% to 13%; P = .9). The occurrence of TEE did not significantly affect other perioperative outcomes. The risk of recurrence and overall survival were not associated with TEE on multivariable analysis. Conclusion We found a high incidence of TEEs (22%) in patients undergoing POC before RC plus PLND, with a 16% incidence in the preoperative period. TEEs in the POC setting leads to invasive procedures; however, we did not find a significant effect on POC completion or postoperative complication risk. Further research is required to determine whether preventative TEE measures during POC can improve clinical outcomes. Micro‐Abstract We hypothesized that the incidence of thromboembolic events (TEEs) in patients receiving preoperative chemotherapy (POC) before radical cystectomy and pelvic lymph node dissection might be severely underappreciated given the association between cisplatin and TEEs. We conducted a retrospective review of 357 consecutive patients who had received POC at our institution and provide a detailed review of the incidence and timing of the TEEs. The overall TEE rate was 22%, with a 16% incidence in the preoperative setting. Forty patients (11.2%) required an inferior vena cava filter. The occurrence of TEEs did not significantly affect other perioperative outcomes, including the risk of recurrence and overall survival.

The Impact of Plasmacytoid Variant Histology on the Survival of Patients with Urothelial Carcinoma of Bladder after Radical Cystectomy

BACKGROUND The clinical significance of the plasmacytoid variant (PCV) in urothelial carcinoma (UC) is currently lacking. OBJECTIVE To compare clinical outcomes of patients with any PCV with that of patients with pure UC treated with radical cystectomy (RC). DESIGN, SETTING, AND PARTICIPANTS We identified 98 patients who had pathologically confirmed PCV UC and 1312 patients with pure UC and no variant history who underwent RC at our institution between 1995 and 2014. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Univariable and multivariable Cox regression and Cox proportional hazards regression to determine if PCV was associated with overall survival (OS). RESULTS AND LIMITATIONS Patients with PCV UC were more likely to have advanced tumor stage (p=0.001), positive lymph nodes (p=0.038), and receive neoadjuvant chemotherapy than those with pure UC (46% vs 22%, p<0.0001). The rate of positive soft tissue surgical margins was over five times greater in the PCV UC group compared with the pure UC group (21% vs 4.1%, respectively, p<0.0001). Median OS for the pure UC versus the PCV patients were 8 yr and 3.8 yr, respectively. On univariable analysis, PCV was associated with an increased risk of overall mortality (hazard ratio=1.34, 95% confidence interval: 1.02-1.78, p=0.039). However, on multivariable analysis adjusted for age, sex, neoadjuvant chemotherapy received, lymph node status, pathologic stage, and soft margin status, the association between PCV and OS was no longer significant (hazard ratio=1.06, 95% confidence interval: 0.78, 1.43, p=0.7). This retrospective study is limited by the lack of pathological reanalysis, and the impact of other concurrent mixed histology cannot be determined in this study. CONCLUSIONS Patients with PCV features have a higher disease burden at RC compared with those with pure UC. However, PCV was not an independent predictor of survival after RC on multivariable analysis, suggesting that PCV histology should not be used as an independent prognostic factor. PATIENT SUMMARY Plasmacytoid urothelial carcinoma is a rare and aggressive form of bladder cancer. Patients with plasmacytoid urothelial carcinoma had worse adverse pathologic features, but this was not associated with worse overall mortality when compared with patients with pure urothelial carcinoma.

Comparison of Post-Radical Cystectomy Ileus Rates Using GIA-80 versus GIA-60 Intestinal Stapler Device

OBJECTIVE To assess the impact on recovery of bowel function using an 80 mm versus 60 mm gastrointestinal anastomosis (GIA) stapler following radical cystectomy and urinary diversion (RC/UD) for bladder cancer. METHODS We identified 696 patients using a prospectively maintained RC/UD database from January 2006 to November 2010. Two nonrandomized consecutive cohorts were compared. Patients between January 2006- and December 2007 (n = 180) were treated using a 60 mm GIA stapler, and 331 patients between January 2008 and December 2010 were subject to an 80 mm GIA stapler. All patients were treated on the same standardized postoperative recovery pathway. After accounting for baseline patient and perioperative characteristics, using a multivariable logistic regression model, we directly compared rates of postoperative ileus using a standardized definition. RESULTS Of 511 evaluable patients, ileus was observed in 32% (57/180) for 60 mm GIA versus 33% (110/331) for the 80 mm GIA. Preoperative renal function, age, gender, body mass index, and type of diversion were comparable between cohorts. On multivariate analysis, stapler size was not significantly associated with the development of ileus (GIA-60 vs GIA-80: OR 1.11; 95% CI 0.75, 1.66; P = .6). Positive fluid balance was associated with an increased risk (P = .019) and female sex a decreased risk (P = .008) of developing ileus compared to patients with negative fluid balance. CONCLUSION The size of the intestinal bowel anastomosis (GIA 80 mm vs 60 mm) does not independently impact the time to bowel recovery following RC/UD.

Formal sacrocolpopexy reduces hypercontinence rates in female neobladder formation

Continent urinary diversion is preferred by some patients and orthotopic urinary diversion (OUD) has become the procedure of choice for most men following cystectomy for invasive bladder cancer. OUD in women, however, is less common, likely due to a high rate of hypercontinence (HC), potentially from lax support of pelvic structures similar to pelvic organ prolapse. As such, we evaluated if abdominal sacrocolpopexy (ASC) at the time of OUD in women led to decreased rates of HC.

Complications of Ileal Conduit Diversion

In 1950 Bricker described the use of ileum for “bladder substitution” after pelvic exenteration [1], and to date it remains the most common form of urinary reconstruction after radical cystectomy [2] due to its simplicity and ease of construction. Despite six decades of experience and numerous advancements in surgical technique, ileal conduit urinary diversion remains associated with significant medical and surgical complications. In this chapter, we review the management of complications associated with ileal conduit urinary diversion.