Faculty Bibliography

The pseudoangiosarcomatous pattern has been described mostly in cutaneous and some visceral squamous cell carcinomas and is unique for its striking morphologic resemblance to angiosarcoma. Herein, we describe the clinicopathologic features of 7 pseudoangiosarcomatous urothelial carcinomas that occurred in the urinary bladder. The patients included 6 men and 1 woman ranging in age from 47 to 87 years (median 70 y). The pseudoangiosarcomatous morphology was observed in 7 urothelial carcinomas including 3 with squamous differentiation and comprised 35% to 85% of the invasive tumor. Histologically, the pseudoangiosarcomatous carcinomas were characterized by tumor cell discohesion and lysis that created pseudolumina formations surrounded by attached residual tumor cells. Detached degenerating tumor cells variably admixed with inflammatory cells were common in the false lumina. Partly intact urothelial carcinoma nests contained irregular or cleft-like spaces and disintegrating tumor cells with stretched intercellular bridges. The tumor was commonly associated with a dense collagenous matrix, often surrounding the lytic nests. Similar tumor cell discohesion and breakdown were observed in 3 tumors with foci of squamous cell differentiation, distinguished by the presence of dyskeratosis and keratin formation. All 7 tumors contained other nonpseudoangiosarcomatous carcinoma components such as conventional urothelial carcinoma (5), squamous differentiation (4), sarcomatoid spindle cell carcinoma (2), small cell carcinoma (1), micropapillary carcinoma (1), and glandular differentiation (1). The pseudoangiosarcomatous urothelial carcinomas were all (7/7) diffusely CK7 positive, most (6/7) were GATA3 positive, and none (0/7) expressed vascular-associated markers. There was no evidence to suggest that apoptosis (by TUNEL assay and cleaved caspase-3 immunostaining) or loss of the adhesion molecules CD138 and e-cadherin were possible causes for the tumor cell discohesion and breakdown. All 7 tumors were high stage at cystectomy and included 1 pT3a, 2 pT3b, and 4 pT4a tumors, and 3 had pelvic lymph node involvement. Follow-up data available in 6 cases revealed a poor outcome with an overall median survival of 8.5 months. In conclusion, we present an unusual morphology of bladder carcinoma that has a striking resemblance to a malignant vasoformative tumor. Our series showed that bladder pseudoangiosarcomatous carcinoma morphology is associated with a higher tumor stage at cystectomy, commonly admixed with other aggressive carcinoma variant morphologies, and portend a poorer outcome. Knowledge of this pattern is also important to avoid misdiagnosis, particularly in limited tissue samples.

BACKGROUND:Radical cystectomy (RC) for bladder cancer is frequently associated with delayed gastrointestinal (GI) recovery that prolongs hospital length of stay (LOS). OBJECTIVE:To assess the efficacy of alvimopan to accelerate GI recovery after RC. DESIGN, SETTING, AND PARTICIPANTS/METHODS:We conducted a randomized double-blind placebo-controlled trial in patients undergoing RC and receiving postoperative intravenous patient-controlled opioid analgesics. INTERVENTION/METHODS:Oral alvimopan 12 mg (maximum: 15 inpatient doses) versus placebo. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS/METHODS:The two-component primary end point was time to upper (first tolerance of solid food) and lower (first bowel movement) GI recovery (GI-2). Time to discharge order written, postoperative LOS, postoperative ileus (POI)-related morbidity, opioid consumption, and adverse events (AEs) were evaluated. An independent adjudication of cardiovascular AEs was performed. RESULTS AND LIMITATIONS/CONCLUSIONS:Patients were randomized to alvimopan (n=143) or placebo (n=137); 277 patients were included in the modified intention-to-treat population. The alvimopan cohort experienced quicker GI-2 recovery (5.5 vs 6.8 d; hazard ratio: 1.8; p<0.0001), shorter mean LOS (7.4 vs 10.1 d; p=0.0051), and fewer episodes of POI-related morbidity (8.4% vs 29.1%; p<0.001). The incidence of opioid consumption and AEs or serious AEs (SAEs) was comparable except for POI, which was lower in the alvimopan group (AEs: 7% vs 26%; SAEs: 5% vs 20%, respectively). Cardiovascular AEs occurred in 8.4% (alvimopan) and 15.3% (placebo) of patients (p=0.09). Generalizability may be limited due to the exclusion of epidural analgesia and the inclusion of mostly high-volume centers utilizing open laparotomy. CONCLUSIONS:Alvimopan is a useful addition to a standardized care pathway in patients undergoing RC by accelerating GI recovery and shortening LOS, with a safety profile similar to placebo. PATIENT SUMMARY/RESULTS:This study examined the effects of alvimopan on bowel recovery in patients undergoing radical cystectomy for bladder cancer. Patients receiving alvimopan experienced quicker bowel recovery and had a shorter hospital stay compared with those who received placebo, with comparable safety. TRIAL REGISTRATION/BACKGROUND:ClinicalTrials.gov identifier NCT00708201.

PURPOSE/OBJECTIVE:Transurethral bladder tumor resection is one of the most commonly performed procedures by practicing urologists for the diagnosis, staging and treatment of nonmuscle invasive bladder cancer. There is wide variation in the technique and quality of transurethral bladder tumor resection among urologists. This is the first and critically important diagnostic and staging tool in the management of bladder cancer, which is a potentially lethal malignancy and the most costly urological malignancy to manage. In this review we provide an evidence-based rationale for the incorporation of novel technologies for transurethral resection of bladder tumor in the setting of previously set standards. MATERIALS AND METHODS/METHODS:A systematic MEDLINE®/PubMed®, Cochrane Library and Ovid MEDLINE® search was performed using 2 separate search queries. The MEDLINE/PubMed search was performed using the key words "transurethral resection bladder tumor," filtering the search to include studies published within the last 5 years, English language and human species. A second search without filters was performed with the same key words in the Cochrane Library and Ovid MEDLINE. Study eligibility was defined based on patients with nonmuscle invasive bladder cancer, treatment with transurethral bladder tumor resection and with variable comparators based on novel technology used. All study designs were accepted except case reports, animal studies, editorials and review articles with various outcome measures reported including tumor detection, residual tumor detection, disease recurrence/progression and adverse events. RESULTS:The literature search ultimately yielded 971 manuscripts for review with 42 meeting inclusion criteria for systematic review. Refinements in technique and surgeon experience are critical for the performance of a thorough, complete, high quality transurethral bladder tumor resection. Recent technological advances including bipolar electrocautery and regional anesthetic techniques may help reduce the complications associated with transurethral bladder tumor resection. Photodynamic diagnosis may help increase the diagnostic accuracy, reduce the recurrence rate and decrease the cost of treating patients with nonmuscle invasive bladder cancer. Repeat transurethral bladder tumor resection and perioperative intravesical chemotherapy remain standard components in select patients with nonmuscle invasive bladder cancer. Appropriate clinical staging and treatment of patients with nonmuscle invasive bladder cancer remain a challenge. CONCLUSIONS:Recent advances in transurethral bladder tumor resection should aid its diagnostic accuracy, reduce recurrences, decrease complications and reduce the cost of management of nonmuscle invasive bladder cancer. Urologists should incorporate these evidence-based strategies into current guideline recommendations to improve patient outcomes following transurethral resection of bladder tumor in everyday practice.

PURPOSE/OBJECTIVE:We evaluated the effect of alvimopan treatment vs placebo on health care utilization and costs related to gastrointestinal recovery in patients treated with radical cystectomy in a randomized, phase 4 clinical trial. MATERIALS AND METHODS/METHODS:Resource utilization data were prospectively collected and evaluated by cost consequence analysis. Hospital costs were estimated from 2012 Medicare reimbursement rates and medication wholesale acquisition costs. Differences in base case mean costs between the study cohorts for total postoperative ileus related costs (hospital days, study drug, nasogastric tubes, postoperative ileus related concomitant medication and postoperative ileus related readmissions) and total combined costs (postoperative ileus related, laboratory, electrocardiograms, nonpostoperative ileus related concomitant medication and nonpostoperative ileus related readmission) were evaluated by probabilistic sensitivity analysis using a bootstrap approach. RESULTS:Mean hospital stay was 2.63 days shorter for alvimopan than placebo (mean±SD 8.44±3.05 vs 11.07±8.23 days, p=0.005). Use of medications or interventions likely intended to diagnose or manage postoperative ileus was lower for alvimopan than for placebo, eg total parenteral nutrition 10% vs 25% (p=0.001). Postoperative ileus related health care costs were $2,340 lower for alvimopan and mean total combined costs were decreased by $2,640 per patient for alvimopan vs placebo. Analysis using a 10,000-iteration bootstrap approach showed that the mean difference in postoperative ileus related costs (p=0.04) but not total combined costs (p=0.068) was significantly lower for alvimopan than for placebo. CONCLUSIONS:In patients treated with radical cystectomy alvimopan decreased hospitalization cost by reducing the health care services associated with postoperative ileus and decreasing the hospital stay.

OBJECTIVES/OBJECTIVE:To investigate perioperative outcomes associated with cystectomy and urinary diversion for treatment-refractory benign urological disease. METHODS:A cohort of patients who underwent cystectomy for infection, fistula, bleeding, incontinence, neurogenic bladder or pain between January 2004 and June 2012 was established. Data included baseline demographics, indications for cystectomy and prior treatments, and complications at 30 and 90 days. Primary outcome measures were 30-day and 30 to 90-day complications. RESULTS:The study group comprised eight males and 18 females. The mean age was 57.8 years (95% CI 50.8-64.7). A total of 19 patients (73%) had resolution of their underlying urological pathology at 90 days. A total of 19 patients (73%) experienced a complication in the first 30 days, of which nine (47%) were Clavien grade III or higher. The most common 30-day complications were urinary tract infection (n = 6, 23%) and wound infection (n = 6, 23%). A total of 44% (4/9) of patients with neurogenic bladder experienced a complication within the first 30 days of cystectomy compared with 100% (8/8) of patients with radiation-induced fistula (P = 0.03) and 78% (7/9) of non-neurogenic, non-radiation-induced fistula patients (P = 0.34). CONCLUSIONS:Cystectomy with urinary diversion for benign disease might be successful, but is associated with a high rate of perioperative complications. Those with radiation-induced fistula are more likely to experience complications, whereas those with neurogenic bladder carry a lower risk. Patients should be counseled appropriately regarding expected postoperative outcomes.

BACKGROUND:Women have disproportionately higher mortality rates relative to incidence for bladder cancer. Multiple etiologies have been proposed, including delayed diagnosis and treatment. Guidelines recommend ruling out malignancy in men and women presenting with hematuria. This study sought to determine the difference in timing from presentation with hematuria to diagnosis of bladder cancer in women versus men. METHODS:This is a retrospective population-based study examining the timing from presentation with hematuria to diagnosis of bladder cancer, based on data from the MarketScan databases, which include enrollees of more than 100 health insurance plans of approximately 40 large US employers from 2004 through 2010. All study patients presented with hematuria and were subsequently diagnosed with bladder cancer. The primary outcome measure was number of days between initial presentation with hematuria and diagnosis of bladder cancer by sex. RESULTS:A total of 5416 men and 2233 women met inclusion criteria. Mean days from initial hematuria claim to bladder cancer claim was significantly longer in women (85.4 versus 73.6 days, P < .001), and the proportion of women with >6 month delay in bladder cancer diagnosis was significantly higher (17.3% versus 14.1%, P < .001). Women were more likely to be diagnosed with urinary tract infection (odds ratio = 2.32, 95% confidence interval = 2.07-2.59) and less likely to undergo abdominal or pelvic imaging (odds ratio = 0.80, 95% confidence interval = 0.71-0.89). CONCLUSIONS:Both men and women experience significant delays between presentation with hematuria and diagnosis of bladder cancer, with longer delays for women. This may be partly responsible for the sex-based discrepancy in outcomes associated with bladder cancer.

OBJECTIVES/OBJECTIVE:Evaluate the efficacy and safety of valrubicin for bacillus Calmette-Guérin (BCG)-refractory carcinoma in situ (CIS) of the bladder based on updated phase III pivotal trial efficacy data together with efficacy and safety data from a supportive phase II/III study. MATERIALS AND METHODS/METHODS:In a phase II/III open-label study (A9303), BCG refractory/intolerant adults with CIS (≥ 1 previous course of BCG or could not complete a BCG course owing to toxicity or contraindication) were randomized to receive 6 or 9 weekly intravesical valrubicin (800 mg) instillations. In the pivotal phase III open-label study, BCG-refractory/recurrent adults with CIS (≥ 2 previous courses of intravesical therapy, including ≥ 1 BCG course) received 6 weekly intravesical valrubicin (800 mg) instillations. Patients with muscle-invasive disease were excluded. Patients underwent a primary disease evaluation (PDE) at 3 months (≈ 6 weeks after last dose) that included cytoscopy, biopsy, and cytology. Disease recurrence was monitored at 3-month intervals. Complete response (CR) was defined as no evidence of disease at the PDE (month 3) and follow-up (month 6). Efficacy data from the pivotal trial reflect updated information based on US Food and Drug Administration review. Safety assessments in A9303 included local bladder adverse events (LBAEs) and other adverse events (AEs). RESULTS:Eighty patients enrolled and 78 completed treatment and underwent the PDE in study A9303; in the pivotal trial, the respective numbers were 90 and 87 patients. In study A9303, 39% of patients had received ≥ 2 previous courses of BCG and 11% had received ≥ 3 courses vs. 70% and 28%, respectively, in the pivotal trial. In both studies, the CR rate was 18%. In A9303, LBAEs were the most common AEs, reported by 86% of patients during treatment and 45% during follow-up; most treatment-related LBAEs were mild to moderate. 2 serious AEs in 1 patient (azotemia/reflux nephropathy) were judged as definitely or possibly treatment related; none of the patient deaths were judged to be related to valrubicin. CONCLUSIONS:Two trials of valrubicin in patients with CIS demonstrate a consistent degree of efficacy in highly pretreated patients (pivotal trial; BCG-refractory patients) and those with fewer previous therapies (A9303; BCG-refractory/intolerant patients).

PURPOSE/OBJECTIVE:Benign ureterointestinal anastomotic stricture is not uncommon after radical cystectomy and urinary diversion. We studied the impact of the running vs the interrupted technique on the ureterointestinal anastomotic stricture rate. MATERIALS AND METHODS/METHODS:From July 2007 to December 2008 interrupted end-to-side anastomoses were created and from January 2009 to July 2010 running anastomoses were created. The primary study end point was time to ureterointestinal anastomotic stricture. RESULTS:Of 266 consecutive patients 258 were alive 30 days after radical cystectomy, including 149 and 109 with an interrupted and a running anastomosis, respectively. The groups did not differ in age, gender, body mass index, age adjusted Charlson comorbidity index, receipt of chemotherapy or radiation, blood loss, operative time, diversion type or postoperative pathological findings. The stricture rate per ureter was 8.5% (25 of 293) and 12.7% (27 of 213) in the interrupted and running groups, respectively (p = 0.14). Univariate analysis suggested that postoperative urinary tract infection (HR 2.1, 95% CI 1.1-4.1, p = 0.04) and Clavien grade 3 or greater complications (HR 2.6, 95% CI 1.4-4.9, p <0.01) were associated with ureterointestinal anastomotic stricture. On multivariate analysis postoperative urinary tract infection (HR 2.4, 95% CI 1.2-5.1, p = 0.02) and running technique (HR 1.9, 95% CI 1.0-3.7, p = 0.05) were associated with ureterointestinal anastomotic stricture. Median time to stricture and followup was 289 (IQR 120-352) and 351 days (IQR 132-719) in the running cohort vs 213 (IQR 123-417) and 497 days (IQR 174-1,289) in the interrupted cohort, respectively. Of the 52 strictures 33 (63%) developed within 1 year. Kaplan-Meier analysis controlling for differential followup showed a trend toward higher freedom from stricture for the interrupted ureterointestinal anastomosis (p = 0.06). CONCLUSIONS:A running anastomosis and postoperative urinary tract infection may be associated with ureterointestinal anastomotic stricture. Larger series with multiple surgeons are needed to confirm these findings.

PURPOSE OF REVIEW/OBJECTIVE:To define the incidence of perioperative morbidity following contemporary radical cystectomy and identify preoperative, intraoperative, and postoperative strategies to reduce complications. RECENT FINDINGS/RESULTS:When complications are methodically and systematically recorded, 64% of patients will sustain a complication within 90 days of radical cystectomy. Various preoperative, postoperative, and intraoperative strategies have been identified to reduce morbidity. Prior to surgery, patients should have reversible medical conditions treated, mechanical bowel preparation can be omitted if using small bowel for reconstruction, venous thromboembolism and antimicrobial infection prophylaxis should be initiated, nutrition should be optimized, and patient education should be provided. During surgery, complications can be attenuated by utilizing meticulous surgical technique, minimizing blood loss, fluid management can be guided by transesophageal cardiovascular Doppler, and lower extremity repositioning should be performed as soon as feasible. After surgery, early mobilization, incentive spirometry, early nasogastric tube removal, alvimopan usage, and judicious jejunostomy tube feeding, or total parenteral nutrition usage may reduce morbidity. SUMMARY/CONCLUSIONS:Morbidity is common following radical cystectomy, but careful attention to preoperative, intraoperative, and postoperative details can help reduce this risk.

Urachal adenocarcinoma has several morphologic presentations that include mucinous, enteric, signet ring cell, and not otherwise specified. Mixtures of these morphologies can occur, and percentage cut-offs are used for classification. The clinical significance of these morphologic types is currently unknown, and genetic analysis that could elucidate possible intertumoral differences has not been performed. In this study, we analyzed the micro-RNA expression profiles of 12 urachal adenocarcinomas classified using strict morphologic criteria (3 pure enteric, 3 pure mucinous, 2 signet ring cell [both 90% signet ring cell], 2 pure not otherwise specified, and 2 mixed cell types). Of 598 unique human micro-RNAs, 333 were expressed in more than 50% of the samples. Hierarchal clustering showed no distinct patterns in the genetic profiles of the morphologic types. However, there were individual micro-RNA differences when the different types were compared individually or grouped together, either by intracellular mucin production or by grouping enteric and signet ring cell together. In the later group, 13 messenger RNA species were differentially expressed (adjusted P value of ≤.05). However, these micro-RNA differences were small, suggesting more biologic similarity than differences among these entities. Thus, this study suggests that the different morphological subtypes may represent patterns of differentiation or a continuum of a single biological tumor type rather than several distinct types that arose from the urachal remnant epithelium. This finding, if further validated in larger studies, may have implications in future clinical therapeutic trials for urachal adenocarcinoma with regard to patient grouping and choice of therapy.